Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Toxicol Pathol. Author manuscript; available in PMC 2007 July 5.
Published in final edited form as:
PMCID: PMC1909756

The State of the Art of the Zebrafish Model for Toxicology and Toxicologic Pathology Research—Advantages and Current Limitations


The zebrafish (Danio rerio) is now the pre-eminent vertebrate model system for clarification of the roles of specific genes and signaling pathways in development. The zebrafish genome will be completely sequenced within the next 1–2 years. Together with the substantial historical database regarding basic developmental biology, toxicology, and gene transfer, the rich foundation of molecular genetic and genomic data makes zebrafish a powerful model system for clarifying mechanisms in toxicity. In contrast to the highly advanced knowledge base on molecular developmental genetics in zebrafish, our database regarding infectious and noninfectious diseases and pathologic lesions in zebrafish lags far behind the information available on most other domestic mammalian and avian species, particularly rodents. Currently, minimal data are available regarding spontaneous neoplasm rates or spontaneous aging lesions in any of the commonly used wild-type or mutant lines of zebrafish. Therefore, to fully utilize the potential of zebrafish as an animal model for understanding human development, disease, and toxicology we must greatly advance our knowledge on zebrafish diseases and pathology.

Keywords: Zebrafish, Danio rerio, genomics, molecular genetics, development, toxicologic pathology, carcinogenesis, toxicology


As the most numerous and phylogenetically diverse group of vertebrates, fish teach us important principles about fundamental processes in vertebrate evolution, development and disease processes. For over 100 years, fish from primitive hagfish to advanced reef fish have yielded unique insights into cell biology, physiology, development, and immunology (258, 418, 545). A high level of conservation of genetic programs controlling development and fundamental physiologic processes is present among all vertebrates, as well as between invertebrates and vertebrates. Endocrine systems are highly conserved between fish and other vertebrates. Fish possess most of the tissue types of mammals except breast, prostate and lung. Fish have served as useful sentinels to detect environmental hazards, and as efficient, cost-effective model systems for mechanistic toxicology and risk assessment for many decades (206, 208). In choosing a model system for conducting particular research, it is essential to realize that no single model is best for addressing all biomedical questions. Each model species has unique strengths and weaknesses (576).

Strengths of the Zebrafish Model System

Zebrafish and other aquarium fish species have distinct advantages as models for biomedical research including much lower husbandry costs than mammals. Oviparous species including the zebrafish have external fertilization and development, facilitating access for observation and manipulation of developing embryos. Oviparous fish species can be cloned quite easily, allowing genetic manipulation for study of haploids, triploids, or tetraploids with androgenesis or gynogenesis (107, 489). Zebrafish are easily housed in compact recirculating systems, breed continuously year-round, and have short generation times of approximately 3–5 months (125). The small size of adult zebafish allows efficient, low-cost evaluation of all major organs on a limited number of slides (168). The small size of embryos and fry minimizes the cost and waste volume for drug and toxicant studies. Thus minute amounts of expensive metabolites or new targeted drugs can be rapidly evaluated.

Unique Advantages of the Zebrafish Model for Study of Development

Among vertebrates, the zebrafish embryo has unrivaled optical clarity, allowing visual tracing of individual cell fates throughout organogenesis. Fluorescent dyes or other markers aid in visualization of cell lineages (104, 105, 273, 279, 474). If inhibitors of pigment formation are included in the rearing medium, cell lineages can be traced throughout the first week of zebrafish development, and immunohistochemical or immunofluorescence studies will reveal specific cell types in whole mount preparations (269). Histological sections of larvae over 1 week of age are required to localize specific cell types. Alternatively, confocal microscopy can optically section these thicker larvae (323). A wide array of histochemical markers for protein and gene expression allows identification of essentially all cell types, and often reveals functional capabilities such as synthesis of nitric oxide or specific neurotransmitters, during development of the major tissues (75, 77, 82, 103, 111, 171, 240, 261, 520, 533, 536, 579, 583).

Immunohistochemical studies have quantified cell proliferation and cell death in specific tissues during development (100, 284, 578). The optical clarity of the embryo coupled with detailed understanding of basic developmental processes and a well-established timetable for specific developmental milestones allows elegant embryonic manipulations to distinguish the relative influences of the genetic composition of a specific cell (cell autonomous effects) versus the influences of the genetic suite of its surrounding environment (non–cell-autonomous effects). For example, at a precise stage of development, specific neurons can be removed from the spinal cord using a micropipette, and can be replaced by those from fish of a different genotype. Then the impact on neuronal fate and innervation of skeletal muscle can be determined (142). Or during various time points in development, single cells, or cell clusters can be removed from specific anatomic fields in the embryo and relocated to other sites to clarify the processes controlling cell fate determination, and revealing when the fate of certain cell types is irreversibly specified (224, 356).

DNA or RNA constructs can be readily microinjected into embryos at the 1-cell or 2-cell stages to study effects of transient gene expression. More uniform tissue expression is achieved with RNA injection (228). With injection of RNA at the 2-cell stage, typically half of the embryo expresses the exogenous construct, with the other half acting as an elegant internal control. Using constructs with a promoter such as that from a heat shock gene, laser probes can elicit transient expression of injected constructs in precise cell types at exact stages of development (203, 238, 288).

Because of these advantages of zebrafish for basic developmental biology and molecular development studies, the zebrafish has emerged as the premier vertebrate model for clarification of the roles of specific genes and signaling pathways in development. The past decade has seen intense worldwide research into molecular genetic mechanisms in cell fate determination, pattern formation, morphogenesis and functional maturation of heart, blood vessels, brain, eye, ear, nose, neural crest, muscle, cartilage, bone, lymphomyeloid system, skin, kidney, and gonad.

Cell Culture Techniques Using Zebrafish Tissues

Cell culture methods are established to create primary and immortal cell lines from adult tissues as well as from embryos (101, 182, 183, 210, 292). Also explants of embryos and adult tissues, such as whole brain, can be cultured to study cell-cell interactions and metabolism (509).

Zebrafish Genomics Initiative

Several transinstitute funding initiatives by the National Institutes of Health (NIH) in the past 5 years have spawned a flurry of activity using the zebrafish as an animal model for understanding human development and disease. The NIH has funded research in zebrafish genomics for the past decade. Recently, Britain's Wellcome Trust has put the zebrafish on the fast track for complete genome sequencing, with a rough draft to be available by the summer of 2003. Among fish species, the most complete database on genomics, molecular genetics and embryology is available for the zebrafish. These data are accessible through the Zebrafish Information Network <> (559) coordinated in conjunction with the NIH-funded Zebrafish International Resource Center (ZIRC) at the University of Oregon. Updated sequencing information is posted on the Sanger Institute/Wellcome Trust web site <>.

Zebrafish Comparative Genomics

Although a rough draft of the human genome is now available, the function of most mammalian genes remains unknown. Because of the rapid embryonic development, optical clarity of zebrafish embryos, and efficiency of mutant screens in zebrafish, we are likely to understand the role of every gene in development in the zebrafish before we have such knowledge for any other vertebrate. It will take much longer to clarify the role of these genes in diseases occurring later in life.

The Zebrafish Genome

Zebrafish have 25 pairs of chromosomes compared to 23 pairs in humans. Evolutionary genetic data indicate that a whole-genome duplication event occurred early in the teleost lineage, after separation of the fish lineage from the tetrapod lineage. So for many genes of mammalian species, duplicate genes (paralogs) occur on separate chromosomes in bony fish. Not all of these gene duplicates have been preserved during evolution (40, 161, 242, 346, 413, 414). On average about 20% of the pairs of duplicated genes have been preserved due to neofunctionalization or subfunctionalization. In neofunctionalization, an entirely new function for a gene evolves. In subfunctionalization, for example, if the original gene of mammals was expressed in 4 tissues during development, each of the duplicate genes of a bony fish might be expressed in 2 of the 4 tissues (166). Although many scientists contend that fish are simpler model systems than mammals, in terms of the molecular genetics, fish are actually more complex. An additional whole-genome duplication likely occurred in trout and salmon following the initial teleost genome duplication, so the salmonids will often have 4 co-orthologs for each gene of mammals (68).

Mutations in one of a pair of duplicated genes in zebrafish may give rise to a simpler phenotype than mutation of the ortholog in mammals. Also, in cases in which mutation of the mammalian ortholog is embryonic lethal, mutation of one of the zebrafish paralogs may give rise to viable animals, allowing better definiton of gene function and clearer understanding of the roles of the gene in signaling pathways.

Investigators worldwide collaborated to create an oligonucleotide-normalized and expressed sequence tag-characterized zebrafish cDNA library which has been used for mapping zebrafish genes, for in situ hybridization studies of gene expression, and now is being used to develop microarray technology for comprehensive evaluation of stage-specific gene expression in zebrafish (97, 289). ZFIN contains a virtual web-based map of the zebrafish genome, integrating data from the various gene mapping projects. A physical map of the zebrafish genome is available, constructed using fluorescence in situ hybridization (FISH) (407). At least 28 groups of genes are syntenic (together on a single chromosome) in zebrafish and humans (28). This shared synteny has aided identification of and positional cloning of candidate disease genes (498, 499).

Zebrafish Mutant Screens

Over a decade ago, geneticist Christiane Nüsslein-Volhard chose zebrafish as the best vertebrate model system for clarifying the roles of specific genes in development. Patterning these studies in zebrafish upon her highly successful Nobel-Prize-winning saturation mutagenesis studies that elucidated the role of every gene and every signal pathway in fruit fly development, Nüsslein-Volhard collaborated with Wolfgang Driever, then at Massachusetts General Hospital, to conduct the first large-scale mutagenesis studies in zebrafish (72, 112, 199, 241, 303, 380). These studies were spectacularly successful, generating thousands of mutant lines of zebrafish with defects in essentially every major organ system, as well as mutant lines with defects in basic embryo patterning. A special issue of the journal Development in 1996 was devoted to describing this cornucopia of mutant lines. The success of these initial mutant screens has stimulated many research centers around the world to continue conducting mutant screens, working toward a complete understanding of molecular, cellular, and functional development of all zebrafish tissues and organ systems. Initial screens focused on several parameters including morphology of embryos using stereoscopic and Nomarsky optics, neuronal pathway arrangements, and markers for expression of panels of genes. Now the focus of mutant screens using zebrafish is broadening to consider functional parameters such as lipid digestion (64, 110, 153), behaviors such as mating, the startle response and feeding, and diseases such as neoplasia or skeletal malformations occurring later in life (5, 160, 397). The ingenuity of future mutant screens will be limited mainly by manpower and funding—these screens are very labor-intensive undertakings.

Creating Mutant Fish

To date, totipotent embryonic stem cells are not available for any fish species. Therefore the homologous recombination methods used for creating knockout mice cannot be used in fish. Chemical mutagens including N-nitroso-N-ethylurea (ENU; 282), psoralens (11), radiation (543), insertional mutagenesis using pseudotyped retroviruses (173, 174, 186), or dominant negative transgenes can be used to create stable mutant lines of fish with “knocked down” gene function. For homozygous lethal or recessive mutations, screening of haploid embryos or early pressure-derived embryos (35) containing the genetic material of just one parent greatly speeds up identification of mutant phenotypes (87). Unlike mammalian species in which haploid embryos do not survive, haploid zebrafish embryos survive for 4 days. These haploid embryos exhibit a well-defined suite of brain abnormalities, however, most organs can be screened for abnormalities associated with mutant genes (543). If transient gene “knockdown” is desired, morpholino antisense oligonucleotides efficiently achieve null phenotypes for most genes evaluated early in development (106, 144, 209). An alternative strategy for gene “knockdown,” albeit a more technically challenging approach, is the use of ribozymes (544). Recently, the Cre-loxP system has been used in zebrafish embryos to achieve precise control of gene expression in a spatially and temporally restricted manner (587).

Creating Transgenic Zebrafish

Transgenic zebrafish are useful for study of the phenotypes resulting from overexpression of selected genes globally, or in a tissue-targeted fashion (256, 313, 398). Transgenic technology also allows “knockdown” of gene function using dominant negative transgenes. Recently, growing numbers of tissue-specific promoters are becoming available to allow very precise targeting of transgene expression (188, 221, 222, 238, 255, 286). Transgenic zebrafish with the green fluorescent protein marker under control of a specific promoter can highlight stage-specific, tissue-specific and cell–type-specific expression of selected genes in developing and adult zebrafish (364, 402).

Transgenes are most commonly introduced by microinjection of constructs into newly fertilized eggs. Electroporation of eggs or sperm has also been used. The most efficient method for introducing transgenes into zebrafish eggs utilizes pseudotyped retroviruses (173, 174, 186); however, use of retrotransposons and integrase is continually being optimized to achieve higher efficiency of stable integration of microinjected transgenes in developing zebrafish (96, 262).

Role of Zebrafish Mutants in Toxicology Research

Mutant lines of zebrafish will help clarify the roles of specific genes and their associated signaling pathways and networks in the pathogenesis of toxicant-induced lesions. Double and triple mutants can clarify the interactions of suites of genes, and these multiple mutants can be produced more efficiently and cheaply in zebrafish than in rodents.

Zebrafish Mutant Models for Understanding Human Development and Disease

Numerous recent review articles have trumpeted praises of the zebrafish model for understanding human development and disease (5, 30, 64, 128, 131, 133, 162, 282, 304, 505, 530, 550, 552, 537, 539, 574, 592). Active research programs are now present worldwide focusing on normal and abnormal development of essentially all organ systems and tissues shared by zebrafish and man, as well as on a variety of pathologic lesions, physiologic processes, and disease conditions including aging, alcoholism, and drug addiction, for which zebrafish can provide mechanistic insight into human disease pathogenesis.

Normal and Perturbed Hemopoiesis in Zebrafish

Several hemato-oncology research groups at Harvard Medical School including those of Leonard Zon and Thomas Look, Graham Lieschke's group from the Ludwig Institute for Cancer Research, Victoria, Australia, and Shu Lin's group at the University of Georgia, together with other collaborators have clarified the role of specific genes in normal and deranged hemopoietic development of zebrafish (6, 42, 53, 121, 310). Several mutant lines of zebrafish have clinical syndromes resembling diseases of humans, such as congenital sideroblastic anemia (67), X-linked sideroblastic anemia (581), hepatoerythropoietic porphyria (547), erythroid myeloproliferative disorders (319). A transgenic zebrafish expressing a RUNX1-CBF2T1 translocation shows a preleukemic syndrome (257). The genetic program for sequential specification of pluripotential precursors followed by divergence of distinct lineages of lymphoid, myeloid and erythroid cells is highly conserved from zebrafish to humans, indicating that zebrafish will continue to provide valuable insights into additional lymphomyeloid disorders of humans (6).

The Zebrafish Immune System

Although the immune system of zebrafish has been less well studied than that of several fish species important in commercial aquaculture such as rainbow trout and channel catfish, this field will grow in importance as we begin to understand more about infectious diseases of zebrafish. Like other bony fish, zebrafish have distinct lymphoid subsets, T and B cells. Willett et al (569-572) describe expression of the recombination activating genes, rag 1 and rag 2 in zebrafish thymus and anterior kidney, the major histolologic sites for production of T cells and B cells, respectively, during zebrafish development. The Zon laboratory at Children's Hospital in Boston, MA has developed mutant lines with defective T cell development. These mutant lines fall into 5 distinct complementation groups (505, 515, 516). Zebrafish possess several novel immune-type receptor genes in comparison to mammals. These genes may shed light on evolution of the innate and adaptive immune systems of vertebrates (314). Recent data indicate that zebrafish novel immune-type receptor genes may represent evolutionary intermediates in the establishment of the leukocyte receptor cluster for cytokine responses in mammals (584). Class I and II major histocompatability proteins are mapped and characterized in zebrafish (492, 493, 497). The promoter region of the Class II A genes is highly conserved between mammals and zebrafish, indicating conservation of gene regulatory mechanisms (492). Independent duplications of Bf and C3 components of the complement system occurred during evolution of the zebrafish (189). Haire et al (201) studied immunoglobulin isotypes and the T cell antigen receptor in zebrafish. Herbomel et al (216, 217) show that macrophages appear in embryos concurrent with embryonic erythrocytes, but at a distinct location compared to other hemopoietic cells. Macrophages develop initially in mesoderm anterior to heart, while primary hemopoiesis occurs ventral to the tail, near the yolk extension. These embryonic macrophages constitute a distinct lineage from the monocyte lineage which gives rise to macrophages in adult vertebrates including zebrafish (465). Embryonic macrophages require an intact M-CSF signaling system to disseminate properly to embryonic tissues, indicated by the failure of macrophage dispersal in the panther mutant lacking functional M-CSF receptors. Antigen receptors on nonspecific cytotoxic cells are similar in zebrafish and channel catfish (251).

Blood Coagulation in Zebrafish

Specialized methods are required to analyze coagulation parameters in zebrafish due to the small size of both early life stages and adults, however, clotting times can be evaluated in blood samples from larvae by 30 hours postfertilization (246, 249). Zebrafish possess both intrinsic and extrinsic clotting pathways containing the same clotting factors present in mammals. Anticoagulants such as warfarin and hirudin act similarly in zebrafish and mammals (244, 245, 247-250). Although nucleated, zebrafish thrombocytes are functionally similar to those of mammals and circulate in the blood by 36 hours postfertilization (247). Like mammals, thrombocyte activation in zebrafish is blocked by drugs inhibiting cyclooxygenase 1, such as aspirin, but not by inhibitors of cyclooxygenase 2 (195, 247). Screens to detect mutants with defective blood coagulation are underway and lines of zebrafish with specific abnormalities in the coagulation system are evident (244).

Cardiovascular Development and Cardiovascular Mutants

The clarity of zebrafish embryos and fry, and the ability of the fish to survive for several days without circulation due to the diffusion of gases through the skin make this an excellent model for study of cardiovascular development (86, 163-165, 309, 318, 321, 405, 456, 462, 479, 552, 553, 556, 582, 583). Mutant lines with defects in contractility (458, 580), rhythmicity (551), heart size, heart tube patterning, valve morphogenesis, and cardiac looping are available. The gridlock (gdl) mutant with abnormal circulation to the tail resembles coarctation of the aorta in man. Babin et al (25) and Durliat et al (138) cloned the zebrafish orthologs for the apolipoprotein E (apoE) and A-1 (apoA-1) genes of humans. These genes regulate lipid uptake and distribution in mammals and ApoE plays a role in Alzheimer's disease in man. ApoE and A-1 are highly expressed in the yolk syncytial layer in zebrafish embryos, a tissue which controls yolk assimilation, and apoE is expressed in brain and eye of developing zebrafish. The roles of these genes in cardiovascular and brain development and disease in zebrafish remain to be explored. Brant Weinstein of the National Institutes of Health coordinates a Web site featuring images of zebrafish cardiovascular development <> or <>. The site features current information on comparative vascular development of various organs.

Neural System and Neural Crest

Some of the most intense research in the zebafish model has focused on genetic mechanisms of cell specification and morphogenesis of the nervous system (52, 142, 357, 358). Mutant lines with extremely specific defects in most components of the nervous system are available. Also mutant lines with defects in neural connections are established (237). The ontogeny of specific behaviors is well defined (156, 172, 443), and neurologic functions such as sleep are being investigated (211). Calcium fluxes can be visualized in individual neurons in the central nervous system of live fry during behaviors such as the escape response (155, 496, 590). Neuronal metabolic profiles are described (534).

Migration pathways of neural crest cells and sequential specification of particular cell types are documented in zebrafish (143, 176, 275, 377, 513). Mutant lines with specific defects in certain aspects of neural crest development are available, with lesions including abnormal pigment patterns, abnormal jaw development, and abnormal enteric neural tissue (20, 140, 213, 265, 343, 394).

Sensory Systems Including Eye, Ear, Taste Bud, and Nose

At least 50 mutant lines with lesions affecting specific cells or layers of the eye are available (46, 65, 327, 328, 375, 541). Also, more sophisticated tests of visual function and ocular motion are being developed (26, 146, 185, 306, 307). All zebrafish mutants with lamination defects in the retina have anomalies of the retinal pigment epithelium (RPE). This suggests that the RPE controls retinal lamination during morphogenesis of eye. The mosaic eyes (moe) mutant shows loss of normal retinal lamination, with loss of the normal localization of dividing retinal cells to the surface of the RPE. Cell–type-specific antibodies and riboprobes show that all retinal cell types differentiate normally, but are misplaced in the moe mutant (252). Normal and abnormal morpohologic and functional development of the olfactory system is understood in detail (287, 426, 561-563). Recent work by Jessen et al (253) shows that the recombination activation genes, rag1 and rag2, which function to generate diversity in the immune system, may perform a similar function in generating a large repertoire of olfactory receptors. Cellular and molecular mechanisms controlling development and function of ear (21, 44, 99, 361, 406, 557) and tastebuds (204) are less well understood than other sensory systems in zebrafish, but are currently being investigated.

Normal and Abnormal Kidney Development

Embryo and fry stages of zebrafish possess a pronephros with a single glomerulus, whereas juvenile and adult stages have a mesonephric kidney. Recent investigations have clarified molecular and cellular aspects of renal development in zebrafish (132, 134, 135, 324-326, 460, 462). Although many aspects of renal development are conserved from zebrafish to mammals, in contrast to mammals, glial-derived neurotrophic factor (GDNF) is not required for kidney morphogenesis in zebrafish (466). Several zebrafish mutants including double bubble resemble human autosomal dominant polycystic kidney disorders. Fleer and elipsa display renal-retinal dysplasia similar to that seen in the human Senior-Loken syndrome (135, 271). Zebrafish with inactivating mutations in the homeobox gene tcf2 (vhnf1) show kidney cysts, underdevelopment of pancreas and liver, and reduction in size of the otic vesicles (494). This zebrafish mutant line is a good model for study of the MODY5 syndrome (maturity-onset diabetes of the young, type V) in humans and familial GCKD (glomerulocystic kidney disease).

Musculoskeletal System

Much is understood regarding the timing and genetic mechanisms controlling development of the axial and appendicular skeleton of zebrafish (158, 362). Shannon Fisher of Johns Hopkins University School of Medicine is screening mutant lines using radiography to detect lesions in the skeletal system (160). The zebrafish chihuahua (chi) mutant shows skeletal dysplasia resembling osteogenesis imperfecta in man (159).

Molecular and cellular development of skeletal muscle, and neuromuscular function in normal and abnormal zebrafish are well studied, although not yet fully understood (39, 73, 74, 200, 224, 229, 236, 363, 376). Mutant screens have identified over 50 genes essential for normal somite development (136, 137, 486). Mutant lines with abnormalities similar to human Duchenne muscular dystrophy are available (54, 55, 83, 396). Mutant lines with altered motility due to abnormal neurotransmitter receptors on nerve and muscle are described (385, 459).

Enteric Tract and Liver

Studies of normal and abnormal development of the enteric tract and liver have continued since the initial mutant screens were conducted in 1996 (98, 193, 285, 390, 424, 425). Mutants with abnormally large or small livers, or with abnormal positioning of the gut and liver are documented (157). Guo et al (198) are using microarray analysis of stage-specific gene expression combined with forward and reverse genetic analyses to clarify the roles of specific genes in liver development. Cheng et al (88) describe dysplastic histologic features in gut of early life stages of certain mutant lines of zebrafish.

Endocrine Organ Systems

Growing international interest is focused on development and function of endocrine systems of vertebrates due to the concern regarding endocrine-disrupting agents in the environment. Whereas most endocrine organs are similar structurally and functionally in fish and mammals, fish have some unique features. Fish interrenal and chromaffin tissue, the homologs of adrenal medulla and cortex, respectively, are not encapsulated and are located surrounding veins in the anterior kidney. Zebrafish thyroid is also not encapsulated and is located surrounding the ventral aorta as it emerges from the bulbus arteriosus. Fish, like birds, have ultimobranchial bodies, homologs of mammalian medullary thyroid tissue, which are located in the transverse septum between heart and esophagus. Surprisingly, although the zebrafish does not have a parathyroid gland, it has functional parathyroid hormones and receptors (438, 439, 524).

Cellular and molecular mechanisms controlling pituitary development are active topics of current research (139, 293, 440, 448), however, knowledge about development of this organ is currently less than that regarding most organ systems of zebrafish. More information is available regarding development of endocrine pancreas (19, 45, 193, 349, 437), thyroid (66, 149, 150, 316, 317, 417, 425, 431, 558), and pineal gland (167, 192, 263, 589). Whitlock et al (564) show a dual origin of cells secreting gonadotropin-releasing hormone (GnRH), with these cells arising in both neural crest and in pituitary placode.

Germ Cell Specification, Gonadal Patterning and Sex Determination

Confirmation of expression of the evolutionarily conserved vasa gene as a marker of germ cells in zebrafish has facilitated study of migration, cell proliferation and cell death patterns of this cell type (57). Weidinger et al (554, 555) and Stars-Gaiano and Lehmann (483) describe the normal migration patterns of zebrafish germ cells and document abnormal homing of germ cells to presumptive gonad in certain mutant lines. Uchida et al (523) document histologic changes occurring during early differentiation of gonad into patterns characteristic of male or female. Chiang et al (92, 93) reveal the role of sox9 genes in gonadal differentiation and in later gonadal function in zebrafish. Bauer and Goetz (32) report a variety of mutant lines of zebrafish with abnormal development of male and female gonads, including lines with defects in various stages of spermatogenesis or oocyte maturation. Some information is available on the structure of zebrafish GnRH (415, 517) and gonadotropin receptors (293). Wu et al (577) and Pang and Ge (392, 393) outline signaling pathways controlling ooctye maturation in zebrafish. Li et al (308) successfully achieved in vitro maturation of zebrafish oocytes, documenting a culture system that may prove useful in future toxicant studies. Likewise, an in vitro culture system is optimized to produce functional sperm from zebrafish germ cells (444). Zebrafish will provide a model system for study of gender-related differences in toxicant responses (113).

Basic Embryo Patterning and Craniofacial Development

Much of the initial embryology studies as well as studies of mutant lines focused on cellular and molecular mechanisms for determination of basic body plans and cell fates (273, 276-279, 347, 351, 365, 366, 451, 452, 473, 474, 511). The initial Tuebingen mutant screen identified a wide variety of mutants with defective epiboly, axis pattterning, gastrulation, dorso-ventral patterning, or anterior-posterior patterning. An example of defective patterning clarifying mechanisms of head formation is the headless (hdl) mutant. This phenotype occurs due to defective tcf3 (T-cell factor 3). Appropriate tcf3 expression is necessary to repress specific wnt target genes, allowing head formation (270). The 1-eyed pinhead (oep) mutant shows defects in L-R asymmetry mimicking some situs inversus syndromes of man such as dextrocardia, cardiac septal defects, or gut malrotation associated with mutations in the CFC gene (47, 49, 194, 450).

Normal and abnormal craniofacial development in zebrafish has been studied intensely (350, 408, 409, 451). A variety of mutant lines show phenotypes resembling congenital malformations occurring in humans.

Study of Aging Using the Zebrafish Model

Karlovich of Stanford University and colleagues (259) cloned the Huntington's disease gene homolog from zebrafish, and will develop a zebrafish model for this progressive neurodegenerative disease of man. Leimer et al (302) cloned the presenilin gene of zebrafish to begin developing a model of Alzheimer's disease. Musa et al (367) studied early life stage expression of 2 zebrafish orthologs of human amyloid precursor protein, and found distinct expression patterns for each of these paralogs in zebrafish. Rubenstein et al (440) are developing a zebrafish model for the study of Parkinson's disease, and have demonstrated destruction of dopaminergic neurons in zebrafish embryos following treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an agent associated with drug-induced Parkinsonism in man.

Data Regarding Toxicant Exposure in Zebrafish

Metabolism of Endogenous and Exogenous Agents and Pharmacokinetics

The database on metabolism in zebrafish is much less complete than that available for certain other highly studied fish species such as rainbow trout. More data are available regarding Phase I than Phase II metabolism in zebrafish. Several cytochrome P450 enzymes from zebrafish have been mapped, but full cDNA sequences are in the public domain only for cyp19a, cyp19b, and cyp26. Cyp1a1 (P4501a1) activity is induced in adults (69, 518) as well as in early life stages of zebrafish (13), and in liver cell cultures (102, 214, 353) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The aryl hydrocarbon receptor (AHR) signaling pathway has been studied extensively in zebrafish (1, 12, 416, 500, 501). Stage-specific expression of ahr, the ahr nuclear translocator (arnt), and cyp1a1 are documented in early life stages of zebrafish (13, 335, 336).

Paralogs of aromatase are present on two separate chromosomes in zebrafish, due to an ancient chromosomal duplication event. These enzymes play key roles in sex steroid metabolism, facilitating androgen conversion to estrogens. Zebrafish cyp19a is expressed in ovary, whereas cyp19b is expressed in brain (93). Appropriate tissue-specific expression of these enzymes is required for normal sexual development (76, 280, 510, 514). Steroid glucuronides, produced in zebrafish testis by metabolism of androgens, are potent pheromones stimulating mating behavior in females (529). Hu et al (235) and Lai et al (295) studied the regulation of steroidogenesis in zebrafish. Zebrafish cyp26 plays an essential role in retinoic acid catabolism in zebrafish and mammals, allowing precise local regulation of retinoid acitivity (320, 422).

Keizer et al (264) studied species differences in acetylcholine esterase inhibition by diazinon in fish. They found that zebrafish are relatively resistant to diazinon compared to other fish species, because their acetylcholine esterase is relatively resistant to inhibition by this pesticide. Donnarumma et al (130) investigated glutathione S-transferase activity in liver of several fish species. They found no activity of this enzyme toward 1,2-epoxy-3-(p-nitrophenoxy) propane in zebrafish liver.

Relatively scant data are available regarding pharmacokinetics of drugs or environmental agents in zebrafish. Hertl and Nagel (220) and Zok et al (591) studied bioconcentration and metabolism of various substituted anilines in zebrafish. Petersen and Kristensen (403) evaluated uptake and elimination of polycyclic aromatic hydrocarbons by early life stages of zebrafish. Gorge and Nagel (190) studied toxicokinetics and metabolism of lindane and atrazine in eggs, larvae and juvenile zebrafish. Andersson et al (9) compared PCB uptake in mature zebrafish from the diet, from intraperitoneal injection, and from implanted intraperitoneal silicone capsules. Neilson et al (374) investigated bioconcentration, metabolism, and toxicity of components of bleached pulp effluent to various life stages of zebrafish. Wiegand et al (568) evaluated uptake, metabolism and toxicity of the algal toxin, microcystin, following bath treatment of various early life stages. Labrot et al (294) studied toxicokinetics of lead and uranium in zebrafish. Wicklund et al (565) investigated effects of zinc on uptake, distribution and elimination of cadmium in zebrafish. Most published zebrafish studies report exposure concentrations, but not tissue concentrations of toxicants, so that quantitative comparison of sensitivity between zebrafish and other species is difficult.

Toxic Endpoints in Risk Assessment—Noncancer Endpoints

For decades worldwide, the zebrafish has been used extensively for environmental toxicity testing, in acute and chronic bioassays to generate mandated water quality criteria. Because of the rapid development and optical clarity of early life stages, the bulk of the toxicology data for zebrafish regards early life stages. To date, the great power of our current knowledge in molecular genetics, genomics, and mechanistic developmental biology have not been fully utilized in toxicology studies. We now have the tools to answer very specific questions in many areas of toxicology and toxicologic pathology. Unfortunately, the strain and source of zebrafish used in many toxicology studies is not reported in the publications. Generalizations regarding the zebrafish based on data from a single genetic line will not likely predict responses for the many wild-type lines and thousands of mutant lines. Much of the basic toxicity data for zebrafish is in unpublished reports.

Acute, Subacute, and Chronic Toxicity Studies

Ansari and Kumar (17) studied effects of the insecticide diazinon on liver protein and nucleic acid metabolism in adult zebrafish. Kumar and Ansari (290) investigated liver toxicity of malathion. Roex et al (429) assessed acute toxicity of parathion and chlorobenzene. Zok et al (591) studied acute toxicity of substituted anilines. Lanzky and Halling-Sorensen (297) found metronidazole to have low acute toxicity to zebrafish. Meinelt et al (341) investigated the influences of calcium concentration and humic acid on toxicity of acriflavine to juvenile zebrafish. Roche et al (428) studied acute and chronic toxicity of colchicine in zebrafish. Labrot et al (294) investigated acute toxicity of lead and uranium in zebrafish, finding lead relatively nontoxic and uranium highly toxic. Van den Belt et al (527) evaluated acute toxicity of cadmium-contaminated clay to zebrafish. Ultraviolet-B light induces oxidant stress in adult zebrafish (85).

Early Life Stage Toxicity

Nearly every class of environmental contaminants has been evaluated for early life stage toxicity in zebrafish. However, only a few recent studies have investigated molecular mechanisms of toxicity. Early life stage toxicity of most metals and several organometallics have been investigated in zebrafish (91, 117-120, 184, 340, 378, 389, 391, 427, 436, 447, 470, 490, 495). Toxicity of a variety of pesticides, organochlorines, and halogenated aromatic hydrocarbons is reported (43, 62, 116, 145, 190, 191, 196, 197, 215, 354, 355, 383, 502, 566, 567). Willey and Krone (573) utilized the vasa gene as a marker of primordial germ cells to track alterations in their homing to gonad caused by endosulfan or nonylphenol. Dong et al (129) applied in situ terminal transferase-mediated nick-end-labeling staining (TUNEL) to demonstrate increased cell death in the dorsal midbrain of TCDD-treated embryos. These investigators could mimic the TCDD-induced cell death with the AHR agonist beta-naphthoflavone, and prevent the increased cell death with the AHR antagonist alpha-naphthoflavone. Another recent study which exploited current molecular genetic tools available for zebrafish demonstrates that TCDD does not inhibit primitive embryonic erythropoiesis, indicated by gata-1, gata-2 markers (41). However, TCDD prevents formation of later definitive erythropoiesis revealed by the scl marker. TCDD causes craniofacial malformations in fish and mammals. TCDD reduces normal expression of the signaling molecule sonic hedgehog (shh) in zebrafish jaw (503). Toxicity of various drugs, endogenous signaling molecules and hormones have been evaluated in zebrafish (33, 202, 218, 219, 224, 383, 384, 538, 588). Akimenko and Ekker (2) show that fin malformations induced by exogenous all-trans retinoic acid are associated with anterior duplication of expression domains of shh. Various industrial chemicals and waste show adverse effects in developing zebrafish (71, 79, 95, 147, 148, 177, 296, 368, 370, 373, 388, 531, 532). Physical stresses such as magnetic fields may perturb zebafish development (85, 179, 488). Skauli et al (469) show an additive interaction of magnetic field stress with the hormone progesterone in causing delayed hatching. The algal toxin microcystin suppresses growth following early life stage exposure (568).

Reproductive Toxicity and Endocrine Disruption

Most structural classes of toxicants including metals, organochlorines, and pesticides (15, 18, 58, 148, 152, 429), halogenated aromatic hydrocarbons (387) substituted anilines (63), synthetic and natural estrogens (8, 526, 528), and other industrial chemicals (79, 230) have been evaluated for reproductive toxicity in zebrafish (61, 272, 293). Potential for disruption of endocrine systems in the zebrafish model has been assessed with a growing list of agents (301, 522).

Neurobehavioral Toxicity

Neurobehavioral effects of a variety of toxicants, drugs, and alcohol have been evaluated in developing or adult zebrafish (491). Samson et al (447) found that impairment of swimming and predator/prey behavior were much more sensitive indicators of toxicity in zebrafish exposed as early life stages to methylmercury than were mortality or morphologic lesions. Both early and recent studies have investigated pathologic lesions and functional impairment of developing zebrafish exposed to ethanol (51, 115, 291). Gerlai et al (181) are using zebrafish to assess genetic factors predisposing lines of fish to alcohol preference. Darland and Dowling (114) are screening mutant lines of zebrafish to identify those with increased preference for exposure to cocaine and for altered responses to cocaine. Thomas (506) studied effects of tetrahydrocannabinol (THC) from marijuana in developing zebrafish.

Disease Resistance and Immune Status

Assays for assessment of disease resistance and immune competence are developed to a much greater extent in the medaka (34, 78, 586) than in zebrafish. Treatment of zebrafish with zinc or copper did not consistently increase their susceptibility to intraperitoneally injected Listeria (435). Zinc exposure suppresses the humoral immune response against Proteus vulgaris, but not against infectious pancreatic necrosis virus in adult zebrafish (449).

Biomarkers in Zebrafish

Surrogate tests to predict chronic toxicity are gaining favor for environmental monitoring of human health and other sentinel species. Data regarding several biomarkers is available in zebrafish. Induction of the cytochrome P4501a1 (Cyp1a1) enzyme has been extensively used to indicate exposure of fish to halogenated hydrocarbons and polycyclic aromatic hydrocarbons. Activity of Cyp1a1 is induced in early life stages as well as adult zebrafish, and in zebrafish cell cultures (13, 69, 102, 214, 353, 518) following exposure to TCDD. A variety of assays of DNA damage may indicate exposure of fish to mutagens (126). Transgenic fish containing shuttle plasmid vectors serve as efficient indicators of exposure to environmental mutagens (3, 4). Schnurstein and Braunbeck (453) have developed an in vitro system using hepatocytes and gill cells to detect mutagenic agents. Troxel et al (519) measured DNA adducts in adult zebrafish injected with the carcinogen aflatoxin B1 (AFB1). Zebrafish are quite resistant to AFB1-induced neoplasia compared to the most sensitive vertebrate species, the rainbow trout. Surprisingly, adduct levels in zebrafish were just 4-fold less than those in the highly sensitive rainbow trout, and were comparable to adduct levels occurring in relatively sensitive mammalian species. Hsu and Deng (234) quantified adduct levels in various organs of zebrafish following bath exposure to benzo[a]pyrene. They found highest adduct levels in intestine and liver. Several investigators have measured plasma vitellogenin levels in zebrafish as an indicator of exposure to environmental estrogens (8, 522).

Use of Zebrafish as Sentinels to Detect Environmental Hazards

Carvan et al (80) developed transgenic lines of zebrafish with response elements to indicate exposure to specific toxicants. The constructs introduced into the zebrafish include aryl hydrocarbon, electrophile, metal, and estrogen response elements. Each reponse element is coupled to a reporter such as luciferase or green fluorescent protein. Zebrafish cell lines containing such reponse elements coupled to reporter genes are also available (81). Zebrafish embryos are sensitive indicators of toxic components in industrial and municipal waste and landfill leachates (169, 170, 243). Chronic bioassays using whole life-cycle tests with zebrafish can detect mortality, growth suppression, reproductive, and developmental toxicity, as well as behavioral toxicity (472).

Spontaneous and Induced Neoplasia in Zebrafish

Carcinogen-Induced Neoplasia

Although the zebrafish was the first fish species in which experimental carcinogenesis was conducted (by Mearle Stanton of the National Cancer Institute in the 1960s; 481, 482), until recently, little additional neoplasia research has used zebrafish (269, 411, 412).

The most comprehensive carcinogenesis studies to date with zebrafish were conducted at Oregon State University (OSU) with funding from the US Army. This research evaluated carcinogenicity of a panel of structurally diverse carcinogens at three development stages in Florida wild-type zebrafish. Carcinogens evaluated in this work included N-nitrosodiethylamine (DEN), aflatoxin B1 (AFB1), methylazoxy-methanol acetate (MAMA), N-methyl-N′-nitro-N-nitrosoguanidine (MNNG), and 7,12-dimethyl-benz[a]anthracene (DMBA). We administered carcinogens by bath to late stage embryos or fry at 2–3 weeks postfertilization. In dietary carcinogenesis studies we fed 2-month-old juvenile fish a semipurified diet (300) containing carcinogen for 3–9 months. For each carcinogen and the 3 developmental stages, we treated fish with at least 3 graded doses of carcinogen up to the maximum tolerated dose.

Zebrafish exposed to most of the carcinogens as fry or embryos display a wide variety of neoplasm types derived from epithelial, mesenchymal, neural, and neural crest tissues. Liver is a primary target organ for most carcinogens, regardless of developmental stage of fish at exposure. We see the greatest diversity of histologic types of neoplasia following early life stage exposure to MAMA, MNNG, or DMBA (212, 476-478, 521). Table 1 indicates the patterns of target organs observed in our carcinogen studies with Florida wild-type zebrafish. Zebrafish of the Florida wt strain are remarkably resistant to carcinogenic effects of AFB1 at all life stages. In dietary studies, neoplasia was not observed following treatment with MNNG or DEN, and substantial incidences of neoplasia occurred with AFB1 only after dietary exposure for 9 months to 100 ppm. Typically low ppb concentrations of AFB1 are used for dietary carcinogenesis studies in rainbow trout to achieve high incidences of liver neoplasia (27). The relative resistance of juvenile zebrafish to most dietary carcinogens when compared to juvenile rainbow trout fed the same carcinogens may occur in part because the growth rate of zebrafish slows substantially as they approach maturity at 3–6 months of age, whereas trout continue to grow at a more rapid rate throughout life. The reasons for the relative resistance of Florida wild-type zebrafish to AFB1 at all life stages are not yet clear. Surprisingly, adduct levels following adult exposure were just 4-fold less than those observed in rainbow trout, and were comparable to adduct levels occurring in relatively sensitive mammalian species (518, 519). Although maximal percent incidences of total neoplasia in the most sensitive life stage were 67, 66, 62, 37, and 32 for DEN, DMBA, MAMA, AFB1, and MNNG, respectively, at most a 32% incidence of liver neoplasia or 15% incidence of gut neoplasia occurred in carcinogen treated fish.

Table 1
Target organs for carcinogen reponses of Florida wild-type zebrafish.

Beckwith et al (36) of Pennsylvania State University report 100% incidence of cutaneous papillomas occurring in 18 zebrafish of the Florida wild-type line within 1 year following 3 adult bath exposures to 2.5–3 mM ENU. We hypothesized that early life stage exposure to ENU might speed up the time to tumor development, and also predicted that the Tuebingen long fin leopard (TL) mutant line with fin overgrowth would likely develop more papillomas at a faster rate on fins than wild-type lines. We administered single 1 hr bath exposures of the maximum tolerated dose of ENU (2.5 mM) to 3-week-old TL fry, and administered 3 doses of 2.5 mM ENU to Tuebingen wild-type (TU) fry at 3, 5, and 7 weeks of age. At 1 year posttreatment in the TL line, and at 1 and 2 years posttreatment in the TU line, we observed no papillomas. In carcinogen-treated fish of both lines, we documented a variety of neoplasm types including hemangiomas and hepatic and neural neoplasia not observed in vehicle or sham control fish of those lines (Spitsbergen and Kent, unpublished data). Several explanations are possible for the differences in our findings in the TL and TU lines at OSU compared to the Florida wild-type line at Pennsylvania State University. Perhaps only the Florida wild-type line has skin that responds to ENU. Perhaps ENU is carcinogenic in zebrafish only after adult exposure of specific genetic lines. Perhaps the Penn. State University zebrafish colony has a unique oncogenic virus and/or tumor promoter contributing to papilloma development. The zebrafish colony at the University of Oregon houses large numbers of zebrafish of the AB line treated as adults with a similar ENU protocol to that used at Pennsylvania State University. Yet cutaneous papillomas are seen at the University of Oregon only in eggbound female broodstock with prolapse of the distal intestine and subsequent chronic irritation of the vent, resulting in hyperplasia or papilloma of the skin of the vent.

Spontaneous Neoplasia

In carcinogen studies at OSU, the spontaneous rate of neoplasia in the Florida wild-type line at 6–14 months of age is 1%, based on 3,000 untreated controls. The most common histologic types of spontaneous neoplasia in this line are seminoma of testis, hepatocellular adenoma, and adenoma of exocrine pancreas, with intestinal adenocarcinoma less common (476-478).

Michael Kent and Jan Spitsbergen of OSU and Monte Westerfield of Univeristy of Oregon are currently investigating spontaneous rates of neoplasia in wild-type and mutant lines of zebrafish. We are evaluating the relative roles of diet, husbandry systems, infectious agents, and genetic influences on rates of neoplasia in various zebrafish lines. As part of this research, we are comparing spontaneous tumor incidences at 2 years of age in replicate groups of AB wild-type zebrafish fed 2 different diets (commercial diet or semipurified diet) and raised at 3 different facitilites at Oregon State University and University of Oregon. We have begun to systematically examine large numbers of retired broodstock histologically over the past year. Since 1999, we have studied diagnostic cases from moribund fish, fish with gross lesions, or sentinel fish submitted to the diagnostic pathology service provided by the Zebrafish International Resource Center at the University of Oregon. We have examined approximately 500 fish in the diagnostic service. Among these diagnostic cases, the most common target tissues for neoplasia are ultimobranchial gland (26/500), testis (22/500), liver (15/500), gut (14/500), peripheral nerve (11/500), and thyroid (6/500). Less common target tissues in diagnostic cases are eye (5/500), nasal sensory neuroepithelium (3/500), blood vessel (2/500), fibroblast (1/500), brain (2/500), gill (1/500), lymphomyeloid system (1/500), pancreas (2/500), notochord (1/500), and pigment cell (1/500). In these studies of spontaneous neoplasia together with our ongoing and historical carcinogen studies, benign and malignant neoplasms occur in nearly every tissue of zebrafish. Tissues in which we have not yet observed neoplasia are pituitary, glial cells of brain, ovary, and the granulocytic lineage of blood (have seen myelodysplasia with granulocytes predominating). Sample sizes in our studies of retired broodstock are currently too small to draw clear conclusions. Fewer than 100 fish per line have been examined from most lines, often of a single cohort raised together in one facility. So far the spectrum of tumor types in most broodstock lines, wild-type or mutant, is similar to that in diagnostic cases, with tumors of testis, liver, and gut most common. AB wild-type zebrafish 1.5–2 years of age show incidences of total neoplasia of approximately 10–15%. Up to 50% of males of the AB line develop seminomas of testis by 1.5–2 years of age.

Medical doctor pathologists, veterinary pathologists and fish pathologists are collaborating to complete a review paper summarizing current information on neoplasia in zebrafish. This information was presented in poster form at scientific meetings (37, 38). This manuscript should be submitted within months, and information with images will be available on the World Wide Web through ZFIN.

Development of Zebrafish Lines Highly Sensitive to Neoplasia

Investigations of spontaneous and carcinogen-induced neoplasia in zebrafish reveal a variety of neoplasms that rarely occur even in carcinogen-treated vertebrates of other species (chordoma, pineocytoma, hepatoblastoma, ocular medulloepithelioma, olfactory esthesioneuroepithelioma). Development of zebrafish lines that show high incidences of specific neoplasms early in life will offer an efficient, cost-effective system for investigating molecular alterations occurring during various phases of the evolution of tumors and for developing novel anticancer therapy.

Jan Spitsbergen, Michael Kent, and Donald Buhler of Oregon State University are investigating carcinogen-induced neoplasia in various wild-type and mutant lines of zebrafish in order to identify lines that develop high incidences of specific histologic types of neoplasia early in life. We have identified several mutant lines that develop 70–90% incidences of liver neoplasia within 6–12 months posttreatment. Certain of these lines rapidly develop highly anaplastic neoplasia, including hepatoblastoma. Some of these mutant lines are susceptible to relatively high incidences of multiple tumor types including hemangioma/hemangiosarcoma, esthesioneuroepithelioma/esthesioneuroblastoma of nose, and myelodysplastic syndrome of hemopoietic tissue. Our finding of myelodysplasia at a relatively high incidence (50% incidence or greater) in mutant lines following carcinogen exposure is particularly exciting because, for unexplained reasons, myeloid hemopoietic neoplasia has not yet been reported in untreated or carcinogen-treated wild-type zebrafish under the conditions studied to date (475).

Leonard Zon and colleagues at Children's Hospital in Boston, Massachusetts are investigating carcinogen responsiveness of mutant lines of zebrafish selected for altered expression of cell cycle genes in embryos and young fry. Several mutant lines show increased cumulative incidences in neoplasia following fry bath treatment with MNNG or DMBA, compared to wild-type siblings when sampled at 3, 6, and 12 months posttreatment (464). Keith Cheng and colleagues at Pennsylvania State University have developed lines of zebrafish with genomic instability and are investigating neoplasm prevalences in these lines (359, 360). Cheng's group is also investigating lines of zebrafish showing dysplasia of various tissues at 7 days of development, predicting that such lesions will be associated with elevated neoplasm risk later in life (88). Thomas Look and colleagues at Harvard Medical School are developing a model for neuroblastoma by engineering overexpression of zebrafish mycn (420).

Oncogenes and Tumor Suppressor Genes in Zebrafish

Functional motifs in oncogenes and tumor suppressor genes tend to be highly conserved among vertebrate species, so that study of oncogenes and tumor suppressor genes in zebrafish will likely provide valuable insights into molecular mechanisms of tumorigenesis and genetic susceptibility to tumors in humans (124, 525). Because interest in neoplasia and carcinogenesis in the zebrafish model has only recently begun to dramatically expand, unfortunately relatively few of the zebrafish orthologs of human tumor suppressor genes and oncogenes have been cloned, fully sequenced and/or mapped. Single orthologs of the human tumor suppressor genes WT1 (266, 471), P53 (90), MEN 1 (268), MADH2, MADH5 (127), PTC1, and PTC2 (305) are fully sequenced and mapped in zebrafish. Full cDNA sequence and mapping data are available for single orthologs of human oncogenes NRAS (89), RET (48), CMYC (455), CKIT (395, 421), PIM1 (239) and MDM2 (504). In contrast to findings in Xenopus, overexpression of mdm2 in developing zebrafish does not cause early increased tumor incidence (504).

Complicating Factors in Zebrafish Toxicologic Pathology Research

Shortage of Basic Data on Zebrafish Pathology

There are scant baseline data on zebrafish pathologic lesions in infectious and noninfectious diseases. Shortly after the widespread use of mutant mice began, industry, academia, and government agencies realized that molecular biology and genetic approaches alone could not adequately predict and systematically characterize the complex phenotypes of mice with single or multiple gene mutations. For example, many lines of knockout mice for which the inactive genes are not related directly to the immune system still are immunodeficient and at high risk for opportunistic infection (60, 433, 575). Thus rigorously trained comparative pathologists are playing a growing role in research with mutant mice. To utilize the potential of zebrafish fully as an animal model for understanding human development, disease, and toxicology, we must greatly advance our knowledge of zebrafish diseases and pathology. Much of the information pertinent to zebrafish infectious diseases is in general reference texts regarding the topic of aquarium fish diseases (379, 487). Since 1999, Michael Kent of Oregon State University, Jennifer Matthews of the University of Oregon, and collaborators have investigated epidemiology, prevention and control of important infectious and noninfectious diseases affecting zebrafish colonies (50, 334).

Infectious Diseases of Zebrafish

Two infectious diseases that commonly occur in well-managed zebrafish colonies are microsporidiosis and mycobacteriosis. Pseudoloma neurophila, a microsporidian infects the central nervous system, cranial and spinal nerves, and skeletal muscle of zebrafish. Severely affected fish may be emaciated, ataxic, or have spinal malformations (123, 333). Michael Kent's research group has developed a polymerase chain reaction test to screen broodstock and derive specific pathogen-free lines. We are uncertain whether vertical transmission of microsporidia can occur in zebrafish. Unfortunately, these parasites are very difficult to inactivate and remove from recirculating husbandry systems. Zebrafish of various lines derived from eggs obtained in the main colony or new Zebrafish International Resource Center Colony at the University of Oregon do not develop microsporidiosis when reared in a flow-through husbandry system at Oregon State University, but do develop microsporidiosis when raised in the recirculating systems at University of Oregon. Thus horizontal transmission of this parasite seems to be important, however, the role of vertical vs horizontal transmission is still unclear. Renibacterium salmoninarum, an important bacterial disease of salmonids, is spread vertically within eggs, but only a few eggs are usually infected. Yet these few infected eggs serve as a source for horizontal transmission in early life stages held in incubation trays (151). Pseudoloma presents particular problems for neurobehavioral toxicity studies. Although Kent's group is investigating possible drug therapy, no recommended therapy methods are yet available.

Piscine mycobacteriosis remains a tenacious problem in aquarium fish colonies. It most often occurs as an opportunistic infection in fish over 1 year of age, especially those stressed by toxicant exposure or adverse environmental conditions. Therefore, mycobacteriosis is a problem in long-term tumor or aging studies. Highly pathogenic strains may cause devastating mortality in otherwise healthy colonies. The sources of infection and epizootiology are not well defined. Mycobacteria may enter fish from food or water, and may possibly be vertically transmitted. Currently no effective chemopreventative or therapeutic regimens are defined for fish (23). Because mycobacterial antigens are potent immune adjuvants, these agents can seriously confound research in disease resistance or immune responses.

Pseudocapillaria tomentosa, a nematode parasite, infects the gut of zebrafish. This parasite occurs commonly in colonies of Florida wild-type lines. Infection causes moderate to severe multifocal to diffuse hyperplasia and dysplasia of the intestine, as well as elevated incidences of intestinal neoplasia. Enteric adenomas and carcinomas occur in close proximity to profiles of nematodes in the gut. The parasite acts as a tumor promoter in carcinogen experiments. In dietary carcinogen studies, zebrafish fed DMBA developed more intestinal neoplasia if infected with the nematode (267).

To date, a pathogenic viral agent has not yet been isolated from or visualized in zebrafish tissues. We are looking for viral agents with ultrastructural studies of fish tissue, viral isolation procedures in fish cell lines, and disease transmission trials in which young zebrafish are injected with tumor tissue or tissue from diseased fish. All vertebrate species that have been studied intensely are host to multiple pathogenic viruses.

Zebrafish are certainly affected by pathogenic and oncogenic viruses that will eventually be identified. Salmonid viruses infectious hematopoietic necrosis virus and infectious pancreatic necrosis virus infect zebrafish and zebrafish cell lines (315), but do not cause clinical disease (298, 457).

A small amount of published information is available regarding zebrafish disease diagnostic procedures and infectious diseases. Astrofsy et al (22) outline diagnostic techniques for clinical investigation of laboratory zebrafish. Menudier et al (345) compared pathogenicity of various strains of Listeria in zebrafish and mice, showing that strains nonpathogenic in mice were sometimes highly pathogenic in zebrafish. Pullium et al (419) document epizootic motile aeromonad septicemia in a zebrafish colony associated with stress due to poor water quality. Edwardsiella ictaluri, a common pathogen of channel catfish, was isolated from moribund danio during a disease outbreak (546). Mills (352) reports on ecological factors influencing digenean trematode infections.

Influence of Diet and Husbandry Systems on Spontaneous Neoplasia

Zebrafish colonies fed commercial diets and maintained in standard recirculating systems have different patterns of neoplasia and spontaneous pathologic lesions than those observed in the Core Fish Facility of the Marine/Freshwater Center at Oregon State University. We have a flow-through system and feed fish a semipurified diet used for over 30 years in carcinogenesis studies in fish. We have not yet seen spontaneous mesenchymal neoplasia, spontaneous neoplasia of the central or peripheral nervous system, or spontaneous thyroid neoplasia in any lines of zebrafish in the Oregon State University center. In contrast, such neoplasms occur quite commonly in diagnostic cases from many labs around the world, even in fish just 6 months of age. These findings suggest that naturally occurring carcinogens may be present in the diet or environment in many zebrafish colonies. Our studies comparing neoplasm incidences in zebrafish of the AB line fed commercial or semipurified diets at 3 separate fish facilities will help shed light on the influences of diet and husbandry on neoplasm patterns.

The Mystery of Hepatic Megalocytosis in Zebrafish

In diagnostic cases from around the world and in about 50% of groups of retired broodstock from standard husbandry systems feeding commercial diets, we see mild to moderate hepatocyte megalocytosis with karyomegaly. From 10 to 100% of the fish in affected lots of broodstock show hepatic megalocytosis. Hepatocyte cytoplasmic volumes and nuclear volumes may be 5–50X normal. We have never seen this megalocytosis in untreated control fish of any line from the Core Fish Facility of the Marine/Freshwater Center at Oregon State University. Data from many vertebrates including zebrafish indicate that hepatocyte megalocytosis is caused by toxicant damage to DNA or the mitotic apparatus (207). The algal toxin microcystin causes hepatic megalocytosis in Atlantic salmon (10). We often see high incidences of hepatocyte megalocytosis in zebrafish following carcinogen exposure. In a given environment, some lines appear more prone to hepatic megalocytosis. In the flow-through quarantine facility at the University of Oregon, the TL line shows megalocytosis, but the TU, Cologne, another long fin, and knorrig lines do not. The toxicant sources causing megalocytosis are uncertain. Dietary components (commercial flake, paramecium cultures), algae or biofilm in hoses/lines, and metabolites of microbes in biofilters may contribute to the problem. In addition to increasing the spontaneous incidences of neoplasia, the toxicant(s) causing megalocytosis may also cause other health problems, reducing early life stage survival, longevity, reproductive potential, immune competence, and disease resistance.

Bile Duct Hyperplasia in the TL Line

In our studies of retired broodstock at OSU and U. of O. mild to severe multifocal to diffuse hyperplasia of bile ducts is present in essentially 100% of broodstock of the TL line by 1.5 year of age. The incidences and severity of these lesions are similar at a given age in fish raised at Oregon State University or University of Oregon. The lesions are not associated with significant inflammation, parasites or other infectious agents, however, the severity is greater in males than in females. Approximately 10% of TL line fish raised in flow-through conditions at the University of Oregon show biliary neoplasia spontaneously by 1.5 years of age. Bile duct hyperplasia is not linked to the long fin mutant gene, as broodstock are not homozygous for this dominant gene, and wild-type siblings have similar incidences and severity of bile duct hyperplasia. Although it is a double mutant, the TL line has been used as a background genetic line for perpetuating other mutant lines in many zebrafish colonies because it is hardy and fecund, so its background genetics are unique. Although the proliferated bile ducts may occupy 50% of the volume of liver of TL line fish by 1.5 year of age, except for elevated incidences of neoplasia, the fish appear clinically healthy and usually breed well. The bile duct hyperplasia seen in TL line zebrafish is not seen in TU wild-type line or in the another long fin (alf ) mutant line on the TU × AB background. The TL line will be a useful model for study of primary biliary cirrhosis and bile duct neoplasia, spontaneous and carcinogen-induced, but would be a poor line to use in toxicant studies in which subtle alterations in bile ducts must be discerned.

The Problem of Skewed Sex Ratios in Cohorts of Zebrafish

At many zebrafish facilities around the world, problems with skewed sex ratios in cohorts of zebrafish can interfere with natural breeding, and can complicate studies such as carcinogen or other toxicant bioassays where balanced sex ratios in control groups are desired. In contrast to mammalian species, sex determination in fish is more flexible, often reversible, and less dictated by genetic factors (29, 122, 442). The relative influences of and interactions between environment, genetics, and toxicants in sex determination in zebrafish are not yet clearly defined. However, genetic as well as environmental factors appear to influence sex determination. The TU line raised in any of the recirculating or flow-through systems at the University of Oregon tends to be predominately female, whereas the AB line reared in the same systems often has an excess of males. We do not see skewed sex ratios in control groups of Florida wt zebrafish in the Core Fish Facility of the Marine/Freshwater Center at Oregon State University, but we often see very skewed sex ratios with the German lines TU and TL, and the AB line. We do not see unbalanced sex ratios in rainbow trout in this facility.

Histopathology and Toxicologic Pathology Literature Regarding Zebrafish

The literature on nonneoplastic pathologic lesions in zebrafish is sparse compared to that for mammals. A few references on nutritional pathology are available (141, 342, 408). Vithelic and Hyde (540) document light-induced retinal damage in albino zebrafish. Ferretti and Geraudi (154) and Geraudi et al (180) show retinoic acid-induced cell death in healing wounds on regenerating fins. Few of the toxicant studies using zebrafish have investigated light microscopic or ultrastructural morphologic alterations. Hisaoka (225, 226) describe histochemical changes including depletion of hepatic glycogen, and light microscopic morphologic lesions including necrosis of neuroepithelium of the central nervous system occurring in zebrafish following embryo exposure to 2-acetylaminofluorene. Burkhardt-Holm et al (71) report ultrastructural alterations in liver, gill and erythrocytes following chronic exposure of embryonic or larval zebrafish to 4-chloroaniline. Oulmi and Braunbeck (388) describe ultrastructural alterations in liver and kidney in zebrafish following embryo microinjection of 4-chloroaniline.

Braunbeck et al (59) document ultrastructural alterations in liver of zebrafish including reduced numbers of peroxisomes following chronic exposure to 4-chloroaniline. Bresch et al (63) evaluated spinal integrity using radiography during a 3-generation life cycle study with 4-chloroaniline. Braunbeck et al (58) show hepatic steatosis occurring in zebrafish chronically exposed to lindane in a full life cycle test. Strmac and Braunbeck (490) indicate that the cardiovascular system is a primary target following sublethal exposure of early life stages of zebrafish to triphenyl tin acetate. They report ultrastructural alterations in liver including depleted glycogen, mitochondrial swelling, and cytoplasmic myelin figures. Dong et al (129) and Henry et al (215) describe light microscopic lesions in zebrafish during the early life stage toxicity syndrome caused by TCDD. As in early life stages of other species of fish exposed to TCDD, the cardiovascular system is the primary target organ system in zebrafish. Ansari et al (18) and Ansari and Kumar (15) show reduced numbers of mature ovarian follicles, hepatomegaly, and alterations in hepatic nucleic acid and protein (16, 17) in zebrafish following chronic sublethal exposure to malathion. Olsson et al (383) studied histologic lesions in offspring following maternal exposure to PCBs or 17-beta-estradiol. Maternal exposure to PCB-104 or 190 causes craniofacial malformations and scoliosis in offspring. Maternal exposure to PCB-104 or 17-beta-estradiol causes tubular nephrosis, and 17-beta-estradiol, PCB-104, or PCB-60 increases ooctye atresia in ovaries, and arrests spermatogenesis in testes in early life stages of progeny. Histologic alterations occur in gonads of both female and male zebrafish given acute bath exposures as adults to the synthetic estrogen 17-alpha-ethynylestradiol (526). Increased atretic follicles and arrested follicular development occur in the gonads of females. In males, spermatogenesis ceases at the spermatogonial stage.

Future Needs and Future Research Directions

The utility of early life stages of zebrafish in high throughput screening systems for drug development is already being exploited (369, 371, 404, 484). The small size of zebrafish embryos and fry, and their ability to be cultured during the first week of life in 96 well microtiter plates make this system ideal for drug discovery and safety testing. Most hydrophilic as well as lipophilic agents are readily absorbed from the culture medium of eggs or fry, facilitating efficient testing of new agents.

To advance the field of zebrafish toxicologic pathology toward the state of the art in mammalian toxicologic pathology, much more data regarding pathologic lesions following acute, subchronic and chronic toxicant exposure will be required. We need to develop a comprehensive database regarding spontaneous and toxicant-induced neoplasia and nonneoplastic lesions in the common wt and mutant lines of zebrafish. Spontaneous aging lesions in various strains of zebrafish need to be investigated. Comprehensive data on metabolism and pharmacokinetics of toxicants in various wt and mutant lines will be essential to support sophisticated toxicologic pathology research. Very little information is available on DNA repair enzymes in various lines of zebrafish. Once the full genomic sequence is available for zebrafish during the coming year, this information will speed the identification of and study of DNA repair enzymes. The cornucopia of markers for protein and gene expression generated for studies of zebrafish development need to be exploited in toxicant studies. To best utilize the zebrafish as a model system for understanding mechanisms in oncogenesis relevant to man, we must clarify the members of families of oncogenes and tumor suppressor genes to sort out their relative roles in tumorigenesis in zebrafish compared to mammals. Duplicate genes for some members of these families are likely to complicate the clarification of signaling pathways in the zebrafish. Microarray technology will likely help in unraveling the complex signaling networks in zebrafish.

In recent years, the Society of Toxicologic Pathology has coordinated working groups of pathologists focused on specific organ systems in rodents. The poster sessions at STP meetings and STP-sponsored monographs on proliferative and nonproliferative lesions for each organ system have established consensus in the field of toxicologic pathology regarding terminology for morphologic diagnosis of pathologic lesions in rodents. We need to establish similar pathology working groups to define diagnostic criteria for proliferative and nonproliferative lesions in the major organ systems of zebrafish. An inadequate number of scientists have sufficient training in anatomy, histology, and pathology of fish including zebrafish to support the growing need for pathology expertise in the study of zebrafish models for human disease. Some short courses in fish diseases and pathology such as the Aquavet program taught each spring at the Marine Biological Laboratory in Woods Hole, Massachusetts can provide an introduction to fish pathology for scientists who already have basic histology and pathology training.

However, more extended residency and/or graduate training for D.V.M. and M.D. pathologists as well as fish biologists will be required in order to establish adequate diagnostic skills to correctly interpret histologic lesions in fish tissues.


Research at Oregon State University and University of Oregon was funded by US Public Health Service grants ES011587-01 and P30ESO3850 from the National Institutes of Environmental Health Sciences, by grant 3P40RR12546 and its supplement 03S1 from the National Center for Research Resources, and by US Army contract DAMD 1791Z1043. We thank Tom Miller, Keri St. Clair, Janelle Bishop-Stewart, Sheila Cleveland, Chance MacDonald, Karen Larison, April Mazanac, Bill Trevarrow, and Dan Arbogast for technical support in our ongoing and past zebrafish studies.


1. Abnet CC, Tanguay RL, Heideman W, Peterson RE. Transactivation activity of human, zebrafish, and rainbow trout aryl hydrocarbon receptors expressed in COS-7 cells: Greater insight into species differences in toxic potency of polychlorinated dibenzo-p-dioxin, dibenzofuran, and biphenyl congeners. Toxicol Appl Pharmacol. 1999;159:41–51. [PubMed]
2. Akimenko MA, Ekker M. Anterior duplication of the Sonic hedgehog expression pattern in the pectoral fin buds of zebrafish treated with retinoic acid. Dev Biol. 1995;170:243–247. [PubMed]
3. Amanuma K, Takeda H, Amanuma H, Aoki Y. Transgenic zebrafish for detecting mutations caused by compounds in aquatic environments. Nat Biotechnol. 2000;18:62–65. [PubMed]
4. Amanuma K, Tone S, Saito H, Shigeoka T, Aoki Y. Mutational spectra of benzo[a]pyrene and MeIQx in rpsL transgenic zebrafish embryos. Mutat Res. 2002;513:83–92. [PubMed]
5. Amatruda JF, Shepard JL, Stern HM, Zon LI. Zebrafish as a cancer model system. Cancer Cell. 2002;1:229–231. [PubMed]
6. Amatruda JF, Zon LI. Dissecting hematopoiesis and disease using the zebrafish. Dev Biol. 1999;216:1–15. [PubMed]
7. Amin S, Desai D, Dai W, Harvey RG, Hecht SS. Tumorigenicity in newborn mice of fjord region and other sterically hindered diol epoxides of benzo[g]chrysene, dibenzo[a,l]pyrene (dibenzo[def,p]chrysene), 4H-cyclopenta[def]chrysene and fluoranthene. Carcinogenesis. 1995;16:2813–2817. [PubMed]
8. Andersen L, Petersen GI, Gessbo A, Oern S, Holbech H, Bjerregaard P, Norrgren L. Zebrafish Danio rerio and roach Rutilus rutilus: Two species suitable for evaluating effects of endocrine disrupting chemicals? Aquatic Ecosystem Health Manage. 2001;4:275–282.
9. Andersson PL, Berg AH, Bjerselius R, Norrgren L, Olsen H, Olsson PE, Orn S, Tysklind M. Bioaccumulation of selected PCBs in zebrafish, three-spined stickleback, and arctic char after three different routes of exposure. Arch Environ Contam Toxicol. 2001;40:519–530. [PubMed]
10. Andersen RJ, Luu HA, Chen DZ, Holmes CF, Kent ML, Le Blanc M, Taylor FJR, Williams DE. Chemical and biological evidence links microcystins to salmon ‘netpen liver disease.’ Toxicon. 1993;31:1315–1323. [PubMed]
11. Ando H, Mishina M. Efficient mutagenesis of zebrafish by a DNA cross-linking agent. Neurosci Lett. 1998;244:81–84. [PubMed]
12. Andreasen EA, Hahn ME, Heideman W, Peterson RE, Tanguay RL. The Zebrafish (Danio rerio) aryl hydrocarbon receptor type 1 is a novel vertebrate receptor. Mol Pharmacol. 2002;62:234–249. [PubMed]
13. Andreasen EA, Spitsbergen JM, Tanguay RL, Heideman W, Peterson RE. Tissue-specific expression of AHR2, ARNT2, and CYP1A in zebrafish embryos and larvae: Effects of developmental stage and 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure. Toxicol Sci. 2002;68:403–419. [PubMed]
14. Ansari BA, Kumar K. Malathion toxicity: Embryotoxicity and survival of hatchlings of zebrafish (Brachydanio rerio) Acta Hydrochim Hydrobiol. 1986;14:567–570.
15. Ansari BA, Kumar K. Malathion toxicity: Effect on the ovary of the zebra fish Brachydanio rerio (Cyprinidae) Int Rev gesamt Hydrobiol Berlin. 1987;72:517–528.
16. Ansari BA, Kumar K. Boletim de fisiologia animal. Vol. 11. Universidade de Sao Paulo; Sao Paulo: 1987. Malathion toxicity: Pathological changes in the liver of zebrafish, Brachydanio rerio (Cyprinidae) pp. 27–34.
17. Ansari BA, Kumar K. Diazinon toxicity: Effect on protein and nucleic acid metabolism in the liver of zebrafish, Brachydanio rerio (Cyprinidae) Sci Total Environ. 1988;76:63–68. [PubMed]
18. Ansari BA, Srivastava R, Kumar K. Boletim de fisiologia animal. Universidade de Sao Paulo; Sao Paulo: 1986. Malathion toxicity: Pathological changes in the ovary of zebrafish, Brachydanio rerio (Cyprinidae) pp. 95–101.
19. Argenton F, Zecchin E, Bortolussi M. Early appearance of pancreatic hormone-expressing cells in the zebrafish embryo. Mech Dev. 1999;87:217–221. [PubMed]
20. Asai R, Taguchi E, Kume Y, Saito M, Kondo S. Zebrafish leopard gene as a component of the putative reaction-diffusion system. Mech Dev. 1999;89:87–92. [PubMed]
21. Ashmore J. Mechanosensation: Swimming round in circles. Curr Biol. 1998;8:R425–R427. [PubMed]
22. Astrofsky KM, Harper CM, Rogers AB, Fox JG. Diagnostic techniques for clinical investigation of laboratory zebrafish. Lab Anim (NY) 2002;31:41–45. [PubMed]
23. Astrofsky KM, Schrenzel MD, Bullis RA, Smolowitz RM, Fox JG. Diagnosis and management of atypical Mycobacterium spp. infections in established laboratory zebrafish (Brachydanio rerio) facilities. Comp Med. 2000;50:666–672. [PubMed]
24. Avaron F, Thaeron C, Cordier MJ, De Hennezel L, Boulekbache H. Characterization of retinoid-induced apoptosis in developing zebrafish (Brachydanio rerio) embryos. Int J Dev Biol. 1997;41:8S–9S.
25. Babin PJ, Thisse C, Durliat M, Andre M, Akimenko MA, Thisse B. Both apolipoprotein E and A-I genes are present in a nonmammalian vertebrate and are highly expressed during embryonic development. Proc Natl Acad Sci USA. 1997;94:8622–8627. [PubMed]
26. Baier H. Zebrafish on the move: Towards a behavior-genetic analysis of vertebrate vision. Curr Opin Neurobiol. 2000;10:451–455. [PubMed]
27. Bailey GS, Williams DE, Hendricks JD. Fish models for environmental carcinogenesis: The rainbow trout. Environ Health Perspect. 1996;104(Suppl 1):5–21. [PMC free article] [PubMed]
28. Barbazuk WB, Korf I, Kadavi C, Heyen J, Tate S, Wun E, Bedell JA, McPherson JD, Johnson SL. The syntenic relationship of the zebrafish and human genomes. Genome Res. 2000;10:1351–1358. [PubMed]
29. Baroiller JF, D'Cotta H. Environment and sex determination in farmed fish. Comp Biochem Physiol C Toxicol Pharmacol. 2001;130:399–409. [PubMed]
30. Barut BA, Zon LI. Realizing the potential of zebrafish as a model for human disease. Physiol Genomics. 2000;2:49–51. [PubMed]
31. Bauer MP, Bridgham JT, Langenau DM, Johnson AL, Goetz FW. Conservation of steroidogenic acute regulatory (StAR) protein structure and expression in vertebrates. Mol Cell Endocrinol. 2000;168:119–125. [PubMed]
32. Bauer MP, Goetz FW. Isolation of gonadal mutations in adult zebrafish from a chemical mutagenesis screen. Biol Reprod. 2001;64:548–554. [PubMed]
33. Baumann M, Sander K. Bipartite axiation follows incomplete epiboly in zebrafish embryos treated with chemical teratogens. J Exp Zool. 1984;230:363–376. [PubMed]
34. Beaman JR, Finch R, Gardner H, Hoffmann F, Rosencrance A, Zelikoff JT. Mammalian immunoassays for predicting the toxicity of malathion in a laboratory fish model. J Toxicol Environ Health A. 1999;56:523–542. [PubMed]
35. Beattie CE, Raible DW, Henion PD, Eisen JS. Early pressure screens. Methods Cell Biol. 1999;60:71–86. [PubMed]
36. Beckwith LG, Moore JL, Tsao-Wu GS, Harshbarger JC, Cheng KC. Ethylnitrosourea induces neoplasia in zebrafish (Danio rerio) Lab Invest. 2000;80:379–385. [PubMed]
37. Beckwith LG, Moore JL, Tsao-Wu GS, Spitsbergen JM, Hendricks JD, Harshbarger JC, Cheng KC. Induced and Spontaneous Neoplasia in Zebrafish (Danio rerio); Presented at Cold Spring Harbor Zebrafish Development and Genetics Meeting; Cold Spring Harbor, New York. 2000.
38. Beckwith LG, Moore JL, Tsao-Wu GS, Spitsbergen JM, Hendricks JD, Kent ML, Ward JM, Fournie JW, Reimschuessel R, Khudoley VV, Harshbarger JC, Cheng KC. Induced and Spontaneous Neoplasia in Zebrafish; Presented at Aquaria Fish Models of Human Disease; San Marcos, Texas. 2000.
39. Behra M, Cousin X, Bertrand C, Vonesch JL, Biellmann D, Chatonnet A, Strahle U. Acetylcholinesterase is required for neuronal and muscular development in the zebrafish embryo. Nat Neurosci. 2002;5:111–118. [PubMed]
40. Beier DR. Zebrafish: Genomics on the fast track. Genome Res. 1998;8:9–17. [PubMed]
41. Belair CD, Peterson RE, Heideman W. Disruption of erythropoiesis by dioxin in the zebrafish. Dev Dyn. 2001;222:581–594. [PubMed]
42. Bennett CM, Kanki JP, Rhodes J, Liu TX, Paw BH, Kieran MW, Langenau DM, Delahaye-Brown A, Zon LI, Fleming MD, Look AT. Myelopoiesis in the zebrafish, Danio rerio. Blood. 2001;98:643–651. [PubMed]
43. Berends AG, Boelhouwers EJ, Thus JL, de Gerlache J, de Rooij CG. Bioaccumulation and lack of toxicity of octachlorodibenzofuran (OCDF) and octachlorodibenzo-p-dioxin (OCDD) to early-life stages of zebra fish (Brachydanio rerio) Chemosphere. 1997;35:853–865. [PubMed]
44. Bever MM, Fekete DM. Atlas of the developing inner ear in zebrafish. Dev Dyn. 2002;223:536–543. [PubMed]
45. Biemar F, Argenton F, Schmidtke R, Epperlein S, Peers B, Driever W. Pancreas development in zebrafish: Early dispersed appearance of endocrine hormone expressing cells and their convergence to form the definitive islet. Dev Biol. 2001;230:189–203. [PubMed]
46. Bilotta J, Saszik S. The zebrafish as a model visual system. Int J Dev Neurosci. 2001;19:621–629. [PubMed]
47. Bisgrove BW, Essner JJ, Yost HJ. Multiple pathways in the midline regulate concordant brain, heart and gut left-right asymmetry. Development. 2000;127:3567–3579. [PubMed]
48. Bisgrove BW, Raible DW, Walter V, Eisen JS, Grunwald DJ. Expression of c-ret in the zebrafish embryo: Potential roles in motoneuronal development. J Neurobiol. 1997;33:749–768. [PubMed]
49. Bisgrove BW, Yost HJ. Classification of left-right patterning defects in zebrafish, mice, and humans. Am J Med Genet. 2001;101:315–323. [PubMed]
50. Bishop-Stewart JK, Matthews JL, Larison K, Spitsbergen J, Westerfield M, Kent ML. Diseases of Zebrafish in Research Facilities; Presented at Fish Health Section of American Fisheries Society; Victoria, British Columbia. 2001.
51. Blader P, Strahle U. Ethanol impairs migration of the prechordal plate in the zebrafish embryo. Dev Biol. 1998;201:185–201. [PubMed]
52. Blader P, Strahle U. Zebrafish developmental genetics and central nervous system development. Hum Mol Genet. 2000;9:945–951. [PubMed]
53. Blake T, Adya N, Kim CH, Oates AC, Zon L, Chitnis A, Weinstein BM, Liu PP. Zebrafish homolog of the leukemia gene CBFB: Its expression during embryogenesis and its relationship to scl and gata-1 in hematopoiesis. Blood. 2000;96:4178–4184. [PubMed]
54. Bolanos-Jimenez F, Bordais A, Behra M, Strahle U, Mornet D, Sahel J, Rendon A. Molecular cloning and characterization of dystrophin and Dp71, two products of the Duchenne Muscular Dystrophy gene, in zebrafish. Gene. 2001;274:217–226. [PubMed]
55. Bolanos-Jimenez F, Bordais A, Behra M, Strahle U, Sahel J, Rendon A. Dystrophin and Dp71, two products of the DMD gene, show a different pattern of expression during embryonic development in zebrafish. Mech Dev. 2001;102:239–241. [PubMed]
56. Bouillet P, Oulad-Abdelghani M, Ward SJ, Bronner S, Chambon P, Dolle P. A new mouse member of the Wnt gene family, mWnt-8, is expressed during early embryogenesis and is ectopically induced by retinoic acid. Mech Dev. 1996;58:141–152. [PubMed]
57. Braat AK, Speksnijder JE, Zivkovic D. Germ line development in fishes. Int J Dev Biol. 1999;43:745–760. [PubMed]
58. Braunbeck T, Gorge G, Storch V, Nagel R. Hepatic steatosis in zebra fish (Brachydanio rerio) induced by long-term exposure to gamma-hexachlorocyclohexane. Ecotoxicol Environ Saf. 1990;19:355–74. [PubMed]
59. Braunbeck T, Storch V, Bresch H. Species-specific reaction of liver ultrastructure in Zebrafish (Brachydanio rerio) and trout (Salmo gairdneri) after prolonged exposure to 4-chloroaniline. Arch Environ Contam Toxicol. 1990;19:405–418. [PubMed]
60. Brayton C, Justice M, Montgomery CA. Evaluating mutant mice: Anatomic pathology. Vet Pathol. 2001;38:1–19. [PubMed]
61. Bresch H. Investigation of the long-term action of xenobiotics on fish with special regard to reproduction. Ecotoxicol Environ Safety. 1982;6:102–112. [PubMed]
62. Bresch H. Early life-stage test in zebrafish versus a growth test in rainbow trout to evaluate toxic effects. Bull Environ Contam Toxicol. 1991;46:641–648. [PubMed]
63. Bresch H, Beck H, Ehlermann D, Schlaszus H, Urbanek M. A long-term toxicity test comprising reproduction and growth of zebrafish with 4-chloroaniline. Arch Environ Contam Toxicol. 1990;19:419–427. [PubMed]
64. Briggs JP. The zebrafish: A new model organism for integrative physiology. Am J Physiol Regul Integr Comp Physiol. 2002;282:R3–R9. [PubMed]
65. Brockerhoff SE, Hurley JB, Niemi GA, Dowling JE. A new form of inherited red-blindness identified in zebrafish. J Neurosci. 1997;17:4236–4242. [PubMed]
66. Brown DD. The role of thyroid hormone in zebrafish and axolotl development. Proc Natl Acad Sci USA. 1997;94:13011–13016. [PubMed]
67. Brownlie A, Donovan A, Pratt SJ, Paw BH, Oates AC, Brugnara C, Witkowska HE, Sassa S, Zon LI. Positional cloning of the zebrafish sauternes gene: A model for congenital sideroblastic anaemia. Nat Genet. 1998;20:244–250. [PubMed]
68. Brunelli JP, Robison BD, Thorgaard GH. Ancient and recent duplications of the rainbow trout Wilms' tumor gene. Genome. 2001;44:455–462. [PubMed]
69. Buchmann A, Wannemacher R, Kulzer E, Buhler DR, Bock KW. Immunohistochemical localization of the cytochrome P450 isozymes LMC2 and LM4B (P4501A1) in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated zebrafish (Brachydanio rerio) Toxicol Appl Pharmacol. 1993;123:160–169. [PubMed]
70. Bunton TE. Experimental chemical carcinogenesis in fish. Toxicol Pathol. 1996;24:603–168. [PubMed]
71. Burkhardt-Holm P, Oulmi Y, Schroeder A, Storch V, Braunbeck T. Toxicity of 4-chloroaniline in early life stages of zebrafish (Danio rerio): II. Cytopathology and regeneration of liver and gills after prolonged exposure to waterborne 4-chloroaniline. Arch Environ Contam Toxicol. 1999;37:85–102. [PubMed]
72. Burkhart JG. Fishing for mutations. Nat Biotechnol. 2000;18:21–22. [PubMed]
73. Buss RR, Drapeau P. Physiological properties of zebrafish embryonic red and white muscle fibers during early development. J Neurophysiol. 2000;84:1545–1557. [PubMed]
74. Buss RR, Drapeau P. Activation of embryonic red and white muscle fibers during fictive swimming in the developing zebrafish. J Neurophysiol. 2002;87:1244–1251. [PubMed]
75. Byrd CA, Brunjes PC. Organization of the olfactory system in the adult zebrafish: Histological, immunohistochemical, and quantitative analysis. J Compar Neurol. 1995;358:247–259. [PubMed]
76. Callard GV, Tchoudakova AV, Kishida M, Wood E. Differential tissue distribution, developmental programming, estrogen regulation and promoter characteristics of cyp19 genes in teleost fish. J Steroid Biochem Mol Biol. 2001;79:305–314. [PubMed]
77. Caminos E, Velasco A, Jarrin M, Lillo C, Jimeno D, Aijon J, Lara JM. A comparative study of protein kinase C-like immunoreactive cells in the retina. Brain Behav Evol. 2000;56:330–339. [PubMed]
78. Carlson EA, Li Y, Zelikoff JT. Exposure of Japanese medaka (Oryzias latipes) to benzo[a]pyrene suppresses immune function and host resistance against bacterial challenge. Aquat Toxicol. 2002;56:289–301. [PubMed]
79. Carlsson G, Orn S, Andersson PL, Soderstrom H, Norrgren L. The impact of musk ketone on reproduction in zebrafish (Danio rerio) Mar Environ Res. 2000;50:237–241. [PubMed]
80. Carvan MJ, 3rd, Dalton TP, Stuart GW, Nebert DW. Transgenic zebrafish as sentinels for aquatic pollution. Ann NY Acad Sci. 2000;919:133–147. [PubMed]
81. Carvan MJ, 3rd, Sonntag DM, Cmar CB, Cook RS, Curran MA, Miller GL. Oxidative stress in zebrafish cells: Potential utility of transgenic zebrafish as a deployable sentinel for site hazard ranking. Sci Total Environ. 2001;274:183–196. [PubMed]
82. Cerda J, Conrad M, Markl J, Brand M, Herrmann H. Zebrafish vimentin: Molecular characterization, assembly properties and developmental expression. Eur J Cell Biol. 1998;77:175–187. [PubMed]
83. Chambers SP, Dodd A, Overall R, Sirey T, Lam LT, Morris GE, Love DR. Dystrophin in adult zebrafish muscle. Biochem Biophys Res Commun. 2001;286:478–483. [PubMed]
84. Chan J, Mikami A, Wang J, Goldstein NB, Thomas M, Roberts TM. Visualizing PI3K Signaling in Apoptosis and Development in Living Zebrafish Embryos; Presented at Zebrafish Development and Genetics; Cold Spring Harbor, New York. 2000.
85. Charron RA, Fenwick JC, Lean DR, Moon TW. Ultraviolet-B radiation effects on antioxidant status and survival in the zebrafish, Brachydanio rerio. Photochem Photobiol. 2000;72:327–333. [PubMed]
86. Chen JN, Fishman MC. Genetic dissection of heart development. Ernst Schering Res Found Workshop. 2000:107–122. [PubMed]
87. Cheng KC, Moore JL. Genetic dissection of vertebrate processes in the zebrafish: A comparison of uniparental and two-generation screens. Biochem Cell Biol. 1997;75:525–533. [PubMed]
88. Cheng KC, Tsao-Wu GS, Moore JL, Wong AC, Beckwith LG, Mohideen MP, Aros M, Chinoy MR. A Histological Screen for Cell Differentiation Mutants in Zebrafish; Presented at Zebrafish Development and Genetics; Cold Spring Harbor, New York. 2000.
89. Cheng R, Bradford S, Barnes D, Williams D, Hendricks J, Bailey G. Cloning, sequencing, and embryonic expression of an N-ras protooncogene isolated from an enriched zebrafish (Danio rerio) cDNA library. Mol Mar Biol Biotechnol. 1997;6:40–47. [PubMed]
90. Cheng R, Ford BL, O'Neal PE, Mathews CZ, Bradford CS, Thongtan T, Barnes DW, Hendricks JD, Bailey GS. Zebrafish (Danio rerio) p53 tumor suppressor gene: cDNA sequence and expression during embryogenesis. Mol Mar Biol Biotechnol. 1997;6:88–97. [PubMed]
91. Cheng SH, Wai AWK, So CH, Wu RSS. Cellular and molecular basis of cadmium-induced deformities in zebrafish embryos. Environ Toxicol Chem. 2000;19:3024–3031.
92. Chiang EF, Pai CI, Wyatt M, Yan YL, Postlethwait J, Chung B. Two sox9 genes on duplicated zebrafish chromosomes: Expression of similar transcription activators in distinct sites. Dev Biol. 2001;231:149–163. [PubMed]
93. Chiang EF, Yan YL, Tong SK, Hsiao PH, Guiguen Y, Postlethwait J, Chung BC. Characterization of duplicated zebrafish cyp19 genes. J Exp Zool. 2001;290:709–714. [PubMed]
94. Childs S, Weinstein BM, Mohideen MA, Donohue S, Bonkovsky H, Fishman MC. Zebrafish dracula encodes ferrochelatase and its mutation provides a model for erythropoietic protoporphyria. Curr Biol. 2000;10:1001–1004. [PubMed]
95. Chou YJ, Dietrich DR. Toxicity of nitromusks in early lifestages of South African clawed frog (Xenopus laevis) and zebrafish (Danio rerio) Toxicol Lett. 1999;111:17–25. [PubMed]
96. Clark KJ, Geurts AM, Stohr M, Bell J, Kamachi U, Hackett PB. Sleeping Beauty Transposons for Gene Discovery and Analysis; Presented at Fifth International Meeting on Zebrafish Development and Genetics; Madison, WI. 2002.
97. Clark MD, Hennig S, Herwig R, Clifton SW, Marra MA, Lehrach H, Johnson SL, Group TW. An oligonucleotide fingerprint normalized and expressed sequence tag characterized zebrafish cDNA library. Genome Res. 2001;11:1594–1602. [PubMed]
98. Clements D, Rex M, Woodland HR. Initiation and early patterning of the endoderm. Int Rev Cytol. 2001;203:383–446. [PubMed]
99. Coimbra RS, Weil D, Brottier P, Blanchard S, Levi M, Hardelin JP, Weissenbach J, Petit C. A subtracted cDNA library from the zebrafish (Danio rerio) embryonic inner ear. Genome Res. 2002;12:1007–1011. [PubMed]
100. Cole LK, Ross LS. Apoptosis in the developing zebrafish embryo. Dev Biol. 2001;240:123–142. [PubMed]
101. Collodi P, Kamei Y, Ernst T, Miranda C, Buhler DR, Barnes DW. Culture of cells from zebrafish (Brachydanio rerio) embryo and adult tissues. Cell Biol Toxicol. 1992;8:43–61. [PubMed]
102. Collodi P, Miranda CL, Zhao X, Buhler DR, Barnes DW. Induction of zebrafish (Brachydanio rerio) P450 in vivo and in cell culture. Xenobiotica. 1994;24:487–493. [PubMed]
103. Connaughton VP, Behar TN, Liu WL, Massey SC. Immunocyto-chemical localization of excitatory and inhibitory neurotransmitters in the zebrafish retina. Vis Neurosci. 1999;16:483–490. [PubMed]
104. Cooper MS, D'Amico LA, Henry CA. Analyzing morphogenetic cell behaviors in vitally stained zebrafish embryos. Methods Mol Biol. 1999;122:185–204. [PubMed]
105. Cooper MS, D'Amico LA, Henry CA. Confocal microscopic analysis of morphogenetic movements. Methods Cell Biol. 1999;59:179–204. [PubMed]
106. Corey DR, Abrams JM. Morpholino antisense oligonucleotides: Tools for investigating vertebrate development. Genome Biol. 2001;2:REVIEWS1015. [PMC free article] [PubMed]
107. Corley-Smith GE, Brandhorst BP, Walker C, Postlethwait JH. Production of haploid and diploid androgenetic zebrafish (including methodology for delayed in vitro fertilization) Methods Cell Biol. 1999;59:45–60. [PubMed]
108. Costaridis P, Horton C, Zeitlinger J, Holder N, Maden M. Endogenous retinoids in the zebrafish embryo and adult. Dev Dyn. 1996;205:41–51. [PubMed]
109. Couch JA, Harshbarger JC. Effects of carcinogenic agents on aquatic animals: An environmental and experimental overview. Environ Carcinogenesis Revs. 1985;3:63–105.
110. Cowley AW., Jr The emergence of physiological genomics. J Vasc Res. 1999;36:83–90. [PubMed]
111. Cox WG, Singer VL. A high-resolution, fluorescence-based method for localization of endogenous alkaline phosphatase activity. J Histochem Cytochem. 1999;47:1443–1456. [PubMed]
112. Currie PD. Zebrafish genetics: Mutant cornucopia. Curr Biol. 1996;6:1548–1552. [PubMed]
113. Curry BB., 3rd Animal models used in identifying gender-related differences. Int J Toxicol. 2001;20:153–160. [PubMed]
114. Darland T, Dowling JE. Behavioral screening for cocaine sensitivity in mutagenized zebrafish. Proc Natl Acad Sci USA. 2001;98:11691–11696. [PubMed]
115. Dasmahapatra A, Tomasiewicz H, Lee PC, Carvan MJ., 3rd Zebrafish alcohol dehydrogenase and its role in ethanol embryotoxicity; Presented at Fifth International Meeting on Zebrafish Development and Genetics; Madison, WI. 2002.
116. Dave G. Effect of pH on pentachlorophenol toxicity to embryos and larvae of zebrafish (Brachydanio rerio) Bull Environ Contam Toxicol. 1984;33:621–630. [PubMed]
117. Dave G. The influence of pH on the toxicity of aluminum, cadmium, and iron to eggs and larvae of the zebrafish, Brachydanio rerio. Ecotoxicol Environ Saf. 1985;10:253–267. [PubMed]
118. Dave G, Andersson K, Berglind R, Hasselrot B. Toxicity of eight solvent extraction chemicals and of cadmium to water fleas, Daphnia magna, rainbow trout, Salmo gairdneri, and zebrafish, Brachydanio rerio. Comp Biochem Physiol C. 1981;69C:83–98. [PubMed]
119. Dave G, Damgaard B, Grande M, Martelin JE, Rosander B, Viktor T. Ring test of an embryo-larval toxicity test with zebrafish (Brachydanio rerio) using chromium and zinc as toxicants. Environ Toxicol Chem. 1987;6:61–71.
120. Dave G, Xiu RQ. Toxicity of mercury, copper, nickel, lead, and cobalt to embryos and larvae of zebrafish, Brachydanio rerio. Arch Environ Contam Toxicol. 1991;21:126–134. [PubMed]
121. Davidson AJ, Zon LI. Turning mesoderm into blood: The formation of hematopoietic stem cells during embryogenesis. Curr Top Dev Biol. 2000;50:45–60. [PubMed]
122. D'Cotta H, Fostier A, Guiguen Y, Govoroun M, Baroiller JF. Search for genes involved in the temperature-induced gonadal sex differentiation in the tilapia, Oreochromis niloticus. J Exp Zool. 2001;290:574–585. [PubMed]
123. de Kinkelin P. Occurrence of a microsporidian infection in zebra danio Brachydanio rerio (Hamilton-Buchanan) J Fish Dis. 1980;3:71–73.
124. Deltour S, Pinte S, Guerardel C, Leprince D. Characterization of HRG22, a human homologue of the putative tumor suppressor gene HIC1. Biochem Biophys Res Commun. 2001;287:427–434. [PubMed]
125. Detrich HW, 3rd, Westerfield M, Zon LI. Overview of the Zebrafish system. Methods Cell Biol. 1999;59:3–10. [PubMed]
126. Deventer K. Detection of genotoxic effects on cells of liver and gills of B. rerio by means of single cell gel electrophoresis. Bull Environ Contam Toxicol. 1996;56:911–918. [PubMed]
127. Dick A, Mayr T, Bauer H, Meier A, Hammerschmidt M. Cloning and characterization of zebrafish smad2, smad3 and smad4. Gene. 2000;246:69–80. [PubMed]
128. Dodd A, Curtis PM, Williams LC, Love DR. Zebrafish: Bridging the gap between development and disease. Hum Mol Genet. 2000;9:2443–2449. [PubMed]
129. Dong W, Teraoka H, Kondo S, Hiraga T. 2,3,7,8-tetrachlorodibenzo-p-dioxin induces apoptosis in the dorsal midbrain of zebrafish embryos by activation of arylhydrocarbon receptor. Neurosci Lett. 2001;303:169–172. [PubMed]
130. Donnarumma L, De Angelis G, Gramenzi F, Vittozzi L. Xenobiotic metabolizing enzyme systems in test fish. III. Comparative studies of liver cytosolic glutathione S-transferases. Ecotoxicol Environ Saf. 1988;16:180–186. [PubMed]
131. Dooley K, Zon LI. Zebrafish: A model system for the study of human disease. Curr Opin Genet Dev. 2000;10:252–256. [PubMed]
132. Dressler GR. Kidney development branches out. Dev Genet. 1999;24:189–193. [PubMed]
133. Driever W, Fishman MC. The zebrafish: Heritable disorders in transparent embryos. J Clin Invest. 1996;97:1788–1794. [PMC free article] [PubMed]
134. Drummond IA, Majumdar A, Hentschel H, Elger M, Solnica-Krezel L, Schier AF, Neuhauss SC, Stemple DL, Zwartkruis F, Rangini Z, Driever W, Fishman MC. Early development of the zebrafish pronephros and analysis of mutations affecting pronephric function. Development. 1998;125:4655–4667. [PubMed]
135. Drummond IA. The zebrafish pronephros: A genetic system for studies of kidney development. Pediatr Nephrol. 2000;14:428–435. [PubMed]
136. Durbin L, Brennan C, Shiomi K, Cooke J, Barrios A, Shanmugalingam S, Guthrie B, Lindberg R, Holder N. Eph signaling is required for segmentation and differentiation of the somites. Genes Dev. 1998;12:3096–3109. [PubMed]
137. Durbin L, Sordino P, Barrios A, Gering M, Thisse C, Thisse B, Brennan C, Green A, Wilson S, Holder N. Anteroposterior patterning is required within segments for somite boundary formation in developing zebrafish. Development. 2000;127:1703–1713. [PubMed]
138. Durliat M, Andre M, Babin PJ. Conserved protein motifs and structural organization of a fish gene homologous to mammalian apolipoprotein E. Eur J Biochem. 2000;267:549–559. [PubMed]
139. Dutta S, Muller J, Burdine R, Heckscher E, Schier AF, Westerfield M, Varga ZM. Smoothened Promotes Pituitary Formation by Suppressing Lens Cell Specification; Presented at Fifth International Meeting on Zebrafish Development and Genetics; Madison, Wisconsin. 2002.
140. Dutton KA, Pauliny A, Lopes SS, Elworthy S, Carney TJ, Rauch J, Geisler R, Haffter P, Kelsh RN. Zebrafish colourless encodes sox10 and specifies non-ectomesenchymal neural crest fates. Development. 2001;128:4113–4125. [PubMed]
141. Eckhert CD, Rowe RI. Embryonic dysplasia and adult retinal dystrophy in boron-deficient zebrafish. J Trace Elements Exper Med. 1999;12:213–219.
142. Eisen JS. Motoneuronal development in the embryonic zebrafish. Development Suppl. 1991;2:141–147. [PubMed]
143. Eisen JS. Development of the neural crest in the zebrafish. Dev Biol. 1993;159:50–59. [PubMed]
144. Ekker SC. Morphants: A new systematic vertebrate functional genomics approach. Yeast. 2000;17:302–306. [PMC free article] [PubMed]
145. Elonen GE, Spehar RL, Holcombe GW, Johnson RD, Fernandez JD, Erickson RJ, Tietge JE, Cook PM. Comparative toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin to seven freshwater fish species during early life-stage development. Environ Toxicol Chem. 1998;17:472–483.
146. Engle EC. Applications of molecular genetics to the understanding of congenital ocular motility disorders. Ann NY Acad Sci. 2002;956:55–63. [PubMed]
147. Ensenbach U, Nagel R. Toxicity of complex chemical mixtures: Acute and long-term effects on different life stages of zebrafish (Brachydanio rerio) Ecotoxicol Environ Saf. 1995;30:151–157. [PubMed]
148. Ensenbach U, Nagel R. Toxicity of binary chemical mixtures: Effects on reproduction of zebrafish (Brachydanio rerio) Arch Environ Contam Toxicol. 1997;32:204–210. [PubMed]
149. Essner JJ, Breuer JJ, Essner RD, Fahrenkrug SC, Hackett PB., Jr The zebrafish thyroid hormone receptor alpha 1 is expressed during early embryogenesis and can function in transcriptional repression. Differentiation. 1997;62:107–117. [PubMed]
150. Essner JJ, Johnson RG, Hackett P. Overexpression of thryroid hormone receptor alpha 1 during zebrafish embryogenesis disrupts hindbrain patterning and implicates retinoic acid receptors in the control of hox gene expression. Differentiation. 1999;65:1–11. [PubMed]
151. Evelyn TPT. Bacterial kidney disease—BKD. In: Inglis V, Roberts RJ, Bromage NR, editors. Bacterial Diseases of Fish. Blackwell Scientific Publications; Oxford, United Kingdom: 1993. pp. 177–195.
152. Faahraeus-Van Ree GE, Payne JF. Effect of toxaphene on reproduction of fish. Chemosphere. 1997;34:855–867. [PubMed]
153. Farber SA, Pack M, Ho SY, Johnson ID, Wagner DS, Dosch R, Mullins MC, Hendrickson HS, Hendrickson EK, Halpern ME. Genetic analysis of digestive physiology using fluorescent phospholipid reporters. Science. 2001;292:1385–1388. [PubMed]
154. Ferretti P, Geraudie J. Retinoic acid-induced cell death in the wound epidermis of regenerating zebrafish fins. Dev Dyn. 1995;202:271–283. [PubMed]
155. Fetcho JR, Cox KJ, O'Malley DM. Monitoring activity in neuronal populations with single-cell resolution in a behaving vertebrate. Histochem J. 1998;30:153–167. [PubMed]
156. Fetcho JR, Liu KS. Zebrafish as a model system for studying neuronal circuits and behavior. Ann NY Acad Sci. 1998;860:333–345. [PubMed]
157. Field HA, Ober E, Verkade H, Liao V, Waldron S, Stainier DY. Liver Development in Zebrafish; Presented at Fifth International Meeting on Zebrafish Development and Genetics; Madison, Wisconsin. 2002.
158. Fisher S, Halpern ME. Patterning the zebrafish axial skeleton requires early chordin function. Nat Genet. 1999;23:442–446. [PubMed]
159. Fisher S, Halpern ME. Zebrafish Chihuahua Produces a Skeletal Dysplasia Analagous to Human Osteogenesis Imperfecta; Presented at Cold Spring Harbor Zebrafish Development and Genetics Meeting; Cold Spring Harbor, New York. 2000.
160. Fisher S, Simmons Q, Hu W, Hammontree T. Genetic Analysis of Skeletal Development; Presented at Fifth International Meeting on Zebrafish Development and Genetics; Madison, Wisconsin. 2002.
161. Fishman MC. Zebrafish genetics: The enigma of arrival. Proc Natl Acad Sci USA. 1999;96:10554–10556. [PubMed]
162. Fishman MC. Genomics. Zebrafish—the canonical vertebrate. Science. 2001;294:1290–1291. [PubMed]
163. Fishman MC, Chien KR. Fashioning the vertebrate heart: Earliest embryonic decisions. Development. 1997;124:2099–2117. [PubMed]
164. Fishman MC, Stainier DY. Cardiovascular development. Prospects for a genetic approach. Circ Res. 1994;74:757–763. [PubMed]
165. Fishman MC, Stainier DY, Breitbart RE, Westerfield M. Zebrafish: Genetic and embryological methods in a transparent vertebrate embryo. Methods Cell Biol. 1997;52:67–82. [PubMed]
166. Force A, Lynch M, Pickett FB, Amores A, Yan YL, Postlethwait J. Preservation of duplicate genes by complementary, degenerative mutations. Genetics. 1999;151:1531–1545. [PubMed]
167. Forsell J, Ekstrom P, Flamarique IN, Holmqvist B. Expression of pineal ultraviolet- and green-like opsins in the pineal organ and retina of teleosts. J Exp Biol. 2001;204:2517–2525. [PubMed]
168. Fournie JW, Hawkins WE, Krol RM, Wolfe MJ. Preparation of whole small fish for histological evaluation. In: Ostrander GM, editor. Techniques in Aquatic Toxicology. Lewis Publishers; Boca Raton, Florida: 1996. pp. 577–588.
169. Fraser JK, Butler CA, Timperley MH, Evans CW. Formation of copper complexes in landfill leachate and their toxicity to zebrafish embryos. Environ Toxicol Chem. 2000;19:1397–1402.
170. Friccius T, Schulte C, Ensenbach U, Seel P, Nagel R. An embryo test using the zebrafish—A new possibility of testing and evaluating the toxicity of industrial waste waters. Vom Wasser Weinheim. 1995;84:407–418.
171. Fritsche R, Schwerte T, Pelster B. Nitric oxide and vascular reactivity in developing zebrafish, Danio rerio. Am J Physiol Regul Integr Comp Physiol. 2000;279:R2200–R2207. [PubMed]
172. Gahtan E, Sankrithi N, Campos JB, O'Malley DM. Evidence for a widespread brain stem escape network in larval zebrafish. J Neurophysiol. 2002;87:608–614. [PubMed]
173. Gaiano N, Amsterdam A, Kawakami K, Allende M, Becker T, Hopkins N. Insertional mutagenesis and rapid cloning of essential genes in zebrafish. Nature. 1996;383:829–832. [PubMed]
174. Gaiano N, Hopkins N. Introducing genes into zebrafish. Biochim Biophys Acta. 1996;1288:O11–O14. [PubMed]
175. Gamse JT, Shen YC, Thisse C, Thisse B, Raymond PA, Halpern ME, Liang JO. Otx5 regulates genes that show circadian expression in the zebrafish pineal complex. Nat Genet. 2002;30:117–121. [PubMed]
176. Garcia-Castro M, Bronner-Fraser M. Induction and differentiation of the neural crest. Curr Opin Cell Biol. 1999;11:695–698. [PubMed]
177. Gard-Terech A, Palla JC. Comparative kinetics study of the evolution of freshwater aquatic toxicity and biodegradability of linear and branched alkylbenzene sulfonates. Ecotoxicol Environ Saf. 1986;12:127–140. [PubMed]
178. Ge W. Roles of the activin regulatory system in fish reproduction. Can J Physiol Pharmacol. 2000;78:1077–1085. [PubMed]
179. Gellert G, Heinrichsdorff J. Effect of age on the susceptibility of zebrafish eggs to industrial wastewater. Water Res. 2001;35:3754–3757. [PubMed]
180. Geraudie J, Monnot MJ, Brulfert A, Ferretti P. Caudal fin regeneration in wild type and long-fin mutant zebrafish is affected by retinoic acid. Int J Dev Biol. 1995;39:373–381. [PubMed]
181. Gerlai R, Lahav M, Guo S, Rosenthal A. Drinks like a fish: Zebra fish (Danio rerio) as a behavior genetic model to study alcohol effects. Pharmacol Biochem Behav. 2000;67:773–782. [PubMed]
182. Ghosh C, Collodi P. Culture of cells from zebrafish (Brachydanio rerio) blastula-stage embryos. Cytotechnol. 1994;14:21–26. [PubMed]
183. Ghosh C, Zhou YL, Collodi P. Derivation and characterization of a zebrafish liver cell line. Cell Biol Toxicol. 1994;10:167–176. [PubMed]
184. Goka K. Embryotoxicity of zinc pyrithione, an antidandruff chemical, in fish. Environ Res. 1999;81:81–83. [PubMed]
185. Goldsmith P. Modelling eye diseases in zebrafish. Neuroreport. 2001;12:A73–A77. [PubMed]
186. Golling G, Amsterdam A, Sun Z, Antonelli M, Maldonado E, Chen W, Burgess S, Haldi M, Artzt K, Farrington S, Lin SY, Nissen RM, Hopkins N. Insertional mutagenesis in zebrafish rapidly identifies genes essential for early vertebrate development. Nat Genet. 2002;31:135–140. [PubMed]
187. Gompel N, Cubedo N, Thisse C, Thisse B, Dambly-Chaudiere C, Ghysen A. Pattern formation in the lateral line of zebrafish. Mech Dev. 2001;105:69–77. [PubMed]
188. Gong Z, Ju B, Wang X, He J, Wan H, Sudha PM, Yan T. Green fluorescent protein expression in germ-line transmitted transgenic zebrafish under a stratified epithelial promoter from keratin8. Dev Dyn. 2002;223:204–215. [PubMed]
189. Gongora R, Figueroa F, Klein J. Independent duplications of Bf and C3 complement genes in the zebrafish. Scand J Immunol. 1998;48:651–658. [PubMed]
190. Gorge G, Nagel R. Kinetics and metabolism of 14C-lindane and 14C-atrazine in early life stages of zebrafish (Brachydanio rerio) Chemosphere. 1990a;21:1125–1137.
191. Gorge G, Nagel R. Toxicity of lindane, atrazine, and deltamethrin to early life stages of zebrafish (Brachydanio rerio) Ecotoxicol Environ Saf. 1990b;20:246–255. [PubMed]
192. Gothilf Y, Coon SL, Toyama R, Chitnis A, Namboodiri MAA, Klein DC. Zebrafish serotonin n-acetyltransferase-2: marker for development of pineal photoreceptors and circadian clock function. Endocrinology. 1999;140:4895–4903. [PubMed]
193. Grapin-Botton A, Melton DA. Endoderm development: From patterning to organogenesis. Trends Genet. 2000;16:124–130. [PubMed]
194. Gritsman K, Zhang J, Cheng S, Heckscher E, Talbot WS, Schier AF. The EGF-CFC protein one-eyed pinhead is essential for nodal signaling. Cell. 1999;97:121–132. [PubMed]
195. Grosser T, Yusuff S, Cheskis E, Pack MA, FitzGerald GA. Developmental expression of functional cyclooxygenases in zebrafish. Proc Natl Acad Sci USA. 2002;99:8418–8423. [PubMed]
196. Groth G, Kronauer K, Freundt KJ. Effects of N,N-dimethylformamide and its degradation products in zebrafish (Brachydanio rerio) embryos. Toxicol In Vitro. 1994;8:401–406. [PubMed]
197. Groth G, Schreeb K, Herdt V, Freundt KJ. Toxicity studies in fertilized zebrafish eggs treated with N-methylamine, N,N-dimethylamine, 2-aminoethanol, isopropylamine, aniline, N-methylaniline, N,N-dimethylaniline, quinone, chloroacetaldehyde, or cyclohexanol. Bull Environ Contam Toxicol. 1993;50:878–882. [PubMed]
198. Guo L, Huang H, Liu Y, Zhou X, Lo LJ, Eun A, Ruan H, He Y, Ma W, Peng J. Gene Mining for Liver Development; Presented at Fifth International Meeting on Zebrafish Development and Genetics; Madison, Wisconsin. 2002.
199. Haffter P, Granato M, Brand M, Mullins MC, Hammerschmidt M, Kane DA, Odenthal J, van Eeden FJ, Jiang YJ, Heisenberg CP, Kelsh RN, Furutani-Seiki M, Vogelsang E, Beuchle D, Schach U, Fabian C, Nusslein-Volhard C. The identification of genes with unique and essential functions in the development of the zebrafish, Danio rerio. Development. 1996;123:1–36. [PubMed]
200. Haines L, Currie PD. Morphogenesis and evolution of vertebrate appendicular muscle. J Anat. 2001;199:205–209. [PubMed]
201. Haire RN, Rast JP, Litman RT, Litman GW. Characterization of three isotypes of immunoglobulin light chains and T-cell antigen receptor alpha in zebrafish. Immunogenetics. 2000;51:915–923. [PubMed]
202. Halling-Sorensen B, Lutzhoft HC, Andersen HR, Ingerslev F. Environmental risk assessment of antibiotics: Comparison of mecillinam, trimethoprim and ciprofloxacin. J Antimicrob Chemother. 2000;46(Suppl 1):53–58. discussion, 63–65. [PubMed]
203. Halloran MC, Sato-Maeda M, Warren JT, Su F, Lele Z, Krone PH, Kuwada JY, Shoji W. Laser-induced gene expression in specific cells of transgenic zebrafish. Development. 2000;127:1953–1960. [PubMed]
204. Hansen A, Reutter K, Zeiske E. Taste bud development in the zebrafish, Danio rerio. Dev Dyn. 2002;223:483–496. [PubMed]
205. Haque M, Anreola F. The cloning and characterization of a novel cytochrome P450 family, CYP26, with specificity toward retinoic acid. Nutr Rev. 1998;56:84–85. [PubMed]
206. Harshbarger JC, Clark JB. Epizootiology of neoplasms in bony fish of North America. Sci Total Environ. 1990;94:1–32. [PubMed]
207. Haschek WM, Rousseaux CG. Fundamentals of Toxicologic Pathology. Academic Press; San Diego, California: 1998.
208. Hatanaka J, Doke N, Harada T, Aikawa T, Enomoto M. Usefulness and rapidity of screening for the toxicity and carcinogenicity of chemicals in the medaka, Oryzias latipes. Japan J Exp Med. 1982;52:243–253. [PubMed]
209. Heasman J. Morpholino oligos: Making sense of antisense? Dev Biol. 2002;243:209–214. [PubMed]
210. Helmrich A, Barnes D. Zebrafish embryonal cell culture. Methods Cell Biol. 1999;59:29–37. [PubMed]
211. Hendricks JC, Sehgal A, Pack AI. The need for a simple animal model to understand sleep. Prog Neurobiol. 2000;61:339–351. [PubMed]
212. Hendricks JD. Development of the Zebra Danio Model: Carcinogenesis and Gene Transfer Studies. US Army, NTIS; Springfield, Virginia: 1996. (Rep. NTIS/AD-A328 886/7; DAMD17-91-Z-1043).
213. Henion PD, Raible DW, Beattie CE, Stoesser KL, Weston JA, Eisen JS. Screen for mutations affecting development of zebrafish neural crest. Developmental Genetics. 1996;18:11–17. [PubMed]
214. Henry TR, Nesbit DJ, Heideman W, Peterson RE. Relative potencies of polychlorinated dibenzo-p-dioxin, dibenzofuran, and biphenyl congeners to induce cytochrome P4501A mRNA in a zebrafish liver cell line. Environ Toxicol Chem. 2001;20:1053–1058. [PubMed]
215. Henry TR, Spitsbergen JM, Hornung MW, Abnet CC, Peterson RE. Early life stage toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in zebrafish (Danio rerio) Toxicol Appl Pharmacol. 1997;142:56–68. [PubMed]
216. Herbomel P, Thisse B, Thisse C. Ontogeny and behaviour of early macrophages in the zebrafish embryo. Development. 1999;126:3735–3745. [PubMed]
217. Herbomel P, Thisse B, Thisse C. Zebrafish early macrophages colonize cephalic mesenchyme and developing brain, retina, and epidermis through a M-CSF receptor-dependent invasive process. Dev Biol. 2001;238:274–288. [PubMed]
218. Herrmann K. Effects of the anticonvulsant drug valproic acid and related substances on the early development of the zebrafish (Brachydanio rerio) Toxicol In Vitro. 1993;7:41–54. [PubMed]
219. Herrmann K. Teratogenic effects of retinoic acid and related substances on the early development of the zebrafish (Brachydanio rerio) as assessed by a novel scoring system. Toxicol In Vitro. 1995;9:267–283. [PubMed]
220. Hertl J, Nagel R. Bioconcentration and metabolism of 3,4-dichloroaniline in different life stages of guppy and zebrafish. Chemosphere. 1993;27:2225–2234.
221. Higashijima S, Hotta Y, Okamoto H. Visualization of cranial motor neurons in live transgenic zebrafish expressing green fluorescent protein under the control of the islet-1 promoter/enhancer. J Neurosci. 2000;20:206–218. [PubMed]
222. Higashijima S, Okamoto H, Ueno N, Hotta Y, Eguchi G. High-frequency generation of transgenic zebrafish which reliably express GFP in whole muscles or the whole body by using promoters of zebrafish origin. Dev Biol. 1997;192:289–299. [PubMed]
223. Hill J, Clarke JD, Vargesson N, Jowett T, Holder N. Exogenous retinoic acid causes specific alterations in the development of the midbrain and hindbrain of the zebrafish embryo including positional respecification of the Mauthner neuron. Mech Dev. 1995;50:3–16. [PubMed]
224. Hirsinger E, Westerfield M. The Progressive Determination of Zebrafish Muscle Cell Lineages; Presented at Fifth International Meeting on Zebrafish Development and Genetics; Madison, Wisconsin. 2002.
225. Hisaoka KK. The effects of 2-acetylaminofluorene on the embryonic development of the zebrafish I. Morphological studies. Cancer Res. 1958;18:527–535. [PubMed]
226. Hisaoka KK. The effects of 2-acetylaminofluorene on the embryonic development of the zebrafish II. Histochemical studies. Cancer Res. 1958;18:664–667. [PubMed]
227. Hjorth JT, Gad J, Cooper H, Key B. A zebrafish homologue of deleted in colorectal cancer (zdcc) is expressed in the first neuronal clusters of the developing brain. Mech Dev. 2001;109:105–109. [PubMed]
228. Holder N, Xu Q. Microinjection of DNA, RNA, and protein into the fertilized zebrafish egg for analysis of gene function. Methods Mol Biol. 1999;97:487–490. [PubMed]
229. Holley SA, Nusslein-Volhard C. Somitogenesis in zebrafish. Curr Top Dev Biol. 2000;47:247–277. [PubMed]
230. Holm G, Hallden T, Norrgren L. Reproductive effects of di-2-ethylhexl phthalate (DEHP) on zebrafish, Brachydanio rerio. Mar Environ Res. 1995;39:357–358.
231. Hoover KL. Use of small fish species in carcinogenicity testing. Natl Cancer Inst Monogr. 1984;65:275–289. [PubMed]
232. Hsu HJ, Wang WD, Hu CH. Ectopic expression of negative ARNT2 factor disrupts fish development. Biochem Biophys Res Commun. 2001;282:487–492. [PubMed]
233. Hsu K, Kanki JP, Look AT. Zebrafish myelopoiesis and blood cell development. Curr Opin Hematol. 2001;8:245–251. [PubMed]
234. Hsu T, Deng F-Y. Studies on the susceptibility of various organs of zebrafish (Brachydanio rerio) to benzo(a)pyrene-induced DNA adduct formation. Chemosphere. 1996;33:1975–1980.
235. Hu MC, Chiang EF, Tong SK, Lai W, Hsu NC, Wang LC, Chung BC. Regulation of steroidogenesis in transgenic mice and zebrafish. Mol Cell Endocrinol. 2001;171:9–14. [PubMed]
236. Hughes SM, Salinas PC. Control of muscle fibre and motoneuron diversification. Curr Opin Neurobiol. 1999;9:54–64. [PubMed]
237. Hutson LD, Chien CB. Wiring the zebrafish: Axon guidance and synaptogenesis. Curr Opin Neurobiol. 2002;12:87–92. [PubMed]
238. Hyatt TM, Ekker SC. Vectors and techniques for ectopic gene expression in zebrafish. Methods Cell Biol. 1999;59:117–126. [PubMed]
239. Icard-Liepkalns C, Haire RN, Strong SJ, Litman GW. Cloning of a cDNA encoding a Pim1 homologue in zebrafish, Danio rerio. Immunogenetics. 1999;49:351–353. [PubMed]
240. Imboden M, Goblet C, Korn H, Vriz S. Cytokeratin 8 is a suitable epidermal marker during zebrafish development. CR Acad Sci III. 1997;320:689–700. [PubMed]
241. Ingham PW. Zebrafish genetics and its implications for understanding vertebrate development. Hum Mol Genet. 1997;6:1755–1760. [PubMed]
242. Ivetac I, Becanovic J, Krishnapillai V. Zebrafish: Genetic tools and genomics. Asia-Pacific J Mol Biol Biotechnol. 2000;8:1–11.
243. Jacobsen F, Folke J. The effect of enzyme treatment on untreated D-stage effluent: Short-term fish early life-stage toxicity test. Environ Toxicol Chem. 1996;15:2272–2274.
244. Jagadeeswaran P, Gregory M, Johnson S, Thankavel B. Haemostatic screening and identification of zebrafish mutants with coagulation pathway defects: an approach to identifying novel haemostatic genes in man. Br J Haematol. 2000;110:946–956. [PubMed]
245. Jagadeeswaran P, Gregory M, Zhou Y, Zon L, Padmanabhan K, Hanumanthaiah R. Characterization of zebrafish full-length prothrombin cDNA and linkage group mapping. Blood Cells Mol Dis. 2000;26:479–489. [PubMed]
246. Jagadeeswaran P, Liu YC. Developmental expression of thrombin in zebrafish embryos: a novel model to study hemostasis. Blood Cells Mol Dis. 1997;23:147–156. [PubMed]
247. Jagadeeswaran P, Liu YC. A hemophilia model in zebrafish: analysis of hemostasis. Blood Cells Mol Dis. 1997;23:52–57. [PubMed]
248. Jagadeeswaran P, Liu YC, Sheehan JP. Analysis of hemostasis in the zebrafish. Methods Cell Biol. 1999;59:337–357. [PubMed]
249. Jagadeeswaran P, Sheehan JP. Analysis of blood coagulation in the zebrafish. Blood Cells Mol Dis. 1999;25:239–249. [PubMed]
250. Jagadeeswaran P, Sheehan JP, Craig FE, Troyer D. Identification and characterization of zebrafish thrombocytes. Br J Haematol. 1999;107:731–738. [PubMed]
251. Jaso-Friedmann L, Peterson DS, Gonzalez DS, Evans DL. The antigen receptor (nccrp-1) on catfish and zebrafish nonspecific cytotoxic cells belongs to a new gene family characterized by an f-box-associated domain. J Mol Evol. 2002;54:386–395. [PubMed]
252. Jensen AM, Walker C, Westerfield M. Mosaic eyes: A zebrafish gene required in pigmented epithelium for apical localization of retinal cell division and lamination. Development. 2001;128:95–105. [PubMed]
253. Jessen JR, Jessen TN, Vogel SS, Lin S. Concurrent expression of recombination activating genes 1 and 2 in zebrafish olfactory sensory neurons. Genesis. 2001;29:156–162. [PubMed]
254. Johnson SL, Zon LI. Genetic backgrounds and some standard stocks and strains used in zebrafish developmental biology and genetics. Methods Cell Biol. 1999;60:357–359. [PubMed]
255. Joore J. Promoter analysis in zebrafish embryos. Methods Mol Biol. 1999;127:155–166. [PubMed]
256. Jowett T. Transgenic zebrafish. Methods Mol Biol. 1999;97:461–486. [PubMed]
257. Kalev-Zylinska ML, Horsfield JA, Flores MV, Postlethwait JH, Vitas MR, Baas AM, Crosier PS, Crosier KE. Runx1 is required for zebrafish blood and vessel development and expression of a human RUNX1-CBF2T1 transgene advances a model for studies of leukemogenesis. Development. 2002;129:2015–2030. [PubMed]
258. Kane AS, Gonzalez JF, Reimschuessel R. Fish and amphibian models used in laboratory research. Lab Anim (NY) 1996;25:33–38.
259. Karlovich CA, John RM, Ramirez L, Stainier DY, Myers RM. Characterization of the Huntington's disease (HD) gene homologue in the zebrafish Danio rerio. Gene. 1998;217:117–125. [PubMed]
260. Karlsson J, von Hofsten J, Olsson PE. Generating transparent zebrafish: A refined method to improve detection of gene expression during embryonic development. Marine Biotechnol. 2001;3:522–527. [PubMed]
261. Kawai H, Arata N, Nakayasu H. Three-dimensional distribution of astrocytes in zebrafish spinal cord. Glia. 2001;36:406–413. [PubMed]
262. Kawakami K. Highly Efficient Transposon-mediated Transgenesis in Zebrafish; Presented at Fifth International Meeting on Zebrafish Development and Genetics; Madison, Wisconsin. 2002.
263. Kazimi N, Cahill GM. Development of a circadian melatonin rhythm in embryonic zebrafish. Developmental Brain Research. 1999;117:47–52. [PubMed]
264. Keizer J, D'Agostino G, Nagel R, Volpe T, Gnemi P, Vittozzi L. Enzymological differences of AChE and diazinon hepatic metabolism: Correlation of in vitro data with the selective toxicity of diazinon to fish species. Sci Total Environ. 1995;171:213–220. [PubMed]
265. Kelsh RN, Eisen JS. The zebrafish colourless gene regulates development of non-ectomesenchymal neural crest derivatives. Development. 2000;127:515–525. [PubMed]
266. Kent J, Coriat AM, Sharpe PT, Hastie ND, van Heyningen V. The evolution of WT1 sequence and expression pattern in the vertebrates. Oncogene. 1995;11:1781–1792. [PubMed]
267. Kent M, Bishop-Stewart J, Matthews J, Spitsbergen J. Pseudocapillaria tomentosa, a pathogen of zebrafish (Danio rerio) held in research colonies. Comparative Pathol. 2002;52:354–358. [PubMed]
268. Khodaei S, O'Brien KP, Dumanski J, Wong FK, Weber G. Characterization of the MEN1 ortholog in zebrafish. Biochem Biophys Res Commun. 1999;264:404–408. [PubMed]
269. Khudoley VV. Use of aquarium fish, Danio rerio and Poecilia reticulata, as test species for evaluation of nitrosamine carcinogenicity. Natl Cancer Inst Monogr. 1984;65:65–70. [PubMed]
270. Kim CH, Oda T, Itoh M, Jiang D, Artinger KB, Chandrasekharappa SC, Driever W, Chitnis AB. Repressor activity of Headless/Tcf3 is essential for vertebrate head formation. Nature. 2000;407:913–916. [PMC free article] [PubMed]
271. Kim E, Arnould T, Sellin LK, Benzing T, Fan MJ, Gruning W, Sokol SY, Drummond I, Walz G. The polycystic kidney disease 1 gene product modulates Wnt signaling. J Biol Chem. 1999;274:4947–4953. [PubMed]
272. Kime DE, Nash JP. Gamete viability as an indicator of reproductive endocrine disruption in fish. Sci Total Environ. 1999;233:123–129.
273. Kimmel CB. Genetics and early development of zebrafish. Trends Genet. 1989;5:283–288. [PubMed]
274. Kimmel CB. Patterning the brain of the zebrafish embryo. Annu Rev Neurosci. 1993;16:707–732. [PubMed]
275. Kimmel CB, Miller CT, Keynes RJ. Neural crest patterning and the evolution of the jaw. J Anat. 2001;199:105–120. [PubMed]
276. Kimmel CB, Miller CT, Moens CB. Specification and morphogenesis of the zebrafish larval head skeleton. Dev Biol. 2001;233:239–257. [PubMed]
277. Kimmel CB, Schilling TF, Hatta K. Patterning of body segments of the zebrafish embryo. Curr Top Dev Biol. 1991;25:77–110. [PubMed]
278. Kimmel CB, Sepich DS, Trevarrow B. Development of segmentation in zebrafish. Development. 1988;104(Suppl):197–207. [PubMed]
279. Kimmel CB, Warga RM. Cell lineage and developmental potential of cells in the zebrafish embryo. Trends Genet. 1988;4:68–74. [PubMed]
280. Kishida M, Callard GV. Distinct cytochrome P450 aromatase isoforms in zebrafish (Danio rerio) brain and ovary are differentially programmed and estrogen regulated during early development. Endocrinology. 2001;142:740–750. [PubMed]
281. Kishida M, McLellan M, Miranda JA, Callard GV. Estrogen and xenoestrogens upregulate the brain aromatase isoform (P450aromB) and perturb markers of early development in zebrafish (Danio rerio) Comp Biochem Physiol B Biochem Mol Biol. 2001;129:261–268. [PubMed]
282. Knapik EW. ENU mutagenesis in zebrafish—From genes to complex diseases. Mamm Genome. 2000;11:511–519. [PubMed]
283. Konig C, Yan YL, Postlethwait J, Wendler S, Campos-Ortega JA. A recessive mutation leading to vertebral ankylosis in zebrafish is associated with amino acid alterations in the homologue of the human membrane-associated guanylate kinase DLG3. Mech Dev. 1999;86:17–28. [PubMed]
284. Korfsmeier KH. PCNA in the ovary of zebrafish (Brachydanio rerio, Ham.-Buch.) Acta Histochem. 2002;104:73–76. [PubMed]
285. Korzh S, Emelyanov A, Korzh V. Developmental analysis of ceruloplasmin gene and liver formation in zebrafish. Mech Dev. 2001;103:137–139. [PubMed]
286. Koster RW, Fraser SE. Tracing transgene expression in living zebrafish embryos. Dev Biol. 2001;233:329–346. [PubMed]
287. Kratz E, Dugas JC, Ngai J. Odorant receptor gene regulation: Implications from genomic organization. Trends Genet. 2002;18:29–34. [PubMed]
288. Krone PH, Lele Z, Sass JB. Heat shock genes and the heat shock response in zebrafish embryos. Biochem Cell Biol. 1997;75:487–497. [PubMed]
289. Kudoh T, Tsang M, Hukriede NA, Chen X, Dedekian M, Clarke CJ, Kiang A, Schultz S, Epstein JA, Toyama R, Dawid IB. A gene expression screen in zebrafish embryogenesis. Genome Res. 2001;11:1979–1987. [PubMed]
290. Kumar K, Ansari BA. Malathion toxicity: Effect on the liver of the fish Brachydanio rerio (Cyprinidae) Ecotoxicol Environ Saf. 1986;12:199–205. [PubMed]
291. Laale HW. Ethanol induced notochord and spinal cord duplications in the embryo of the zebrafish, Brachydanio rerio. J Exp Zool. 1971;177:51–64. [PubMed]
292. Laale HW. Culture and preliminary observations of follicular isolates from adult zebra fish, Brachydanio rerio. Can J Zool. 1977;55:304–309. [PubMed]
293. Laan M, Richmond H, He C, Campbell RK. Zebrafish as a model for vertebrate reproduction: Characterization of the first functional zebrafish (Danio rerio) gonadotropin receptor. Gen Comp Endocrinol. 2002;125:349–364. [PubMed]
294. Labrot F, Narbonne JF, Ville P, Saint Denis M, Ribera D. Acute toxicity, toxicokinetics, and tissue target of lead and uranium in the clam Corbicula fluminea and the worm Eisenia fetida: Comparison with the fish Brachydanio rerio. Arch Environ Contam Toxicol. 1999;36:167–178. [PubMed]
295. Lai WW, Hsiao PH, Guiguen Y, Chung BC. Cloning of zebrafish cDNA for 3beta-hydroxysteroid dehydrogenase and P450scc. Endocr Res. 1998;24:927–931. [PubMed]
296. Lange M, Gebauer W, Markl J, Nagel R. Comparison of testing acute toxicity on embryo of zebrafish, Brachydanio rerio and RTG-2 cytotoxicity as possible alternatives to the acute fish test. Chemosphere. 1995;30:2087–2102.
297. Lanzky PF, Halling-Sorensen B. The toxic effect of the antibiotic metronidazole on aquatic organisms. Chemosphere. 1997;35:2553–2561. [PubMed]
298. LaPatra SE, Barone L, Jones GR, Zon LI. Effects of infectious hematopoietic necrosis virus and infectious pancreatic necrosis virus infection on hematopoietic precursors of the zebrafish. Blood Cells Mol Dis. 2000;26:445–452. [PubMed]
299. Law JM. Mechanistic considerations in small fish carcinogenicity testing. ILAR J. 2001;42:274–284. [PubMed]
300. Lee BC, Hendricks JD, Bailey GS. Toxicity of mycotoxins in the feed of fish. In: Smith JE, editor. Mycotoxins and Animal Feedstuff: Natural Occurrence, Toxicity and Control. CRC Press; Boca Raton, Florida: 1991. pp. 607–626.
301. Legler J, Broekhof JLM, Brouwer A, Lanser PH, Murk AJ, van der Saag PT, Vethaak A, Wester P, Zivkovic D, van der Burg B. A novel in vivo bioassay for (xeno-)estrogens using transgenic zebrafish. Environ Sci Technol. 2000;34:4439–4444.
302. Leimer U, Lun K, Romig H, Walter J, Gruenberg J, Brand M, Haass C. Zebrafish (Danio rerio) presenilin promotes aberrant amyloid beta-peptide production and requires a critical aspartate residue for its function in amyloidogenesis. Biochemistry (Washington) 1999;38:13602–13609. [PubMed]
303. Lekven AC, Helde KA, Thorpe CJ, Rooke R, Moon RT. Reverse genetics in zebrafish. Physiol Genomics. 2000;2:37–48. [PubMed]
304. Lele Z, Krone PH. The zebrafish as a model system in developmental, toxicological and transgenic research. Biotechnol Adv. 1996;14:57–72. [PubMed]
305. Lewis KE, Concordet JP, Ingham PW. Characterisation of a second patched gene in the zebrafish Danio rerio and the differential response of patched genes to Hedgehog signalling. Dev Biol. 1999;208:14–29. [PubMed]
306. Li L. Genetic and epigenetic analysis of visual system functions of zebrafish. Prog Brain Res. 2001;131:555–563. [PubMed]
307. Li L. Zebrafish mutants: Behavioral genetic studies of visual system defects. Dev Dyn. 2001;221:365–372. [PubMed]
308. Li S, Mao Z, Han W, Sun Z, Yan W, Chen H, Yan S. In vitro oocyte maturation in the zebra fish, Brachydanio rerio, and the fertilization and development of the mature egg. Chin J Biotechnol. 1993;9:247–255. [PubMed]
309. Liang D, Chang JR, Chin AJ, Smith A, Kelly C, Weinberg ES, Ge R. The role of vascular endothelial growth factor (VEGF) in vasculogenesis, angiogenesis, and hematopoiesis in zebrafish development. Mech Dev. 2001;108:29–43. [PubMed]
310. Liao EC, Trede NS, Ransom D, Zapata A, Kieran M, Zon LI. Non-cell autonomous requirement for the bloodless gene in primitive hematopoiesis of zebrafish. Development. 2002;129:649–659. [PubMed]
311. Lieschke GJ. Zebrafish—An emerging genetic model for the study of cytokines and hematopoiesis in the era of functional genomics. Int J Hematol. 2001;73:23–31. [PubMed]
312. Lieschke GJ, Oates AC, Crowhurst MO, Ward AC, Layton JE. Morphologic and functional characterization of granulocytes and macrophages in embryonic and adult zebrafish. Blood. 2001;98:3087–3096. [PubMed]
313. Lin S. Transgenic zebrafish. Methods Mol Biol. 2000;136:375–383. [PubMed]
314. Litman GW, Hawke NA, Yoder JA. Novel immune-type receptor genes. Immunol Rev. 2001;181:250–259. [PubMed]
315. Liu X, Collodi P. Novel form of fibronectin from zebrafish mediates infectious hematopoietic necrosis virus infection. J Virol. 2002;76:492–498. [PMC free article] [PubMed]
316. Liu YW, Chan WK. Thyroid hormones are important for embryonic to larval transitory phase in zebrafish. Differentiation. 2002;70:36–45. [PubMed]
317. Liu Y-W, Lo L-J, Chan W-K. Temporal expression and T3 induction of thyroid hormone receptors alpha 1 and beta 1 during early embryonic and larval development in zebrafish, Danio rerio. Mol Cell Endocrinol. 2000;159:187–195. [PubMed]
318. Lohr JL, Yost HJ. Vertebrate model systems in the study of early heart development: Xenopus and zebrafish. Am J Med Genet. 2000;97:248–257. [PubMed]
319. Long Q, Huang H, Shafizadeh E, Liu N, Lin S. Stimulation of erythropoiesis by inhibiting a new hematopoietic death receptor in transgenic zebrafish. Nat Cell Biol. 2000;2:549–552. [PubMed]
320. Loudig O, Babichuk C, White J, Abu-Abed S, Mueller C, Petkovich M. Cytochrome P450RAI (CYP26) promoter: A distinct composite retinoic acid response element underlies the complex regulation of retinoic acid metabolism. Mol Endocrinol. 2000;14:1483–1497. [PubMed]
321. Luttun A, Carmeliet G, Carmeliet P. Vascular progenitors: From biology to treatment. Trends Cardiovasc Med. 2002;12:88–96. [PubMed]
322. Ma PM. Catecholaminergic systems in the zebrafish. III. Organization and projection pattern of medullary dopaminergic and noradrenergic neurons. J Comp Neurol. 1997;381:411–427. [PubMed]
323. Macdonald R. Zebrafish immunohistochemistry. Methods Mol Biol. 1999;127:77–88. [PubMed]
324. Majumdar A, Drummond IA. Podocyte differentiation in the absence of endothelial cells as revealed in the zebrafish avascular mutant, cloche. Dev Genet. 1999;24:220–229. [PubMed]
325. Majumdar A, Drummond IA. The zebrafish floating head mutant demonstrates podocytes play an important role in directing glomerular differentiation. Dev Biol. 2000;222:147–157. [PubMed]
326. Majumdar A, Lun K, Brand M, Drummond IA. Zebrafish no isthmus reveals a role for pax2.1 in tubule differentiation and patterning events in the pronephric primordia. Development. 2000;127:2089–2098. [PubMed]
327. Malicki J. Harnessing the power of forward genetics—analysis of neuronal diversity and patterning in the zebrafish retina. Trends Neurosci. 2000;23:531–41. [PubMed]
328. Malicki JJ, Pujic Z, Thisse C, Thisse B, Wei X. Forward and reverse genetic approaches to the analysis of eye development in zebrafish. Vision Res. 2002;42:527–533. [PubMed]
329. Manickam P, Vogel AM, Agarwal SK, Oda T, Spiegel AM, Marx SJ, Collins FS, Weinstein BM, Chandrasekharappa SC. Isolation, characterization, expression and functional analysis of the zebrafish ortholog of MEN1. Mamm Genome. 2000;11:448–454. [PubMed]
330. Markopez LJ, Cuesta N, Markinez A, Montuenga L, Cuttitta F. Proadrenomedullin N-terminal 20 peptide (PAMP) immunoreactivity in vertebrate juxtaglomerular granular cells identified by both light and electron microscopy. Gen Comp Endocrinol. 1999;116:192–203. [PubMed]
331. Maruyama K, Tsukada T, Honda M, Nara-Ashizawa N, Noguchi K, Cheng J, Ohkura N, Sasaki K, Yamaguchi K. Complementary DNA structure and genomic organization of Drosophila menin. Mol Cell Endocrinol. 2000;168:135–140. [PubMed]
332. Mathieu M, Tagliafierro G, Angelini C, Vallarino M. Organization of vasoactive intestinal peptide-like immunoreactive system in the brain, olfactory organ and retina of the zebrafish, Danio rerio, during development. Brain Research. 2001;888:235–247. [PubMed]
333. Matthews JL, Brown AMV, Larison K, Bishop-Stewart JK, Rogers P, Kent ML. Pseudoloma neurophilia n. g., n. sp., a new microsporidium from the central nervous system of the zebrafish (Danio rerio) J Eukaryotic Microbiol. 2001;48:227–233. [PubMed]
334. Matthews JL, Spitsbergen J, Bishop-Stewart JK, Westerfield M, Kent ML. A Summary of Common Diseases of Laboratory Zebrafish; Presented at Fifth International Meeting on Zebrafish Development and Genetics; Madison, Wisconsin. 2002.
335. Mattingly CJ. Ah receptor action in developing zebrafish (Danio rerio) Dissertation Abstracts International Part B: Science and Engineering. 2000;60:5012.
336. Mattingly CJ, McLachlan JA, Toscano WA., Jr Green fluorescent protein (GFP) as a marker of aryl hydrocarbon receptor (AhR) function in developing zebrafish (Danio rerio) Environ Health Perspect. 2001;109:845–849. [PMC free article] [PubMed]
337. Mattingly CJ, Toscano WA. Posttranscriptional silencing of cytochrome P4501A1 (CYP1A1) during zebrafish (Danio rerio) development. Dev Dyn. 2001;222:645–654. [PubMed]
338. Maul RS, Sachi Gerbin C, Chang DD. Characterization of mouse epithelial protein lost in neoplasm (EPLIN) and comparison of mammalian and zebrafish EPLIN. Gene. 2001;262:155–160. [PubMed]
339. McGowan RA, Martin CC. DNA methylation and genome imprinting in the zebrafish, Danio rerio: Some evolutionary ramifications. Biochem Cell Biol. 1997;75:499–506. [PubMed]
340. Meinelt T, Playle RC, Pietrock M, Burnison BK, Wienke A, Steinberg CEW. Interaction of cadmium toxicity in embryos and larvae of zebrafish (Danio rerio) with calcium and humic substances. Aquatic Toxicology. 2001;54:205–215. [PubMed]
341. Meinelt T, Rose A, Pietrock M. Effects of calcium content and humic substances on the toxicity of acriflavine to juvenile zebrafish Danio rerio. J Aquatic Animal Health. 2002;14:35–38.
342. Meinelt T, Schulz C, Wirth M, Kuerzinger H, Steinberg C. Dietary fatty acid composition influences the fertilization rate of zebrafish (Danio rerio Hamilton-Buchanan) J Appl Ichthyol. 1999;15:19–23.
343. Mellgren EM, Johnson SL. The evolution of morphological complexity in zebrafish stripes. Trends Genet. 2002;18:128–134. [PubMed]
344. Meng A, Jessen JR, Lin S. Transgenesis. Methods Cell Biol. 1999;60:133–148. [PubMed]
345. Menudier A, Rougier FP, Bosgiraud C. Comparative virulence between different strains of Listeria in zebrafish (Brachydanio rerio) and mice. Pathologie Biologie. 1996;44:783–789. [PubMed]
346. Metscher BD, Ahlberg PE. Zebrafish in context: Uses of a laboratory model in comparative studies. Dev Biol. 1999;210:1–14. [PubMed]
347. Meyer A, Malaga-Trillo E. Vertebrate genomics: More fishy tales about Hox genes. Curr Biol. 1999;9:R210–R213. [PubMed]
348. Mhanni AA, Yoder JA, Dubesky C, McGowan RA. Cloning and sequence analysis of a zebrafish cDNA encoding DNA (cytosine-5)-methyltransferase-1. Genesis. 2001;30:213–219. [PubMed]
349. Milewski WM, Duguay SJ, Chan SJ, Steiner DF. Conservation of PDX-1 structure, function, and expression in zebrafish. Endocrinology. 1998;139:1440–1449. [PubMed]
350. Miller CT, Schilling TF, Lee K, Parker J, Kimmel CB. sucker encodes a zebrafish Endothelin-1 required for ventral pharyngeal arch development. Development. 2000;127:3815–3828. [PubMed]
351. Miller-Bertoglio VE, Fisher S, Sanchez A, Mullins MC, Halpern ME. Differential regulation of chordin expression domains in mutant zebrafish. Dev Biol. 1997;192:537–550. [PubMed]
352. Mills CA. Age- and density-dependent growth within populations of the ectoparasitic digenean Transversotrema patialense on the fish host. Int J Parasitol. 1980;10:287–291.
353. Miranda CL, Collodi P, Zhao X, Barnes DW, Buhler DR. Regulation of cytochrome P450 expression in a novel liver cell line from zebrafish (Brachydanio rerio) Arch Biochem Biophys. 1993;305:320–327. [PubMed]
354. Mizell M, Romig E, Stegeman J, Smolowitz R, Katayani R. Biological Bulletin. Vol. 191. Marine Biological Laboratory; Woods Hole: 1996. Zebrafish embryo monitoring of the aquatic environment: Dose-response synergism revealed in combinations of pollutant chemical mixtures; pp. 292–294.
355. Mizell M, Romig ES. The aquatic vertebrate embryo as a sentinel for toxins: Zebrafish embryo dechorionation and perivitelline space microinjection. Int J Dev Biol. 1997;41:411–423. [PubMed]
356. Mizuno T, Shinya M, Takeda H. Cell and tissue transplantation in zebrafish embryos. Methods Mol Biol. 1999;127:15–28. [PubMed]
357. Moens CB, Fritz A. Techniques in neural development. Methods Cell Biol. 1999;59:253–272. [PubMed]
358. Moens CB, Prince VE. Constructing the hindbrain: Insights from the zebrafish. Dev Dyn. 2002;224:1–17. [PubMed]
359. Moore JL, Breneman C, Mohideen MPK, Cheng KC. Zebrafish Loss of Heterozygosity Mutants and Cancer; Presented at Fifth International Meeting on Zebrafish Development and Genetics; Madison, Wisconsin. 2002.
360. Moore JL, Tsao-Wu GS, Steudel K, Morgan JT, Cheng KC. Zebrafish Loss of Heterozygosity Mutants and Cancer; Presented at Cold Spring Harbor Zebrafish Development and Genetics Meeting; Cold Spring Harbor, New York. 2000.
361. Moorman SJ. Development of sensory systems in zebrafish (Danio rerio) ILAR J. 2001;42:292–298. [PubMed]
362. Morin-Kensicki EM, Eisen JS. Sclerotome development and peripheral nervous system segmentation in embryonic zebrafish. Development. 1997;124:159–167. [PubMed]
363. Moss JB, Price AL, Raz E, Driever W, Rosenthal N. Green fluorescent protein marks skeletal muscle in murine cell lines and zebrafish. Gene. 1996;173:89–98. [PubMed]
364. Motoike T, Loughna S, Perens E, Roman BL, Liao W, Chau TC, Richardson CD, Kawate T, Kuno J, Weinstein BM, Stainier DY, Sato TN. Universal GFP reporter for the study of vascular development. Genesis. 2000;28:75–81. [PubMed]
365. Mullins MC. Embryonic axis formation in the zebrafish. Methods Cell Biol. 1999;59:159–178. [PubMed]
366. Mullins MC, Nusslein-Volhard C. Mutational approaches to studying embryonic pattern formation in the zebrafish. Curr Opin Genet Dev. 1993;3:648–654. [PubMed]
367. Musa A, Lehrach H, Russo VA. Distinct expression patterns of two zebrafish homologues of the human APP gene during embryonic development. Dev Genes Evol. 2001;211:563–567. [PubMed]
368. Nagel R, Bresch H, Caspers N, Hansen PD, Markert M, Munk R, Scholz N, ter Hofte BB. Effect of 3,4-dichloroaniline on the early life stages of the zebrafish (Brachydanio rerio): Results of a comparative laboratory study. Ecotoxicol Environ Saf. 1991;21:157–164. [PubMed]
369. Nasevicius A, Ekker SC. The zebrafish as a novel system for functional genomics and therapeutic development applications. Curr Opin Mol Ther. 2001;3:224–228. [PubMed]
370. Naudin S, Pella H, Charlon N, Garric J, Bergot P. Abnormal fish larvae detection by image analysis. Aquat Living Resour. 1996;9:281–287.
371. Navara CS, Benyumov A, Vassilev A, Narla RK, Ghosh P, Uckun FM. Vanadocenes as potent anti-proliferative agents disrupting mitotic spindle formation in cancer cells. Anticancer Drugs. 2001;12:369–376. [PubMed]
372. Nechiporuk A, Finney JE, Keating MT, Johnson SL. Assessment of polymorphism in zebrafish mapping strains. Genome Res. 1999;9:1231–1238. [PubMed]
373. Neilson AH, Allard AS, Fischer S, Malmberg M, Viktor T. Incorporation of a subacute test with zebra fish into a hierarchical system for evaluating the effect of toxicants in the aquatic environment. Ecotoxicol Environ Saf. 1990;20:82–97. [PubMed]
374. Neilson AH, Allard AS, Reiland S, Remberger M, Tarnholm A, Viktor T, Landner L. Tri- and tetra-chloroveratrole, metabolites produced by bacterial O-methylation of tri- and tetra-chloroguaiacol: An assessment of their bioconcentration potential and their effects on fish reproduction. Can J Fish Aquat Sci. 1984;41:1502–1512.
375. Neuhauss SC, Biehlmaier O, Seeliger MW, Das T, Kohler K, Harris WA, Baier H. Genetic disorders of vision revealed by a behavioral screen of 400 essential loci in zebrafish. J Neurosci. 1999;19:8603–8615. [PubMed]
376. Nguyen PV, Aniksztejn L, Catarsi S, Drapeau P. Maturation of neuromuscular transmission during early development in zebrafish. J Neurophysiol. 1999;81:2852–2861. [PubMed]
377. Nieto MA. The early steps of neural crest development. Mech Dev. 2001;105:27–35. [PubMed]
378. Niimi AJ, LaHam QN. Relative toxicity of organic and inorganic compounds of selenium to newly hatched zebrafish (Brachydanio rerio) Can J Zool. 1976;54:501–509. [PubMed]
379. Noga EJ. Fish Diseases: Diagnosis and Treatment. Iowa State University Press; Ames, Iowa: 1996.
380. Nusslein-Volhard C. Of flies and fishes. Science. 1994;266:572–574. [PubMed]
381. Oberemm A, Becker J, Codd GA, Steinberg C. Effects of cyanobacterial toxins and aqueous crude extracts of cyanobacteria on the development of fish and amphibians. Environ Toxicol. 1999;14:77–88.
382. Oberemm A, Fastner J, Steinberg EW. Effects of microcystin-LR and cyanobacterial crude extracts on embryo-larval development of zebrafish (Danio rerio) Water Res. 1997;31:2918–2921.
383. Olsson P-E, Westerlund L, Teh SJ, Billsson K, Berg AH, Tysklind M, Nilsson J, Eriksson L, Hinton DE. Effects of maternal exposure to estrogen and PCB on different life stages of zebrafish (Danio rerio) Ambio. 1999;28:100–106.
384. Olsson PE, Westerlund L, Willsson K, Schopen A, Hyllner J. Oestrogen Induced Developmental Disturbances and Hepatic Gene Expression; Proceedings of the EMBO-Workshop on Reproduction and Early Development; Bergen, Norway. 1998.
385. Ono F, Higashijima S, Shcherbatko A, Fetcho JR, Brehm P. Paralytic zebrafish lacking acetylcholine receptors fail to localize rapsyn clusters to the synapse. J Neurosci. 2001;21:5439–5448. [PubMed]
386. Orkin SH, Zon LI. Genetics of erythropoiesis: induced mutations in mice and zebrafish. Annu Rev Genet. 1997;31:33–60. [PubMed]
387. Orn S, Andersson PL, Forlin L, Tysklind M, Norrgren L. The impact on reproduction of an orally administered mixture of selected PCBs in zebrafish (Danio rerio) Arch Environ Contam Toxicol. 1998;35:52–57. [PubMed]
388. Oulmi Y, Braunbeck T. Toxicity of 4-chloroaniline in early lifestages of zebrafish (Brachydanio rerio): I. Cytopathology of liver and kidney after microinjection. Arch Environ Contam Toxicol. 1996;30:390–402. [PubMed]
389. Ozoh PT. Effects of reversible incubations of zebrafish eggs in copper and lead ions with or without shell membranes. Bull Environ Contam Toxicol. 1980;24:270–275. [PubMed]
390. Pack M, Solnica-Krezel L, Malicki J, Neuhauss SC, Schier AF, Stemple DL, Driever W, Fishman MC. Mutations affecting development of zebrafish digestive organs. Development. 1996;123:321–328. [PubMed]
391. Palmer FB, Butler CA, Timperley MH, Evans CW. Toxicity to embryo and adult zebrafish of copper complexes with two malonic acids as models for dissolved organic matter. Environ Toxicol Chem. 1998;17:1538–1545.
392. Pang Y, Ge W. Activin stimulation of zebrafish oocyte maturation in vitro and its potential role in mediating gonadotropin-induced oocyte maturation. Biol Reprod. 1999;61:987–992. [PubMed]
393. Pang Y, Ge W. Gonadotropin and activin enhance maturational competence of oocytes in the zebrafish (Danio rerio) Biol Reprod. 2002;66:259–265. [PubMed]
394. Parichy DM, Mellgren EM, Rawls JF, Lopes SS, Kelsh RN, Johnson SL. Mutational analysis of endothelin receptor b1 (rose) during neural crest and pigment pattern development in the zebrafish Danio rerio. Dev Biol. 2000;227:294–306. [PubMed]
395. Parichy DM, Rawls JF, Pratt SJ, Whitfield TT, Johnson SL. Zebrafish sparse corresponds to an orthologue of c-kit and is required for the morphogenesis of a subpopulation of melanocytes, but is not essential for hematopoiesis or primordial germ cell development. Development. 1999;126:3425–3436. [PubMed]
396. Parsons MJ, Campos I, Hirst EM, Stemple DL. Removal of dystroglycan causes severe muscular dystrophy in zebrafish embryos. Development. 2002;129:3505–3512. [PubMed]
397. Patton EE, Zon LI. The art and design of genetic screens: Zebrafish. Nat Rev Genet. 2001;2:956–966. [PubMed]
398. Paul TA, Burns JC, Shike H, Getchell R, Bowser PR, Whitlock KE, Casey JW. Reporter gene expression in fish following cutaneous infection with pantropic retroviral vectors. Mar Biotechnol. 2001;3:81–87. [PubMed]
399. Paw BH, Zon LI. Zebrafish: A genetic approach in studying hematopoiesis. Curr Opin Hematol. 2000;7:79–84. [PubMed]
400. Paw BH. Cloning of the zebrafish retsina blood mutation: A genetic model for dyserythropoiesis and erythroid cytokinesis. Blood Cells Mol Dis. 2001;27:62–64. [PubMed]
401. Payne TL, Skobe Z, Yelick PC. Regulation of tooth development by the novel type I TGFbeta family member receptor Alk8. J Dent Res. 2001;80:1968–1973. [PubMed]
402. Perz-Edwards A, Hardison NL, Linney E. Retinoic acid-mediated gene expression in transgenic reporter zebrafish. Dev Biol. 2001;229:89–101. [PubMed]
403. Petersen GI, Kristensen P. Bioaccumulation of lipophilic substances in fish early life stages. Environ Toxicol Chem. 1998;17:1385–1395.
404. Peterson RT, Link BA, Dowling JE, Schreiber SL. Small molecule developmental screens reveal the logic and timing of vertebrate development. Proc Natl Acad Sci USA. 2000;97:12965–12969. [PubMed]
405. Pham VN, Roman BL, Weinstein BM. Isolation and expression analysis of three zebrafish angiopoietin genes. Dev Dyn. 2001;221:470–474. [PubMed]
406. Phillips BT, Bolding K, Riley BB. Zebrafish fgf3 and fgf8 encode redundant functions required for otic placode induction. Dev Biol. 2001;235:351–365. [PubMed]
407. Phillips RB, Reed KM. Localization of repetitive DNAs to zebrafish (Danio rerio) chromosomes by fluorescence in situ hybridization (FISH) Chromosome Res. 2000;8:27–35. [PubMed]
408. Phromkunthong W, Storch V, Braunbeck T. Sexual dimorphism in the reaction of zebrafish (Brachydanio rerio) to ascorbic acid deficiency: Induction of steatosis in hepatocytes of male fish. J Appl ichthyol/Zeitschrift fur Angewandte Ichthyol, Berlin. 1994;10:146–153.
409. Piotrowski T, Nusslein-Volhard C. The endoderm plays an important role in patterning the segmented pharyngeal region in zebrafish (Danio rerio) Dev Biol. 2000;225:339–356. [PubMed]
410. Piotrowski T, Schilling TF, Brand M, Jiang YJ, Heisenberg CP, Beuchle D, Grandel H, van Eeden FJ, Furutani-Seiki M, Granato M, Haffter P, Hammerschmidt M, Kane DA, Kelsh RN, Mullins MC, Odenthal J, Warga RM, Nusslein-Volhard C. Jaw and branchial arch mutants in zebrafish II: Anterior arches and cartilage differentiation. Development. 1996;123:345–356. [PubMed]
411. Pliss GB, Khudoley VV. Tumor induction by carcinogenic agents in aquarium fish. J Natl Cancer Inst. 1975;55:129–136. [PubMed]
412. Pliss GB, Zabezhinski MA, Petrov AS, Khudoley VV. Peculiarities of N-nitramines carcinogenic action. Arch Geschwulstforsch. 1982;52:629–634. [PubMed]
413. Postlethwait J, Amores A, Force A, Yan YL. The zebrafish genome. Methods Cell Biol. 1999;60:149–163. [PubMed]
414. Postlethwait JH, Talbot WS. Zebrafish genomics: From mutants to genes. Trends Genet. 1997;13:183–190. [PubMed]
415. Powell JF, Krueckl SL, Collins PM, Sherwood NM. Molecular forms of GnRH in three model fishes: Rockfish, medaka and zebrafish. J Endocrinol. 1996;150:17–23. [PubMed]
416. Powell WH, Hahn ME. The evolution of aryl hydrocarbon signaling proteins: Diversity of ARNT isoforms among fish species. Mar Environ Res. 2000;50:39–44. [PubMed]
417. Power DM, Llewellyn L, Faustino M, Nowell MA, Bjornsson BT, Einarsdottir IE, Canario AV, Sweeney GE. Thyroid hormones in growth and development of fish. Comp Biochem Physiol C Toxicol Pharmacol. 2001;130:447–459. [PubMed]
418. Powers DA. Fish as model systems. Science. 1989;246:352–358. [PubMed]
419. Pullium JK, Dillehay DL, Webb S. High mortality in zebrafish (Danio rerio) Contemp Top Lab Anim Sci. 1999;38:80–83. [PubMed]
420. Rauh-Adelmann C, Kanki J, Delahaye-Brown A, Look AT. Molecular Cloning of the Zebrafish mycn (zmycn) and Tyrosine Hydroxylase (zth) Genes: A Potential Transgenic Model for Neuroblastoma in Zebrafish; Presented at Zebrafish Development and Genetics Meeting; Cold Spring Harbor, New York. 2000.
421. Rawls JF, Johnson SL. Zebrafish kit mutation reveals primary and secondary regulation of melanocyte development during fin stripe regeneration. Development. 2000;127:3715–3724. [PubMed]
422. Ray WJ, Bain G, Yao M, Gottlieb DI. CYP26, a novel mammalian cytochrome P450, is induced by retinoic acid and defines a new family. J Biol Chem. 1997;272:18702–18708. [PubMed]
423. Razani H, Nanba K, Murachi S. Chronic toxic effect of phenol on zebrafish Brachydanio rerio. Bull Jap Soc Sci Fish/Nissuishi. 1986;52:1553–1558.
424. Reiter JF, Alexander J, Rodaway A, Yelon D, Patient R, Holder N, Stainier DY. Gata5 is required for the development of the heart and endoderm in zebrafish. Genes Dev. 1999;13:2983–2995. [PubMed]
425. Reiter JF, Kikuchi Y, Stainier DY. Multiple roles for Gata5 in zebrafish endoderm formation. Development. 2001;128:125–135. [PubMed]
426. Reyes R, Vitebsky A, Whitlock KE. Isolation and Characterization of the Laure Olfactory Behavioral Mutant; Presented at Fifth International Meeting on Zebrafish Development and Genetics; Madison, Wisconsin. 2002.
427. Roales RR, Perlmutter A. Toxicity of zinc and cygon, applied singly and jointly, to zebrafish embryos. Bull Environ Contam Toxicol. 1974;12:475–480. [PubMed]
428. Roche H, Boge G, Peres G. Acute and chronic toxicities of colchicine in Brachydanio rerio. Bull Environ Contam Toxicol. 1994;52:69–73. [PubMed]
429. Roex EW, Giovannangelo M, van Gestel CA. Reproductive impairment in the zebrafish, Danio rerio, upon chronic exposure to 1,2,3-trichlorobenzene. Ecotoxicol Environ Saf. 2001;48:196–201. [PubMed]
430. Roex EW, van Langen MC, van Gestel CA. Acute toxicity of two compounds with different modes of action to the zebrafish, Danio rerio. Bull Environ Contam Toxicol. 2002;68:269–274. [PubMed]
431. Rohr KB, Concha ML. Expression of nk2.1a during early development of the thyroid gland in zebrafish. Mech Dev. 2000;95:267–270. [PubMed]
432. Roman BL, Weinstein BM. Building the vertebrate vasculature: Research is going swimmingly. Bioessays. 2000;22:882–893. [PubMed]
433. Roths JB, Foxworth WB, McArthur MJ, Montgomery CA, Kier AB. Spontaneous and engineered mutant mice as models for experimental and comparative pathology: History, comparison, and developmental technology. Lab Anim Sci. 1999;49:12–34. [PubMed]
434. Rougier F, Menudier A, Bosgiraud C, Nicolas JA. Copper and zinc exposure of zebrafish, Brachydanio rerio (Hamilton-Buchaman): Effects in experimental Listeria infection. Ecotoxicol Environ Saf. 1996;34:134–140. [PubMed]
435. Rougier F, Menudier A, Troutaud D, Bosgiraud C, Ndoye A, Nicolas JA, Deschaux P. In vivo effect of zinc and copper on the development of listeriosis in zebrafish, Brachydanio rerio (Hamilton-Buchanan) J Fish Dis. 1992;15:453–456.
436. Rowe RI, Bouzan C, Nabili S, Eckhert CD. The response of trout and zebrafish embryos to low and high boron concentrations is U-shaped. Biol Trace Elem Res. 1998;66:261–270. [PubMed]
437. Roy S, Qiao T, Wolff C, Ingham PW. Hedgehog signaling pathway is essential for pancreas specification in the zebrafish embryo. Curr Biol. 2001;11:1358–1363. [PubMed]
438. Rubin DA, Hellman P, Zon LI, Lobb CJ, Bergwitz C, Juppner H. A G protein-coupled receptor from zebrafish is activated by human parathyroid hormone and not by human or teleost parathyroid hormone-related peptide. Implications for the evolutionary conservation of calcium-regulating peptide hormones. J Biol Chem. 1999;274:23035–23042. [PubMed]
439. Rubin DA, Juppner H. Zebrafish express the common parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R) and a novel receptor (PTH3R) that is preferentially activated by mammalian and fugufish parathyroid hormone-related peptide. J Biol Chem. 1999;274:28185–28190. [PubMed]
440. Rubinstein AL, McKinley E, Blavo D, Cato C. A Parkinson's Disease Model for Drug Screening; Presented at Fifth International Meeting on Zebrafish Development and Genetics; Madison, Wisconsin. 2002.
441. Sahly I, Andermann P, Petit C. The zebrafish eya1 gene and its expression pattern during embryogenesis. Dev Genes Evol. 1999;209:399–410. [PubMed]
442. Saillant E, Fostier A, Haffray P, Menu B, Thimonier J, Chatain B. Temperature effects and genotype-temperature interactions on sex determination in the European sea bass (Dicentrarchus labrax L.) J Exp Zool. 2002;292:494–505. [PubMed]
443. Saint-Amant L, Drapeau P. Time course of the development of motor behaviors in the zebrafish embryo. J Neurobiol. 1998;37:622–632. [PubMed]
444. Sakai N. Transmeiotic differentiation of zebrafish germ cells into functional sperm in culture. Development. 2002;129:3359–3365. [PubMed]
445. Sakamoto H, Ukena K, Tsutsui K. Activity and localization of 3 beta-hydroxysteroid dehydrogenase-delta5-delta4-isomerase in the zebrafish central nervous system. J Comp Neurol. 2001;439:291–305. [PubMed]
446. Saloman DS, Bianco C, Ebert AD, Khan NI, De Santis M, Normanno N, Wechselberger C, Seno M, Williams K, Sanicola M, Foley S, Gullick WJ, Persico G. The EGF-CFC family: Novel epidermal growth factor-related proteins in development and cancer. Endocr Relat Cancer. 2000;7:199–226. [PubMed]
447. Samson JC, Goodridge R, Olobatuyi F, Weis JS. Delayed effects of embryonic exposure of zebrafish (Danio rerio) to methylmercury (MeHg) Aquat Toxicol. 2001;51:369–376. [PubMed]
448. Sanders LH, Whitlock KE. Genetic Background Affects the Phenotypic Severity of the Masterblind (mbl) Mutant; Presented at Fifth International Meeting on Zebrafish Development and Genetics; Madison, Wisconsin. 2002. p. 405.
449. Sarot DA, Perlmutter A. The toxicity of zinc to the immune response of the zebrafish, Brachydanio rerio, injected with viral and bacterial antigens. Transactions of the American Fisheries Society. 1976;105:456–459.
450. Schier AF, Neuhauss SC, Helde KA, Talbot WS, Driever W. The one-eyed pinhead gene functions in mesoderm and endoderm formation in zebrafish and interacts with no tail. Development. 1997;124:327–342. [PubMed]
451. Schilling TF. Genetic analysis of craniofacial development in the vertebrate embryo. Bioessays. 1997;19:459–468. [PubMed]
452. Schilling TF, Knight RD. Origins of anteroposterior patterning and Hox gene regulation during chordate evolution. Phil Trans R Soc Lond B Biol Sci. 2001;356:1599–1613. [PMC free article] [PubMed]
453. Schnurstein A, Braunbeck T. Tail moment versus tail length—Application of an in vitro version of the comet assay in biomonitoring for genotoxicity in native surface waters using primary hepatocytes and gill cells from zebrafish (Danio rerio) Ecotoxicol Environ Saf. 2001;49:187–196. [PubMed]
454. Schreiber-Agus N, Chin L, Chen K, Torres R, Thomson CT, Sacchettini JC, DePinho RA. Evolutionary relationships and functional conservation among vertebrate Max-associated proteins: The zebra fish homolog of Mxi1. Oncogene. 1994;9:3167–377. [PubMed]
455. Schreiber-Agus N, Horner J, Torres R, Chiu FC, DePinho RA. Zebra fish myc family and max genes: Differential expression and oncogenic activity throughout vertebrate evolution. Mol Cell Biol. 1993;13:2765–2775. [PMC free article] [PubMed]
456. Schwerte T, Pelster B. Digital motion analysis as a tool for analysing the shape and performance of the circulatory system in transparent animals. J Exp Biol. 2000;203(Pt 11):1659–1669. [PubMed]
457. Seeley RJ, Perlmutter A, Seeley VA. Inheritance and longevity of infectious pancreatic necrosis virus in the zebra fish, Brachydanio rerio (Hamilton-Buchanan) Appl Environ Micro. 1977;34:50–55. [PMC free article] [PubMed]
458. Sehnert AJ, Huq A, Weinstein BM, Walker C, Fishman M, Stainier DY. Cardiac troponin T is essential in sarcomere assembly and cardiac contractility. Nat Genet. 2002;31:106–110. [PubMed]
459. Sepich DS, Wegner J, O'Shea S, Westerfield M. An altered intron inhibits synthesis of the acetylcholine receptor alpha-subunit in the paralyzed zebrafish mutant nic1. Genetics. 1998;148:361–372. [PubMed]
460. Serluca FC, Drummond IA, Fishman MC. Endothelial signaling in kidney morphogenesis. A role for hemodynamic forces. Curr Biol. 2002;12:492–497. [PubMed]
461. Serluca FC, Fishman MC. Cell lineage tracing in heart development. Methods Cell Biol. 1999;59:359–365. [PubMed]
462. Serluca FC, Fishman MC. Pre-pattern in the pronephric kidney field of zebrafish. Development. 2001;128:2233–2241. [PubMed]
463. Sheehan J, Templer M, Gregory M, Hanumanthaiah R, Troyer D, Phan T, Thankavel B, Jagadeeswaran P. Demonstration of the extrinsic coagulation pathway in teleostei: Identification of zebrafish coagulation factor VII. Proc Natl Acad Sci USA. 2001;98:8768–8773. [PubMed]
464. Shepard JL, Amatruda JF, Ziai J, Stern HM, Finkelstein D, Lindahl K, Hersey C, Aster J, Kutok J, Glickman J, Freedman M, Spitsbergen J, Zhou Y, Zon LI. A Genetic Screen for Mutations Affecting Cell Proliferation and Cancer Susceptibility in the Zebrafish; Presented at Fifth International Meeting on Zebrafish Development and Genetics; Madison, Wisconsin. 2002. p. 69.
465. Shepard JL, Zon LI. Developmental derivation of embryonic and adult macrophages. Curr Opin Hematol. 2000;7:3–8. [PubMed]
466. Shepherd IT, Beattie CE, Raible DW. Functional analysis of zebrafish GDNF. Dev Biol. 2001;231:420–435. [PubMed]
467. Simon R, Tietge JE, Michalke B, Degitz S, Schramm KW. Iodine species and the endocrine system: Thyroid hormone levels in adult Danio rerio and developing Xenopus laevis. Anal Bioanal Chem. 2002;372:481–485. [PubMed]
468. Sisinno CL, Oliveira-Filho EC, Dufrayer MC, Moreira JC, Paumgartten FJ. Toxicity evaluation of a municipal dump leachate using zebrafish acute tests. Bull Environ Contam Toxicol. 2000;64:107–113. [PubMed]
469. Skauli KS, Reitan JB, Walther BT. Hatching in zebrafish (Danio rerio) embryos exposed to a 50 Hz magnetic field. Bioelectromagnetics. 2000;21:407–410. [PubMed]
470. Skidmore JF. Resistance to zinc sulphate of the zebrafish (Brachydanio rerio Hamilton-Buchanan) at different phases of its life history. Ann Appl Biol. 1965;56:47–53. [PubMed]
471. Smith SI, Down M, Power M, Boyd AW. Experimental Haematology. Queensland Institute of Medical Research; P.O. Royal Brisbane Hospital, Brisbane, Qld 4029, Australia: 1999. Isolation and characterization of a cDNA encoding zebrafish (Danio rerio) WT-1. GenBank Accession AF144550.
472. Smolders R, Bervoets L, De BG, Blust R. Integrated condition indices as a measure of whole effluent toxicity in zebrafish (Danio rerio) Environ Toxicol Chem. 2002;21:87–93. [PubMed]
473. Solnica-Krezel L. Pattern formation in zebrafish—Fruitful liaisons between embryology and genetics. Curr Top Dev Biol. 1999;41:1–35. [PubMed]
474. Solnica-Krezel L, Stemple DL, Driever W. Transparent things: Cell fates and cell movements during early embryogenesis of zebrafish. Bioessays. 1995;17:931–939. [PubMed]
475. Spitsbergen JM, Kent ML, Bishop-Stewart J, Miller T, Matthews J, Buhler DR. Spontaneous and Carcinogen-Induced Neoplasia and Other Lesions in Wild-type and Mutant Lines of Zebrafish; Presented at Fifth International Meeting on Zebrafish Development and Genetics; Madison, Wisconsin. 2002. p. 509.
476. Spitsbergen JM, Tsai H, Reddy A, Hendricks J. Response of zebrafish to a panel of structurally diverse carcinogens. Proc Am Assoc Cancer Res. 1997;38:354.
477. Spitsbergen JM, Tsai HW, Reddy A, Miller T, Arbogast D, Hendricks JD, Bailey GS. Neoplasia in zebrafish (Danio rerio) treated with 7,12-dimethylbenz[a]anthracene by two exposure routes at different developmental stages. Toxicol Pathol. 2000;28:705–715. [PubMed]
478. Spitsbergen JM, Tsai HW, Reddy A, Miller T, Arbogast D, Hendricks JD, Bailey GS. Neoplasia in zebrafish (Danio rerio) treated with N-methyl-N′-nitro-N -nitrosoguanidine by three exposure routes at different developmental stages. Toxicol Pathol. 2000;28:716–725. [PubMed]
479. Stainier DY. Zebrafish genetics and vertebrate heart formation. Nat Rev Genet. 2001;2:39–48. [PubMed]
480. Stainier DY, Weinstein BM, Detrich HW, 3rd, Zon LI, Fishman MC. Cloche, an early acting zebrafish gene, is required by both the endothelial and hematopoietic lineages. Development. 1995;121:3141–3150. [PubMed]
481. Stanton M. Hepatic neoplasms of aquarium fish exposed to Cycas cercinalis. Fed Proc. 1966;26:661.
482. Stanton MF. Diethylnitrosamine-induced hepatic degeneration and neoplasia in the aquarium fish, Brachydanio rerio. JNCI. 1965;34:117–130. [PubMed]
483. Starz-Gaiano M, Lehmann R. Moving towards the next generation. Mech Dev. 2001;105:5–18. [PubMed]
484. Stern HM, Murphey RD, Shepard JL, Amatruda JF, King RW, Zon LI. A screen for small molecule suppressors of the cancer-susceptible crash&burn cell cycle mutant; Presented at Fifth International Meeting on Zebrafish Development and Genetics; Madison, Wisconsin. 2002. p. 443.
485. Sternberg H, Moav B. Regulation of the growth hormone gene by fish thyroid/retinoid receptors. Fish Physiol Biochem. 1999;20:331–339.
486. Stickney HL, Barresi MJ, Devoto SH. Somite development in zebrafish. Dev Dyn. 2000;219:287–303. [PubMed]
487. Stoskopf M. Fish Medicine. WB Saunders Company; Philadelphia, Pennsylvania: 1993.
488. Straehle U, Jesuthasan S. Ultraviolet irradiation impairs epiboly in zebrafish embryos: Evidence for a microtubule-dependent mechanism of epiboly. Development. 1993;119:909–919. [PubMed]
489. Streisinger G. Attainment of minimal biological variability and measurements of genetoxicity: Production of homozygous diploid zebra fish. In: Hoover KL, editor. Use of Small Fish Species in Carcinogen Testing. National Cancer Institute; Bethesda, Maryland: 1984. pp. 53–58. [PubMed]
490. Strmac M, Braunbeck T. Effects of triphenyltin acetate on survival, hatching success, and liver ultrastructure of early life stages of zebrafish (Danio rerio) Ecotoxicol Environ Saf. 1999;44:25–39. [PubMed]
491. Sukhanova ME. Changes in behavior of Brachydanio rerio evoked by beta-phenylethanol. J Ichthyol. 1993;33:118–122.
492. Sultmann H, Mayer WE, Figueroa F, O'HUigin C, Klein J. Zebrafish Mhc class II alpha chain-encoding genes: Polymorphism, expression, and function. Immunogenetics. 1993;38:408–420. [PubMed]
493. Sultmann H, Sato A, Murray BW, Takezaki N, Geisler R, Rauch GJ, Klein J. Conservation of Mhc class III region synteny between zebrafish and human as determined by radiation hybrid mapping. J Immunol. 2000;165:6984–6993. [PubMed]
494. Sun Z, Hopkins N. vhnf1, the MODY5 and familial GCKD-associated gene, regulates regional specification of the zebrafish gut, pronephros, and hindbrain. Genes Dev. 2001;15:3217–3229. [PubMed]
495. Svenson A, Viktor T, Remberger M. Toxicity of elemental sulfur in sediments. Environ Toxicol Water Qual. 1998;13:217–224.
496. Takahashi M, Narushima M, Oda Y. In vivo imaging of functional inhibitory networks on the Mauthner cell of larval zebrafish. J Neurosci. 2002;22:3929–3938. [PubMed]
497. Takami K, Zaleska-Rutczynska Z, Figueroa F, Klein J. Linkage of LMP, TAP, and RING3 with Mhc class I rather than class II genes in the zebrafish. J Immunol. 1997;159:6052–6060. [PubMed]
498. Talbot WS, Hopkins N. Zebrafish mutations and functional analysis of the vertebrate genome. Genes Dev. 2000;14:755–762. [PubMed]
499. Talbot WS, Schier AF. Positional cloning of mutated zebrafish genes. Methods Cell Biol. 1999;60:259–286. [PubMed]
500. Tanguay RL, Abnet CC, Heideman W, Peterson RE. Cloning and characterization of the zebrafish (Danio rerio) aryl hydrocarbon receptor. Biochim Biophys Acta. 1999;1444:35–48. [PubMed]
501. Tanguay RL, Andreasen E, Heideman W, Peterson RE. Identification and expression of alternatively spliced aryl hydrocarbon nuclear translocator 2 (ARNT2) cDNAs from zebrafish with distinct functions. Biochim Biophys Acta. 2000;1494:117–128. [PubMed]
502. Teraoka H, Dong W, Ogawa S, Tsukiyama S, Okuhara Y, Niiyama M, Ueno N, Peterson RE, Hiraga T. 2,3,7,8-Tetrachlorodibenzo-p-dioxin toxicity in the zebrafish embryo: Altered regional blood flow and impaired lower jaw development. Toxicol Sci. 2002;65:192–199. [PubMed]
503. Teraoka H, Dong W, Okuhara Y, Urakawa S, Iwasa H, Kawakami A, Ueno N, Stegeman J, Peterson RE, Hiraga T. Involvement of Hedgehog Signal in Jaw Development and Inhibitory Effects by 2,3,7,8-tetrachlorodibenzo-p-dioxin in Zebrafish Embryo; Presented at Fifth International Meeting on Zebrafish Development and Genetics; Madison, Wisconsin. 2002.
504. Thisse C, Neel H, Thisse B, Daujat S, Piette J. The Mdm2 gene of zebrafish (Danio rerio): Preferential expression during development of neural and muscular tissues, and absence of tumor formation after over-expression of its cDNA during early embryogenesis. Differentiation. 2000;66:61–70. [PubMed]
505. Thisse C, Zon LI. Organogenesis—Heart and blood formation from the zebrafish point of view. Science. 2002;295:457–462. [PubMed]
506. Thomas RJ. The toxicologic and teratologic effects of delta-9-tetrahydrocannabinol in the zebrafish embryo. Toxicol Appl Pharmacol. 1975;32:184–190. [PubMed]
507. Thompson MA, Ransom DG, Pratt SJ, MacLennan H, Kieran MW, Detrich HW, 3rd, Vail B, Huber TL, Paw B, Brownlie AJ, Oates AC, Fritz A, Gates MA, Amores A, Bahary N, Talbot WS, Her H, Beier DR, Postlethwait JH, Zon LI. The cloche and spadetail genes differentially affect hematopoiesis and vasculogenesis. Dev Biol. 1998;197:248–269. [PubMed]
508. Tomatis L. Prenatal exposure to chemical carcinogens and its effect on subsequent generations. Natl Cancer Inst Monogr. 1979;51:159–184. [PubMed]
509. Tomizawa K, Nakayasu H. Ex vivo culture of isolated zebrafish whole brain. J Neurosci Methods. 2001;107:31–38. [PubMed]
510. Tong SK, Chiang EF, Hsiao PH, Chung B. Phylogeny, expression and enzyme activity of zebrafish cyp19 (P450 aromatase) genes. J Steroid Biochem Mol Biol. 2001;79:299–303. [PubMed]
511. Topczewski J, Solnica-Krezel L. Cytoskeletal dynamics of the zebrafish embryo. Methods Cell Biol. 1999;59:205–226. [PubMed]
512. Traber PG. Transcriptional regulation in intestinal development. Implications for colorectal cancer. Adv Exp Med Biol. 1999;470:1–14. [PubMed]
513. Trainor PA, Krumlauf R. Patterning the cranial neural crest: Hindbrain segmentation and Hox gene plasticity. Nat Rev Neurosci. 2000;1:116–124. [PubMed]
514. Trant JM, Gavasso S, Ackers J, Chung BC, Place AR. Developmental expression of cytochrome P450 aromatase genes (CYP19a and CYP19b) in zebrafish fry (Danio rerio) J Exp Zool. 2001;290:475–483. [PubMed]
515. Trede NS, Zapata A, Zon LI. Fishing for lymphoid genes. Trends Immunol. 2001;22:302–307. [PubMed]
516. Trede NS, Zon LI. Development of T-cells during fish embryogenesis. Dev Comp Immunol. 1998;22:253–263. [PubMed]
517. Troskie B, Illing N, Rumbak E, Sun YM, Hapgood J, Sealfon S, Conklin D, Millar R. Identification of three putative GnRH receptor subtypes in vertebrates. Gen Comp Endocrinol. 1998;112:296–302. [PubMed]
518. Troxel CM, Buhler DR, Hendricks JD, Bailey GS. CYP1A induction by beta-naphthoflavone, Aroclor 1254, and 2,3,7,8-tetrachlorodibenzo- p-dioxin and its influence on aflatoxin B1 metabolism and DNA adduction in zebrafish. Toxicol Appl Pharmacol. 1997;146:69–78. [PubMed]
519. Troxel CM, Reddy AP, O'Neal PE, Hendricks JD, Bailey GS. In vivo aflatoxin B1 metabolism and hepatic DNA adduction in zebrafish (Danio rerio) Toxicol Appl Pharmacol. 1997;143:213–220. [PubMed]
520. Tsai CW, Tseng JJ, Lin SC, Chang CY, Wu JL, Horng JF, Tsay HJ. Primary structure and developmental expression of zebrafish sodium channel Na(v)1.6 during neurogenesis. DNA Cell Biol. 2001;20:249–255. [PubMed]
521. Tsai H. Evaluation of Zebrafish (Brachydanio rerio) as a Model for Carcinogenesis. Oregon State University; Corvallis, Oregon: 1996. PhD thesis.
522. Tyler CR, Van der Eerden B, Jobling S, Panter G, Sumpter JP. Measurement of vitellogenin, a biomarker for exposure to oestrogenic chemicals, in a wide variety of cyprinid fish. J Comp Physiol. 1996;166:418–426.
523. Uchida D, Yamashita M, Kitano T, Iguchi T. Oocyte apoptosis during the transition from ovary-like tissue to testes during sex differentiation of juvenile zebrafish. J Exp Biol. 2002;205:711–718. [PubMed]
524. Usdin TB, Wang T, Hoare SR, Mezey E, Palkovits M. New members of the parathyroid hormone/parathyroid hormone receptor family: The parathyroid hormone 2 receptor and tuberoinfundibular peptide of 39 residues. Front Neuroendocrinol. 2000;21:349–383. [PubMed]
525. Van Beneden RJ, Ostrander GK. Expression of oncogenes and tumor suppressor genes in teleost fish. In: Malins DC, Ostrander GK, editors. Aquatic Toxicology: Molecular, Biochemical and Cellular Perspectives. CRC Press, Inc; Boca Raton, Florida: 1994.
526. Van den Belt K, Wester PW, van der Ven L, Verheyen R, Witters H. Effects of ethynylestradiol on the reproductive physiology in zebrafish (Danio rerio): Time dependency and reversibility. Environ Toxicol Chem. 2002;21:767–775. [PubMed]
527. Van den Belt K, Van Puymbroeck S, Witters H. Toxicity of cadmium-contaminated clay to the zebrafish Danio rerio. Arch Environ Contam Toxicol. 2000;38:191–196. [PubMed]
528. Van den Belt K, Verheyen R, Witters H. Reproductive effects of ethynylestradiol and 4t-octylphenol on the zebrafish (Danio rerio) Arch Environ Contam Toxicol. 2001;41:458–467. [PubMed]
529. van den Hurk R, Schoonen WG, van Zoelen GA, Lambert JG. The biosynthesis of steroid glucuronides in the testis of the zebrafish, Brachydanio rerio, and their pheromonal function as ovulation inducers. Gen Comp Endocrinol. 1987;68:179–188. [PubMed]
530. van Heyningen V. Model organisms illuminate human genetics and disease. Mol Med. 1997;3:231–237. [PMC free article] [PubMed]
531. van Leeuwen CJ, Adema DMM, Hermens J. Quantitative structure-activity relationships for fish early life stage toxicity. Aquat Toxicol. 1990;16:321–334.
532. van Leeuwen CJ, Grootelaar EM, Niebeek G. Fish embryos as teratogenicity screens: A comparison of embryotoxicity between fish and birds. Ecotoxicol Environ Saf. 1990;20:42–52. [PubMed]
533. Van Nassauw L, Harrisson F, Callebaut M. Localization of smooth-muscle markers in the ovaries of some ectothermic vertebrates. Anat Rec. 1991;229:439–446. [PubMed]
534. van Raamsdonk W, de Graaf F, van Asselt E, Diegenbach PC, Mos W, van Noorden CJ, Roberts BL, Smit-Onel MJ. Metabolic profiles of spinal motoneurons in fish as established by quantitative enzyme histochemistry. Comp Biochem Physiol Comp Physiol. 1992;102:631–636. [PubMed]
535. van Raamsdonk W, Heyting C, Pool CW, Smit-Onel MJ, Groen JL. Differentiation of neurons and radial glia in the spinal cord of the teleost Brachydanio rerio (the zebrafish): An immunocytochemical study. Int J Dev Neurosci. 1984;2:471–481.
536. van Raamsdonk W, Tekronnie G, Pool CW, van de Laarse W. An immune histochemical and enzymic characterization of the muscle fibres in myotomal muscle of the teleost Brachydanio rerio, Hamilton-Buchanan. Acta Histochem. 1980;67:200–216. [PubMed]
537. Vanchieri C. Move over, mouse: Make way for the woodchucks, ferrets, and zebrafish. J Natl Cancer Inst. 2001;93:418–419. [PubMed]
538. Vandersea MW, Fleming P, McCarthy RA, Smith DG. Fin duplications and deletions induced by disruption of retinoic acid signaling. Dev Genes Evol. 1998;208:61–68. [PubMed]
539. Vascotto SG, Beckham Y, Kelly GM. The zebrafish's swim to fame as an experimental model in biology. Biochem Cell Biol. 1997;75:479–485. [PubMed]
540. Vihtelic TS, Hyde DR. Light-induced rod and cone cell death and regeneration in the adult albino zebrafish (Danio rerio) retina. J Neurobiol. 2000;44:289–307. [PubMed]
541. Vihtelic TS, Hyde DR. Zebrafish mutagenesis yields eye morphological mutants with retinal and lens defects. Vision Res. 2002;42:535–540. [PubMed]
542. Von Hertell U, Hoerstgen-Schwark G, Langholz HJ, Jung B. Family studies on genetic variability in growth and reproductive performance between and within test fish populations of the zebrafish, Brachydanio rerio. Aquaculture. 1990;85:307–315.
543. Walker C. Haploid screens and gamma-ray mutagenesis. Methods Cell Biol. 1999;60:43–70. [PubMed]
544. Walker K, Xie Y, Li Y, Zhu Q, Xu W, Wagner, TE, Chen X. Cytoplasmic expression of ribozyme in zebrafish using a T7 autogene system. Curr Issues in Mol Biol. 2001;3:1–6. [PubMed]
545. Walter RB. Aquaria fish models of human disease. Mar Biotechnol. 2001;3:S1–S2. [PubMed]
546. Waltman WD, Shotts EB, Blazer VS. Recovery of Edwardsiella ictaluri from danio (Danio devario) Aquaculture. 1985;46:63–66.
547. Wang H, Long Q, Marty SD, Sassa S, Lin S. A zebrafish model for hepatoerythropoietic porphyria. Nat Genet. 1998;20:239–243. [PubMed]
548. Wang X, Chu LT, He J, Emelyanov A, Korzh V, Gong Z. A novel zebrafish bHLH gene, neurogenin3, is expressed in the hypothalamus. Gene. 2001;275:47–55. [PubMed]
549. Wannemacher R, Rebstock A, Kulzer E, Schrenk D, Bock KW. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on reproduction and oogenesis in zebrafish (Brachydanio rerio) Chemosphere. 1992;24:1361–1368.
550. Ward AC, Lieschke GJ. The zebrafish as a model system for human disease. Front Biosci. 2002;7:d827–d833. [PubMed]
551. Warren KS, Baker K, Fishman MC. The slow mo mutation reduces pacemaker current and heart rate in adult zebrafish. Am J Physiol Heart Circ Physiol. 2001;281:H1711–H1719. [PubMed]
552. Warren KS, Fishman MC. Physiological genomics: Mutant screens in zebrafish. Am J Physiol. 1998;275:H1–H7. [PubMed]
553. Warren KS, Wu JC, Pinet F, Fishman MC. The genetic basis of cardiac function: Dissection by zebrafish (Danio rerio) screens. Philos Trans Roy Soc Lond B Biol Sci. 2000;355:939–944. [PMC free article] [PubMed]
554. Weidinger G, Wolke U, Koprunner M, Klinger M, Raz E. Identification of tissues and patterning events required for distinct steps in early migration of zebrafish primordial germ cells. Development. 1999;126:5295–5307. [PubMed]
555. Weidinger G, Wolke U, Koprunner M, Thisse C, Thisse B, Raz E. Regulation of zebrafish primordial germ cell migration by attraction towards an intermediate target. Development. 2002;129:25–36. [PubMed]
556. Weinstein BM. What guides early embryonic blood vessel formation? Dev Dyn. 1999;215:2–11. [PubMed]
557. Wellerdieck C, Oles M, Pott L, Korsching S, Gisselmann G, Hatt H. Functional expression of odorant receptors of the zebrafish Danio rerio and of the nematode C. elegans in HEK293 cells. Chem Senses. 1997;22:467–476. [PubMed]
558. Wendl T, Lun K, Mione M, Favor J, Brand M, Wilson SW, Rohr KB. pax2.1 is required for the development of thyroid follicles in zebrafish. Development. 2002;129:3751–3760. [PubMed]
559. Westerfield M, Doerry E, Kirkpatrick AE, Douglas SA. Zebrafish informatics and the ZFIN database. Methods Cell Biol. 1999;60:339–355. [PubMed]
560. Whitfield TT, Riley BB, Chiang MY, Phillips B. Development of the zebrafish inner ear. Dev Dyn. 2002;223:427–458. [PubMed]
561. Whitlock KE, Newton LA, Boyce ML. Adult Zebrafish Retain Olfactory Memories Formed as Juveniles; Presented at Fifth International Meeting on Zebrafish Development and Genetics; Madison, Wisconsin. 2002.
562. Whitlock KE, Westerfield M. A transient population of neurons pioneers the olfactory pathway in the zebrafish. J Neurosci. 1998;18:8919–8927. [PubMed]
563. Whitlock KE, Westerfield M. The olfactory placodes of the zebrafish form by convergence of cellular fields at the edge of the neural plate. Development. 2000;127:3645–3653. [PubMed]
564. Whitlock KE, Wolf CD, Boyce ML. Gonadotropin Releasing Hormone (GnRH) Neuroendocrine Cells have Origins in both Neural Crest and Pituitary Placodes; Presented at Fifth International Meeting on Zebrafish Development and Genetics; Madison, Wisconsin. 2002.
565. Wicklund A, Runn P, Norrgren L. Cadmium and zinc interactions in fish: effects of zinc on the uptake, organ distribution, and elimination of 109Cd in the zebrafish, Brachydanio rerio. Arch Environ Contam Toxicol. 1988;17:345–354. [PubMed]
566. Wiegand C, Krause E, Steinberg C, Pflugmacher S. Toxicokinetics of atrazine in embryos of the zebrafish (Danio rerio) Ecotoxicol Environ Saf. 2001;49:199–205. [PubMed]
567. Wiegand C, Pflugmacher S, Giese M, Frank H, Steinberg C. Uptake, toxicity, and effects on detoxication enzymes of atrazine and trifluoroacetate in embryos of zebrafish. Ecotoxicol Environ Saf. 2000;45:122–131. [PubMed]
568. Wiegand C, Pflugmacher S, Oberemm A, Meems N, Beattie KA, Steinberg CEW, Codd GA. Uptake and effects of microcystin-LR on detoxication enzymes of early life stages of the zebra fish (Danio rerio) Environ Toxicol. 1999;14:89–95.
569. Willett CE, Cherry JJ, Steiner LA. Characterization and expression of the recombination activating genes (rag1 and rag2) of zebrafish. Immunogenetics. 1997;45:394–404. [PubMed]
570. Willett CE, Cortes A, Zuasti A, Zapata AG. Early hematopoiesis and developing lymphoid organs in the zebrafish. Dev Dyn. 1999;214:323–336. [PubMed]
571. Willett CE, Kawasaki H, Amemiya CT, Lin S, Steiner LA. Ikaros expression as a marker for lymphoid progenitors during zebrafish development. Dev Dyn. 2001;222:694–698. [PubMed]
572. Willett CE, Zapata AG, Hopkins N, Steiner LA. Expression of zebrafish rag genes during early development identifies the thymus. Dev Biol. 1997;182:331–341. [PubMed]
573. Willey JB, Krone PH. Effects of endosulfan and nonylphenol on the primordial germ cell population in pre-larval zebrafish embryos. Aquat Toxicol. 2001;54:113–123. [PubMed]
574. Wixon J. Featured organism: Danio rerio, the zebrafish. Yeast. 2000;17:225–231. [PMC free article] [PubMed]
575. Wood PA. Phenotype assessment: Are you missing something? Comp Med. 2000;50:12–15. [PubMed]
576. Woodhead AD. Nonmammalian Models in Biomedical Research. CRC Press; Boca Raton, Florida: 1989.
577. Wu T, Patel H, Mukai S, Melino C, Garg R, Ni X, Chang J, Peng C. Activin, inhibin, and follistatin in zebrafish ovary: Expression and role in oocyte maturation. Biol Reprod. 2000;62:1585–1592. [PubMed]
578. Wullimann MF, Knipp S. Proliferation pattern changes in the zebrafish brain from embryonic through early postembryonic stages. Anat Embryol (Berl) 2000;202:385–400. [PubMed]
579. Wullimann MF, Rink E. Detailed immunohistology of Pax6 protein and tyrosine hydroxylase in the early zebrafish brain suggests role of Pax6 gene in development of dopaminergic diencephalic neurons. Brain Res Dev Brain Res. 2001;131:173–191. [PubMed]
580. Xu X, Meiler SE, Zhong TP, Mohideen M, Crossley DA, Burggren WW, Fishman MC. Cardiomyopathy in zebrafish due to mutation in an alternatively spliced exon of titin. Nat Genet. 2002;30:205–209. [PubMed]
581. Yamamoto M, Nakajima O. Animal models for X-linked sideroblastic anemia. Int J Hematol. 2000;72:157–164. [PubMed]
582. Yelon D. Cardiac patterning and morphogenesis in zebrafish. Dev Dyn. 2001;222:552–563. [PubMed]
583. Yelon D, Horne SA, Stainier DY. Restricted expression of cardiac myosin genes reveals regulated aspects of heart tube assembly in zebrafish. Dev Biol. 1999;214:23–37. [PubMed]
584. Yoder JA, Mueller MG, Wei S, Corliss BC, Prather DM, Willis T, Litman RT, Djeu JY, Litman GW. Immune-type receptor genes in zebrafish share genetic and functional properties with genes encoded by the mammalian leukocyte receptor cluster. Proc Natl Acad Sci USA. 2001;98:6771–6776. [PubMed]
585. Yosha SF, Cohen GM. Effect of intermittent chlorination of developing zebrafish embryos (Brachydanio rerio) Bull Environ Contam Toxicol. 1979;21:703–710. [PubMed]
586. Zelikoff JT, Raymond A, Carlson E, Li Y, Beaman JR, Anderson M. Biomarkers of immunotoxicity in fish: From the lab to the ocean. Toxicol Lett. 2000;112:113. 325–331. [PubMed]
587. Zhang J, Halpern M. Cre-loxP Recombination Activity in the Zebrafish Embryo; Presented at Fifth International Meeting on Zebrafish Development and Genetics; Madison, Wisconsin. 2002.
588. Zhang Z, Balmer JE, Lovlie A, Fromm SH, Blomhoff R. Specific teratogenic effects of different retinoic acid isomers and analogs in the developing anterior central nervous system of zebrafish. Dev Dyn. 1996;206:73–86. [PubMed]
589. Zhdanova IV, Wang SY, Leclair OU, Danilova NP. Melatonin promotes sleep-like state in zebrafish. Brain Res. 2001;903:263–268. [PubMed]
590. Zimprich F, Ashworth R, Bolsover S. Real-time measurements of calcium dynamics in neurons developing in situ within zebrafish embryos. Pflugers Arch. 1998;436:489–493. [PubMed]
591. Zok S, Gorge G, Kalsch W, Nagel R. Bioconcentration, metabolism and toxicity of substituted anilines in the zebrafish (Brachydanio rerio) Sci Total Environ. 1991;109:110. 411–421. [PubMed]
592. Zon LI. Zebrafish: A new model for human disease. Genome Res. 1999;9:99–100. [PubMed]