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1.  TERBUTALINE IMPAIRS THE DEVELOPMENT OF PERIPHERAL NORADRENERGIC PROJECTIONS: IMPLICATIONS FOR AUTISM SPECTRUM DISORDERS AND PHARMACOTHERAPY OF PRETERM LABOR 
Terbutaline, a β2-adrenoceptor agonist, is used off-label for long-term management of preterm labor; such use is associated with increased risk of neurodevelopmental disorders, including autism spectrum disorders. We explored the mechanisms underlying terbutaline’s effects on development of peripheral sympathetic projections in developing rats. Terbutaline administration on postnatal days 2–5 led to immediate and persistent deficiencies in cardiac norepinephrine levels, with greater effects in males than in females. The liver showed a lesser effect; we reasoned that the tissue differences could represent participation of retrograde trophic signaling from the postsynaptic site to the developing neuronal projection, since hepatic β2-adrenoceptors decline in the perinatal period. Accordingly, when we gave terbutaline earlier, on gestational days 17–20, we saw the same deficiencies in hepatic norepinephrine that had been seen in the heart with the later administration paradigm. Administration of isoproterenol, which stimulates both β1- and β2-subtypes, also had trophic effects that differed in direction and critical period from those elicited by terbutaline; methoxamine, which stimulates α1-adrenoceptors, was without effect. Thus, terbutaline, operating through trophic interactions with β2-adrenoceptors, impairs development of noradrenergic projections in a manner similar to that previously reported for its effects on the same neurotransmitter systems in the immature cerebellum. Our results point to the likelihood of autonomic dysfunction in individuals exposed prenatally to terbutaline; in light of the connection between terbutaline and autism, these results could also contribute to autonomic dysregulation seen in children with this disorder.
doi:10.1016/j.ntt.2012.07.003
PMCID: PMC3492522  PMID: 22813780
Autism; β-Adrenergic agonists; Norepinephrine; Preterm delivery; Sympathetic nervous system; Terbutaline
2.  Disruption of social approach by MK-801, amphetamine, and fluoxetine in adolescent C57BL/6J mice 
Autism is a severe neurodevelopmental disorder, diagnosed on the basis of core behavioral symptoms. Although the mechanistic basis for the disorder is not yet known, genetic analyses have suggested a role for abnormal excitatory/inhibitory signaling systems in brain, including dysregulation of glutamatergic neurotransmission. In mice, the constitutive knockdown of NMDA receptors leads to social deficits, repetitive behavior, and self-injurious responses that reflect aspects of the autism clinical profile. However, social phenotypes differ with age: mice with reduced NMDA-receptor function exhibit hypersociability in adolescence, but markedly deficient sociability in adulthood. The present studies determined whether acute disruption of NMDA neurotransmission leads to exaggerated social approach, similar to that observed with constitutive disruption, in adolescent C57BL/6J mice. The effects of MK-801, an NMDA receptor antagonist, were compared with amphetamine, a dopamine agonist, and fluoxetine, a selective serotonin reuptake inhibitor, on performance in a three-chamber choice task. Results showed that acute treatment with MK-801 led to social approach deficits at doses without effects on entry numbers. Amphetamine also decreased social preference, but increased number of entries at every dose. Fluoxetine (10 mg/kg) had selective effects on social novelty preference. Withdrawal from a chronic ethanol regimen decreased activity, but did not attenuate sociability. Low doses of MK-801 and amphetamine were also evaluated in a marble-burying assay for repetitive behavior. MK-801, at a dose that did not disrupt sociability or alter entries, led to a profound reduction in marble-burying. Overall, these findings demonstrate that moderate alteration of NMDA, dopamine, or serotonin function can attenuate social preference in wild type mice.
doi:10.1016/j.ntt.2012.07.007
PMCID: PMC3509253  PMID: 22898204
amphetamine; autism; ethanol withdrawal; repetitive behavior; social approach; stereotypy
3.  Using mouse models of autism spectrum disorders to study the neurotoxicology of gene-environment interactions 
To better study the role of genetics in autism, mouse models have been developed which mimic the genetics of specific autism spectrum and related disorders. These models have facilitated research on the role genetic susceptibility factors in the pathogenesis of autism in the absence of environmental factors. Inbred mouse strains have been similarly studied to assess the role of environmental agents on neurodevelopment, typically without the complications of genetic heterogeneity of the human population. What has not been as actively pursued, however, is the methodical study of the interaction between these factors (e.g., gene and environmental interactions in neurodevelopment). This review suggests that a genetic predisposition paired with exposure to environmental toxicants play an important role in the etiology of neurodevelopmental disorders including autism, and may contribute to the largely unexplained rise in the number of children diagnosed with autism worldwide. Specifically, descriptions of the major mouse models of autism and toxic mechanisms of prevalent environmental chemicals are provided followed by a discussion of current and future research strategies to evaluate the role of gene and environment interactions in neurodevelopmental disorders.
doi:10.1016/j.ntt.2012.08.007
PMCID: PMC3538113  PMID: 23010509
Autism; Mouse Model; Genetics; Environmental Pollutants
4.  Cytokine dysregulation in autism spectrum disorders (ASD): Possible role of the environment 
Autism spectrum disorders (ASD) are neurodevelopmental diseases that affect an alarming number of individuals. The etiological basis of ASD is unclear, and evidence suggests it involves both genetic and environmental factors. There are many reports of cytokine imbalances in ASD. These imbalances could have a pathogenic role, or they may be markers of underlying genetic and environmental influences. Cytokines act primarily as mediators of immunological activity, but they also have significant interactions with the nervous system. They participate in normal neural development and function, and inappropriate activity can have a variety of neurological implications. It is therefore possible that cytokine dysregulation contributes directly to neural dysfunction in ASD. Further, cytokine profiles change dramatically in the face of infection, disease, and toxic exposures. Therefore, imbalances may represent an immune response to environmental contributors to ASD. The following review is presented in two main parts. First, we discuss select cytokines implicated in ASD, including IL-1Β, IL-6, IL-4, IFN-γ, and TGF-Β, and focus on their role in the nervous system. Second, we explore several neurotoxic environmental factors that may be involved in the disorders, and focus on their immunological impacts. This review represents an emerging model that recognizes the importance of both genetic and environmental factors in ASD etiology. We propose that the immune system provides critical clues regarding the nature of the gene by environment interactions that underlie ASD pathophysiology.
doi:10.1016/j.ntt.2012.07.006
PMCID: PMC3554862  PMID: 22918031
Autism spectrum disorder; cytokine; toxicant; immunology; environment; neurodevelopment
5.  Neuronal connectivity as a convergent target of gene-environment interactions that confer risk for Autism Spectrum Disorders 
Evidence implicates environmental factors in the pathogenesis of Autism Spectrum Disorders (ASD). However, the identity of specific environmental chemicals that influence ASD risk, severity or treatment outcome remains elusive. The impact of any given environmental exposure likely varies across a population according to individual genetic substrates, and this increases the difficulty of identifying clear associations between exposure and ASD diagnoses. Heritable genetic vulnerabilities may amplify adverse effects triggered by environmental exposures if genetic and environmental factors converge to dysregulate the same signaling systems at critical times of development. Thus, one strategy for identifying environmental risk factors for ASD is to screen for environmental factors that modulate the same signaling pathways as ASD susceptibility genes. Recent advances in defining the molecular and cellular pathology of ASD point to altered patterns of neuronal connectivity in the developing brain as the neurobiological basis of these disorders. Studies of syndromic ASD and rare highly penetrant mutations or CNVs in ASD suggest that ASD risk genes converge on several major signaling pathways linked to altered neuronal connectivity in the developing brain. This review briefly summarizes the evidence implicating dysfunctional signaling via Ca2+-dependent mechanisms, extracellular signal-regulated kinases (ERK)/phosphatidylinositol-3-kinases (PI3K) and neuroligin-neurexin-SHANK as convergent molecular mechanisms in ASD, and then discusses examples of environmental chemicals for which there is emerging evidence of their potential to interfere with normal neuronal connectivity via perturbation of these signaling pathways.
doi:10.1016/j.ntt.2012.12.001
PMCID: PMC3610799  PMID: 23269408
autism spectrum disorders; gene-environment interactions; neuronal connectivity; organophosphorus pesticides (OPs); polyaromatic hydrocarbons (PAHs); polychlorinated biphenyls (PCBs)
6.  Does the home environment and the sex of the child modify the adverse effects of prenatal exposure to chlorpyrifos on child working memory? 
Neurotoxicology and teratology  2012;34(5):534-541.
Prenatal exposure to chlorpyrifos (CPF), an organophosphorus insecticide, has long been associated with delayed neurocognitive development and most recently with decrements in working memory at age 7. In the current paper, we expanded the previous work on CPF to investigate how additional biological and social environmental factors might create or explain differential neurodevelopmental susceptibility, focusing on main and moderating effects of the quality of the home environment (HOME) and child sex. We evaluate how the quality of the home environment (specifically, parental nurturance and environmental stimulation) and child sex interact with the adverse effects of prenatal CPF exposure on working memory at child age 7 years. We did not observe a remediating effect of a high quality home environment (either parental nurturance or environmental stimulation) on the adverse effects of prenatal CPF exposure on working memory. However, we detected a borderline significant interaction between prenatal exposure to CPF and child sex (B (95% CI) for interaction term = −1.714 (−3.753 to 0.326)) suggesting males experience a greater decrement in working memory than females following prenatal CPF exposure. In addition, we detected a borderline interaction between parental nurturance and child sex (B (95% CI) for interaction term = 1.490 (−0.518 to 3.499)) suggesting that, in terms of working memory, males benefit more from a nurturing environment than females. To our knowledge, this is the first investigation into factors that may inform an intervention strategy to reduce or reverse the cognitive deficits resulting from prenatal CPF exposure.
doi:10.1016/j.ntt.2012.07.004
PMCID: PMC3901426  PMID: 22824009
chlorpyrifos; neurodevelopment; working memory; HOME inventory; sex-specific
7.  Neurobehavioral phenotype of C57BL/6J mice prenatally and neonatally exposed to cigarette smoke 
Although maternal cigarette smoking during pregnancy is a well-documented risk factor for a variety of adverse pregnancy outcomes, how prenatal cigarette smoke exposure affects postnatal neurobehavioral/cognitive development remains poorly defined. In order to investigate the cause of an altered behavioral phenotype, mice developmentally exposed to a paradigm of ‘active’ maternal cigarette smoke is needed. Accordingly, cigarette smoke exposed (CSE) and air-exposed C57BL/6J mice were treated for 6 h per day in paired inhalation chambers throughout gestation and lactation and were tested for neurobehavioral effects while controlling for litter effects. CSE mice exhibited less than normal anxiety in the elevated zero maze, transient hypoactivity during a 1 h locomotor activity test, had longer latencies on the last day of cued Morris water maze testing, impaired hidden platform learning in the Morris water maze during acquisition, reversal, and shift trials, and impaired retention for platform location on probe trials after reversal but not after acquisition or shift. CSE mice also showed a sexually dimorphic response in central zone locomotion to a methamphetamine challenge (males under-responded and females over-responded), and showed reduced anxiety in the light-dark test by spending more time on the light side. No differences on tests of marble burying, acoustic startle response with prepulse inhibition, Cincinnati water maze, matching-to-sample Morris water maze, conditioned fear, forced swim, or MK-801-induced locomotor activation were found. Collectively, the data indicate that developmental cigarette smoke exposure induces subnormal anxiety in a novel environment, impairs spatial learning and reference memory while sparing other behaviors (route-based learning, fear conditioning, and forced swim immobility). The findings add support to mounting evidence that developmental cigarette smoke exposure has long-term adverse effects on brain function.
doi:10.1016/j.ntt.2013.01.001
PMCID: PMC3593942  PMID: 23314114
behavior; cigarette smoke; tobacco; inhalation exposure; pregnancy; prenatal
8.  Different Patterns of Regional Purkinje Cell Loss in the Cerebellar Vermis as a Function of the Timing of Prenatal Ethanol Exposure in an Ovine Model 
Studies in rat models of fetal alcohol spectrum disorders have indicated that the cerebellum is particularly vulnerable to ethanol-induced Purkinje cell loss during the third trimester-equivalent, with striking regional differences in vulnerability in which early-maturing regions in the vermis show significantly more loss than the late-maturing regions. The current study tested the hypothesis that the sheep model will show similar regional differences in fetal cerebellar Purkinje cell loss when prenatal binge ethanol exposure is restricted to the prenatal period of brain development equivalent to the third trimester and also compared the pattern of loss to that produced by exposure during the first trimester-equivalent. Pregnant Suffolk sheep were assigned to four groups: first trimester-equivalent saline control group, first trimester-equivalent ethanol group (1.75 g/kg/day), third trimester-equivalent saline control group, and third trimester-equivalent ethanol group (1.75 g/kg/day). Ethanol was administered as an intravenous infusion on 3 consecutive days followed by a 4-day ethanol-free interval, to mimic a weekend binge drinking pattern. Animals from all four groups were sacrificed and fetal brains were harvested on gestation day 133. Fetal cerebellar Purkinje cell counts were performed in an early-maturing region (lobules I-X) and a late-maturing region (lobules VIc-VII) from mid-sagittal sections of the cerebellar vermis. As predicted, the third trimester-equivalent ethanol exposure caused a significant reduction in the fetal cerebellar Purkinje cell volume density and Purkinje cell number in the early-maturing region, but not in the late-maturing region. In contrast, the first trimester-equivalent ethanol exposure resulted in significant reductions in both the early and late-maturing regions. These data confirmed the previous findings in rat models that third trimester-equivalent prenatal ethanol exposure resulted in regionally-specific Purkinje cell loss in the early-maturing region of the vermis, and further demonstrated that first trimester ethanol exposure caused more generalized fetal cerebellar Purkinje cell loss, independent of the cerebellar vermal region. These findings support the idea that prenatal ethanol exposure in the first trimester interferes with the genesis of Purkinje cells in an unselective manner, whereas exposure during the third trimester selectively kills post-mitotic Purkinje cells in specific vermal regions during a vulnerable period of differentiation and synaptogenesis.
doi:10.1016/j.ntt.2012.11.001
PMCID: PMC3594353  PMID: 23195754
Cerebellum; ovine; ethanol; teratogenicity; Purkinje cells
9.  Children with Heavy Prenatal Alcohol Exposure have Different Frequency Domain Signal Characteristics when Producing Isometric Force 
To extend our current understanding of the teratogenic effects of prenatal alcohol exposure on the control of isometric force, the present study investigated the signal characteristics of power spectral density functions resulting from sustained control of isometric force by children with and without heavy prenatal exposure to alcohol. It was predicted that the functions associated with the force signals would be fundamentally different for the two groups. Twenty-five children aged between 7 and 17 years with heavy prenatal alcohol exposure and 21 non-alcohol exposed control children attempted to duplicate a visually represented target force by pressing on a load cell. The level of target force (5 and 20% of maximum voluntary contraction) and the time interval between visual feedback (20ms, 320ms and 740ms) were manipulated. A multivariate spectral estimation method with sinusoidal windows was applied to individual isometric force-time signals. Analysis of the resulting power spectral density functions revealed that the alcohol-exposed children had a lower mean frequency, less spectral variability, greater peak power and a lower frequency at which peak power occurred. Furthermore, mean frequency and spectral variability produced by the alcohol-exposed group remained constant across target load and visual feedback interval, suggesting that these children were limited to making long-time scale corrections to the force signal. In contrast, the control group produced decreased mean frequency and spectral variability as target force and the interval between visual feedback increased, indicating that when feedback was frequently presented these children used the information to make short-time scale adjustments to the ongoing force signal. Knowledge of these differences could facilitate the design of motor rehabilitation exercises that specifically target isometric force control deficits in alcohol-exposed children.
doi:10.1016/j.ntt.2012.11.003
PMCID: PMC3603370  PMID: 23238099
Fetal alcohol syndrome; power spectrum density
10.  Maternal Transfer of BDE-47 to Offspring and Neurobehavioral Development in C57BL/6J Mice 
Neurotoxicology and teratology  2012;34(6):571-580.
Polybrominated diphenyl ethers (PBDEs) are flame retardants used worldwide in a variety of commercial goods, and are now widely found in both environmental and biological samples. BDE-47 is one of the most pervasive of these PBDE congeners and therefore is of particular concern. In this study C57BL/6J mice were exposed perinatally to 0.03, 0.1 or 1 mg/kg/day of BDE-47, a dose range chosen to encompass human exposure levels. Tissue levels of BDE-47 were measured in the blood, brain, fat and milk of dams and in whole fetal homogenate and blood and brain of pups on gestational day (GD) 15, and postnatal days (PND) 1, 10 and 21. From GD 15 to PND 1 levels of BDE-47 increased within dam tissue and then decreased from PND 1 to 21. Over the period of lactation levels in dam milk were comparatively high when compared to both brain and blood for all dose groups. Measurable levels of BDE-47 were found in the fetus on GD 15 confirming gestational exposure. From PND 1 to 21, levels of BDE-47 in pup tissue increased over the period of lactation due to the transfer of BDE-47 through milk. Behavioral tests of fine motor function and learning and memory were carried out between postnatal weeks 5–17 in order to evaluate the neurobehavioral toxicity of BDE-47. Behavioral deficits were only seen in the Barnes spatial maze where mice in the three exposure groups had longer latencies and traveled longer distances to find the escape hole when compared to vehicle control mice. These results support the conclusions that perinatal exposure to BDE-47 can have neurodevelopmental consequences, and that lactational exposure represents a significant exposure risk during development.
doi:10.1016/j.ntt.2012.09.005
PMCID: PMC3501584  PMID: 23022914
Flame retardant; BDE-47; Polybrominated Diphenyl Ether; Neurotoxicity; Neurodevelopment; Behavior; Bioaccumulation; GC/MS
11.  MODIFICATION OF NEUROBEHAVIORAL EFFCTS OF MERCURY BY A GENETIC POLYMORPHISM OF COPROPORPHYRINOGEN OXIDASE IN CHILDREN 
Neurotoxicology and teratology  2012;34(5):513-521.
Mercury (Hg) is neurotoxic, and children may be particularly susceptible to this effect. A current major challenge is the identification of children who may be uniquely susceptible to Hg toxicity because of genetic disposition. We examined the hypothesis that CPOX4, a genetic variant of the heme pathway enzyme coproporphyrinogen oxidase (CPOX) that affects susceptibility to mercury toxicity in adults, also modifies the neurotoxic effects of Hg in children. Five hundred seven children, 8–12 years of age at baseline, participated in a clinical trial to evaluate the neurobehavioral effects of Hg from dental amalgam tooth fillings in children. Subjects were evaluated at baseline and at 7 subsequent annual intervals for neurobehavioral performance and urinary mercury levels. Following the completion of the clinical trial, genotyping assays for CPOX4 allelic status were performed on biological samples provided by 330 of the trial participants. Regression modeling strategies were employed to evaluate associations between CPOX4 status, Hg exposure, and neurobehavioral test outcomes. Among girls, few significant CPOX4-Hg interactions or independent main effects for Hg or CPOX4 were observed. In contrast, among boys, numerous significant interaction effects between CPOX4 and Hg were observed spanning all 5 domains of neurobehavioral performance. All underlying dose-response associations between Hg exposure and test performance were restricted to boys with the CPOX4 variant, and all of these associations were in the expected direction where increased exposure to Hg decreased performance. These findings are the first to demonstrate genetic susceptibility to the adverse neurobehavioral effects of Hg exposure in children. The paucity of responses among same-age girls with comparable Hg exposure provides evidence of sexual dimorphism in genetic susceptibility to the adverse neurobehavioral effects of Hg in children and adolescents.
doi:10.1016/j.ntt.2012.06.004
PMCID: PMC3462250  PMID: 22765978
mercury; behavior; neurotoxicity; genetic polymorphism; CPOX4; children
12.  CHLORPYRIFOS DEVELOPMENTAL NEUROTOXICITY: INTERACTION WITH GLUCOCORTICOIDS IN PC12 CELLS 
Neurotoxicology and teratology  2012;34(5):505-512.
Prenatal coexposures to glucocorticoids and organophosphate pesticides are widespread. Glucocorticoids are elevated by maternal stress and are commonly given in preterm labor; organophosphate exposures are virtually ubiquitous. We used PC12 cells undergoing neurodifferentiation in order to assess whether dexamethasone enhances the developmental neurotoxicity of chlorpyrifos, focusing on concentrations relevant to human exposures. By themselves, each agent reduced the number of cells and the combined exposure elicited a correspondingly greater effect than with either agent alone. There was no general cytotoxicity, as cell growth was actually enhanced, and again, the combined treatment evoked greater cellular hypertrophy than with the individual compounds. The effects on neurodifferentiation were more complex. Chlorpyrifos alone had a promotional effect on neuri to genesis whereas dexamethasone impaired it; combined treatment showed an overall impairment greater than that seen with dexamethasone alone. The effect of chlorpyrifos on differentiation into specific neurotransmitter phenotypes was shifted by dexamethasone. Either agent alone promoted differentiation into the dopaminergic phenotype at the expense of the cholinergic phenotype. However, in dexamethasone-primed cells, chlorpyrifos actually enhanced cholinergic neurodifferentiation instead of suppressing this phenotype. Our results indicate that developmental exposure to glucocorticoids, either in the context of stress or the therapy of preterm labor, could enhance the developmental neurotoxicity of organophosphates and potentially of other neurotoxicants, as well as producing neurobehavioral outcomes distinct from those seen with either individual agent.
doi:10.1016/j.ntt.2012.07.002
PMCID: PMC3462281  PMID: 22796634
Chlorpyrifos; Dexamethasone; Glucocorticoids; Organophosphate pesticides; PC12 cells; Preterm delivery
13.  DOES MECHANISM MATTER? UNRELATED NEUROTOXICANTS CONVERGE ON CELL CYCLE AND APOPTOSIS DURING NEURODIFFERENTIATION 
Neurotoxicology and Teratology  2012;34(4):395-402.
Mechanistically unrelated developmental neurotoxicants often produce neural cell loss culminating in similar functional and behavioral outcomes. We compared an organophosphate pesticide (diazinon), an organochlorine pesticide (dieldrin) and a metal (Ni2+) for effects on the genes regulating cell cycle and apoptosis in differentiating PC12 cells, an in vitro model of neuronal development. Each agent was introduced at 30 μM for 24 or 72 hr, treatments devoid of cytotoxicity. Using microarrays, we examined the mRNAs encoding nearly 400 genes involved in each of the biological processes. All three agents targeted both the cell cycle and apoptosis pathways, evidenced by significant transcriptional changes in 40–45% of the cell cycle-related genes and 30–40% of the apoptosis-related genes. There was also a high degree of overlap as to which specific genes were affected by the diverse agents, with 80 cell cycle genes and 56 apoptosis genes common to all three. Concordance analysis, which assesses stringent matching of the direction, magnitude and timing of the transcriptional changes, showed highly significant correlations for pairwise comparisons of all the agents, for both cell cycle and apoptosis. Our results show that otherwise disparate developmental neurotoxicants converge on common cellular pathways governing the acquisition and programmed death of neural cells, providing a specific link to cell deficits. Our studies suggest that identifying the initial mechanism of action of a developmental neurotoxicant may be strategically less important than focusing on the pathways that converge on common final outcomes such as cell loss.
doi:10.1016/j.ntt.2012.04.008
PMCID: PMC3404226  PMID: 22546817
Apoptosis; Cell cycle; Diazinon; Dieldrin; Nickel; PC12 cells
14.  Effect of chronic glutathione deficiency on the behavioral phenotype of Gclm(−/−) knockout mice 
Neurotoxicology and Teratology  2012;34(4):450-457.
Enhanced oxidative stress or deficient oxidative stress response in the brain is associated with neurodegenerative disorders and behavioral abnormalities. Previously we generated a knockout mouse line lacking the gene encoding γ-glutamylcysteine ligase modifier subunit (GCLM). Gclm(−/−) knockout (KO) mice are viable and fertile, yet exhibit only 9–35% of wild-type levels of reduced glutathione (GSH) in tissues, making them a useful model for chronic GSH depletion. Having the global absence of this gene, KO mice—from the time of conception and throughout postnatal life—experience chronic oxidative stress in all tissues, including brain. Between postnatal day (P) 60 and P100, we carried out behavioral phenotyping tests in adults, comparing male and female Gclm(−/−) with Gclm(+/+) wild-type (WT) littermates. Compared with WT, KO mice exhibited: subnormal anxiety in the elevated zero maze; normal overall exploratory open-field activity, but slightly more activity in the peripheral zones; normal acoustic startle and prepulse inhibition reactions; normal novel object recognition with increased time attending to the stimulus objects; slightly reduced latencies to reach a random marked platform in the Morris water maze; normal spatial learning and memory in multiple phases of the Morris water maze; and significantly greater hyperactivity in response to methamphetamine in the open field. These findings are in general agreement with two prior studies on these mice and suggest that the brain is remarkably resilient to lowered GSH levels, implying significant reserve capacity to regulate reactivity oxygen species—but with regional differences such that anxiety and stimulated locomotor control brain regions might be more vulnerable.
doi:10.1016/j.ntt.2012.04.009
PMCID: PMC3404268  PMID: 22580179
acoustic startle response; elevated zero maze; GSH; reduced glutathione; locomotor activity; Morris water maze; novel object recognition
15.  Memory ability and hippocampal volume in adolescents with prenatal drug exposure 
Neurotoxicology and Teratology  2012;34(4):434-441.
The objective of the present study was to examine the influence of prenatal drug exposure (PDE) on memory performance and supporting brain structures (i.e., hippocampus) during adolescence. To achieve this goal, declarative memory ability and hippocampal volume were examined in a well-characterized sample of 138 adolescents (76 with a history of PDE and 62 from a non-exposed comparison group recruited from the same community, mean age = 14 years). Analyses adjusted for: age at time of the assessments, gender, IQ, prenatal exposure to alcohol and tobacco, and indices of early childhood environment (i.e., caregiver depression, potential for child abuse, and number of caregiver changes through 7 years of age). Results revealed adolescents with a history of PDE performed worse on the California Verbal Learning Test – Child Version (CVLT-C), worse on story recall from the Children’s Memory Scale (CMS), and had larger hippocampal volumes, even after covariate adjustment. Hippocampal volume was negatively correlated with memory performance on the CVLT-C, with lower memory scores associated with larger volumes. These findings provide support for long-term effects of PDE on memory function and point to neural mechanisms that may underlie these outcomes.
doi:10.1016/j.ntt.2012.05.054
PMCID: PMC3405159  PMID: 22652523
Prenatal drug exposure; Memory; Hippocampus; Development; Adolescent brain
16.  Neurobehavioral deficits at age 7 years associated with prenatal exposure to toxicants from maternal seafood diet 
Neurotoxicology and teratology  2012;34(4):466-472.
To determine the possible neurotoxic impact of prenatal exposure to polychlorinated biphenyls (PCBs), we analyzed banked cord blood from a Faroese birth cohort for PCBs. The subjects were born in 1986–1987, and 917 cohort members had completed a series of neuropsychological tests at age 7 years. Major PCB congeners (118, 138, 153, and 180), the calculated total PCB concentration, and the PCB exposure estimated in a structural equation model showed weak associations with test deficits, with statistically significant negative associations only with the Boston Naming test. Likewise, neither hexachlorobenzene nor p,p'-dichlorodiphenyldichloroethylene showed clear links to neurobehavioral deficits. Thus, these associations were much weaker than those associated with the cord-blood mercury concentration, and adjustment for mercury substantially attenuated the regression coefficients for PCB exposure. When the outcomes were joined into motor and verbally mediated functions in a structural equation model, the PCB effects remained weak and virtually disappeared after adjustment for methylmercury exposure, while mercury remained statistically significant. Thus, in the presence of elevated methylmercury exposure, PCB neurotoxicity may be difficult to detect, and PCB exposure does not explain the methylmercury neurotoxicity previously reported in this cohort.
doi:10.1016/j.ntt.2012.06.001
PMCID: PMC3407364  PMID: 22705177
Methylmercury compounds; Neuropsychological tests; Polychlorinated biphenyls; Prenatal exposure delayed effects; Preschool child
17.  Developmental sub-chronic exposure to chlorpyrifos reduces anxiety-related behavior in zebrafish larvae 
Neurotoxicology and teratology  2012;34(4):458-465.
Neurobehavioral disorders such as anxiety, autism, and attention deficit hyperactivity disorders are typically influenced by genetic and environmental factors. Although several genetic risk factors have been identified in recent years, little is known about the environmental factors that either cause neurobehavioral disorders or contribute to their progression in genetically predisposed individuals. One environmental factor that has raised concerns is chlorpyrifos, an organophosphate pesticide that is widely used in agriculture and is found ubiquitously in the environment. In the present study, we examined the effects of sub-chronic chlorpyrifos exposure on anxiety-related behavior during development using zebrafish larvae. We found that sub-chronic exposure to 0.01 or 0.1 μM chlorpyrifos during development induces specific behavioral defects in 7-day-old zebrafish larvae. The larvae displayed decreases in swim speed and thigmotaxis, yet no changes in avoidance behavior were seen. Exposure to 0.001 μM chlorpyrifos did not affect swimming, thigmotaxis, or avoidance behavior and exposure to 1 μM chlorpyrifos induced behavioral defects, but also induced defects in larval morphology. Since thigmotaxis, a preference for the edge, is an anxiety-related behavior in zebrafish larvae, we propose that sub-chronic chlorpyrifos exposure interferes with the development of anxiety-related behaviors. The results of this study provide a good starting point for examination of the molecular, cellular, developmental, and neural mechanisms that are affected by environmentally relevant concentrations of organophosphate pesticides. A more detailed understanding of these mechanisms is important for the development of predictive models and refined health policies to prevent toxicant-induced neurobehavioral disorders.
doi:10.1016/j.ntt.2012.04.010
PMCID: PMC3573706  PMID: 22579535
Organophosphates; Zebrafish; High-throughput assay; Anxiety behavior; Development
18.  Methylmercury tolerance is associated with the humoral stress factor gene Turandot A 
Neurotoxicology and teratology  2012;34(4):387-394.
Methylmercury (MeHg) is an environmental neurotoxicant that targets the developing nervous system. In an effort to understand mechanisms of MeHg toxicity we have identified candidate genes that confer tolerance to MeHg using a Drosophila model. Whole genome transcript profiling of developing larval brains of MeHg-tolerant and non-tolerant flies has identified Turandot A (TotA) as a potential MeHg tolerance gene. TotA is a secreted humoral stress response factor in Drosophila that is a direct target of conserved innate immunity signaling pathways. Here we characterize TotA expression in newly generated isogenic lines (isolines) of flies derived from our previously established MeHg-tolerant and non-tolerant populations. TotA mRNA transcript and protein expression is seen to be higher in the tolerant isolines than the non-tolerant lines. Elevated TotA expression in the tolerant lines was seen to span all the larval developmental stages pointing toward a difference in the TotA gene regulation between the MeHg tolerant and non-tolerant strains. We show that TotA is most highly expressed in the fat body (liver equivalent) and is selectively upregulated in the fat body of tolerant flies relative to brain and gut tissues. Fat body-specific transgenic expression of TotA invokes MeHg tolerance as seen by enhanced development of flies reared on MeHg food. In addition, cell based assays show that high TotA expressing C6 cells are more tolerant to MeHg than the low TotA expressing S2 cells. Knockdown of TotA in the C6 cells trends toward a reduction in MeHg tolerance. Identification of TotA as a MeHg tolerance gene suggests a role for conserved cytokine/immune signaling pathways in modulating MeHg toxicity.
doi:10.1016/j.ntt.2012.04.007
PMCID: PMC3619209  PMID: 22546818
Methylmercury; Turandot A; Neurotoxicity; Mercury resistance; Innate immunity; Drosophila
19.  Early adolescent cocaine use as determined by hair analysis in a prenatal cocaine exposure cohort 
Neurotoxicology and teratology  2010;33(1):88-99.
Background
Preclinical and other research suggest that youth with prenatal cocaine exposure (PCE) may be at high risk for cocaine use due to both altered brain development and exposure to unhealthy environments.
Methods
Participants are early adolescents who were prospectively enrolled in a longitudinal study of PCE prior to or at birth. Hair samples were collected from the youth at ages 10½ and 12½ (N=263). Samples were analyzed for cocaine and its metabolites using ELISA screening with gas chromatography/mass spectroscopy (GC/MS) confirmation of positive samples. Statistical analyses included comparisons between the hair-positive and hair-negative groups on risk and protective factors chosen a priori as well as hierarchical logistical regression analyses to predict membership in the hair-positive group.
Results
Hair samples were positive for cocaine use for 14% (n=36) of the tested cohort. Exactly half of the hair-positive preteens had a history of PCE. Group comparisons revealed that hair-negative youth had significantly higher IQ scores at age 10½; the hair-positive youth had greater availability of cigarettes, alcohol, and other drugs in the home; caregivers with more alcohol problems and depressive symptoms; less nurturing home environments; and less positive attachment to their primary caregivers and peers. The caregivers of the hair-positive preteens reported that the youth displayed more externalizing and social problems, and the hair-positive youth endorsed more experimentation with cigarettes, alcohol, and/or other drugs. Mental health problems, peer drug use, exposure to violence, and neighborhood characteristics did not differ between the groups. Regression analyses showed that the availability of drugs in the home had the greatest predictive value for hair-positive group membership while higher IQ, more nurturing home environments, and positive attachment to caregivers or peers exerted some protective effect.
Conclusion
The results do not support a direct relationship between PCE and early adolescent experimentation with cocaine. Proximal risk and protective factors—those associated with the home environment and preteens' caregivers—were more closely related to early cocaine use than more distal factors such as neighborhood characteristics. Consistent with theories of adolescent problem behavior, the data demonstrate the complexity of predicting pre-adolescent drug use and identify a number of individual and contextual factors that could serve as important foci for intervention.
doi:10.1016/j.ntt.2010.07.003
PMCID: PMC3675882  PMID: 20647046
Prenatal cocaine exposure; Early adolescents; Hair; Drug testing; Substance abuse
21.  LOW-LEVEL LEAD EXPOSURE TRIGGERS NEURONAL APOPTOSIS IN THE DEVELOPING MOUSE BRAIN 
Neurotoxicology and teratology  2011;33(4):473-480.
While the toxic effects of lead have been recognized for millennia, it has remained a significant public health concern due to its continued use and toxicological potential. Of particular interest is the increased susceptibility of young children to the toxic effects of lead. Although the exact mechanism(s) for lead toxicity is currently not well understood, research has established that it can be a potent NMDA antagonist. Previous research has established that exposure to NMDA antagonists during the brain growth spurt period (first 2 weeks of life in mice) can produce apoptotic neurodegeneration throughout the brain. Based on this information, the ability of lead exposure (2 injections of 350 mg/kg lead 4 h apart) to produce apoptosis in the neonatal mouse brain was assessed histologically 8–24 h after treatment using activated caspase-3 immunohistochemistry, De Olmos silver technique, Nissl staining, and electron microscopy. Lead exposure produced significant neurodegeneration in the caudate/putamen, hippocampus, subiculum, and superficial and deep cortical layers of the frontal cortical regions. Further ultrastructural examination revealed cellular profiles consistent with apoptotic cell death. Statistical results showed that lead exposure significantly increased apoptotic neurodegeneration above that seen in normal controls in animals treated at postnatal day 7, but not on day 14. The results of this study may provide a basis for further elucidation of mechanisms through which the immature nervous system may be particularly susceptible to lead exposure.
doi:10.1016/j.ntt.2011.05.006
PMCID: PMC3661300  PMID: 21640820
lead; NMDA antagonist; apoptosis; neurodevelopment; neurotoxicity
22.  Neurobehavioral Outcomes of Infants Exposed to MDMA (Ecstasy) and Other Recreational Drugs During Pregnancy 
Neurotoxicology and Teratology  2012;34(3):303-310.
3,4-methylenedioxymethamphetamine (MDMA) or “Ecstasy” is one of the most widely used illicit recreational drugs among young adults. MDMA is an indirect monoaminergic agonist and reuptake inhibitor that primarily affects the serotonin system. Preclinical studies in animals have found prenatal exposure related to neonatal tremors and long-term learning and memory impairments. To date, there are no prospective studies of the sequelae of prenatal exposure to MDMA in humans, despite concerns about its potential for harmful effects to the fetus. The present study is the first to prospectively identify MDMA-using women during pregnancy and to document patterns and correlates of use with neonatal and early infancy outcomes of offspring.
All mothers and infants were prospectively recruited through the Case Western Reserve University (CWRU) and University of East London (UEL) Drugs and Infancy Study (DAISY) that focused on recreational drug use in pregnant women. Women were interviewed about substance use prior to and during pregnancy and infants were seen at 1 and 4 months using standardized, normative assessments of neonatal behavior, and cognitive and motor development, including the NICU Network Neurobehavioral Scale (NNNS), the Bayley Mental and Motor Development Scales (MDI, PDI), and the Alberta Infant Motor Scales (AIMS). The sample was primarily middle class with some university education and in stable partner relationships. The majority of women recruited had taken a number of illicit drugs prior to or during pregnancy. Group differences between those polydrug using women who had specifically used MDMA during pregnancy (n = 28) and those who had not (n = 68) were assessed using chi-square and t-tests. MDMA and other drug effects were assessed through multiple regression analyses controlling for confounding variables.
Women who used MDMA during pregnancy had fewer prior births and more negative sequelae associated with their drug use, including more health, work, and social problems. MDMA exposed infants differed in sex ratio (more male births) and had poorer motor quality and lower milestone attainment at 4 months, with a dose-response relationship to amount of MDMA exposure. These findings suggest risk to the developing infant related to MDMA exposure and warrant continued follow-up to determine whether early motor delays persist or resolve.
doi:10.1016/j.ntt.2012.02.001
PMCID: PMC3367027  PMID: 22387807
Methylenedioxymethamphetamine “MDMA”; “Ecstasy”; infant development; drugs; sex ratio; motor skills; Townes-Brocks
23.  Adult Neuropsychological Performance Following Prenatal and Early Postnatal Exposure to Tetrachloroethylene (PCE)-contaminated Drinking Water 
Neurotoxicology and teratology  2012;34(3):350-359.
This population-based retrospective cohort study examined adult performance on a battery of neuropsychological tests in relation to prenatal and early postnatal exposure to tetrachloroethylene (PCE)-contaminated drinking water on Cape Cod, Massachusetts. Subjects were identified through birth records from 1969 through 1983. Exposure was modeled using pipe network information from town water departments, a PCE leaching and transport algorithm, EPANet water flow modeling software, and a Geographic Information System (GIS). Results of crude and multivariate analyses among 35 exposed and 28 unexposed subjects showed no association between prenatal and early postnatal exposure and decrements on tests that assess abilities in the domains of omnibus intelligence, academic achievement or language. The results were suggestive of an association between prenatal and early postnatal PCE exposure and diminished performance on tests that assessed abilities in the domains of visuospatial functioning, learning and memory, motor, attention and mood. Because the sample size was small, most findings were not statistically significant. Future studies with larger sample sizes should be conducted to further define the neuropsychological consequences of early developmental PCE exposure.
doi:10.1016/j.ntt.2012.04.001
PMCID: PMC3553661  PMID: 22522125
Tetrachloroethylene; PCE; development; neuropsychological assessment
24.  Central nervous system function and organophosphate insecticide use among pesticide applicators in the Agricultural Health Study 
Neurotoxicology and teratology  2011;34(1):168-176.
Acute organophosphate (OP) pesticide exposure is associated with adverse central nervous system (CNS) outcomes, however, little is known about the neurotoxicity of chronic exposures that do not result in acute poisoning. To examine associations between long-term pesticide use and CNS function, neurobehavioral (NB) tests were administered to licensed pesticide applicators enrolled in the Agricultural Health Study (AHS) in Iowa and North Carolina. Between 2006 and 2008, 701 male participants completed nine NB tests to assess memory, motor speed and coordination, sustained attention, verbal learning and visual scanning and processing. Data on ever-use and lifetime days of use of 16 OP pesticides were obtained from AHS interviews conducted before testing between 1993 and 2007 and during the NB visit. The mean age of participants was 61 years (SD = 12). Associations between pesticide use and NB test performance were estimated with linear regression controlling for age and outcome-specific covariates. NB test performance was associated with lifetime days of use of some pesticides. Ethoprop was significantly associated with reduced performance on a test of motor speed and visual scanning. Malathion was significantly associated with poor performance on a test of visual scanning and processing. Conversely, we observed significantly better test performance for five OP pesticides. Specifically, chlorpyrifos, coumaphos, parathion, phorate, and tetrachlorvinphos were associated with better verbal learning and memory; coumaphos was associated with better performance on a test of motor speed and visual scanning; and parathion was associated with better performance on a test of sustained attention. Several associations varied by state. Overall, our results do not provide strong evidence that long-term OP pesticide use is associated with adverse CNS-associated NB test performance among this older sample of pesticide applicators. Potential reasons for these mostly null associations include a true absence of effect as well as possible selective participation by healthier applicators.
doi:10.1016/j.ntt.2011.08.014
PMCID: PMC3601543  PMID: 21907279
agricultural workers; epidemiology; organophosphates; neuropsychological testing; pesticide exposure
25.  Perinatal ethanol exposure alters met-enkephalin levels of male and female rats 
Neurotoxicology and teratology  2006;28(2):238-244.
This study used a rat model of Fetal Alcohol Syndrome to investigate whether combined prenatal and postnatal ethanol exposure affects met-enkephalin levels in the brains of male and female Long–Evans adult rats. Intragastric ethanol was administered to a group of rats (ET) from gestational day (GD) 1 through 22 and from postnatal day (PD) 2 through 10. The control groups consisted of a nontreated control group (NTC) and an intubated control group (IC) that received the intragastric intubation procedure but no exposure to ethanol. We measured met-enkephalin levels in the prefrontal cortex, nucleus accumbens, hypothalamus, central and basolateral nucleus of amygdala and ventral tegmental area. Met-enkephalin levels in the hypothalamus of male and female ET animals were significantly higher than those in either the NTC or IC animals. Met-enkephalin levels in the central nucleus of the amygdala of male and female ET animals were significantly lower than the levels in the NTC animals. Met-enkephalin levels in the nucleus accumbens of ET females were significantly greater than those in the IC females. These results demonstrate that the combination of prenatal and postnatal ethanol exposure affects basal met-enkephalin levels in specific regions in a sex-specific manner. These changes in met-enkephalin levels may explain how early ethanol exposure affects opioid-regulated behaviors such as social play, sexual behavior, and other social behaviors.
doi:10.1016/j.ntt.2005.12.004
PMCID: PMC3596822  PMID: 16457985
Fetal alcohol syndrome; Social behavior; Opioid; Prenatal alcohol; Sex-dependent differences; Fetal alcohol spectrum disorder

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