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1.  Genetic variants within the MHC region are associated with immune responsiveness to childhood vaccinations☆ 
Vaccine  2013;31(46):5381-5391.
The influence of genetic variability within the major histocompatibility complex (MHC) region on variations in immune responses to childhood vaccination was investigated. The study group consisted of 135 healthy infants who had been immunized with hepatitis B (HBV), 7-valent pneumococcal conjugate (PCV7), and diphtheria, tetanus, acellular pertussis (DTaP) vaccines according to standard childhood immunization schedules. Genotype analysis was performed on genomic DNA using Illumina Goldengate MHC panels (Mapping and Exon Centric). At the 1 year post vaccination check-up total, isotypic, and antigen-specific serum antibody levels were measured using multiplex immunoassays. A number of single nucleotide polymorphisms (SNPs) within MHC Class I and II genes were found to be associated with variations in the vaccine specific antibody responses and serum levels of immunoglobulins (IgG, IgM) and IgG isotypes (IgG1, IgG4) (all at p< 0.001). Linkage disequilibrium patterns and functional annotations showed that significant SNPs were strongly correlated with other functional regulatory SNPs. These SNPs were found to regulate the expression of a group of genes involved in antigen processing and presentation including HLA-A, HLA-C, HLA-G, HLA-H, HLA-DRA, HLA-DRB1, HLA-DRB5, HLA-DQA1, HLA-DQB1, HLA-DOB, and TAP-2. The results suggest that genetic variations within particular MHC genes can influence immune response to common childhood vaccinations, which in turn may influence vaccine efficacy.
PMCID: PMC4640212  PMID: 24075919
Major histocompatibility complex; Genetic polymorphism; Childhood vaccine; Immune response
Toxicology letters  2014;230(2):263-270.
Perfluorinated compounds (PFCs) have been recognized as an important class of environmental contaminants commonly detected in blood samples of both wildlife and humans. These compounds have been in use for more than 60 years as surface treatment chemicals, polymerization aids, and surfactants. They possess a strong carbon-fluorine bond, which leads to their environmental persistence. There is evidence from both epidemiology and laboratory studies that PFCs may be immunotoxic, affecting both cell-mediated and humoral immunity. Reported effects of PFCs include decreased spleen and thymus weights and cellularity, reduced antibody production, reduced survival after influenza infection, and altered cytokine production. Immunosuppression is a critical effect associated with exposure to PFCs, as it has been reported to reduce antibody responses to vaccination in children. Mounting evidence suggests that immunotoxicity in experimental animals can occur at serum concentrations below, within, or just above the reported range for highly exposed humans and wildlife. Considering bioaccumulation and exposure to multiple PFCs, the risk of immunotoxicity for humans and wildlife cannot be discounted. This review will discuss current and recently published work exploring the immunomodulatory effects of PFCs in experimental animals and humans.
PMCID: PMC4439925  PMID: 24503008
perfluorinated compounds; immunosuppression; PPAR-α receptor; cytokine; vaccination
3.  Genetic Variants in the Major Histocompatibility Complex Class I and Class II Genes Are Associated With Diisocyanate-Induced Asthma 
To investigate the association between single nucleotide polymorphisms (SNPs) located across the major histocompatibility complex and susceptibility to diisocyanate-induced asthma (DA).
The study population consisted of 140 diisocyanate-exposed workers. Genotyping was performed using the Illumina GoldenGate major histocompatibility complex panels.
The HLA-E rs1573294 and HLA-DPB1 rs928976 SNPs were associated with an increased risk of DA under dominant (odds ratio [OR], 6.27; 95% confidence interval [CI], 2.37 to 16.6; OR, 2.79, 95% CI, 0.99 to 7.81, respectively) and recessive genetic models (OR, 6.27, 95% CI, 1.63 to 24.13; OR, 10.10, 95% CI, 3.16 to 32.33, respectively). The HLA-B rs1811197, HLA-DOA rs3128935, and HLA-DQA2 rs7773955 SNPs conferred an increased risk of DA in a dominant model (OR, 7.64, 95% CI, 2.25 to 26.00; OR, 19.69, 95% CI, 2.89 to 135.25; OR, 8.43, 95% CI, 3.03 to 23.48, respectively).
These results suggest that genetic variations within HLA genes play a role in DA risk.
PMCID: PMC4572490  PMID: 24709764
4.  Immunomodulatory activity of orphan drug Elmiron® in female B6C3F1/N mice 
Interstitial cystitis (IC) is a chronic disorder characterized by bladder discomfort and urinary urgency in the absence of identifiable infection. Despite the expanding use in treatment of IC and other chronic conditions, the effects of Elmiron® treatment on immune system remain unknown. Therefore, female B6C3F1/N mice were orally administered Elmiron® daily for 28-days at doses of 63, 125, 250, 500 or 1000 mg/kg to evaluate its immunomodulatory effects. Mice treated with Elmiron® had a significant increase in absolute numbers of splenic macrophages (63, 500 and 1000 mg/kg) and natural killer (NK) cells (250 and 1000 mg/kg). Elmiron® treatment did not affect the humoral immune response or T cell proliferative response. However, innate immune responses such as phagocytosis by liver macrophages (1000 mg/kg) and NK cell activity were enhanced (500 and 1000 mg/kg). Further analysis using a disease resistance model showed that Elmiron® -treated mice demonstrated significantly increased anti-tumor activity against B16F10 melanoma cells at the 500 and 1000 mg/kg doses. Collectively, we conclude that Elmiron® administration stimulates the immune system, increasing numbers of specific cell populations and enhancing macrophage phagocytosis and NK cell activity in female B6C3F1/N mice. This augmentation may have largely contributed to the reduced number of B16F10 melanoma tumors.
PMCID: PMC4080314  PMID: 24657363
Immunotoxicity; Orphan drug; sodium pentosan polysulfate; interstitial cystitis
5.  A Murine Inhalation Model to Characterize Pulmonary Exposure to Dry Aspergillus fumigatus Conidia 
PLoS ONE  2014;9(10):e109855.
Most murine models of fungal exposure are based on the delivery of uncharacterized extracts or liquid conidia suspensions using aspiration or intranasal approaches. Studies that model exposure to dry fungal aerosols using whole body inhalation have only recently been described. In this study, we aimed to characterize pulmonary immune responses following repeated inhalation of conidia utilizing an acoustical generator to deliver dry fungal aerosols to mice housed in a nose only exposure chamber. Immunocompetent female BALB/cJ mice were exposed to conidia derived from Aspergillus fumigatus wild-type (WT) or a melanin-deficient (Δalb1) strain. Conidia were aerosolized and delivered to mice at an estimated deposition dose of 1×105 twice a week for 4 weeks (8 total). Histopathological and immunological endpoints were assessed 4, 24, 48, and 72 hours after the final exposure. Histopathological analysis showed that conidia derived from both strains induced lung inflammation, especially at 24 and 48 hour time points. Immunological endpoints evaluated in bronchoalveolar lavage fluid (BALF) and the mediastinal lymph nodes showed that exposure to WT conidia led to elevated numbers of macrophages, granulocytes, and lymphocytes. Importantly, CD8+ IL17+ (Tc17) cells were significantly higher in BALF and positively correlated with germination of A. fumigatus WT spores. Germination was associated with specific IgG to intracellular proteins while Δalb1 spores elicited antibodies to cell wall hydrophobin. These data suggest that inhalation exposures may provide a more representative analysis of immune responses following exposures to environmentally and occupationally prevalent fungal contaminants.
PMCID: PMC4207673  PMID: 25340353
6.  Immunomodulatory effects of black cohosh (Actaea racemosa) extract in female B6C3F1/N mice 
Toxicology  2013;308:146-157.
Black cohosh extracts (BCE; Actaea racemosa) are being used worldwide as an alternative to hormone replacement therapy for the management of menstrual and menopausal symptoms, yet the effects of BCE on the immune system are largely unknown. Female B6C3F1/N mice were treated daily with BCE (0, 62.5, 125, 250, 500, or 1000 mg/kg) for 28 days by oral gavage. Liver weights were significantly increased (26%–32%) at the 1000 mg/kg dose. Dose-related increases in mean corpuscular volume and mean corpuscular hemoglobin were observed. Decreasing trends were observed in all thymic T cell populations, with the most notable dose-responsive effects on immature thymocytes. In the spleen, dose-related decreases were observed in all cell phenotypes evaluated, reaching the level of statistical significance at the 1000 mg/kg BCE dose. Splenic natural killer (NK) cell numbers were significantly decreased at all BCE doses, with the exception of absolute NK numbers at the 125 mg/kg dose. No effects were observed on T-dependent antibody responses of the humoral immune system, including the antibody-forming cell response to sheep erythrocytes (sRBC) and IgM antibody levels to both sRBC and keyhole limpet hemocyanin. Cytotoxic T cell (TCTL) activity was increased, as was the mixed leukocyte response in one of two studies. Anti-CD3 mediated proliferation and the delayed-type hypersensitivity response were unaffected. No effects were observed on innate immunity or on bone marrow cellularity and colony-forming units. Overall, BCE exposure in B6C3F1/N mice for 28 days at doses up to 1000 mg/kg had minimal immune effects, with the exception of an increased TCTL response.
PMCID: PMC3684955  PMID: 23571075
black cohosh extract; Actaea racemosa; immunotoxicity; immunomodulation; herbal medicines; immune system
7.  Criteria for Environmentally Associated Autoimmune Diseases 
Journal of autoimmunity  2012;39(4):253-258.
Increasing evidence supports a role for the environment in the development of autoimmune diseases, as reviewed in the accompanying three papers from the National Institute of Environmental Health Sciences Expert Panel Workshop. An important unresolved issue, however, is the development of criteria for identifying autoimmune disease phenotypes for which the environment plays a causative role, herein referred to as environmentally associated autoimmune diseases. There are several different areas in which such criteria need to be developed, including: 1) identifying the necessary and sufficient data to define environmental risk factors for autoimmune diseases meeting current classification criteria; 2) establishing the existence of and criteria for new environmentally associated autoimmune disorders that do not meet current disease classification criteria; and 3) identifying in clinical practice specific environmental agents that induce autoimmune disease in individual patients. Here we discuss approaches that could be useful for developing criteria in these three areas, as well as factors that should be considered in evaluating the evidence for criteria that can distinguish individuals with such disorders from individuals without such disorders with high sensitivity and specificity. Current studies suggest that multiple lines of complementary evidence will be important and that in many cases there will be clinical, serologic, genetic, epigenetic, and/or other laboratory features that could be incorporated as criteria for environmentally associated autoimmune diseases to improve diagnosis and treatment and possibly allow for preventative strategies in the future.
PMCID: PMC3468712  PMID: 22771005
autoimmune disease; environmental risk factors; criteria
8.  Genetic Variants in Antioxidant Genes Are Associated With Diisocyanate-Induced Asthma 
Toxicological Sciences  2012;129(1):166-173.
Diisocyanates are a common cause of occupational asthma, but risk factors are not well defined. A case-control study was conducted to investigate whether genetic variants of antioxidant defense genes, glutathione S-transferases (GSTM1, GSTT1, GSTM3, GSTP1), manganese superoxide dismutase (SOD2), and microsomal epoxide hydrolase (EPHX1) are associated with increased susceptibility to diisocyanate-induced asthma (DA). The main study population consisted of 353 Caucasian French-Canadians from among a larger sample of 410 diisocyanate-exposed workers in three groups: workers with specific inhalation challenge (SIC) confirmed DA (DA+, n = 95); symptomatic diisocyanate workers with a negative SIC (DA−, n = 116); and asymptomatic exposed workers (AW, n = 142). Genotyping was performed on genomic DNA, using a 5′-nuclease PCR assay. The SOD2 rs4880, GSTP1 rs1695, and EPHX1 rs2740171 variants were significantly associated with DA in both univariate and multivariate analyses. In the first logistic regression model comparing DA+ and DA− groups, SOD2 rs4880, GSTM1 (null), GSTP1 rs762803, and EPHX1 rs2854450 variants were associated with DA (p = 0.004, p = 0.047, p = 0.021, p <0.001, respectively). Genotype combinations GSTT1*GSTP1 rs762803, GSTM1*EPHX1 rs2854450, EPHX1 rs2740168*EPHX1 rs1051741, and GSTP1 rs762803*EPHX1 rs2740168 were also associated with DA in this model (p = 0.027, p = 0.002, p = 0.045, p = 0.044, respectively). The GSTP1 rs1695 and EPHX1 rs1051741 and rs2740171 variants showed an association with DA in the second model comparing DA+ and AW groups (p = 0.040, p = 0.019, p = 0.002, respectively). The GSTM3 rs110913*EPHX1 rs1051741 genotype combination was also associated with DA under this model (p = 0.042). The results suggest that variations in SOD2, GST, and EPHX1 genes and their interactions contribute to DA susceptibility.
PMCID: PMC3499076  PMID: 22610343
diisocyanates;  occupational asthma;  antioxidant;  genetics;  single-nucleotide polymorphism.
9.  Prevalence and Sociodemographic Correlates of Antinuclear Antibodies In the United States 
Arthritis and Rheumatism  2012;64(7):2319-2327.
To estimate the prevalence, types and sociodemographic and biobehavioral correlates of antinuclear antibodies (ANA) in the United States (U.S.).
Cross-sectional analysis of 4,754 individuals from the National Health and Nutrition Examination Survey (NHANES) 1999–2004. ANA by indirect immunofluorescence, including cellular staining patterns and specific autoantibody reactivities by immunoprecipitation in those with ANA.
ANA prevalence in the U.S. population ages 12 years and older was 13.8% (95% CI, 12.2% to 15.5%). ANA increased with age (P = 0.01) and were more prevalent among females than males (17.8% vs. 9.6%, P < 0.001), with the female to male ratio peaking at 40–49 years of age. ANA prevalence was modestly higher in African Americans than whites (adjusted prevalence odds ratio [POR], 1.30; 95% CI, 1.00 to 1.70). Remarkably, ANA were less common in overweight and obese (adjusted POR, 0.74; 95% CI, 0.59 to 0.94) individuals than persons of normal weight. No significant associations were seen with education, family income, alcohol use, smoking history, serum levels of cotinine or C-reactive protein. In ANA-positive individuals, nuclear patterns were seen in 84.6%, cytoplasmic patterns in 21.8%, and nucleolar patterns in 6.1%, and the most common specific autoantibodies were anti-Ro (3.9%) and anti-Su (2.4%).
These findings suggest that over 32 million persons in the U.S. have ANA and the prevalence is higher among females, older individuals, African Americans and those with normal weight. These data will serve as a useful baseline for future investigations of predictors and changes in ANA prevalence over time.
PMCID: PMC3330150  PMID: 22237992
Antinuclear antibodies; epidemiology; NHANES
10.  Fungal and Atopic Sensitization are Low among Farmers in the Agricultural Health Study 
Clinical Summary
Prevalence of fungal sensitization and atopy was lower among farmers than the US population. Fungal sensitization was related to growing specific agricultural commodities.
PMCID: PMC3387290  PMID: 22633325
fungal sensitization; atopy; agriculture; farmers; specific and total IgE
11.  The Toxicology Education Summit: Building the Future of Toxicology Through Education 
Toxicological Sciences  2012;127(2):331-338.
Toxicology and careers in toxicology, as well as many other scientific disciplines, are undergoing rapid and dramatic changes as new discoveries, technologies, and hazards advance at a blinding rate. There are new and ever increasing demands on toxicologists to keep pace with expanding global economies, highly fluid policy debates, and increasingly complex global threats to public health. These demands must be met with new paradigms for multidisciplinary, technologically complex, and collaborative approaches that require advanced and continuing education in toxicology and associated disciplines. This requires paradigm shifts in educational programs that support recruitment, development, and training of the modern toxicologist, as well as continued education and retraining of the midcareer professional to keep pace and sustain careers in industry, government, and academia. The Society of Toxicology convened the Toxicology Educational Summit to discuss the state of toxicology education and to strategically address educational needs and the sustained advancement of toxicology as a profession. The Summit focused on core issues of: building for the future of toxicology through educational programs; defining education and training needs; developing the “Total Toxicologist”; continued training and retraining toxicologists to sustain their careers; and, finally, supporting toxicology education and professional development. This report summarizes the outcomes of the Summit, presents examples of successful programs that advance toxicology education, and concludes with strategies that will insure the future of toxicology through advanced educational initiatives.
PMCID: PMC3355314  PMID: 22461448
toxicology; education
12.  Alterations in regulatory T-cells: Rediscovered pathways in immunotoxicology 
Journal of immunotoxicology  2011;8(4):251-257.
In addition to the effector T-cells subsets, T-cells can also differentiate into cells that play a suppressive or regulatory role in adaptive immune responses. The cell types currently identified as regulatory T-cells (Tregs) include natural or thymic-derived Tregs, T-cells which express Foxp3+CD25+CD4+ and can suppress immune responses to autoreactive T-cells, as well as inducible Tregs, that are generated from naïve T-cells in the periphery after interaction with antigens presented by dendritic cells. Inducible Tregs include TH3 cells, Tr1 cells, and Foxp3+-inducible Tregs. Tregs have been shown to be critical in the maintenance of immune responses and T-cell homeostasis. These cells play an important role in suppressing responses to self-antigens and in controlling inappropriate responses to non-self-antigens, such as commensal bacteria or food in the gut. For example, depletion of CD4+CD25+ Tregs from mice resulted in the development of multi-organ autoimmune diseases. CD4+CD25+ Tregs and/or IL-10-producing Tr1 cells are capable of suppressing or attenuating TH2 responses to allergens. Moreover, adoptive transfer of CD4+CD25+ Tregs from healthy to diseased animals resulted in the prevention or cure of certain autoimmune diseases, and was able to induce transplantation tolerance. Clinical improvement seen after allergen immunotherapy for allergic diseases such as rhinitis and asthma is associated with the induction of IL-10- and TGFβ-producing Tr1 cells as well as FoxP3-expressing IL-10 T-cells, with resulting suppression of the TH2 cytokine milieu. Activation, expansion, or suppression of CD4+CD25+ Tregs in vivo by xenobiotics, including drugs, may therefore represent a relevant mechanism underlying immunotoxicity, including immunosuppression, allergic asthma, and autoimmune diseases.
PMCID: PMC3448276  PMID: 21848365
Regulatory T-cells; immunosuppression; allergy; autoimmunity
13.  Benzene and Its Principal Metabolites Modulate Proinflammatory Cytokines and Growth Factors in Human Epidermal Keratinocyte Cultures 
In vitro toxicology  1997;10(4):429-436.
Benzene is an established leukemogen and hematotoxin in humans. However, the finding that benzene is a multiple-site carcinogen in rodents raises the possibility that other tissues could be susceptible to benzene-induced carcinogenicity, especially since a significant excess of squamous cell carcinomas and papillomas arise from epidermal and oral keratinocytes in benzene-exposed rats. Since inflammation and sustained hyperplasia are two integral components in carcinogenesis, the elaboration of proinflammatory cytokines and growth factors by keratinocytes might provide a mechanistic link between tumor initiation and promotion in benzene-induced cancers. We observed that the principal benzene metabolites, represented by hydroquinone, 1,4-benzoquinone, phenol, 1,2,4-benzenetriol, and catechol, significantly alters the production of transforming growth factor of (TGF)-α and interleukin (IL)-8 in human epidermal keratinocyte cultures. These cytokines represent the primary growth promoting factor and neutrophil chemotactant in the skin, respectively. Cytokine secretion correlated with the known redox potential of individual benzene metabolites and antioxidants, including dimethyl sulfoxide, 1,1,3,3-tetramethylthiourea, and N-acetylcysteine, attenuated the response. Binary combinations of selected benzene metabolites synergized in the induction of IL-8, while benzene, by itself, induced about a three-fold increase in IL-8 production. Taken together, our studies suggest that benzene and many of its phase I metabolites induce inflammatory cytokines and growth factors and this occurs through direct covalent binding or the generation of reactive oxygen species by autooxidation and reduction. The elaboration of proinflammatory cytokines and growth factors by keratinocytes in response to benzene and its principal metabolites may participate in benzene-induced skin carcinogenesis.
PMCID: PMC3001413  PMID: 21160545
14.  Breaking Patterns of Environmentally Influenced Disease for Health Risk Reduction: Immune Perspectives 
Environmental Health Perspectives  2010;118(8):1091-1099.
Diseases rarely, if ever, occur in isolation. Instead, most represent part of a more complex web or “pattern” of conditions that are connected via underlying biological mechanisms and processes, emerge across a lifetime, and have been identified with the aid of large medical databases.
We have described how an understanding of patterns of disease may be used to develop new strategies for reducing the prevalence and risk of major immune-based illnesses and diseases influenced by environmental stimuli.
Examples of recently defined patterns of diseases that begin in childhood include not only metabolic syndrome, with its characteristics of inflammatory dysregulation, but also allergic, autoimmune, recurrent infection, and other inflammatory patterns of disease. The recent identification of major immune-based disease patterns beginning in childhood suggests that the immune system may play an even more important role in determining health status and health care needs across a lifetime than was previously understood.
Focusing on patterns of disease, as opposed to individual conditions, offers two important venues for environmental health risk reduction. First, prevention of developmental immunotoxicity and pediatric immune dysfunction can be used to act against multiple diseases. Second, pattern-based treatment of entryway diseases can be tailored with the aim of disrupting the entire disease pattern and reducing the risk of later-life illnesses connected to underlying immune dysfunction. Disease-pattern–based evaluation, prevention, and treatment will require a change from the current approach for both immune safety testing and pediatric disease management.
PMCID: PMC2920092  PMID: 20483701
asthma; developmental immunotoxicity; health risks; immune dysfunction; inflammation; intervention; metabolic syndrome; patterns of disease; prevention; safety testing
15.  Pharmacologic Inhibition of COX-1 and COX-2 in Influenza A Viral Infection in Mice 
PLoS ONE  2010;5(7):e11610.
We previously demonstrated that cyclooxygenase (COX)-1 deficiency results in greater morbidity and inflammation, whereas COX-2 deficiency leads to reduced morbidity, inflammation and mortality in influenza infected mice.
Methodology/Principal Findings
We investigated the effects of COX-1 and COX-2 inhibitors in influenza A viral infection. Mice were given a COX-1 inhibitor (SC-560), a COX-2 inhibitor (celecoxib) or no inhibitor beginning 2 weeks prior to influenza A viral infection (200 PFU) and throughout the course of the experiment. Body weight and temperature were measured daily as indicators of morbidity. Animals were sacrificed on days 1 and 4 post-infection and bronchoalveolar lavage (BAL) fluid was collected or daily mortality was recorded up to 2 weeks post-infection. Treatment with SC-560 significantly increased mortality and was associated with profound hypothermia and greater weight loss compared to celecoxib or control groups. On day 4 of infection, BAL fluid cells were modestly elevated in celecoxib treated mice compared to SC-560 or control groups. Viral titres were similar between treatment groups. Levels of TNF-α and G-CSF were significantly attenuated in the SC-560 and celecoxib groups versus control and IL-6 levels were significantly lower in BAL fluid of celecoxib treated mice versus control and versus the SC-560 group. The chemokine KC was significantly lower in SC-560 group versus control.
Treatment with a COX-1 inhibitor during influenza A viral infection is detrimental to the host whereas inhibition of COX-2 does not significantly modulate disease severity. COX-1 plays a critical role in controlling the thermoregulatory response to influenza A viral infection in mice.
PMCID: PMC2904706  PMID: 20657653
16.  Arsenic Exposure In utero Exacerbates Skin Cancer Response in Adulthood with Contemporaneous Distortion of Tumor Stem Cell Dynamics 
Cancer research  2008;68(20):8278-8285.
Arsenic is a carcinogen with transplacental activity that can affect human skin stem cell population dynamics in vitro by blocking exit into differentiation pathways. Keratinocyte stem cells (KSC) are probably a key target in skin carcinogenesis. Thus, we tested the effects of fetal arsenic exposure in Tg.AC mice, a strain sensitive to skin carcinogenesis via activation of the v-Ha-ras transgene likely in KSCs. After fetal arsenic treatment, offspring received topical 12-O-tetradecanoyl phorbol-13-acetate (TPA) through adulthood. Arsenic alone had no effect, whereas TPA alone induced papillomas and squamous cell carcinomas (SCC). However, fetal arsenic treatment before TPA increased SCC multiplicity 3-fold more than TPA alone, and these SCCs were much more aggressive (invasive, etc.). Tumor v-Ha-ras levels were 3-fold higher with arsenic plus TPA than TPA alone, and v-Ha-ras was over expressed early on in arsenic-treated fetal skin. CD34, considered a marker for both KSCs and skin cancer stem cells, and Rac1, a key gene stimulating KSC self-renewal, were greatly increased in tumors produced by arsenic plus TPA exposure versus TPA alone, and both were elevated in arsenic-treated fetal skin. Greatly increased numbers of CD34-positive probable cancer stem cells and marked over expression of RAC1 protein occurred in tumors induced by arsenic plus TPA compared with TPA alone. Thus, fetal arsenic exposure, although by itself oncogenically inactive in skin, facilitated cancer response in association with distorted skin tumor stem cell signaling and population dynamics, implicating stem cells as a target of arsenic in the fetal basis of skin cancer in adulthood.
PMCID: PMC2652700  PMID: 18922899
17.  Evidence for infection, inflammation and shock in sudden infant death: parallels between a neonatal rat model of sudden death and infants who died of sudden infant death syndrome 
Innate immunity  2008;14(3):145-152.
This study compared pathological findings from a neonatal rat model of sudden death with those from 40 sudden infant death syndrome (SIDS) infants collected at autopsy. In the rat model, influenza A virus was administered intranasally on postnatal day 10, and on day 12 a sublethal, intraperitoneal dose of Escherichia coli endotoxin; mortality was 80%. Tissue samples from the animals and infants were fixed in formaldehyde, embedded in paraffin, and sections stained with hematoxylin and eosin. Tissues from the SIDS specimens were additionally cultured for bacteria and viruses; post-mortem blood samples were evaluated for signs of inflammation. All sections were examined by a pediatric forensic pathologist familiar with SIDS pathology. Comparisons between the rat model and the human SIDS cases revealed that both exhibited gross and microscopic pathology related to organ shock, possibly associated with the presence of endotoxin. Uncompensated shock appeared to be a likely factor that caused death in both infants and rat pups. Response to a shock-inducing event might have played an important role in the events leading to death. The similarities between the neonatal rats and the human cases indicate that further research with the model might elucidate additional aspects of SIDS pathology.
PMCID: PMC2679510  PMID: 18562573
Endotoxin; organ shock; sudden infant death syndrome; SIDS; thymic involution
18.  Chronic arsenic exposure increases TGFalpha concentration in bladder urothelial cells of Mexican populations environmentally exposed to inorganic arsenic☆ 
Toxicology and applied pharmacology  2006;222(3):264-270.
Inorganic arsenic (iAs) is a well-established carcinogen and human exposure has been associated with a variety of cancers including those of skin, lung, and bladder. High expression of transforming growth factor alpha (TGF-α) has associated with local relapses in early stages of urinary bladder cancer. iAs exposures are at least in part determined by the rate of formation and composition of iAs metabolites (MAsIII, MAsV, DMAsIII, DMAsV). This study examines the relationship between TGF-α concentration in exfoliated bladder urothelial cells (BUC) separated from urine and urinary arsenic species in 72 resident women (18-51 years old) from areas exposed to different concentrations of iAs in drinking water (2-378 ppb) in central Mexico. Urinary arsenic species, including trivalent methylated metabolites were measured by hydride generation atomic absorption spectrometry method. The concentration of TGF-α in BUC was measured using an ELISA assay. Results show a statistically significant positive correlation between TGF-α concentration in BUC and each of the six arsenic species present in urine. The multivariate linear regression analyses show that the increment of TGF-α levels in BUC was importantly associated with the presence of arsenic species after adjusting by age, and presence of urinary infection. People from areas with high arsenic exposure had a significantly higher TGF-α concentration in BUC than people from areas of low arsenic exposure (128.8 vs. 64.4 pg/mg protein; p<0.05). Notably, exfoliated cells isolated from individuals with skin lesions contained significantly greater amount of TGF-α than cells from individuals without skin lesions: 157.7 vs. 64.9 pg/mg protein (p=0.003). These results suggest that TGF-α in exfoliated BUC may serve as a susceptibility marker of adverse health effects on epithelial tissue in arsenic-endemic areas.
PMCID: PMC2632965  PMID: 17267001
Transforming growth factor alpha; Susceptibility marker; Bladder urothelial cells; Arsenic; Trivalent arsenic; Urine metabolites; Arsenic-skin lesions; Hyperkeratosis; Hypo-hyperpigmentation
19.  Meeting Report: Moving Upstream—Evaluating Adverse Upstream End Points for Improved Risk Assessment and Decision-Making 
Environmental Health Perspectives  2008;116(11):1568-1575.
Assessing adverse effects from environmental chemical exposure is integral to public health policies. Toxicology assays identifying early biological changes from chemical exposure are increasing our ability to evaluate links between early biological disturbances and subsequent overt downstream effects. A workshop was held to consider how the resulting data inform consideration of an “adverse effect” in the context of hazard identification and risk assessment.
Our objective here is to review what is known about the relationships between chemical exposure, early biological effects (upstream events), and later overt effects (downstream events) through three case studies (thyroid hormone disruption, antiandrogen effects, immune system disruption) and to consider how to evaluate hazard and risk when early biological effect data are available.
Each case study presents data on the toxicity pathways linking early biological perturbations with downstream overt effects. Case studies also emphasize several factors that can influence risk of overt disease as a result from early biological perturbations, including background chemical exposures, underlying individual biological processes, and disease susceptibility. Certain effects resulting from exposure during periods of sensitivity may be irreversible. A chemical can act through multiple modes of action, resulting in similar or different overt effects.
For certain classes of early perturbations, sufficient information on the disease process is known, so hazard and quantitative risk assessment can proceed using information on upstream biological perturbations. Upstream data will support improved approaches for considering developmental stage, background exposures, disease status, and other factors important to assessing hazard and risk for the whole population.
PMCID: PMC2592280  PMID: 19057713
adverse health effects; androgen antagonists; hazard identification; immunotoxicants; risk assessment; science policy; thyroid hormone; toxicologic assessments
20.  It's all about sex: male-female differences in lung development and disease 
Accumulating evidence suggests that gender impacts the incidence, susceptibility and severity of several lung diseases. Gender also influences lung development and physiology. Data from both human and animal studies suggests that sex hormones may contribute to disease pathogenesis or serve as protective factors, depending on the disease involved. In this review, the influence of gender and sex hormones on lung development and pathology will be discussed, with specific emphasis on pulmonary fibrosis, asthma and cancer.
PMCID: PMC2391086  PMID: 17764971
21.  Immunotoxicogenomics: The potential of genomics technology in the immunotoxicity risk assessment process 
Evaluation of xenobiotic-induced changes in gene expression as a method to identify and classify potential toxicants is being pursued by industry and regulatory agencies worldwide. A workshop was held at the Research Triangle Park campus of the Environmental Protection Agency to discuss the current state of the science of “immunotoxicogenomics”, and to explore the potential role of genomics techniques for immunotoxicity testing. The genesis of the workshop was the current lack of widely accepted triggering criteria for Tier 1 immunotoxicity testing in the context of routine toxicity testing data, the realization that traditional screening methods would require an inordinate number of animals and are inadequate to handle the number of chemicals that may need to be screened (e.g., high production volume compounds) and the absence of an organized effort to address the state of the science of toxicogenomics in the identification of immunotoxic compounds. The major focus of the meeting was on the theoretical and practical utility of genomics techniques to 1) replace or supplement current immunotoxicity screening procedures, 2) provide insight into potential modes or mechanisms of action, and 3) provide data suitable for immunotoxicity hazard identification or risk assessment. The latter goal is of considerable interest to a variety of stakeholders as a means to reduce animal use and to decrease the cost of conducting and interpreting standard toxicity tests. A number of data gaps were identified that included a lack of dose response and kinetic data for known immunotoxic compounds and a general lack of data correlating genomic alterations to functional changes observed in vivo. Participants concluded that a genomics approach to screen chemicals for immunotoxic potential or to generate data useful to risk assessors holds promise, but that routine use of these methods is years in the future. However, recent progress in molecular immunology has made mode and mechanism of action studies much more practical. Furthermore, a variety of published immunotoxicity studies suggest that microarray analysis is already a practical means to explore pathway-level changes that lead to altered immune function. To help move the science of immunotoxicogenomics forward, a partnership of industry, academia and government was suggested to address data gaps, validation, quality assurance, and protocol development.
PMCID: PMC1847338  PMID: 16882865
22.  Genisten stimulation of immune response in B6C3F1 mice is affected by exposure duration, gender and litter order1 
The Journal of nutrition  2005;135(10):2449-2456.
The objective of this study was to determine if the immune responses could be differentially modulated by the phytoestrogen genistein (GEN) in mice from the first and second litters, and if the effects were persistent or reversible. B6C3F1 mice were exposed to a control or GEN-containing diet at 25, 250 and 1250 μg/g for the first litters, and 500 μg/g for the second litters from day 0 of gestation to PND22, and through feed after weaning. At PND42, an increase in the anti-CD3 antibody-stimulated splenic T cell proliferation and the percentages of T cells was observed in mice from the first litters at 250 and 1250 μg/g GEN but not from the second litters. At PND84, the activity of IL-2-treated NK cells was significantly increased by GEN in mice from the second litters but not from the first litters. The activity of cytotoxic T cells (CTLs) was also significantly increased by GEN in male mice from the second litters. However, the increases in the CTL activity were not significant when the male mice were shifted from GEN-containing food to control food at PND22. Additionally, the increases in T-cell activities in female mice from the first litters and male mice from the second litters were associated with a decrease in the percentage of CD4+CD25+ T regulatory cells. Overall, the results demonstrated that GEN could enhance the immune responses in mice from the first and second litters; however, the effects varied depending on the exposure duration, gender, and litter order.
PMCID: PMC1315296  PMID: 16177211
genistein; developmental exposure; immune stimulation and litter order; CTLs, cytotoxic T cells; DES, diethylstilbestrol; ER, estrogen receptors; E:T, effector:target ratio; F1M = F1 males; F1F = F1 females; FITC, fluorescein isothiocyanate; GD, gestation day; GEN, genistein; mAb, monoclonal antibody; NCTR, the National Center for Toxicological Research; PND, postnatal day; PE, phycoerythrin
23.  Spontaneous Airway Hyperresponsiveness in Estrogen Receptor-α–deficient Mice 
Rationale: Airway hyperresponsiveness is a critical feature of asthma. Substantial epidemiologic evidence supports a role for female sex hormones in modulating lung function and airway hyperresponsiveness in humans.
Objectives: To examine the role of estrogen receptors in modulating lung function and airway responsiveness using estrogen receptor–deficient mice.
Methods: Lung function was assessed by a combination of whole-body barometric plethysmography, invasive measurement of airway resistance, and isometric force measurements in isolated bronchial rings. M2 muscarinic receptor expression was assessed by Western blotting, and function was assessed by electrical field stimulation of tracheas in the presence/absence of gallamine. Allergic airway disease was examined after ovalbumin sensitization and exposure.
Measurements and Main Results: Estrogen receptor-α knockout mice exhibit a variety of lung function abnormalities and have enhanced airway responsiveness to inhaled methacholine and serotonin under basal conditions. This is associated with reduced M2 muscarinic receptor expression and function in the lungs. Absence of estrogen receptor-α also leads to increased airway responsiveness without increased inflammation after allergen sensitization and challenge.
Conclusions: These data suggest that estrogen receptor-α is a critical regulator of airway hyperresponsiveness in mice.
PMCID: PMC1899278  PMID: 17095746
lung function; asthma; hyperreactivity; M2 muscarinic receptor; estrogen receptor
24.  Spontaneous Airway Hyperresponsiveness in Estrogen Receptor-α–deficient Mice 
Airway hyperresponsiveness is a critical feature of asthma. Substantial epidemiologic evidence supports a role for female sex hormones in modulating lung function and airway hyperresponsiveness in humans.
To examine the role of estrogen receptors in modulating lung function and airway responsiveness using estrogen receptor–deficient mice.
Lung function was assessed by a combination of whole-body barometric plethysmography, invasive measurement of airway resistance, and isometric force measurements in isolated bronchial rings. M2 muscarinic receptor expression was assessed by Western blotting, and function was assessed by electrical field stimulation of tracheas in the presence/absence of gallamine. Allergic airway disease was examined after ovalbumin sensitization and exposure.
Measurements and Main Results
Estrogen receptor-α knockout mice exhibit a variety of lung function abnormalities and have enhanced airway responsiveness to inhaled methacholine and serotonin under basal conditions. This is associated with reduced M2 muscarinic receptor expression and function in the lungs. Absence of estrogen receptor-α also leads to increased airway responsiveness without increased inflammation after allergen sensitization and challenge.
These data suggest that estrogen receptor-α is a critical regulator of airway hyperresponsiveness in mice.
PMCID: PMC1899278  PMID: 17095746
lung function; asthma; hyperreactivity; M2 muscarinic receptor; estrogen receptor
25.  A Statistical Model for Assessing Genetic Susceptibility as a Risk Factor in Multifactorial Diseases: Lessons from Occupational Asthma 
Environmental Health Perspectives  2006;115(2):231-234.
Incorporating the influence of genetic variation in the risk assessment process is often considered, but no generalized approach exists. Many common human diseases such as asthma, cancer, and cardiovascular disease are complex in nature, as they are influenced variably by environmental, physiologic, and genetic factors. The genetic components most responsible for differences in individual disease risk are thought to be DNA variants (polymorphisms) that influence the expression or function of mediators involved in the pathological processes.
The purpose of this study was to estimate the combinatorial contribution of multiple genetic variants to disease risk.
We used a logistic regression model to help estimate the joint contribution that multiple genetic variants would have on disease risk. This model was developed using data collected from molecular epidemiology studies of allergic asthma that examined variants in 16 susceptibility genes.
Based on the product of single gene variant odds ratios, the risk of developing asthma was assigned to genotype profiles, and the frequency of each profile was estimated for the general population. Our model predicts that multiple disease variants broaden the risk distribution, facilitating the identification of susceptible populations. This model also allows for incorporation of exposure information as an independent variable, which will be important for risk variants associated with specific exposures.
The present model provided an opportunity to estimate the relative change in risk associated with multiple genetic variants. This will facilitate identification of susceptible populations and help provide a framework to model the genetic contribution in probabilistic risk assessment.
PMCID: PMC1817705  PMID: 17384770
asthma; genetics; polygenic diseases; risk assessment; susceptibility genes

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