Moderate Prenatal Alcohol Exposure Increases Toll-like Receptor Activity in Umbilical Cord Blood at Birth: A Pilot Study.

The prevalence of prenatal alcohol exposure (PAE) is increasing, with evidence suggesting that PAE is linked to an increased risk of infections. PAE is hypothesized to affect the innate immune system, which identifies pathogens through pattern recognition receptors, of which toll-like receptors (TLRs) are key components. We hypothesized that light-to-moderate PAE would impair immune responses, as measured by a heightened response in cytokine levels following TLR stimulation.

Trichloroethylene metabolite modulates DNA methylation-dependent gene expression in Th1-polarized CD4+ T cells from autoimmune-prone mice.

Trichloroethylene (TCE) is an industrial solvent and widespread environmental contaminant associated with CD4+ T-cell activation and autoimmune disease. Prior studies showed that exposure to TCE in the drinking water of autoimmune-prone mice expanded effector/memory CD4+ T cells with an interferon-γ (IFN-γ)-secreting Th1-like phenotype. However, very little is known how TCE exposure skews CD4+ T cells towards this pro-inflammatory Th1 subset.

Developmental trichloroethylene exposure enhances predictive markers of autoimmunity in a sex-specific manner in disease-resistant female mice.

Trichloroethylene (TCE) is a widely used industrial chemical and common environmental pollutant. Exposure to TCE promotes CD4 T cell-driven autoimmunity including autoimmune hepatitis (AIH) in both humans and female autoimmune-prone mice. Because the developing immune system is more sensitive during development, we predicted that non- autoimmune-prone, C57/Bl6 (B6) mice would exhibit some autoimmune-related changes using the Developmental Origins of Health and Disease (DOHaD) model of exposure.

Sex-Dependent Effects on Liver Inflammation and Gut Microbial Dysbiosis After Continuous Developmental Exposure to Trichloroethylene in Autoimmune-Prone Mice.

Trichloroethylene (TCE) is a common environmental toxicant linked with hypersensitivity and autoimmune responses in humans and animal models. While autoimmune diseases are more common in females, mechanisms behind this disparity are not clear. Recent evidence suggests that autoimmunity may be increasing in males, and occupational studies have shown that TCE-mediated hypersensitivity responses occur just as often in males.

Studying the Effect of Maternal Pregestational Diabetes on Fetal Neurodevelopment Using Magnetoencephalography.

Developmental origin of health and disease states that an adverse intrauterine environment can lead to different diseases in later life. In this study, we aimed to explore the effect of maternal pregestational diabetes on the fetal brain activity using magnetoencephalography (MEG). Forty participants were included in an observational study with 9 type 1 and 19 type 2 diabetic pregnant women compared with data from 12 nondiabetic participants.

Complex epigenetic patterns in cerebellum generated after developmental exposure to trichloroethylene and/or high fat diet in autoimmune-prone mice.

Trichloroethylene (TCE) is an environmental contaminant associated with immune-mediated inflammatory disorders and neurotoxicity. Based on known negative effects of developmental overnutrition on neurodevelopment, we hypothesized that developmental exposure to high fat diet (HFD) consisting of 40% kcal fat would enhance neurotoxicity of low-level (6 μg per kg per day) TCE exposure in offspring over either stressor alone. Male offspring were evaluated at ∼6 weeks of age after exposure beginning 4 weeks preconception in the dams until weaning.

Continuous Developmental and Early Life Trichloroethylene Exposure Promoted DNA Methylation Alterations in Polycomb Protein Binding Sites in Effector/Memory CD4 T Cells.

Trichloroethylene (TCE) is an industrial solvent and drinking water pollutant associated with CD4 T cell-mediated autoimmunity. In our mouse model, discontinuation of TCE exposure during adulthood after developmental exposure did not prevent immunotoxicity. To determine whether persistent effects were linked to epigenetic changes we conducted whole genome reduced representation bisulfite sequencing (RRBS) to evaluate methylation of CpG sites in autosomal chromosomes in activated effector/memory CD4 T cells.

Epigenetic underpinnings of developmental immunotoxicity and autoimmune disease.

The concordance rate for developing autoimmune disease in identical twins is around 50% demonstrating that gene and environmental interactions contribute to disease etiology. The environmental contribution to autoimmune disease is a wide-ranging concept including exposure to immunotoxic environmental chemicals. Because the immune system is immature during development suggests that adult-onset autoimmunity may originate when the immune system is particularly sensitive.

Exposure to per-fluoroalkyl and polyfluoroalkyl substances leads to immunotoxicity: epidemiological and toxicological evidence.

In this perspective, we evaluate key and emerging epidemiological and toxicological data concerning immunotoxicity of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) and seek to reconcile conflicting conclusions from two reviews published in 2016. We summarize ways that immunosuppression and immunoenhancement are defined and explain how specific outcomes are used to evaluate immunotoxicity in humans and experimental animals. We observe that different approaches to defining immunotoxicological outcomes, particularly those that do not produce clinical disease, may lead to different conclusions from epidemiological and toxicological studies.

Irreversible effects of trichloroethylene on the gut microbial community and gut-associated immune responses in autoimmune-prone mice.

The developing immune system is particularly sensitive to immunotoxicants. This study assessed trichloroethylene (TCE)-induced effects on the gut microbiome and cytokine production during the development in mice. Mice were exposed to TCE (0.

Opposing Actions of Developmental Trichloroethylene and High-Fat Diet Coexposure on Markers of Lipogenesis and Inflammation in Autoimmune-Prone Mice.

Trichloroethylene (TCE) is a widespread environmental pollutant associated with immunotoxicity and autoimmune disease. Previous studies showed that mice exposed from gestation through early life demonstrated CD4+ T cell alterations and autoimmune hepatitis. Determining the role of one environmental risk factor for any disease is complicated by the presence of other stressors.

Trichloroethylene-induced alterations in DNA methylation were enriched in polycomb protein binding sites in effector/memory CD4 T cells.

Exposure to industrial solvent and water pollutant trichloroethylene (TCE) can promote autoimmunity, and expand effector/memory (CD62L) CD4 T cells. In order to better understand etiology reduced representation bisulfite sequencing was used to study how a 40-week exposure to TCE in drinking water altered methylation of ∼337 770 CpG sites across the entire genome of effector/memory CD4 T cells from MRL+/+ mice. Regardless of TCE exposure, 62% of CpG sites in autosomal chromosomes were hypomethylated (0-15% methylation), and 25% were hypermethylated (85-100% methylation).

Estimated Maternal Pesticide Exposure from Drinking Water and Heart Defects in Offspring.

Our objective was to examine the relationship between estimated maternal exposure to pesticides in public drinking water and the risk of congenital heart defects (CHD). We used mixed-effects logistic regression to analyze data from 18,291 nonsyndromic cases with heart defects from the Texas Birth Defects Registry and 4414 randomly-selected controls delivered in Texas from 1999 through 2005. Water district-level pesticide exposure was estimated by linking each maternal residential address to the corresponding public water supply district's measured atrazine levels.

Exposure Cessation During Adulthood Did Not Prevent Immunotoxicity Caused by Developmental Exposure to Low-Level Trichloroethylene in Drinking Water.

Exposure to the water pollutant trichloroethylene (TCE) can promote autoimmunity in both humans and rodents. Using a mouse model we have shown that chronic adult exposure to TCE at 500 μg/ml in drinking water generates autoimmune hepatitis in female MRL+/+ mice. There is increasing evidence that developmental exposure to certain chemicals can be more toxic than adult exposure.

A single dose of trichloroethylene given during development does not substantially alter markers of neuroinflammation in brains of adult mice.

Trichloroethylene (TCE) is a widespread environmental contaminant associated with developmental immunotoxicity and neurotoxicity. Previous studies have shown that MRL mice exposed to TCE from gestation through early-life demonstrate robust increases in inflammatory markers in peripheral CD4 T-cells, as well as glutathione depletion and increased oxidative stress in cerebellum-associated with alterations in behavior. Since increased oxidative stress is associated with neuroinflammation, we hypothesized that neuroinflammatory markers could be altered relative to unexposed mice.

Maternal autoimmune disease and birth defects in the National Birth Defects Prevention Study.

Background: Little is known about the association between maternal autoimmune disease or its treatment and the risk of birth defects. We examined these associations using data from the National Birth Defects Prevention Study, a multi-site, population-based, case-control study.

Methods: Analyses included 25,116 case and 9897 unaffected control infants with estimated delivery dates between 1997 and 2009.

Chronic exposure to trichloroethylene increases DNA methylation of the Ifng promoter in CD4 T cells.

CD4 T cells in female MRL+/+ mice exposed to solvent and water pollutant trichloroethylene (TCE) skew toward effector/memory CD4 T cells, and demonstrate seemingly non-monotonic alterations in IFN-γ production. In the current study we examined the mechanism for this immunotoxicity using effector/memory and naïve CD4 T cells isolated every 6 weeks during a 40 week exposure to TCE (0.5mg/ml in drinking water).

Chronic exposure to water pollutant trichloroethylene increased epigenetic drift in CD4(+) T cells.

Aim: Autoimmune disease and CD4(+) T-cell alterations are induced in mice exposed to the water pollutant trichloroethylene (TCE). We examined here whether TCE altered gene-specific DNA methylation in CD4(+) T cells as a possible mechanism of immunotoxicity.

Materials & Methods: Naive and effector/memory CD4(+) T cells from mice exposed to TCE (0.

Inflammatory and oxidative stress-related effects associated with neurotoxicity are maintained after exclusively prenatal trichloroethylene exposure.

Trichloroethylene (TCE) is a widespread environmental toxicant with immunotoxic and neurotoxic potential. Previous studies have shown that continuous developmental exposure to TCE encompassing gestation and early life as well as postnatal only exposure in the drinking water of MRL+/+ mice promoted CD4 T cell immunotoxicity, glutathione depletion and oxidative stress in the cerebellum, as well increased locomotor activity in male offspring. The purpose of this study was to characterize the effects of exclusively prenatal exposure on these parameters.

Modeling toxicodynamic effects of trichloroethylene on liver in mouse model of autoimmune hepatitis.

Chronic exposure to industrial solvent and water pollutant trichloroethylene (TCE) in female MRL+/+mice generates disease similar to human autoimmune hepatitis. The current study was initiated to investigate why TCE-induced autoimmunity targeted the liver. Compared to other tissues the liver has an unusually robust capacity for repair and regeneration.

Differential immunotoxicity induced by two different windows of developmental trichloroethylene exposure.

Developmental exposure to environmental toxicants may induce immune system alterations that contribute to adult stage autoimmune disease. We have shown that continuous exposure of MRL+/+ mice to trichloroethylene (TCE) from gestational day (GD) 0 to postnatal day (PND) 49 alters several aspects of CD4(+) T cell function. This window of exposure corresponds to conception-adolescence/young adulthood in humans.

Metabolic changes and DNA hypomethylation in cerebellum are associated with behavioral alterations in mice exposed to trichloroethylene postnatally.

Previous studies demonstrated that low-level postnatal and early life exposure to the environmental contaminant, trichloroethylene (TCE), in the drinking water of MRL+/+ mice altered glutathione redox homeostasis and increased biomarkers of oxidative stress indicating a more oxidized state. Plasma metabolites along the interrelated transmethylation pathway were also altered indicating impaired methylation capacity. Here we extend these findings to further characterize the impact of TCE exposure in mice exposed to water only or two doses of TCE in the drinking water (0, 2, and 28mg/kg/day) postnatally from birth until 6weeks of age on redox homeostasis and biomarkers of oxidative stress in the cerebellum.

Increased maternal cytokine production and congenital heart defects.

Congenital heart defects (CHDs) are a major cause of infant mortality. Most CHDs are thought to result from genetic, lifestyle, and environmental factors that include maternal obesity, diabetes, toxicant exposure, and alterations in anti-oxidant capacity. Since these well-documented risk factors are also associated with immune dysregulation, we sought to compare the maternal immune response in mothers carrying a fetus with a CHD with those mothers whose pregnancies were not affected by any birth defect.

Postnatal exposure to trichloroethylene alters glutathione redox homeostasis, methylation potential, and neurotrophin expression in the mouse hippocampus.

Previous studies have shown that continuous exposure throughout gestation until the juvenile period to environmentally relevant doses of trichloroethylene (TCE) in the drinking water of MRL+/+ mice promoted adverse behavior associated with glutathione depletion in the cerebellum indicating increased sensitivity to oxidative stress. The purpose of this study was to extend our findings and further characterize the impact of TCE exposure on redox homeostasis and biomarkers of oxidative stress in the hippocampus, a brain region prone to oxidative stress. Instead of a continuous exposure, the mice were exposed to water only or two environmentally relevant doses of TCE in the drinking water postnatally from birth until 6 weeks of age.