Epigenetic disruption and glucose homeostasis changes following low-dose maternal bisphenol A exposure.
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ABSTRACT:
SUBMITTER: Chang H
PROVIDER: S-EPMC6061978 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Bisphenol A (BPA) is an estrogenic endocrine disruptor widely used in the production of plastics. Increasing evidence indicates that in utero BPA exposure affects sexual differentiation and behavior; however, the mechanisms underlying these effects are unknown. We hypothesized that BPA may disrupt epigenetic programming of gene expression in the brain. Here, we provide evidence that maternal exposure during pregnancy to environmentally relevant doses of BPA (2, 20, and 200 µg/kg/d) in mice induces sex-specific, dose-dependent (linear and curvilinear), and brain region-specific changes in expression of genes encoding estrogen receptors (ERs; ER? and ER?) and estrogen-related receptor-? in juvenile offspring. Concomitantly, BPA altered mRNA levels of epigenetic regulators DNA methyltransferase (DNMT) 1 and DNMT3A in the juvenile cortex and hypothalamus, paralleling changes in estrogen-related receptors. Importantly, changes in ER? and DNMT expression in the cortex (males) and hypothalamus (females) were associated with DNA methylation changes in the ER? gene. BPA exposure induced persistent, largely sex-specific effects on social and anxiety-like behavior, leading to disruption of sexually dimorphic behaviors. Although postnatal maternal care was altered in mothers treated with BPA during pregnancy, the effects of in utero BPA were not found to be mediated by maternal care. However, our data suggest that increased maternal care may partially attenuate the effects of in utero BPA on DNA methylation. Overall, we demonstrate that low-dose prenatal BPA exposure induces lasting epigenetic disruption in the brain that possibly underlie enduring effects of BPA on brain function and behavior, especially regarding sexually dimorphic phenotypes.
| S-EPMC3683772 | biostudies-literature
Project description:Animal studies have linked perinatal bisphenol A (BPA) exposure to altered DNA methylation, but little attention is given to analyzing multiple physiologically relevant doses. Utilizing the viable yellow agouti (A(vy)) mouse, we examine the effects of developmental exposure through maternal diet to 50 ng BPA/kg (n = 14 litters), 50 ?g BPA/kg (n = 9 litters), or 50 mg BPA/kg (n = 13 litters) on global and candidate gene methylation at postnatal day 22. Global methylation analysis reveals hypermethylation in tail tissue of a/a and A(vy)/a offspring across all dose groups compared with controls (n = 11 litters; P < 0.02). Analysis of coat color phenotype replicates previous work showing that the distribution of 50 mg BPA/kg A(vy)/a offspring shifts toward yellow (P = 0.006) by decreasing DNA methylation in the retrotransposon upstream of the Agouti gene (P = 0.03). Maternal exposure to 50 ?g or 50 ng BPA/kg, however, results in altered coat color distributions in comparison with control (P = 0.04 and 0.02), but no DNA methylation effects at the Agouti gene are noted. DNA methylation at the CDK5 activator-binding protein (Cabp(IAP)) metastable epiallele shows hypermethylation in the 50 ?g BPA/kg offspring, compared with controls (P = 0.02). Comparison of exposed mouse liver BPA levels to human fetal liver BPA levels indicates that the three experimental exposures are physiologically relevant. Thus, perinatal BPA exposure affects offspring phenotype and epigenetic regulation across multiple doses, indicating the need to evaluate dose effects in human clinical and population studies.
| S-EPMC3570056 | biostudies-literature
Project description:Bisphenol A (BPA) is a high production volume chemical with hormone-like properties that has been implicated as a potential carcinogen. Early-life exposure has been linked to increased risk for precancerous lesions in mammary and prostate glands and the uterus, but no prior study has shown a significant association between BPA exposure and cancer development.We explored the effects of BPA exposure during gestation and lactation on adult incidence of hepatic tumors in mice.Isogenic mice were perinatally exposed to BPA through maternal diets containing one of four environmentally relevant doses of BPA (0, 50 ng, 50 ?g, or 50 mg per kilogram of diet), and we followed approximately one male and one female per litter until they were 10 months of age. Animals were tested for known risk factors for hepatocellular carcinoma, including bacterial and viral infections.We found dose-dependent incidence of hepatic tumors in 10-month-old BPA-exposed mice. Of the offspring examined, 23% presented with hepatic tumors or preneoplastic lesions. We observed a statistically significant dose-response relationship, with an odds ratio for neoplastic and preneoplastic lesions of 7.23 (95% CI: 3.23, 16.17) for mice exposed to 50 mg BPA/kg diet compared with unexposed controls. Observed early disease onset, absence of bacterial or viral infection, and lack of characteristic sexual dimorphism in tumor incidence support a nonclassical etiology.To our knowledge, this is the first report of a statistically significant association between BPA exposure and frank tumors in any organ. Our results link early-life exposure to BPA with the development of hepatic tumors in rodents, and have potential implications for human health and disease.
| S-EPMC4014767 | biostudies-other
Project description:Exposure to endocrine-disrupting chemicals such as Bisphenol-A (BPA) is associated with an increase in obesity prevalence. Diet is the primary cause of human exposure to this contaminant. BPA promotes obesity by inducing adipocyte dysfunction and altering adipogenesis. Contradictory evidence and unanswered questions are reported in the literature concerning the BPA effects on adipogenesis. To clarify this issue, we tested the effects of prolonged low-dose BPA exposure on different phases of adipogenesis in committed 3T3L1 and uncommitted NIH3T3 preadipocytes. Our findings show that BPA effects on the adipogenesis are mediated by epigenetic mechanisms by reducing peroxisome proliferator-activated receptor gamma (Ppar?) promoter methylation in preadipocytes. Nevertheless, in BPA-exposed 3T3L1, Ppar? expression only transiently increases as lipid accumulation at day 4 of differentiation, without altering the adipogenic potential of the precursor cells. In the absence of differentiation mix, BPA does not make the 3T3L1 an in vitro model of spontaneous adipogenesis and the effects on the Ppar? expression are still limited at day 4 of differentiation. Furthermore, BPA exposure does not commit the NIH3T3 to the adipocyte lineage, although Ppar? overexpression is more evident both in preadipocytes and during the adipocyte differentiation. Interestingly, termination of the BPA exposure restores the Ppar? promoter methylation and inflammatory profile of the 3T3L1 cells. This study shows that BPA induces epigenetic changes in a key adipogenic gene. These modifications are reversible and do not affect preadipocyte commitment and/or differentiation. We identify an alternative transcriptional mechanism by which BPA affects gene expression and demonstrate how the challenge of preventing exposure is fundamental for human health.
| S-EPMC7696502 | biostudies-literature
Project description:Bisphenol S (BPS), an analogue of the controversial bisphenol A (BPA) that is found in epoxy resins and plastics, is a potential endocrine-disrupting chemical that can mimic endogenous hormone signaling. However, little is known about the behavioral or immunologic effects of BPS. The purpose of this study was to examine the impact of diets in BPS-treated mice in relation to hyperglycemia, development of type 1 diabetes, immunomodulation, and behavioral changes. Adult male and female nonobese diabetic excluded flora (NODEF) mice were exposed to environmentally relevant doses of BPS (VH, 30, or 300 μg/kg BW) and fed either a soy-based diet, a phytoestrogen-free diet, or a Western diet. NODEF male mice fed a soy-based diet exhibited a decreased curiosity/desire to explore, and possibly increased anxiety-like behavior and decreased short-term memory when exposed to BPS (300 μg/kg BW). In addition, these mice had significant increases in non-fasting blood glucose levels along with increased insulin sensitivity, impaired glucose tolerance, resistance to fasting and proinflammation. Although BPS had little effect on the glucose parameters in NODEF male mice fed a Western diet, there were decreases in %CD24+CD5+ and %B220+CD40L-cell populations and increases in distance traveled during the novel object test, suggesting hyperactivity. NODEF females fed a phytoestrogen-free diet exhibited slight decreases in time spent immobile during the tail suspension test in both the 30 and 300 μg/kg BW dose groups along with increases in %CD4+CD8+ and %Mac3+CD45R+ cell populations, signifying increased hyperactivity and anxiety-like behavior. In conclusion, BPS-exposed NODEF mice exhibited sex and diet-related changes in hyperglycemia, behaviors and immune endpoints.
| S-EPMC8277757 | biostudies-literature
Project description:Conditions during fetal development influence health and disease in adulthood, especially during critical windows of organogenesis. Fetal exposure to the endocrine disrupting chemical, bisphenol A (BPA) affects the development of multiple organ systems in rodents and monkeys. However, effects of BPA exposure on cardiac development have not been assessed. With evidence that maternal BPA is transplacentally delivered to the developing fetus, it becomes imperative to examine the physiological consequences of gestational exposure during primate development. Herein, we evaluate the effects of daily, oral BPA exposure of pregnant rhesus monkeys (Macaca mulatta) on the fetal heart transcriptome. Pregnant monkeys were given daily oral doses (400 µg/kg body weight) of BPA during early (50-100 ± 2 days post conception, dpc) or late (100 ± 2 dpc--term), gestation. At the end of treatment, fetal heart tissues were collected and chamber specific transcriptome expression was assessed using genome-wide microarray. Quantitative real-time PCR was conducted on select genes and ventricular tissue glycogen content was quantified. Our results show that BPA exposure alters transcription of genes that are recognized for their role in cardiac pathophysiologies. Importantly, myosin heavy chain, cardiac isoform alpha (Myh6) was down-regulated in the left ventricle, and 'A Disintegrin and Metalloprotease 12', long isoform (Adam12-l) was up-regulated in both ventricles, and the right atrium of the heart in BPA exposed fetuses. BPA induced alteration of these genes supports the hypothesis that exposure to BPA during fetal development may impact cardiovascular fitness. Our results intensify concerns about the role of BPA in the genesis of human metabolic and cardiovascular diseases.
| S-EPMC3934879 | biostudies-literature
Project description:Great attention has been paid in recent years to the harmful effects of various chemicals that interfere with our natural hormone balance, collectively known as endocrine-disrupting chemicals (EDCs) or endocrine disruptors. The effects on the reproductive system of bisphenol A (BPA) and phthalates have received particular attention: while they have a short half-life, they are so widespread that human exposure can be considered as continuous. Evidence is often limited to the animal model, disregarding the likelihood of human exposure to a mixture of contaminants. Data from animal models show that maternal exposure probably has harmful effects on the male fetus, with an increased risk of urogenital developmental abnormalities. After birth, exposure is associated with changes in the hypothalamic-pituitary-testicular axis, hindering the development and function of the male genital pathways through the mediation of inflammatory mechanisms and oxidative stress. The epidemiological and clinical evidence, while generally confirming the association between reproductive abnormalities and some phthalate esters and BPA, is more contradictory, with wildly different findings. The aim of this review is therefore to provide an update of the potential mechanisms of the damage caused by BPA and phthalates to reproductive function and a review of the clinical evidence currently available in the literature.
| S-EPMC7074154 | biostudies-literature
Project description:BackgroundNano-titanium dioxide (nano-TiO2) is amongst the most widely utilized engineered nanomaterials (ENMs). However, little is known regarding the consequences maternal ENM inhalation exposure has on growing progeny during gestation. ENM inhalation exposure has been reported to decrease mitochondrial bioenergetics and cardiac function, though the mechanisms responsible are poorly understood. Reactive oxygen species (ROS) are increased as a result of ENM inhalation exposure, but it is unclear whether they impact fetal reprogramming. The purpose of this study was to determine whether maternal ENM inhalation exposure influences progeny cardiac development and epigenomic remodeling.ResultsPregnant FVB dams were exposed to nano-TiO2 aerosols with a mass concentration of 12.09 ± 0.26 mg/m3 starting at gestational day five (GD 5), for 6 h over 6 non-consecutive days. Aerosol size distribution measurements indicated an aerodynamic count median diameter (CMD) of 156 nm with a geometric standard deviation (GSD) of 1.70. Echocardiographic imaging was used to assess cardiac function in maternal, fetal (GD 15), and young adult (11 weeks) animals. Electron transport chain (ETC) complex activities, mitochondrial size, complexity, and respiration were evaluated, along with 5-methylcytosine, Dnmt1 protein expression, and Hif1α activity. Cardiac functional analyses revealed a 43% increase in left ventricular mass and 25% decrease in cardiac output (fetal), with an 18% decrease in fractional shortening (young adult). In fetal pups, hydrogen peroxide (H2O2) levels were significantly increased (~ 10 fold) with a subsequent decrease in expression of the antioxidant enzyme, phospholipid hydroperoxide glutathione peroxidase (GPx4). ETC complex activity IV was decreased by 68 and 46% in fetal and young adult cardiac mitochondria, respectively. DNA methylation was significantly increased in fetal pups following exposure, along with increased Hif1α activity and Dnmt1 protein expression. Mitochondrial ultrastructure, including increased size, was observed at both fetal and young adult stages following maternal exposure.ConclusionsMaternal inhalation exposure to nano-TiO2 results in adverse effects on cardiac function that are associated with increased H2O2 levels and dysregulation of the Hif1α/Dnmt1 regulatory axis in fetal offspring. Our findings suggest a distinct interplay between ROS and epigenetic remodeling that leads to sustained cardiac contractile dysfunction in growing and young adult offspring following maternal ENM inhalation exposure.
| S-EPMC6582485 | biostudies-literature
Project description:Bisphenol AF (BPAF) is extensively used as a raw material in industry, resulting in its widespread distribution in the aqueous environment. However, the effect of BPAF on the hypothalamic-pituitary-thyroidal (HPT) axis remains unknown. For elucidating the disruptive effects of BPAF on thyroid function and expression of the representative genes along the HPT axis in zebrafish (Danio rerio) embryos, whole-body total 3,3',5-triiodothyronine (TT3), total 3,5,3',5'-tetraiodothyronine (TT4), free 3,3',5-triiodothyronine (FT3) and free 3,5,3',5'-tetraiodothyronine (FT4) levels were examined following 168 h post-fertilization exposure to different BPAF concentrations (0, 5, 50 and 500 ?g/L). The results showed that whole-body TT3, TT4, FT3 and FT4 contents decreased significantly with the BPAF treatment, indicating an endocrine disruption of thyroid. The expression of thyroid-stimulating hormone-? and thyroglobulin genes increased after exposing to 50 ?g/L BPAF in seven-day-old larvae. The expressions of thyronine deiodinases type 1, type 2 and transthyretin mRNAs were also significantly up-regulated, which were possibly associated with a deterioration of thyroid function. However, slc5a5 gene transcription was significantly down-regulated at 50 ?g/L and 500 ?g/L BPAF exposure. Furthermore, tr? and tr? genes were down-regulated transcriptionally after BPAF exposure. It demonstrates that BPAF exposure triggered thyroid endocrine toxicity by altering the whole-body contents of thyroid hormones and changing the transcription of the genes involved in the HPT axis in zebrafish larvae.
| S-EPMC4627017 | biostudies-literature
Project description:Epigenetic changes such as DNA cytosine methylation modulate gene function across brain and are implicated in the pathophysiology of neurodevelopmental disorders including schizophrenia and autism. Epigenetic changes can be caused by environmental exposures such as inflammation, and may at least partly explain why prenatal exposure to inflammation increase risk of neurodevelopmental disorders. We used an MIA mouse model to investigate the postnatal epigenetic changes associated with exposure to the viral analogue PolyI:C. The effect of dietary supplement with omega-3 polyunsaturated fatty acids (PUFA) on exposed mice was also examined. Methylation was estimated genome-wide across gene regulatory regions. Widespread epigenetic changes were observed following exposure to inflammation during prenatal life. The differentially methylated gene set was enriched for genes involved in nervous system development and function. Omega-3 intervention modified the epigenetic profile, including a number of genes which were affected by MIA. These experiments indicate that environmental and genetic risk factors modulate similar biological pathways that are associated with neurodevelopmental disorders.
2019-08-15 | GSE102942 | GEO