Maternal Bisphenol A Exposure Research Articles

Important roles of Hif1a in maternal or adult BPA exposure induced pancreatic injuries

Bisphenol A (BPA) is a monomer to produce polycarbonate plastics and can be released into the environment through human activities, leading to its accumulation in animals, plants and humans through direct contact or environmental exposure. Epidemiological studies have reported that BPA exposure is associated with metabolic disorders. The pancreas is an important endocrine organ and plays an important role in metabolic disorders. To explore the possible long-term effects of BPA exposure on neonatal health, bioinformatic methods were used to identify differentially expressed genes (DEGs) by comparing the neonatal pancreas after maternal exposure to BPA with the adult pancreas after direct exposure to BPA. Two datasets about BPA exposure and pancreatic abnormality, GSE82175 and GSE126297 in Gene Expression Omnibus (GEO) at the National Center for Biotechnology Information (NCBI) were collected. Control (or BPA-exposed) offspring (maternal exposure) and Control (or BPA-exposed) adults (direct exposure) were defined as Control (or BPA) groups. The results showed that BPA disturbed the normal function of the pancreas in both offspring and adults, with offspring showing higher susceptibility to BPA than adults. Seventeen insulin secretion-related DEGs (Stxbp5l, Fam3d, Mia3, Igf1, Hif1a, Aqp1, Kif5b, Tiam1, Map4k4, Cyp51, Pde1c, Rab3c, Arntl, Clock, Edn3, Kcnb1, and Krt20) in the BPA group were identified, and 15 regulator DEGs (Zfp830, 4931431B13Rik, Egr1, Ddit4l, Cep55, G530011O06Rik, Hspa1b, Hspa1a, Cox6a2, Ibtk, Banf1, Slc35b2, Golt1b, Lrp8, and Pttg1) with opposite expression trends and a regulator gene Cerkl with the similar expression trend in the Control and BPA groups were identified. Hif1α might be an important molecular target for pancreatic cancer caused by BPA exposure, and pregnancy is a critical window of susceptibility to BPA exposure.

Gestational bisphenol A exposure advances puberty onset in female offspring: Critical time window identification

Increasing evidence shows that the early onset of puberty in female offspring may be caused by maternal prenatal exposure to bisphenol A (BPA) during pregnancy; however, the critical time window of maternal prenatal BPA exposure remains unknown. Here, we identify the critical time window of gestational BPA exposure that induces early onset of puberty in female offspring. Pregnant CD-1 mice were gavaged with BPA (8 mg/kg) daily during the early gestational stage (GD1–GD6), middle gestational stage (GD7–GD12) or late gestational stage (GD13–GD18). We show that maternal BPA exposure during the early and middle gestational stages could advance the vaginal opening time and increase the serum levels of kisspeptin-10 and GnRH in the female offspring at PND 34. Mechanistically, maternal BPA exposure during early and middle gestation could significantly increase CpG island methylation in the Eed gene promoters but reduce the mRNA expression of Eed in the hypothalamus tissues of the female offspring. In conclusion, the critical period of maternal BPA exposure-induced early onset of puberty in female offspring is early and middle gestation; this BPA-induced early onset of puberty might be partly attributed to epigenetic programming of the Eed gene in the hypothalamus. This study provides important insights regarding the relationship and the mechanisms between BPA and offspring pubertal development.

The effects of prenatal bisphenol A exposure on brain volume of children and young mice

Bisphenol A (BPA) is a synthetic chemical used for the manufacturing of plastics, epoxy resin, and many personal care products. This ubiquitous endocrine disruptor is detectable in the urine of over 80% of North Americans. Although adverse neurodevelopmental outcomes have been observed in children with high gestational exposure to BPA, the effects of prenatal BPA on brain structure remain unclear. Here, using magnetic resonance imaging (MRI), we studied the associations of maternal BPA exposure with children's brain structure, as well as the impact of comparable BPA levels in a mouse model. Our human data showed that most maternal BPA exposure effects on brain volumes were small, with the largest effects observed in the opercular region of the inferior frontal gyrus (ρ = −0.2754), superior occipital gyrus (ρ = −0.2556), and postcentral gyrus (ρ = 0.2384). In mice, gestational exposure to an equivalent level of BPA (2.25 μg BPA/kg bw/day) induced structural alterations in brain regions including the superior olivary complex (SOC) and bed nucleus of stria terminalis (BNST) with larger effect sizes (1.07≤ Cohens d ≤ 1.53). Human (n = 87) and rodent (n = 8 each group) sample sizes, while small, are considered adequate to perform the primary endpoint analysis. Combined, these human and mouse data suggest that gestational exposure to low levels of BPA may have some impacts on the developing brain at the resolution of MRI.

General Health of Pregnant Sprague-Dawley Rats and Neonates’ Small Intestine Morphology Upon Maternal Bisphenol A Exposure: A Preliminary Study

Associations between xenoestrogen bisphenol A (BPA) and multiple types of diseases, including metabolic syndrome, have been recorded in various studies. However, certain subsets of the human population are particularly more vulnerable to BPA repercussions, such as pregnant women, neonates, and children. This study was conducted to investigate the effects of BPA exposure during pregnancy on the general health of mothers and the histopathology of neonates’ small intestines. Eighteen Sprague-Dawley rats were divided into three groups: control, vehicle Tween-80, and 5mg/kg/day BPA after positive mating was confirmed. Physiological parameters consisted of body weight, waist circumference, water, and food intake, and blood pressures were measured at pregnancy day -1 or 2, 7, and 14 to see whether BPA exposure could exert obesogenic impacts on pregnant rats. Newborns were sacrificed to collect blood plasma for BPA analysis and intestinal samples for histopathological examination. Maternal BPA exposure did not affect the physiological parameters of pregnant rats. The number of pups delivered per litter and the sex ratio of BPA offsprings was not significantly different to those of control and vehicle groups (p>0.05). Likewise, the small intestine morphology of BPA neonates was comparable to those of controls and vehicles (preserved structure and absence of inflammatory cells infiltration). The nonsignificant difference in plasma BPA levels of control and BPA-exposed mothers and neonates may explain these findings. Future longitudinal studies which include the dose-dependent impacts of BPA on pregnant mothers’ health and neonates’ small intestine would be more beneficial.

Bisphenol a Interferes with Uterine Artery Features and Impairs Rat Feto-Placental Growth.

Bisphenol A (BPA) is a widespread environmental contaminant, found in human fluids and tissues. Maternal BPA exposure is associated with alterations in pregnancy outcomes. Because maternal uterine circulation plays a crucial role in normal placenta and fetal growth, we hypothesized that BPA compromises the function of uterine arteries (UAs) and fetoplacental development. Female rats were orally administered with BPA (2.5, 25 and 250 µg/kg/day) or with its vehicle (ethanol) for 30 days before pregnancy and during the first 20 days of pregnancy. To compare the effect of BPA in the reproductive vs. systemic circulation, it was tested on UAs and mesenteric arteries (MAs). Arteries were isolated and examined by pressure myography. Moreover, fetuses and placentas were weighed to provide an index of reproductive performance. In UAs of BPA-treated rats, lumen diameter, acetylcholine-relaxation and expressions of endothelial nitric oxide synthase 3 (NOS3), estrogen receptor α (ERα) and peroxisome proliferator-activated receptor ɣ (PPARɣ) were reduced. Conversely, no changes were observed in MAs. BPA treatment also reduced placental weights, while fetal weights were increased. For the first time, our results indicate that UAs represent a specific target of BPA during pregnancy and provide insight into the molecular mechanisms that underlie its negative effects on pregnancy outcomes.

Maternal Bisphenol A (BPA) Exposure Alters Cerebral Cortical Morphogenesis and Synaptic Function in Mice.

Early-life exposure to bisphenol A (BPA), synthetic compound used in polycarbonate plastic, is associated with altered cognitive and emotional behavior later in life. However, the brain mechanism underlying the behavioral deficits is unknown. Here, we show that maternal BPA exposure disrupted self-renewal and differentiation of neural progenitors during cortical development. The BPA exposure reduced the neuron number, whereas it increased glial cells in the cerebral cortex. Also, synaptic formation and transmission in the cerebral cortex were suppressed after maternal BPA exposure. These changes appeared to be associated with autophagy as a gene ontology analysis of RNA-seq identified an autophagy domain in the BPA condition. Mouse behavioral tests revealed that maternal BPA caused hyperactivity and social deficits in adult offspring. Together, these results suggest that maternal BPA exposure leads to abnormal cortical architecture and function likely by activating autophagy.

Prenatal Bisphenol a Exposure, DNA Methylation, and Low Birth Weight: A Pilot Study in Taiwan.

Prenatal exposure to bisphenol A (BPA) may increase the risk of abnormal birth outcomes, and DNA methylation might mediate these adverse effects. This study aimed to investigate the effects of maternal BPA exposure on maternal and fetal DNA methylation levels and explore whether epigenetic changes are related to the associations between BPA and low birth weight. We collected urine and blood samples originating from 162 mother-infant pairs in a Taiwanese cohort study. We measured DNA methylation using the Illumina Infinium HumanMethylation 450 BeadChip in 34 maternal blood samples with high and low BPA levels based on the 75th percentile level (9.5 μg/g creatinine). Eighty-seven CpGs with the most differentially methylated probes possibly interacting with BPA exposure or birth weight were selected using two multiple regression models. Ingenuity pathway analysis (IPA) was utilized to narrow down 18 candidate CpGs related to disease categories, including developmental disorders, skeletal and muscular disorders, skeletal and muscular system development, metabolic diseases, and lipid metabolism. We then validated these genes by pyrosequencing, and 8 CpGs met the primer design score requirements in 82 cord blood samples. The associations among low birth weight, BPA exposure, and DNA methylation were analyzed. Exposure to BPA was associated with low birth weight. Analysis of the epigenome-wide findings did not show significant associations between BPA and DNA methylation in cord blood of the 8 CpGs. However, the adjusted odds ratio for the dehydrogenase/reductase member 9 (DHRS9) gene, at the 2nd CG site, in the hypermethylated group was significantly associated with low birth weight. These results support a role of BPA, and possibly DHRS9 methylation, in fetal growth. However, additional studies with larger sample sizes are warranted.

Interaction of prenatal bisphenols, maternal nutrients, and toxic metal exposures on neurodevelopment of 2-year-olds in the APrON cohort

BackgroundEpidemiological studies suggest that Bisphenol-A (BPA) is a developmental neurotoxicant, but the modifying effects of maternal nutrient status or neurotoxicant metal co-exposures have not been reported. Bisphenol-S (BPS) is being used as a BPA-alternative, but few epidemiological studies have evaluated its effects. ObjectivesTo examine if prenatal maternal BPA or BPS exposure are associated with children’s neurodevelopment at two years of age while adjusting for effect-measure modification by sex, maternal nutrients, and co-exposure to neurotoxic metals. MethodsTotal BPA and BPS concentrations were analyzed in spot maternal urine from the second trimester; metals and maternal nutrient status were analyzed in blood. Child neurodevelopment was evaluated with the Bayley Scales of Infant Development-III (Bayley-III) at age 2 (394 maternal-child pairs) and linear regression was used to investigate associations. ResultsAmong nutrients and neurotoxic metals, selenium (Se) and cadmium (Cd) were the most significant predictors of Bayley-III scale scores. Higher maternal Cd was significantly correlated with poorer motor performance (p < 0.01), and higher levels of maternal Se were significantly associated with poorer performance on the cognitive, motor, and adaptive behavior scales (p < 0.05). While maternal Cd did not modify relationships between bisphenol exposures and Bayley-III scores, both maternal Se and child sex were significant effect-measure modifiers. Associations between BPA exposure and social emotional scores were negative for boys (p = 0.056) but positive for girls (p = 0.046). Higher exposure to bisphenols was associated with lower motor scores among children with lower levels of maternal Se. ConclusionHigher maternal Cd was associated with poorer motor development, but it was not an effect-measure modifier of bisphenols’ effects on motor development. Maternal Se may be protective against adverse effects of bisphenols, and additional nutrient-bisphenol interaction studies examining sex-specific effects of BPA and BPS on child development are warranted.

Association of urinary bisphenols during pregnancy with maternal, cord blood and childhood thyroid function

BackgroundMost pregnant women are exposed to bisphenols, a group of chemicals that can interfere with various components of the thyroid system. ObjectivesTo investigate the association of maternal urinary bisphenol concentrations during pregnancy with maternal, newborn and early childhood thyroid function. MethodsThis study was embedded in Generation R, a prospective, population-based birth cohort (Rotterdam, the Netherlands). Maternal urine samples were analyzed for eight bisphenols at early (<18), mid (18–25) and late (>25 weeks) pregnancy. Maternal serum thyroid stimulating hormone (TSH), free thyroxine (FT4) and total thyroxine (TT4) were measured in early pregnancy and child TSH and FT4 were measured in cord blood and childhood. ResultsThe final study population comprised 1,267 mothers, 853 newborns and 882 children. Of the eight bisphenols measured, only bisphenol A (BPA) was detected in >50% of samples at all three time-points and bisphenol S (BPS) at the first time-point. There was no association of BPA or the bisphenol molar sum with maternal thyroid function. Higher BPS concentrations were associated with a higher maternal TT4 (β [95% CI] per 1 (natural-log) unit increase: 0.97 [0.03 to 1.91]) but there was no association with TSH or FT4. Furthermore, higher BPS was associated with an attenuation of the association between maternal FT4 and TSH (Pinteraction = 0.001). There was no association of early or mid-pregnancy BPA or early pregnancy BPS with cord blood or childhood TSH and FT4. A higher late pregnancy maternal BPA exposure was associated with a higher TSH in female newborns (Pinteraction = 0.06) and a higher FT4 during childhood in males (Pinteraction = 0.08). DiscussionOur findings show that exposure to bisphenols may interfere with the thyroid system during pregnancy. Furthermore, the potential developmental toxicity of exposure to bisphenols during pregnancy could affect the thyroid system in the offspring in a sex-specific manner.

Paternal bisphenol A exposure in mice impairs glucose tolerance in female offspring

Humans are ubiquitously exposed bisphenol A (BPA), and epidemiological studies show a positive association between BPA exposure and diabetes risk, but the impact of parental exposure on offspring diabetes risk in humans is unknown. Our previous studies in mice show disruption of metabolic health upon maternal BPA exposure. The current study was undertaken to determine whether exposure in fathers causes adverse metabolic consequences in offspring. Male C57BL/6 J mice were exposed to BPA in the diet beginning at 5 weeks of age resulting in the following dietary exposure groups: Control (0 μg/kg/day), Lower BPA (10 μg/kg/day) and Upper BPA (10 mg/kg/day). After 12 weeks of dietary exposure, males were mated to control females. Mothers and offspring were maintained on the control diet. Post-pubertal paternal BPA exposure did not affect offspring body weight, body composition or glucose tolerance. However, when fathers were exposed to BPA during gestation and lactation, their female offspring displayed impaired glucose tolerance in the absence of compromised in vivo insulin sensitivity or reduced ex vivo glucose-stimulated insulin secretion. Male offspring exhibited normal glucose tolerance. Taken together, these studies show there is an early window of susceptibility in which paternal BPA exposure can cause sex-specific impairments in glucose homeostasis.

Prenatal exposure to multiple phenolic compounds, fetal reproductive hormones, and the second to fourth digit ratio of children aged 10 years in a prospective birth cohort

Select phenols are known to possess hormone-disrupting properties, but no previous study has addressed the potential effects of prenatal exposure to phenol mixtures on fetal reproductive hormones and children’s second to fourth digit (2D: 4D) ratio, a marker for in utero testosterone (T) exposure. We aimed to explore interrelations of prenatal phenol exposures individually and in mixtures, cord serum reproductive hormones, and 2D: 4D ratio of children aged 10 years. Urinary 11 phenol concentrations were determined from 392 pregnant women participating in a longitudinal birth cohort. We estimated associations of prenatal phenol exposures individually and in mixtures with cord reproductive hormones and children’s 2D:4D ratio using three statistical approaches, including generalized linear models (GLMs), elastic net regression (ENR) models and Bayesian kernel machine regression (BKMR) models. In female newborns, the three models showed that maternal triclosan (TCS) concentrations were significantly negatively associated with cord serum T levels [regression coefficient (β) = -0.076, 95% confidence interval (CI): 0.138, −0.013; p = 0.018]. Additionally, maternal urinary bisphenol A (BPA) levels were related to decreases in 2D:4D ratio of the left hand in girls by GLMs (β = −0.003, 95% CI: 0.007, −0.001; p = 0.024) and ENR models, but not BKMR models. We provided evidence that prenatal TCS exposure predicted lower cord serum T levels, and maternal BPA exposure was related to decreased 2D:4D ratio of the left hand in females.

Association between prenatal bisphenol a exposure and promoter hypermethylation of CAPS2, TNFRSF25, and HKR1 genes in cord blood

In utero exposure to bisphenol A (BPA) in early stages of development has been reported to exert adverse health effects on offspring later in life. Epigenetic alterations, particularly DNA methylation, may be one plausible biological mechanism involved. We examined the association between maternal BPA exposure and DNA methylation in cord blood. We randomly selected 96 paired samples of maternal urine and infant cord blood collected from the Shanghai-Minhang Birth Cohort. BPA levels in maternal urine were measured using high-performance liquid chromatography (HPLC). Three cord blood samples with maternal BPA levels >2.0 μg/g Cr and three samples with undetected BPA were randomly selected for genome-wide methylation analysis using methylated DNA binding domain sequencing (MBD-Seq). The genes with hypermethylated promoter regions were chosen for validation using quantitative methylation-specific polymerase chain reaction (Q-MSP). Based on MBD-seq results, we observed that maternal BPA exposure was primarily associated with hypermethylation of genes involved in signal transduction in the nervous system. Using Q-MSP, we further validated the association between maternal BPA exposure and promoter hypermethylation of three genes in multiple linear regression models: a log unit increase in BPA was associated with 12.63% (95%CI: 7.99, 17.26), 11.17%, (95%CI: 3.31, 19.02), and 16.57% (95% CI: 10.59, 22.56) increase in promoter of CAPS2, TNFRSF25, and HKR1 methylation, respectively. Our findings provide evidence that in utero exposure to BPA could alter the offspring's epigenome by altering DNA methylation pattern.

Adverse reproductive function induced by maternal BPA exposure is associated with abnormal autophagy and activating inflamation via mTOR and TLR4/NF-κB signaling pathways in female offspring rats

Bisphenol A (BPA) can affect reproductive function, but its mechanism of reproductive toxicity is unclear, and the effect of BPA on the onset of puberty was inconsistent. The main purpose of this study is to investigate the effects of perinatal exposure to BPA on the onset of puberty and reproductive function, and its mechanism from the aspect of autophagy and inflammation in ovarian and uterus tissues of female offspring. Twenty-one pregnant SD rats were randomly divided into three groups: Control group, 1 μg/mL BPA (LBPA) and 10 μg/mL BPA group (HBPA) via drinking water from gestational day 6 to the end of lactation. After weaning, female offspring rats were fed a normal diet and drinking water for 5 weeks. The levels of E2, LH, FSH, T, and IL-6 and TNF-α, and the onset of puberty, and morphological changes in ovarian and uterine were determined in female offspring at 8 weeks. The levels of TLR4, NF-κB, PI3K/Akt/mTOR and autophagy related protein in uterine tissue were also detected. Our results indicated that perinatal exposure to BPA advanced puberty, which was associated with increased serum E2, LH and FSH levels. There was a significantly thin endometrium epithelium in HBPA group compared with control group, which may affect reproductive function. The adverse effect of perinatal BPA exposure on reproductive function maybe was associated with the activation of inflammation and abnormal autophagy via TLR4/NF-κB and mTOR signaling pathways respectively in female offspring.

Prenatal exposure to bisphenol A alters the transcriptome-interactome profiles of genes associated with Alzheimer\u2019s disease in the offspring hippocampus

Our recent study revealed that prenatal exposure to bisphenol A (BPA) disrupted the transcriptome profiles of genes in the offspring hippocampus. In addition to genes linked to autism, several genes associated with Alzheimer’s disease (AD) were found to be differentially expressed, although the association between BPA-responsive genes and AD-related genes has not been thoroughly investigated. Here, we demonstrated that in utero BPA exposure also disrupted the transcriptome profiles of genes associated with neuroinflammation and AD in the hippocampus. The level of NF-κB protein and its AD-related target gene Bace1 were significantly increased in the offspring hippocampus in a sex-dependent manner. Quantitative RT-PCR analysis also showed an increase in the expression of Tnf gene. Moreover, the reanalysis of transcriptome profiling data from several previously published BPA studies consistently showed that BPA-responsive genes were significantly associated with top AD candidate genes. The findings from this study suggest that maternal BPA exposure may increase AD risk in offspring by dysregulating genes associated with AD neuropathology and inflammation and reveal a possible relationship between AD and autism, which are linked to the same environmental factor. Sex-specific effects of prenatal BPA exposure on the susceptibility of AD deserve further investigation.

The effects of maternal exposure to BPA during pregnancy on the male reproductive system and the testicular microRNA expression profile.

The effect of prenatal bisphenol A (BPA) exposure is increasingly concerned. We investigated the effect of maternal BPA exposure during pregnancy on male offspring and its potential mechanism. Thirty pregnant Sprague Dawley (SD) rats were randomly divided into exposed and control groups. At PND56, the number of sperm, luteinizing hormone, and testosterone in the BPA-exposed group decreased, and testicular tissue structure was damaged in offsprings. At GD20, the miRNA profile in the testis of male offspring was examined and the expression levels of 28 deregulated miRNAs were validated by qRT-PCR. We found that miR-361-5p, miR-203a-3p, and miR-19b-2-5p had significantly different expression levels in the testis. These results suggest that maternal exposure to BPA can lead to differential changes in progeny miRNAs, which will provide direction for future in-depth mechanisms of reproductive injury.

Urinary bisphenol A concentrations and adiposity measures at age 7 years in a prospective birth cohort

Bisphenol A (BPA) exposure during early life may increase risk of childhood obesity, however, prospective evidence of birth cohort is limited and inconclusive. We aimed to explore the associations of maternal and childhood BPA exposure with child adiposity measures, including body mass index, waist circumference and skinfold thickness and waist to height ratio of children at 7 years. 430 mother-child pairs were examined from a population-based prospective cohort in a rural area of East China. BPA concentrations of spot urine samples were quantified in mothers and their children aged 3 and 7 years. Maternal urinary BPA concentration was significantly positively associated with waist circumference in children aged 7 years (β = 0.508 cm, 95% CI: 0.067, 0.950). These significant associations were not modified by child sex, but they were only observed among girls in sex-stratified analyses. Risk of central obesity related to prenatal BPA exposure was significantly higher in the second and the third tertile than those in the first tertile (odds ratio, OR = 2.510, 95% CI = 1.146, 5.499; OR = 2.584, 95% CI = 1.186, 5.631, respectively; p for trend = 0.022). The present findings suggested that prenatal exposure to BPA may enhance waist circumference of children and thereby increase risk of central obesity in school-age girls.

Parental preconception and prenatal urinary bisphenol A and paraben concentrations and child behavior.

The Environment and Reproductive Health (EARTH) Study is a prospective cohort of couples from a fertility clinic at Massachusetts General Hospital. The Centers for Disease Control and Prevention (CDC) quantified BPA, butylparaben, ethylparaben, methylparaben, and propylparaben concentrations in multiple urine samples collected before conception and during pregnancy. From the eligible parents (N = 220), we enrolled 158 children between 2 and 9 years of age. The parents completed the Behavior-Assessment-System-for-Children-2 (BASC-2). We estimated covariate-adjusted associations of average parental preconception and prenatal ln-transformed urinary BPA and sum of paraben concentrations (∑paraben) with BASC-2 scores using linear regression with generalized estimating equations. Median urinary BPA and Σparaben concentrations were 1.2 and 189 μg/L in mothers preconception and 1.7 and 25 μg/L in fathers preconception, respectively. Among all children, parental BPA and ∑paraben concentrations were not associated with BASC-2 behavioral symptoms index, internalizing, or externalizing problems scores. Point estimates ranged from -1.5 to 1.4 with wide 95% confidence intervals that included the null value. In this fertility clinic cohort, parental preconception and maternal prenatal BPA and paraben concentrations were not associated with problem behaviors among children. However, our small sample sizes reduced the precision of our results.

Maternal environmental exposure to bisphenols and epigenome-wide DNA methylation in infant cord blood.

Maternal prenatal exposures, including bisphenol A (BPA), are associated with offspring’s risk of disease later in life. Alterations in DNA methylation may be a mechanism through which altered prenatal conditions (e.g. maternal exposure to environmental toxicants) elicit this disease risk. In the Michigan Mother and Infant Pairs Cohort, maternal first-trimester urinary BPA, bisphenol F, and bisphenol S concentrations were tested for association with DNA methylation patterns in infant umbilical cord blood leukocytes (N = 69). We used the Illumina Infinium MethylationEPIC BeadChip to quantitatively evaluate DNA methylation across the epigenome; 822 020 probes passed pre-processing and quality checks. Single-site DNA methylation and bisphenol models were adjusted for infant sex, estimated cell-type proportions (determined using cell-type estimation algorithm), and batch as covariates. Thirty-eight CpG sites [false discovery rate (FDR) <0.05] were significantly associated with maternal BPA exposure. Increasing BPA concentrations were associated with lower DNA methylation at 87% of significant sites. BPA exposure associated DNA methylation sites were enriched for 38 pathways significant at FDR <0.05. The pathway or gene-set with the greatest odds of enrichment for differential methylation (FDR <0.05) was type I interferon receptor binding. This study provides a novel understanding of fetal response to maternal bisphenol exposure through epigenetic change.

Prenatal exposure to BPA and birth outcomes- The TMICS Group

TPS 742: Adverse birth outcomes 1, Exhibition Hall, Ground floor, August 27, 2019, 3:00 PM - 4:30 PM Background: Bisphenol A (BPA) is mainly used to produce polycarbonate (PC) and epoxy resins. It exerts estrogenic and antiandrogenic effects by interacting with estrogen receptors (ERs) and antagonizing the androgen receptor (AR). However, the findings of prenatal exposure and birth outcomes in human epidemiologic study are inconsistent. Methods: Five hundred and fifty-five pregnant women without adverse pregnancy outcomes were enrolled from Taiwan island-wide and maternal urine was collected in the third trimester. Generalized additive model-penalized regression splines and a multivariable regression model were employed to determine the effects of BPA exposure on birth outcomes. Results: The detection rate was 83.1%; geometric mean of BPA levels for maternal urine was 0.95 μg/g cre. A significant negative association was found between the natural logarithm of pregnant women’s BPA levels and the Z-score of neonatal head circumference (β= -0.05cm, p value = 0.03). Pregnant women in the group with BPA above medium had a significantly longer anogenital distance (AGD, the distance from the center of the anus to the underside of the scrotum; β = 2.06 cm, p = 0.03) in boy. Conclusion: This study revealed the significant association between maternal BPA exposure and birth outcomes.

Maternal Exposure to Bisphenol A Combined with High-Fat Diet-Induced Programmed Hypertension in Adult Male Rat Offspring: Effects of Resveratrol.

Maternal exposure to endocrine disrupting chemicals (EDCs) and a high-fat intake may induce the developmental programming of hypertension in adult offspring. Bisphenol A (BPA) is one of the most commonly environmental EDCs. As the nitric oxide (NO) and aryl hydrocarbon receptor (AHR) signaling pathways both contribute to the pathogenesis of hypertension, we evaluated whether resveratrol, an antioxidant and an AHR antagonist, can prevent hypertension programmed by a maternal BPA and HF diet. Sixteen-week-old male rat offspring were assigned to six groups (n = 8 per group): Control, HF (D12331, Research Diets), BPA (50 μg/kg/day), HF + BPA, BPA + R (resveratrol 50mg/L in drinking water throughout pregnancy and lactation), and HF + BPA + R. Maternal BPA exposure exacerbated hypertension programmed by HF consumption in adult male offspring, which was protected by maternal resveratrol therapy. The BPA and HF diet synergistically induced oxidative stress in offspring kidneys, which resveratrol treatment prevented. We observed that HF + BPA-induced programmed hypertension was associated with a decreased NO bioavailability, increased oxidative stress, and an activated AHR signaling pathway. The beneficial effects of resveratrol are relevant to restoring NO bioavailability, reducing oxidative stress, and antagonizing the AHR signaling pathway. Our results cast a new light on resveratrol as a reprogramming strategy to protect against hypertension programmed by combined BPA and HF exposure, but this strategy has yet to be translated into clinical applications.