Prenatal Bisphenol A Exposure Research Articles

Prenatal and childhood exposure to endocrine-disrupting chemicals and early thelarche in 8-year-old girls: A prospective study using Bayesian kernel regression

BackgroundStudies on the combined effects of persistent and non-persistent endocrine-disrupting chemicals (EDCs) on puberty are insufficient. To date, no studies have analyzed breast development at age 8 years, a key criterion for determining precocious puberty. We investigated the relationship between prenatal or childhood exposure to EDC mixtures and early thelarche, defined as breast development before age 8 years in girls. MethodsThis prospective study included 211 girls with data on prenatal and 8-year-old exposure of cadmium (Cd), lead, mercury, bisphenol-A (BPA), 3-phenoxybenzoic acid, and three phthalate metabolites from the Environment and Development of Children cohort. Prenatal exposure was assessed through samples from pregnant women at 14–27th weeks of gestation. Tanner staging was assessed by a pediatric endocrinologist. The relationship between single and mixed chemical exposures and outcomes was assessed using logistic regression, generalized additive models (GAM), and Bayesian kernel machine regression (BKMR) models. ResultsEarly thelarche was observed in 42 (19.9%) girls at age 8 years. In the logistic regression models, the risk of early thelarche increased with increased exposure to Cd in their mothers (adjusted odds ratio [aOR] per interquartile range [IQR] = 1.80, 95% confidence interval [CI] 1.23–2.65) but decreased with prenatal BPA exposure (aOR per IQR = 0.57, 95% CI 0.35–0.92). None of the 8-year-old chemical exposures was associated with early thelarche. In the GAM, early thelarche was positively correlated with prenatal Cd and inversely associated with prenatal BPA exposure (p = 0.004 for Cd and p = 0.036 for BPA). In the BKMR models, an increase in log-transformed prenatal Cd concentrations from the 25th to 75th percentile was associated with an increase in the estimated probability of early thelarche at age 8 years (risk difference: 0.46 [95% credible interval: 0.04–0.88]) when other chemicals were set at their median values. ConclusionsConsidering the combined effects of persistent and non-persistent chemical mixtures, maternal Cd exposure during the second trimester may be associated with early thelarche in 8-year-old girls.

Male autism spectrum disorder is linked to brain aromatase disruption by prenatal BPA in multimodal investigations and 10HDA ameliorates the related mouse phenotype

Male sex, early life chemical exposure and the brain aromatase enzyme have been implicated in autism spectrum disorder (ASD). In the Barwon Infant Study birth cohort (n = 1074), higher prenatal maternal bisphenol A (BPA) levels are associated with higher ASD symptoms at age 2 and diagnosis at age 9 only in males with low aromatase genetic pathway activity scores. Higher prenatal BPA levels are predictive of higher cord blood methylation across the CYP19A1 brain promoter I.f region (P = 0.009) and aromatase gene methylation mediates (P = 0.01) the link between higher prenatal BPA and brain-derived neurotrophic factor methylation, with independent cohort replication. BPA suppressed aromatase expression in vitro and in vivo. Male mice exposed to mid-gestation BPA or with aromatase knockout have ASD-like behaviors with structural and functional brain changes. 10-hydroxy-2-decenoic acid (10HDA), an estrogenic fatty acid alleviated these features and reversed detrimental neurodevelopmental gene expression. Here we demonstrate that prenatal BPA exposure is associated with impaired brain aromatase function and ASD-related behaviors and brain abnormalities in males that may be reversible through postnatal 10HDA intervention.

Prenatal low-dose Bisphenol A exposure impacts cortical development via cAMP-PKA-CREB pathway in offspring.

Bisphenol A (BPA) is a widely used plasticizer known to cause various disorders. Despite a global reduction in the use of BPA-containing products, prenatal exposure to low-dose BPA, even those below established safety limits, has been linked to neurological and behavioral deficits in childhood. The precise mechanisms underlying these effects remain unclear. In the present study, we observed a significant increase in the number of cortical neurons in offspring born to dams exposed to low-dose BPA during pregnancy. We also found that this prenatal exposure to low-dose BPA led to increased proliferation but reduced migration of cortical neurons. Transcriptomic analysis via RNA sequencing revealed an aberrant activation of the cAMP-PKA-CREB pathway in offspring exposed to BPA. The use of H89, a selective PKA inhibitor, effectively rescued the deficits in both proliferation and migration of cortical neurons. Furthermore, offspring from dams exposed to low-dose BPA exhibited manic-like behaviors, including hyperactivity, anti-depressant-like responses, and reduced anxiety. While H89 normalized hyperactivity, it didn't affect the other behavioral changes. These results suggest that the overactivation of PKA plays a causative role in BPA-induced changes in neuronal development. Our data also indicate that manic-like behaviors induced by prenatal low-dose BPA exposure may be influenced by both altered neuronal development and abnormal PKA signaling in adulthood.

Distinct gut flora profile induced by postnatal trans-fat diet in gestationally bisphenol A-exposed rats.

There has been much evidence showing the repercussions of prenatal bisphenol A (BPA) exposure with a postnatal high fat-diet (HFD) on offspring's health. However, the information on how the interaction between these two variables affects the gut microbiome is rather limited. Hence, we investigated the impact of a postnatal trans fat diet (TFD) on the gut microbiome of offspring exposed to BPA during the prenatal period in an animal model. Pregnant rats were divided into 5 mg/kg/day BPA, vehicle Tween80 (P80) or control (CTL) drinking water until delivery (N = 6 per group). Then, weaned male pups were further subdivided into three normal diet (ND) groups (CTLND, P80ND, and BPAND) and three TFD groups (CTLTFD, P80TFD, and BPATFD) (n = 6 per group). 180-250 g of faecal samples were collected on days 50 and 100 to assess the composition of the offspring's intestinal flora using next-generation sequencing. The alpha diversity indices of TFD offspring with and without BPA were markedly lower than their ND counterparts (p<0.001-p<0.05). The beta diversity, hierarchical cluster and network analyses of the offspring's microbiome demonstrated that the microbiome species of the TFD group with and without BPA were distinctly different compared to the ND group. Consistently, TFD and ND offspring pairings exhibited a higher number of significantly different species (p<0.0001-p<0.05) compared to those exposed to prenatal BPA exposure and different life stages comparisons, as shown by the multivariate parametric analysis DESeq2. Predictive functional profiling of the offspring's intestinal flora demonstrated altered expressions of genes involved in metabolic pathways. In summary, the gut flora composition of the rat offspring may be influenced by postnatal diet instead of prenatal exposure to BPA. Our data indicate the possibility of perturbed metabolic functions and epigenetic modifications, in offspring that consumed TFD, which may theoretically lead to metabolic diseases in middle or late adulthood. Further investigation is necessary to fully understand these implications.

Hypothalamic vasopressin sex differentiation is observed by embryonic day 15 in mice and is disrupted by the xenoestrogen bisphenol A

Arginine vasopressin (AVP) neurons of the hypothalamic paraventricular region (AVPPVN) mediate sex-biased social behaviors across most species, including mammals. In mice, neural sex differences are thought to be established during a critical window around birth ( embryonic (E) day 18 to postnatal (P) day 2) whereby circulating testosterone from the fetal testis is converted to estrogen in sex-dimorphic brain regions. Here, we found that AVPPVN neurons are sexually dimorphic by E15.5, prior to this critical window, and that gestational bisphenol A (BPA) exposure permanently masculinized female AVPPVN neuronal numbers, projections, and electrophysiological properties, causing them to display male-like phenotypes into adulthood. Moreover, we showed that nearly twice as many neurons that became AVP+ by P0 were born at E11 in males and BPA-exposed females compared to control females, suggesting that AVPPVN neuronal masculinization occurs between E11 and P0. We further narrowed this sensitive period to around the timing of neurogenesis by demonstrating that exogenous estrogen exposure from E14.5 to E15.5 masculinized female AVPPVN neuronal numbers, whereas a pan-estrogen receptor antagonist exposed from E13.5 to E15.5 blocked masculinization of males. Finally, we showed that restricting BPA exposure to E7.5-E15.5 caused adult females to display increased social dominance over control females, consistent with an acquisition of male-like behaviors. Our study reveals an E11.5 to E15.5 window of estrogen sensitivity impacting AVPPVN sex differentiation, which is impacted by prenatal BPA exposure.

Prenatal exposure to low-dose bisphenol A disrupts hippocampal DNA methylation and demethylation in male rat offspring.

Earlier research has demonstrated that developmental exposure to bisphenol A (BPA) has persistent impacts on both adult brain growth and actions. It has been suggested that BPA might obstruct the methylation coding of the genes in the brain. In this study, the methylation changes in the hippocampus tissue of male rat pups were examined following prenatal BPA exposure. Pregnant Sprague-Dawley rats were treated with either vehicle (tocopherol-stripped corn oil) or BPA (4, 40, or 400μg/kg·body weight/day) throughout the entire duration of gestation and lactation. At 3weeks of age, the male rat offspring were euthanized, and the hippocampus were dissected out for analysis. The expression levels of DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) and DNA demethylases (TET1, Gadd45a, Gadd45b, and Apobec1) were analyzed in the hippocampus by means of quantitative real-time polymerase chain reaction and Western blotting, respectively. The results showed that prenatal exposure to BPA upregulated the expression of enzymes associated with DNA methylation and demethylation processes in the hippocampus of male rat offspring. These findings suggest that prenatal exposure to a low dose of BPA could potentially disrupt the balance of methylation and demethylation in the hippocampus, thereby perturbing epigenetic modifications. This may represent a neurotoxicity mechanism of BPA.

Neurodevelopmental effects of prenatal Bisphenol A exposure on the role of microRNA regulating NMDA receptor subunits in the male rat hippocampus

Maternal bisphenol A (BPA) exposure has been reported to cause learning and memory deficits in born offspring. However, little is known that this impairment is potentially caused by epigenetic modulation on the development of NMDA receptor subunits. This study investigates the effect of prenatal BPA exposure on the hippocampal miR-19a and miR-539, which are responsible for regulating NMDA receptor subunits as well as learning and memory functions. Pregnant Sprague Dawley rats were orally administered with 5 mg/kg/day of BPA from pregnancy day 1 (PD1) until gestation day 21 (GD21), while control mothers received no BPA. The mothers were observed daily until GD21 for either a cesarean section or spontaneous delivery. The male offspring were sacrificed when reaching GD21 (fetus), postnatal days 7, 14, 21 (PND7, 14, 21) and adolescent age 35 (AD35) where their hippocampi were dissected from the brain. The expression of targeted miR-19a, miR-539, GRIN2A, and GRIN2B were determined by qRT-PCR while the level of GluN2A and GluN2B were estimated by western blot. At AD35, the rats were assessed with neurobehavioral tests to evaluate their learning and memory function. The findings showed that prenatal BPA exposure at 5 mg/kg/day significantly reduces the expression of miR-19a, miR-539, GRIN2A, and GRIN2B genes in the male rat hippocampus at all ages. The level of GluN2A and GluN2B proteins is also significantly reduced when reaching adolescent age. Consequently, the rats showed spatial and fear memory impairments when reaching AD35. In conclusion, prenatal BPA exposure disrupts the role of miR-19a and miR-539 in regulating the NMDA receptor subunit in the hippocampus which may be one of the causes of memory and learning impairment in adolescent rats.

Developmental programming: An exploratory analysis of pancreatic islet compromise in female sheep resulting from gestational BPA exposure

Developmental exposure to endocrine disruptors like bisphenol A (BPA) are implicated in later-life metabolic dysfunction. Leveraging a unique sheep model of developmental programming, we conducted an exploratory analysis of the programming effects of BPA on the endocrine pancreas. Pregnant ewes were administered environmentally relevant doses of BPA during gestational days (GD) 30–90, and pancreata from female fetuses and adult offspring were analyzed. Prenatal BPA exposure induced a trend toward decreased islet insulin staining and β-cell count, increased glucagon staining and α-cell count, and increased α-cell/β-cell ratio. Findings were most consistent in fetal pancreata assessed at GD90 and in adult offspring exposed to the lowest BPA dose. While not assessed in fetuses, adult islet fibrosis was increased. Collectively, these data provide further evidence that early-life BPA exposure is a likely threat to human metabolic health. Future studies should corroborate these findings and decipher the molecular mechanisms of BPA's developmental endocrine toxicity.

Developmental Programming: Impact of Prenatal Exposure to Bisphenol A on Senescence and Circadian Mediators in the Liver of Sheep.

Prenatal exposure to endocrine disruptors such as bisphenol A (BPA) plays a critical role in the developmental programming of liver dysfunction that is characteristic of nonalcoholic fatty liver disease (NAFLD). Circadian and aging processes have been implicated in the pathogenesis of NAFLD. We hypothesized that the prenatal BPA-induced fatty-liver phenotype of female sheep is associated with premature hepatic senescence and disruption in circadian clock genes. The expression of circadian rhythm and aging-associated genes, along with other markers of senescence such as telomere length, mitochondrial DNA copy number, and lipofuscin accumulation, were evaluated in the liver tissue of control and prenatal BPA groups. Prenatal BPA exposure significantly elevated the expression of aging-associated genes GLB1 and CISD2 and induced large magnitude differences in the expression of other aging genes-APOE, HGF, KLOTHO, and the clock genes PER2 and CLOCK-in the liver; the other senescence markers remained unaffected. Prenatal BPA-programmed aging-related transcriptional changes in the liver may contribute to pathological changes in liver function, elucidating the involvement of aging genes in the pathogenesis of liver steatosis.

Prenatal to preschool exposure of nonylphenol and bisphenol A exposure and neurodevelopment in young children

Nonylphenol (NP) and bisphenol A (BPA) are produced in large quantities worldwide as multipurpose agents. However, studies on relations between NP and BPA exposure and childhood neurodevelopment are few, and the results are inconsistent. This study aimed to investigate associations between prenatal and early childhood NP and BPA exposure and neurodevelopment in mother-child pairs. Pregnant women at 27-38 weeks' gestation were recruited, as were children 2-3 years of age (n=94) and 4-6 years of age (n=56) years. Urine was collected to assess NP and BPA exposure. Bayley Scales of Infant and Toddler Development (3rd edition; Bayley-III), Wechsler Preschool and Primary Scale of Intelligence (4th edition), and the Full Scale Intelligence Quotient (WPPSI-IV-FSIQ) were used to assess the neurodevelopment of the children. The detection rate and concentration of NP and BPA in the urine of children 4-6 years old were higher than in those 2-3 years old. Children were divided into a high concentration group (3rd tertile) and a reference group (1st and 2nd tertiles) based on natural log-transformed urine concentration of NP and BPA. Girls' Bayley-III motor scores in the high concentration group were higher than those of the BPA reference group of urine of mothers (β=6.85, 95% confidence interval [CI]: 1.58-12.13). Boys' FSIQ in the higher concentration group were significantly lower than those in children 2-3 years old in the NP reference group (β=-11.29, 95% CI: -18.62 to -3.96) (all, p<0.05). Prenatal and childhood exposure to NP and BPA may have different effects on the neurodevelopment of young children, and there are no consistent effects between boys and girls.

Adulthood bisphenol A exposure induces anxiety in male mice via downregulation of alpha-1D adrenergic receptor in paraventricular thalamus

Bisphenol A (BPA), a ubiquitous endocrine disrupting chemical, is widely used in household plastic products. Large amounts of evidence indicate prenatal and postnatal BPA exposure causes neurodevelopmental disorders such as anxiety and autism. However, the neuronal mechanisms underlying the neurotoxic effects of adulthood BPA exposure remain poorly understood. Here, we provided evidences that adult mice treated with BPA (0.45 mg/kg/day) during 3 weeks exhibited sex-specific anxiety like behaviors. We demonstrated that the BPA-induced anxiety in male mice, but not in female mice, was closely associated with hyperactivity of glutamatergic neurons in the paraventricular thalamus (PVT). Acute chemogenetic activation of PVT glutamatergic neurons caused similar effects on anxiety as observed in male mice exposed to BPA. In contrast, acute chemogenetic inhibition of PVT glutamatergic neurons reduced BPA-induced anxiety in male mice. Concomitantly, the BPA-induced anxiety was related with a down-regulation of alpha-1D adrenergic receptor in the PVT. Taken together, the present study indicated a previously unknown target region in the brain for neurotoxic effects of BPA on anxiety and implicated a possible molecular mechanism of action.

The effects of trans fat diet intake on metabolic parameters and pancreatic tissue in offspring of prenatal bisphenol A exposed rats

Bisphenol A (BPA) is a plasticiser used in the manufacturing of many products and its effects on human health remain controversial. Up till now, BPA involvement in metabolic syndrome risk and development is still not fully understood. In this study, we aimed to investigate the effect of prenatal BPA exposure with postnatal trans-fat diet intake on metabolic parameters and pancreatic tissue histology. Eighteen pregnant rats were divided into control (CTL), vehicle tween 80 (VHC), and BPA (5 mg/kg/day) from gestational day (GD) 2 until GD 21, then their weaning rat’s offspring were fed with normal diet (ND) or trans-fat diet (TFD) from postnatal week (PNW) 3 until PNW 14. The rats were then sacrificed and the blood (biochemical analysis) and pancreatic tissues (histological analysis) were collected. Glucose, insulin, and lipid profile were measured. The study has shown that there was no significant difference between groups with regard to glucose, insulin, and lipid profiles (p > 0.05). All pancreatic tissues showed normal architecture with irregular islets of Langerhans in TFD intake groups compared to offspring that consumed ND. Furthermore, the pancreatic histomorphometry was also affected whereby the study findings revealed that there was a significant increase in the mean number of pancreatic islets in rats from BPA-TFD group (5.987 ± 0.3159 islets/field, p = 0.0022) compared to those fed with ND and BPA non-exposed. In addition, the results have found that prenatal BPA exposure resulted in a significant decrease in the pancreatic islets diameter of the BPA-ND group (183.3 ± 23.28 µm, p = 0.0022) compared to all other groups. In conclusion, prenatal BPA exposure with postnatal TFD in the offspring may affect glucose homeostasis and pancreatic islets in adulthood, and the effect may be more aggravated in late adulthood.

Bisphenol-A (BPA) Impairs Hippocampal Neurogenesis via Inhibiting Regulation of the Ubiquitin Proteasomal System.

The ubiquitin-proteasome system (UPS) controls protein homeostasis to maintain cell functionality and survival. Neurogenesis relies on proteasome function, and a defective proteasome system during brain development leads to neurological disorders. An endocrine-disrupting xenoestrogen bisphenol-A (BPA) used in plastic products adversely affects human health and causes neurotoxicity. Previously, we reported that BPA reduces neural stem cells (NSCs) proliferation and differentiation, impairs myelination and mitochondrial protein import, and causes excessive mitochondrial fragmentation leading to cognitive impairments in rats. Herein, we examined the effect(s) of prenatal BPA exposure on UPS functions during NSCs proliferation and differentiation in the hippocampus. Rats were orally treated with 40µg/kg body weight BPA during day 6 gestation to day 21 postnatal. BPA significantly reduced proteasome activity in a cellular extract of NSCs. Immunocytochemistry exhibited a significant reduction of 20S proteasome/Nestin+ and PSMB5/Nestin+ cells in NSCs culture. BPA decreased 20S/Tuj1+ and PSMB5/Tuj1+ cells, indicating disrupted UPS during neuronal differentiation. BPA reduced the expression of UPS genes, 20S, and PSMB5 protein levels and proteasome activity in the hippocampus. It significantly reduced overall protein synthesis by the loss of Nissl substances in the hippocampus. Pharmacological activation of UPS by a bioactive triterpenoid 18α-glycyrrhetinic acid (18α GA) caused increased proteasome activities, significantly increased neurosphere size and number, and enhanced NSCs proliferation in BPA exposed culture, while proteasome inhibition by MG132 further aggravates BPA-mediated effects. In silico studies demonstrated that BPA strongly binds to catalytic sites of UPS genes (PSMB5, TRIM11, Parkin, and PSMD4) which may result in UPS inactivation. These results suggest that BPA significantly reduces NSCs proliferation by impairing UPS, and UPS activation by 18α GA could suppress BPA-mediated neurotoxicity and exerts neuroprotection.

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.

RF22 | PMON11 Non-coding RNA Signatures of Prenatal BPA Exposure in Liver and Muscle of Female Sheep

Abstract Prenatal exposure to bisphenol-A (BPA), an ubiquitously present endocrine-disrupting chemicals, induces peripheral insulin resistance as well as lipotoxicity and oxidative stress in the liver and muscle along with tissue-specific transcriptional changes in female sheep. To gain a mechanistic understanding of contributors to these liver and muscle-specific transcriptional changes, we hypothesized that prenatal BPA exposure impacts non-coding RNA (ncRNA), regulators of transcriptional and post-transcriptional control of coding RNAs. We sequenced ncRNA (including lncRNA, microRNA, snoRNA, and snRNA) in the liver and muscle obtained during the late follicular phase from 21-month-old control and prenatal BPA-treated (0.5mg/kg/day from days 30 to 90 of gestation; Term: 147days) female sheep (n=4 control and 4 prenatal BPA treated). The sequence data were subjected to differential expression analysis and multivariate modeling to identify specific ncRNA signatures. In the liver, 77 lncRNA (49 down, 28 up), 14 microRNAs (6 down, 8 up), 127 snoRNAs (63 down, 64 up) and 55 snRNAs (15 down, 40 up) were dysregulated (FDR&amp;lt;0.1, absolute log2FC&amp;gt;0.5) with BPA exposure. In the muscle 6 lncRNA were upregulated and 65 snoRNAs (47 down, 18 up) were dysregulated (FDR&amp;lt;0.1, absolute log2FC&amp;gt;0.5). Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) plots identified microRNAs MIR200B, MIR409, MIR30B, and MIR154A in the liver and miRNAs MIR26B, MIR29A, MIR125B, and MIR127 in muscle and several uncharacterized ncRNAs as signatures of prenatal BPA exposure. Multiple ncRNA signatures correlated with coding genes including LCORL, MED17, and ZNF41 in the liver, but none were correlated in the muscle. Among the coding genes which correlated with ncRNA, LCORL is reported to be related to steatosis of the liver in geese, a feature also observed in livers from prenatal BPA-treated female sheep. Since lipid accumulation in the liver may result from increased fatty acid biosynthesis, MED17 which is involved in transcriptional activation of lipogenic genes that correlated with multiple ncRNA in the liver may be a contributor to the steatosis observed in this model. In addition, MIR200B and MIR30B in the liver and MIR26B and MIR29A in the muscle are linked to lipid dysfunction, endoplasmic reticulum stress, and fibrosis. These findings provide mechanistic clues into the role of ncRNA in the prenatal BPA-induced lipid accumulation and oxidative stress in the liver and muscle, contributors to metabolic dysfunction observed in this female sheep model of gestational BPA exposure. In addition, findings from this precocial model of human translational relevance is a step towards gaining mechanistic insights in the programming of metabolic dysfunctions from environmental exposure to BPA, an endocrine disruptor of public health relevance. Presentation: Sunday, June 12, 2022 1:06 p.m. - 1:11 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

The Current Findings on the Impact of Prenatal BPA Exposure on Metabolic Parameters: In Vivo and Epidemiological Evidence.

Metabolic syndrome (MS) is a multifactorial disease entity and is not fully understood. Growing evidence suggests that early exposure to bisphenol A (BPA) is a significant risk factor for the development of metabolic diseases. BPA is a monomer used in the manufacturing of polycarbonate plastics, thermal receipt paper, and epoxy resins. Owing to its widespread use, BPA has been detected in human fluids and tissues, including blood, placental breast milk, and follicular fluid. In the present review, we aimed to review the impact of prenatal exposure to different doses of BPA on metabolic parameters as determined by in vivo and epidemiological studies. The PubMed, Scopus, and Web of Science electronic databases were searched to identify articles published during a period of 15 years from 2006 to 2021, and 29 studies met the criteria. Most studies demonstrated that prenatal exposure to low BPA concentrations correlated with alterations in metabolic parameters in childhood and an increased risk of metabolic diseases, such as obesity and type 2 diabetes mellitus (T2DM), in adulthood. Therefore, prenatal exposure to low doses of BPA may be associated with an increased risk of obesity and T2DM in a sex-specific manner.

Maternal bisphenol A and triclosan exposure and allergic diseases in childhood: a meta-analysis of cohort studies.

Bisphenol A (BPA) and triclosan (TCS) are both endocrine-disrupting chemicals (EDCs), and pregnant women are usually exposed to them through daily consumption. This study aimed to explore the relationship between prenatal BPA and TCS exposure and allergic diseases in childhood by systematic review and meta-analysis. We searched the topic of prenatal BPA and TCS exposure and allergic diseases in childhood published before March 22, 2021, in four databases, including PubMed, Web of Science, Embase, and Cochrane. Statistical analysis was completed using Stata software (version 16.0). Seven papers on BPA and four papers on TCS were included in this meta-analysis. The association between prenatal exposure to BPA and total allergic diseases in childhood showed a pooled effect estimate of 1.13 (95% CI, 1.04, 1.23), with I2 = 0.0% (P = 0.615). The effect estimates between BPA exposure and each allergic disease were 1.18 (95% CI, 1.02, 1.36) for wheezing, 1.23 (95% CI, 1.01, 1.50) for asthma, 1.03 (95% CI, 0.89, 1.18) for eczema/rashes or hives, and 1.19 (95% CI, 0.91, 1.56) for aeroallergies. Prenatal exposure to TCS had no association with the four types of allergic disease in childhood. BPA exposure during the prenatal period was positively associated with allergic disease in childhood. Strengthening prenatal EDC exposure control is necessary for child health.

Prenatal Bisphenol a Exposure and Postnatal Trans Fat Diet Alter Small Intestinal Morphology and Its Global DNA Methylation in Male Sprague-Dawley Rats, Leading to Obesity Development.

In this study, we aimed to determine whether a postnatal trans fat diet (TFD) could aggravate prenatal bisphenol A (BPA) exposure effects on offspring’s small intestine and adulthood obesity, due to the relatively sparse findings on how the interaction between these two variables interrupt the small intestinal cells. Twelve pregnant rats were administered with either unspiked drinking water (control; CTL) or BPA-spiked drinking water throughout pregnancy. Twelve weaned pups from each pregnancy group were then given either a normal diet (ND) or TFD from postnatal week (PNW) 3 until PNW14, divided into control offspring on normal diet (CTL-ND), BPA-exposed offspring on normal diet (BPA-ND), control offspring on trans fat diet (CTL-TFD), and BPA offspring on trans fat diet (BPA-TFD) groups. Body weight (BW), waist circumference, and food and water intake were measured weekly in offspring. At PNW14, small intestines were collected for global DNA methylation and histological analyses. Marked differences in BW were observed starting at PNW9 in BPA-TFD (389.5 ± 10.0 g; p < 0.05) relative to CTL-ND (339.0 ± 7.2 g), which persisted until PNW13 (505.0 ± 15.6 g). In contrast, water and food intake between offspring were significantly different (p < 0.01–0.05) at earlier ages only (PNW4–6 and PNW7–9, respectively). Furthermore, substantial differences in the general parameters of the intestinal structures were exclusive to ileum crypt length alone, whereby both BPA-ND (150.5 ± 5.1 μm; p < 0.001), and BPA-TFD (130.3 ± 9.9 μm; p < 0.05) were significantly longer than CTL-ND (96.8 ± 8.9 μm). Moreover, BPA-ND (2.898 ± 0.147%; p < 0.05) demonstrated global small intestinal hypermethylation when compared to CTL-ND and CTL-TFD (1.973 ± 0.232% and 1.913 ± 0.256%, respectively). Prenatal BPA exposure may significantly affect offspring’s physiological parameters and intestinal function. Additionally, our data suggest that there might be compensatory responses to postnatal TFD in the combined BPA prenatal group (BPA-TFD).

Prenatal bisphenol A exposure in relation to behavioral outcomes in girls aged 4–5 and modification by socio-demographic factors in The Infant Development and Environment Study (TIDES)

Bisphenol A (BPA) is a polymer used in the production of polycarbonate plastics and epoxy resins. An estrogen mimic, prenatal BPA exposure has been associated with several behavioral outcomes in children; however, the impact of maternal demographic and economic factors on associations between BPA and child behavioral outcomes have not been examined. The objective of this study was to examine associations between prenatal maternal urinary BPA and behavior in 4–5 year old girls, and to assess whether socio-demographic factors modify this relationship. Mothers enrolled in The Infant Development and Environment Study (TIDES) provided a single spot urine at enrollment (median gestational age 11 weeks) and completed the Behavior Assessment System for Children-2 (BASC-2) and Social Responsiveness Scale-2 (SRS-2) when their daughters were 4–5 years of age. Mother-daughter pairs with complete phthalate, BASC-2, SRS-2, and covariate data were included in this analysis (N = 244). BPA was detectable in 93 % of urine samples. We used multivariable linear regression analyses to estimate associations between maternal urinary log10-transformed BPA concentration and BASC-2 subscale and composite scores and SRS-2 Total Score. To examine the role of socioeconomic and demographic factors associated with study site, we stratified by TIDES center, comparing those enrolled at University of Rochester Medical Center (URMC), a predominately lower socioeconomic population, and those enrolled elsewhere: University of Washington, University of Minnesota, and University of California San Francisco, whose populations share similar higher socioeconomic demographic characteristics. Across all centers, no associations were seen between BPA and BASC-2 or SRS-2 scores. When stratifying by center, BPA was significantly associated with greater social impairment as measured by the SRS-2 Total Score (β-coefficient [95 % confidence intervals]: 5.1 [1.0, 9.2]) in URMC participants (N = 61). In non-URMC participants (N = 183), BPA was significantly associated with lower BASC-2 Internalizing composite (−3.3 [−6.7, 0.0]) and Depression subscale scores (−3.4 [−6.7, 0.0]) while no associations were seen between BPA and SRS-2 scores. Our findings suggest that sociodemographic factors may modify the impacts of maternal prenatal BPA on developmental endpoints.

Evaluation of p21 expression and related autism-like behavior in Bisphenol-A exposed offspring of Wistar albino rats.

Bisphenol A (BPA), an endocrine disruptor, may be involved in the etiology of autism spectrum disorders (ASD); however, the mechanism of neuronal and astrocytic damage remains ambiguous. A possible role of altered expression of p21 in autistic-like behavior in rat offspring was examined with prenatal and postnatal BPA exposure. Wistar albino dams were exposed to BPA (5mg/kg) intraperitoneally throughout pregnancy and until the third postnatal day (PND). Pups were examined on 21st PND for behavioral test. Blood samples were collected for serum lactate levels and pups were sacrificed. Right frontal cortices were dissected out and processed for H&E, immunohistochemical analysis, and gene expression. Anxiety like behavior and thigmotaxis along with reduction in serum lactate concentrations were observed in pups exposed to BPA. Decline in neuronal number and decreased astrocytic population with reduced dendritic spines were revealed by H&E and immunohistochemical analysis, respectively, in right frontal cortices. Over expression of p21 was also detected in BPA-exposed offspring. Over expression of p21 may be associated with autistic behavior. Further studies are recommended to explore the structural alterations in other white matter pathways in frontal cortices.