Epigenetic responses following maternal dietary exposure to physiologically relevant levels of bisphenol A

Abstract

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 (Avy) mouse, we examine the effects of developmental exposure through maternal diet to 50 ng BPA/kg (n = 14 litters), 50 μg 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 Avy/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 Avy/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 μg 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 (CabpIAP) metastable epiallele shows hypermethylation in the 50 μg 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.

Longitudinal epigenetic drift in mice perinatally exposed to lead

“…Though the induced shift is small, multiple studies have shown correlations with small absolute methylation shifts in transposons are associated with human aging and exposure to air pollution. 20,31,32 Imprinted genes are often used as candidate loci for environmentally induced epigenetic change, making a study of their natural change in DNA methylation over the life-course a valuable baseline measurement. 33,34 For example, human insulin-like growth factor 2 (IGF2) DNA methylation has been positively correlated with age in multiple cross-sectional studies.…”

“…Imprinted genes contain parent-of-origin epigenetic marks, including differentially methylated regions (DMRs), resulting in mono-allelic expression. These commonly used biomarkers host CpG islands that are variably methylated 19 or differentially methylated, 18,20 respectively, and environmental exposures have been shown to stably influence their epigenetic marks and subsequent gene expression. [21][22][23][24] Therefore, measuring the relative change in DNA methylation from early to adult life in epigenetically labile regions is crucial to determining whether early life Pb exposure can alter the magnitude or direction of epigenetic drift.…”

Stat3 is a candidate epigenetic biomarker of perinatal Bisphenol A exposure associated with murine hepatic tumors with implications for human health

“…42 For example, total liver BPA measurements in animals fed the highest dose of BPA, 50 mg/kg chow, ranged from 9.5 to 870 mg/kg liver, which encompasses the maximum human environmental exposure indicated by human fetal liver measurements, ranging from below the limit of quantitation (LOQ) to 96.8 mg BPA/kg liver. 42 Anderson et al 42 reported BPA concentrations of < LOQ-11.3 mg/kg liver (mean 2 mg/ kg; median 0.6 mg/kg) and < LOQ-13 mg/kg liver (mean 2.8 mg/kg; median 0.3 mg/kg) in livers from mice fed diets containing BPA at 50 mg/kg chow and 50 ng/kg chow, respectively. 3 This mating scheme produced approximately 50% wild type (a/a) offspring and approximately 50% heterozygous (A vy /a) offspring.…”

“…The majority of A vy /a mice were euthanized on post-natal day (PND) 22. 32 A subset of wild type (a/a) mice (approximately 1 male and 1 female per litter for each BPA diet group) were then housed with a same-sex A vy /a sibling and fed the standard phytoestrogen-free control diet until they were euthanized at 10 months of age, as described by Anderson et al (Table 1). 50 During dissection of both PND22 and 10-month animals, liver tissue was collected and flash frozen in liquid nitrogen.…”

“…24,42 Further, several comparisons yielded p-values between 0.05 and 0.1, indicating that several additional data points may have reached our chosen threshold for statistical significant (P<0.05) given a larger sample size and therefore greater power to detect small effect sizes.…”