Bisphenol A Exposure Disrupts Metabolic Health Across Multiple Generations in the Mouse

Abstract

Accumulating evidence has suggested that a suboptimal early life environment produces multigenerational developmental defects. A proposed mechanism is stable inheritance of DNA methylation. Here we show that maternal bisphenol A (BPA) exposure in C57BL/6 mice produces multigenerational metabolic phenotypes in their offspring. Using various methods including dual-energy X-ray absorptiometry analyses, glucose tolerance tests, and perifusion islet studies, we showed that exposure to 10 μg/kg/d and 10 mg/kg/d BPA in pregnant F0 mice was associated with higher body fat and perturbed glucose homeostasis in F1 and F2 male offspring but not female offspring. To provide insight into the mechanism of the multigenerational metabolic abnormalities, we investigated the maternal metabolic milieu and inheritance of DNA methylation across generations. We showed that maternal glucose homeostasis during pregnancy was altered in the F0 but not F1 female mice. The results suggested that a compromised maternal metabolic milieu may play a role in the health of the F1 offspring but cannot account for all of the observed multigenerational phenotypes. We further demonstrated that the metabolic phenotypes in the F1 and F2 BPA male offspring were linked to fetal overexpression of the imprinted Igf2 gene and increased DNA methylation at the Igf2 differentially methylated region 1. Studies in H19(Δ3.8/+) mouse mutants supported the role of fetal Igf2 overexpression in altered adult glucose homeostasis. We conclude that early life BPA exposure at representative human exposure levels can perturb metabolic health across multiple generations in the mouse through stable inheritance of DNA methylation changes at the Igf2 locus.

Bisphenol S instead of bisphenol A: a story of reproductive disruption by regretable substitution - a review

“…The influence of several EDCs was demonstrated on the course of development of male gametes, sperm (Li et al 2011;Knez et al 2014) and female gametes, oocytes, as well as embryonic development of males and females (Mok-Lin et al 2010;Xiao et al 2011). Moreover, the effect of EDCs on the reproduction of adult individuals, including transgenerational inheritance, has been described (Susiarjo et al 2015;Ziv-Gal et al 2015). Therefore, reproductive functions represent crucial targets of the EDCs' negative effects.…”

An assessment of molecular pathways of obesity susceptible to nutrient, toxicant and genetically induced epigenetic perturbation

“…This was correlated with loss of imprinted monoallelic expression of Igf2 and Igf2 overexpression. A follow up study showed that these epigenetic changes coincide with increased body fat, insulin resistance and glucose intolerance only in adult male offspring [164]. In contrast to the study by Mackay and colleagues described above [161], females were seemingly unaffected.…”

Developmental Origins of Common Disease: Epigenetic Contributions to Obesity

“…We identified five studies that examined the effects of in utero exposure to polycyclic aromatic hydrocarbons (PAHs) (42), bisphenol A (BPA) (35), dichlorodiphenyltrichloroethane (DDT) (34), methoxychlor (24), or the jet fuel JP-8 (36) on obesity phenotypes. Each of the studies provides preliminary evidence of the adipogenic potential of xenobiotic exposures to alter the epigenome in utero and contribute to later life obesity.…”

“…Susiarjo et al (35) exposed dams to either NC, a low dose of BPA (10 μg/kg per day), or a high dose of BPA (10 mg/kg per day) from 2 weeks before conception through lactation. F1 offspring exposed to low or high BPA doses had higher body weight and fat mass, greater glucose intolerance, and altered insulin secretion compared with unexposed offspring.…”