title: 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.
authors: Department of Cell and Developmental Biology (M.S., F.X., M.S., M.S.B.), Center of Excellence in Environmental Toxicology (M.S., F.X., R.A.S., M.S.B.), Center for Research on Reproduction and Women's Health (M.S., F.X., A.B., R.A.S., M.S.B.), and Division of Neonatology (A.B., R.A.S.), Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104; and Division of Endocrinology and Metabolism (C.L.), The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
authors: Martha
authors: M
authors: Susiarjo
authors: Frances
authors: F
authors: Xin
authors: Amita
authors: A
authors: Bansal
authors: Martha
authors: M
authors: Stefaniak
authors: Changhong
authors: C
authors: Li
authors: Rebecca A
authors: RA
authors: Simmons
authors: Marisa S
authors: MS
authors: Bartolomei
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D001724:Birth Weight / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D018811:Maternal Exposure; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology; D010636:Phenols / Q000633:toxicity*; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D005947:Glucose; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds