Sex-Specific Modulation of Fetal Adipogenesis by Gestational Bisphenol A and Bisphenol S Exposure

Endocrinology. 2017 Nov 1;158(11):3844-3858. doi: 10.1210/en.2017-00615.


The endocrine-disrupting chemical bisphenol A (BPA) increases adipose tissue mass in vivo and promotes adipogenesis in vitro; however, mechanisms explaining BPA's obesogenic effect remain unknown. We investigated the effects of gestational BPA and its analog, bisphenol S (BPS), exposure on the adipogenic differentiation ability of fetal preadipocytes and the role of endoplasmic reticulum stress in regulating this process. Pregnant sheep (n = 7 to 8 per group) mated to the same male were exposed to BPA or BPS from days 30 to 100 of gestation; pregnancies were terminated 20 days later. Adipose tissue was harvested and fetal preadipocytes isolated. Adipose tissue gene expression, adipocyte size, preadipocyte gene expression, adipogenic differentiation, and dynamic expression of genes involved in adipogenesis and endoplasmic reticulum stress were assessed. Gestational BPA enhanced adipogenic differentiation in female, but not male, preadipocytes. The unfolded protein response (UPR) pathway was upregulated in BPA-exposed female preadipocytes supportive of a higher endoplasmic reticulum stress. Increased expression of estradiol receptor 1 and glucocorticoid receptor in female preadipocytes suggests that this may be a potential cause behind the sex-specific effects observed upon BPA exposure. Gestational BPS affected adipogenic terminal differentiation gene expression in male preadipocytes, but not adipogenic differentiation potential. We demonstrate that gestational BPA exposure can modulate the differentiation ability of fetal preadipocytes. UPR upregulation in gestationally BPA-exposed female preadipocytes may contribute to the increased preadipocyte's adipogenic ability. The marked sex-specific effect of BPA highlights higher susceptibility of females to bisphenol A and potentially, a higher risk to develop obesity in adulthood.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / drug effects
  • Adipocytes / physiology
  • Adipogenesis / drug effects*
  • Animals
  • Benzhydryl Compounds / toxicity*
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Female
  • Fetus / drug effects*
  • Fetus / physiology
  • Humans
  • Male
  • Phenols / toxicity*
  • Pregnancy
  • Prenatal Exposure Delayed Effects / chemically induced*
  • Prenatal Exposure Delayed Effects / metabolism*
  • Sex Characteristics
  • Sheep
  • Sulfones / toxicity*


  • Benzhydryl Compounds
  • Phenols
  • Sulfones
  • bis(4-hydroxyphenyl)sulfone
  • bisphenol A