Epigenetic disruption and glucose homeostasis changes following low-dose maternal bisphenol A exposure

Abstract

Developmental exposure to bisphenol A (BPA) has been linked to impaired glucose homeostasis and pancreatic function in adulthood, which has been hypothesized to result from the disruption of pancreatic β-cell development at early life. Here we evaluated whether maternal BPA exposure disrupts β-cell development and glucose tolerance and the role of epigenetic modifications of key regulator in this process. We found that maternal exposure to BPA (10 μg kg^-1 d^-1) reduced the pancreatic β-cell mass and the expression of pancreatic and duodenal homeobox 1 (<i>Pdx1</i>) at birth, as well as the expression of <i>Pdx1</i> at gestational day (GD) 15.5. In parallel with the decreased expression of <i>Pdx1</i>, histones H3 and H4 deacetylation, along with demethylation of histone 3 lysine 4 (H3K4) and methylation of histone 3 lysine 9 (H3K9), were found at the promoter of <i>Pdx1</i>, while no significant changes in DNA methylation status were detected at this region. Moreover, these alterations were observed in adult life along with impaired glucose tolerance. We conclude that maternal exposure to BPA reduces pancreatic β-cell mass at birth by reducing PDX1⁺ progenitors during fetal development through altering the histone modifications of <i>Pdx1</i>, which can be propagated to later life and increase the susceptibility to glucose intolerance.