Epigenetic Modification of the Cpt1a Gene at Birth by Developmental Bisphenol A (BPA) Exposure May Program Microvesicular Steatosis in Adult Male Rats Consuming a High‐fat Diet

Abstract

Developmental bisphenol A (BPA) exposure causes adulthood hepatic steatosis in rats. To investigate potential epigenetic mechanisms behind developmental BPA-induced hepatic steatosis, pregnant Sprague-Dawley rats were dosed with vehicle (oil) or BPA (100 mg/kg/day) from gestational day 6 to postnatal day (PND) 21. After weaning, offspring consumed a control (C) or a high fat (HF) diet until PND110. Both BPA and HF diet increased the fat/lean ratio in adult males. On PND110, Oil-HF, BPA-C and BPA-HF males had higher hepatic lipids than Oil-C; microvesicular steatosis was marked in BPA-HF males, and less severe in Oil-HF males. In females, neither BPA nor a HF diet affected any of the factors above. On PND1, BPA increased hepatic triglycerides and free fatty acids, and modified hepatic fatty acid composition in males, but not females. In PND1 males, BPA increased hepatic Fat/Cd36 expression, and decreased the expression of triglyceride synthesis- and β-oxidation-related genes (Dgat, Agpat6, Cebpa, Cebpb, Pck1, Acox1, Cpt1a, Cybb). In PND1 females, BPA only increased the expression of Lpl, Fasn, and Dgat. BPA altered DNA methylation, histone marks (H3Ac, H4Ac, H3Me2K4, H3Me3K36), and decreased the binding of several transcription factors (Pol II, C/EBPβ, SREBP1) within the male Cpt1a gene, the key β-oxidation enzyme. These data suggest that developmental BPA exposure reprograms hepatic β-oxidation capacity in males, potentially thorough epigenetic regulation, and further prevents the appropriate response to a HF diet.