Developmental bisphenol A (BPA) exposure leads to sex-specific modification of hepatic gene expression and epigenome at birth that may exacerbate high-fat diet-induced hepatic steatosis

作者：Strakovsky Rita S; Wang Huan; Engeseth Nicki J; Flaws Jodi A; Helferich William G; Pan Yuan Xiang^*; Lezmi Stephane

来源：Toxicology and Applied Pharmacology, 2015, 284(2): 101-112.

DOI：10.1016/j.taap.2015.02.021

• Bisphenol A (BPA)
• Adiposity
• Endocrine disrupting chemical (EDC)
• NAFLD
• Methylation
• Histones

Developmental bisphenol A (BPA) exposure increases adulthood hepatic steatosis with reduced mitochondrial function. To investigate the potential epigenetic mechanisms behind developmental BPA-induced hepatic steatosis, pregnant Sprague-Dawley rats were dosed with vehicle (oil) or BPA (100 mu g/kg/day) from gestational day 6 until postnatal day (PND) 21. After weaning, offspring were either challenged with a high-fat (HF; 45% fat) or remained on a control (C) diet until PND110. From PND60 to 90, both BPA and HF diet increased the fat/lean ratio in males only, and the combination of BPA and HF diet appeared to cause the highest ratio. On PND110, Oil-HF, BPA-C, and BPA-HF males had higher hepatic lipid accumulation than Oil-C, with microvesicular steatosis being marked in the BPA-HF group. Furthermore, on PND1, BPA increased and modified hepatic triglyceride (TG) and free fatty acid (FFA) compositions in males only. In PND1 males, BPA increased hepatic expression of FFA uptake gene Fat/Cd36, and decreased the expression of TG synthesis- and beta-oxidation-related genes (Dgat, Agpat6, Cebp alpha, Cebp beta, Pck1, Acox1, Cpt1a, Cybb). BPA altered DNA methylation and histone marks (H3Ac, H4Ac, H3Me2K4, H3Me3K36), and decreased the binding of several transcription factors (Pol II, C/EBP beta, SREBP1) within the male Cpt1a gene, the key beta-oxidation enzyme. In PND1 females, BPA only increased the expression of genes involved in FFA uptake and TG synthesis (Lpl, Fasn, and Dgat). These data suggest that developmental BPA exposure alters and reprograms hepatic alpha-oxidation capacity in males, potentially through the epigenetic regulation of genes, and further alters the response to a HF diet.

• 出版日期2015-4-15