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.
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 (100μg/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 β-oxidation-related genes (Dgat, Agpat6, Cebpα, Cebpβ, 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/EBPβ, SREBP1) within the male Cpt1a gene, the key β-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 β-oxidation capacity in males, potentially through the epigenetic regulation of genes, and further alters the response to a HF diet.
Department of Food Science and Human Nutrition, University of Illinois Urbana-Champaign, USA.
Rita S
RS
Strakovsky
Department of Food Science and Human Nutrition, University of Illinois Urbana-Champaign, USA.
Huan
H
Wang
Department of Food Science and Human Nutrition, University of Illinois Urbana-Champaign, USA.
Nicki J
NJ
Engeseth
Department of Comparative Biosciences, University of Illinois Urbana-Champaign, USA.
Jodi A
JA
Flaws
Department of Food Science and Human Nutrition, University of Illinois Urbana-Champaign, USA.
William G
WG
Helferich
Department of Food Science and Human Nutrition, University of Illinois Urbana-Champaign, USA. Electronic address: yxpan@illinois.edu.
Yuan-Xiang
YX
Pan
Department of Pathobiology, University of Illinois Urbana-Champaign, USA. Electronic address: slezmi@illinois.edu.
Stéphane
S
Lezmi
D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D019175:DNA Methylation / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects*; D044127:Epigenesis, Genetic / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000235:genetics / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D010636:Phenols / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D005230:Fatty Acids, Nonesterified; D010636:Phenols; D014157:Transcription Factors; D014280:Triglycerides; C006780:bisphenol A; D000098826:Bisphenol A Compounds
Adiposity; Bisphenol A (BPA); Endocrine disrupting chemical (EDC); Histones; Methylation; NAFLD