Developmental Bisphenol A ( ) 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 (100I1/4g/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 and HF diet increased the fat/lean ratio in males only, and the combination of 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, increased and modified hepatic triglyceride (TG) and free (FFA) compositions in males only. In PND1 males, increased hepatic expression of FFA uptake gene Fat/Cd36, and decreased the expression of TG synthesis- and I2-oxidation-related genes (Dgat, Agpat6, CebpI+-, CebpI2, Pck1, Acox1, Cpt1a, Cybb). altered DNA methylation and histone marks (H3Ac, H4Ac, H3Me2K4, H3Me3K36), and decreased the binding of several transcription factors (Pol II, C/EBPI2, SREBP1) within the male Cpt1a gene, the key I2-oxidation enzyme. In PND1 females, only increased the expression of genes involved in FFA uptake and TG synthesis (Lpl, Fasn, and Dgat). These data suggest that developmental exposure alters and reprograms hepatic I2-oxidation capacity in males, potentially through the epigenetic regulation of genes, and further alters the response to a HF diet.
Liu Y., Liang Y., Wishart D.S. (2015) PolySearch 2.0: A significantly improved text-mining system for discovering associations between human diseases, genes, drugs, metabolites, toxins, and more. Nucleic Acids Res. 2015 Jul 1;43(Web Server Issue):W535-42.
Cheng D., Knox C., Young N., Stothard P., Damaraju S., Wishart D.S. (2008) PolySearch: a web-based text mining system for extracting relationships between human diseases, genes, mutations, drugs and metabolites. Nucleic Acids Res. 2008 Jul 1;36(Web Server Issue):W399-405.
This project is supported by the Canadian Institutes of Health Research (award #111062), Alberta Innovates - Health Solutions, and by The Metabolomics Innovation Centre (TMIC), a nationally-funded research and core facility that supports a wide range of cutting-edge metabolomic studies. TMIC is funded by Genome Alberta, Genome British Columbia, and Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $900 million in funding from the federal government.