Effect of PFOA on DNA Methylation and Alternative Splicing in Mouse Liver.

Perfluorooctanoic acid (PFOA) is a persistent organic pollutant prevalent in the environment and implicated in damage to the liver leading to a fatty liver phenotype called hepatocellular steatosis. Our goal is to provide a basis for PFOA-induced hepatocellular steatosis in relation to epigenetic alterations and mRNA splicing. Young adult female mice exposed to different concentrations of PFOA showed an increase in liver weight with decreased global DNA methylation (5-mC). At higher concentrations, the expression of DNA methyltransferase 3A (Dnmt3a) was significantly reduced and the expression of tet methycytosine dioxygenase 1 (Tet1) was significantly increased. There was no significant change in the other Dnmts and Tets. PFOA exposure significantly increased the expression of cell cycle regulators and anti-apoptotic genes. The expression of multiple genes involved in mTOR (mammalian target of rapamycin) signaling pathway were altered significantly with reduction in Pten (phosphatase and tensin homolog, primary inhibitor of mTOR pathway) expression. Multiple splicing factors whose protein but not mRNA levels affected by PFOA exposure were identified. The changes in protein abundance of the splicing factors was also reflected in altered splicing pattern of their target genes, which provided new insights on the previously unexplored mechanisms of PFOA-mediated hepatotoxicity and pathogenesis.