Epigenetic toxicity of PFOA and GenX in HepG2 cells and their roles in lipid metabolism

By Yi Wen, Niharika Mirji, and Joseph Irudayaraj
Toxicol In Vitro
February 25, 2020
DOI: 10.1016/j.tiv.2020.104797

Perfluorooctanoic acid (PFOA), an extremely persistent perfluoroalkyl substance (PFAS), and 2,3,3,3-Tetrafluoro-2-(heptafluoropropoxy) propanoic acid (GenX), its shorter chain alternative, have been implicated in hepatocellular damage with unusual fat deposit and liver enlargement. In this study we explored the underlying mechanisms of PFOA and GenX induced hepatocellular damage. Liver hepatocellular carcinoma cell line HepG2 was used as a model to study induced liver inflammation in vitro at the cellular, genetic, and epigenetic levels. HepG2 cells were exposed to PFOA or GenX for 48 h and the DNA and RNA were extracted and analyzed. mRNA expression of PFOA exposed cells showed that the cell cycle genes were affected significantly, as well as the ten-eleven translocation methylcytosine dioxygenases (TETs) and the essential lipid metabolism genes. However, GenX did not have as significant an effect on the expression levels. Global methylation levels of HepG2 cells was found to be inversely proportion to PFOA exposure levels and had corresponding trends with mRNA expression of most genes of interest. Upon comparison, the global methylation level of GenX decreased and then increased. Our work points to the fact that PFOA induced epigenetic changes may play a major role in lipid metabolism gene regulation contributing to higher levels of epigenetic toxicity than GenX.

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