Abstract 6278: Per- polyfluoroalkyl substance (PFAS) modulates steatosis and fibrogenic signaling in hepatocellular carcinoma cells

Abstract Perfluorooctanoic acid (PFOA), heptafluorobutyric acid (HFBA), and perfluorotetradecanoic acid (PFTA) are the per- and polyfluoroalkyl substances (PFAS) and organic pollutants that predominantly exist in the environment. Exposure to PFAS affects immune, thyroid and kidney function, lipid and insulin dysregulation, liver disease, and cancer. Mechanisms underlying the impact of low and physiologically relevant concentration of PFAS in liver diseases remain elusive. In the current study, we investigated the effect of PFOA, HFBA, and PFTA on cell proliferation, steatosis, and fibrogenic signaling in hepatocytes and liver cancer cell models. Exposure of PFOA and PFBA (10 to 1000 nM) specifically promoted cell proliferation in non-tumor derived HepaRG liver cells and in hepatocellular carcinoma HepG2 cells. PFASs increased the expression of TNFα and IL6 inflammatory markers and produced endogenous reactive oxygen species (ROS) production. Further, PFAS enhanced cell steatosis in liver (HepaRG and HepG2) cells which was accompanied by upregulation of steatotic, and fibrogenic markers as well as activated Unfolded Protein Response (UPR) signaling. RNA-seq data suggested that chronic exposures of PFOA modulated the expression of fatty acid/lipid metabolic gene expression that is involved in the development of fatty liver disease. Collectively our data suggests that chronic exposure to low concentration of PFAS may modulate cell steatosis and fibrogenic signaling in hepatocytes and HCC cells by activation of UPR signaling. Citation Format: Qi Qi, Suryakant Niture, Sashi Gadi, Deepak Kumar. Per- polyfluoroalkyl substance (PFAS) modulates steatosis and fibrogenic signaling in hepatocellular carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6278.