Bile acid metabolism disorder mediates hepatotoxicity of Nafion by-product 2 and perfluorooctane sulfonate in male PPAR?-KO mice

Perfluorooctane sulfonate (PFOS) and Nafion by-product 2 (H-PFMO2OSA) induce hepatotoxicity in male mice via ac-tivation of the peroxisome proliferator-activated receptor alpha (PPAR alpha) pathway; however, accumulating evidence sug-gests that PPAR alpha-independent pathways also play a vital role in hepatotoxicity after exposure to per- and polyfluoroalkyl substances (PFASs). Thus, to assess the hepatotoxicity of PFOS and H-PFMO2OSA more comprehen-sively, adult male wild-type (WT) and PPAR alpha knockout (PPAR alpha-KO) mice were exposed to PFOS and H-PFMO2OSA (1 or 5 mg/kg/d) for 28 d via oral gavage. Results showed that although elevations in alanine transami-nase (ALT) and aspartate aminotransferase (AST) were alleviated in PPAR alpha-KO mice, liver injury, including liver enlargement and necrosis, was still observed after PFOS and H-PFMO2OSA exposure. Liver transcriptome analysis identified fewer differentially expressed genes (DEGs) in the PPAR alpha-KO mice than in the WT mice, but more DEGs as-sociated with the bile acid secretion pathway after PFOS and H-PFMO2OSA treatment. Total bile acid content in the liver was increased in the 1 and 5 mg/kg/d PFOS-exposed and 5 mg/kg/d H-PFMO2OSA-exposed PPAR alpha-KO mice. Furthermore, in PPAR alpha-KO mice, proteins showing changes in transcription and translation levels after PFOS and H-PFMO2OSA exposure were involved in the synthesis, transportation, reabsorption, and excretion of bile acids. Thus, exposure to PFOS and H-PFMO2OSA in male PPAR alpha-KO mice may disturb bile acid metabolism, which is not under the control of PPAR alpha.