GenX analogs exposure induced greater hepatotoxicity than GenX mainly via activation of PPAR pathway while caused hepatomegaly in the absence of PPAR in female mice

Despite their use as substitutes for perfluorooctanoic acid, the potential toxicities of hexafluoropropylene oxide dimer acid (HFPO-DA, commercial name: GenX) and its analogs (PFDMOHxA, PFDMO2HpA, and PFDMO2OA) remain poorly understood. To assess the hepatotoxicity of these chemicals on females, each chemical was orally administered to female C57BL/6 mice at the dosage of 0.5 mg/kg/d for 28 d. The contribution of peroxisome proliferator-activated receptors (PPAR alpha and gamma) and other nuclear receptors involving in these toxic effects of GenX and its analogs were identified by employing two PPAR knockout mice (PPAR alpha(-/-) and PPAR gamma(Delta Hep)) in this study. Results showed that the hepatotoxicity of these chemicals increased in the order of GenX < PFDMOHxA < PFDMO2HpA < PFDMO2OA. The increases of relative liver weight and liver injury markers were significantly much lower in PPAR alpha(-/-) mice than in PPAR alpha(+/+) mice after GenX analog exposure, while no significant differences were observed between PPAR gamma(Delta Hep) and its corresponding wildtype groups (PPAR gamma(F/F) mice), indicating that GenX analog induce hepatotoxicity mainly via PPAR alpha instead of PPAR gamma. The PPAR alpha-dependent complement pathways were inhibited in PFDMO2HpA and PFDMO2OA exposed PPAR alpha(+/+) mice, which might be responsible for the observed liver inflammation. In PPAR alpha(-/-) mice, hepatomegaly and increased liver lipid content were observed in PFDMO2HpA and PFDMO2OA treated groups. The activated pregnane X receptor (PXR) and constitutive activated receptor (CAR) pathways in the liver of PPAR alpha(-/-) mice, which were highlighted by bioinformatics analysis, provided a reasonable explanation for hepatomegaly in the absence of PPAR alpha. Our results indicate that GenX analogs could induce more serious hepatotoxicity than GenX whether there is a PPAR alpha receptor or not. These chemicals, especially PFDMO2HpA and PFDMO2OA, may not be appropriate PFOA alternatives.