Exposure to a GenX Homologue Results in Sexually Dimorphic Bile Acid Metabolism Disorders Mediated by Hepatic PPARα in Mice

2-[2-(Trifluoromethoxy)hexafluoropropoxy]tetrafluoropropanoic acid (PFDMO2HpA), a homologue of hexafluoropropylene oxide dimer (HFPO-DA, commercial name: GenX) has been detected in human serum. While GenX exposure is known to induce hepatomegaly and disturb bile acid metabolism in mouse, limited research has addressed the effects of PFDMO2HpA. This study investigated the effects of PFDMO2HpA (0, 0.004, 0.02, 0.1, or 0.5 mg/kg/d) on mice liver function following 28 days of exposure, with a focus on sex-specific differences. Hepatomegaly has been observed in 0.1 and 0.5 mg/kg/d groups, determining the reference dose (RfD) of PFDMO2HpA as 6.67 ng/kg/d. PFDMO2HpA concentrations in serum and liver showed a dose-dependent increase in both sexes, with females showing significantly higher levels than males in 0.1 and 0.5 mg/kg/d groups. Similar trend was also observed in hepatomegaly and total bile acid levels, which remained influenced by sex even after accounting for internal exposure levels. Although both sexes exhibited pronounced activation of peroxisome proliferator-activated receptor alpha (PPARα) pathway, a higher number of differentially expressed genes were observed in females, with genes related to bile acid secretion exclusively enriched. Notably, PFDMO2HpA exposure did not influence these parameters in hepatocyte-specific PPARα knockout males or females. These results indicate that PFDMO2HpA-induced disturbances in total bile acid levels are sex-specific and are dependent on hepatocyte PPARα signaling.