PFOS and PFOA exposure induces liver injury and sex-dependent immune effects in C57BL/6 mice

Per- and polyfluoroalkyl substances (PFASs) are persistent environmental contaminants. Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), representing carboxylate and sulfonate subclasses, are among the most frequently detected PFASs in biomonitoring studies. We characterized the hepatotoxicity and immunotoxicity of PFOS and PFOA in male and female C57BL/6-Elite mice exposed via oral gavage for 28 (1.5 mg/kg/day) or 56 days (0.166-1.5 mg/kg/day). Both compounds caused pancreatic atrophy, hepatomegaly, elevated serum biomarkers of liver injury, and decreased serum triglyceride levels across sexes and exposure durations. Liver transcriptomics revealed enrichment of PPAR signaling, lipid metabolism disruption, and AGE-RAGE pathways. Immunotoxicity assessments showed PFOS-induced cytokine suppression (interleukin-4 [IL-4], IL-17α, tumor necrosis factor-alpha [TNF-α], and monocyte chemoattractant protein-1 [MCP-1]) in males, while females exhibited minimal cytokine changes but altered thymocyte development. Overall, PFASs caused sex-independent hepatic and pancreatic toxicity but sex-dependent immune effects. Limitations include asymmetric dosing and lack of estrous monitoring; future studies should integrate histopathology and gene expression confirmatory analysis.