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

## TL;DR

Exposure to PFOS and PFOA causes liver and pancreatic damage in mice, with immune effects differing between males and females.

## Contribution

This study reveals sex-dependent immune effects and shared hepatic toxicity of PFOS and PFOA in mice.

## Key findings

- PFOS and PFOA caused hepatomegaly, pancreatic atrophy, and elevated liver injury biomarkers in both sexes.
- Males showed cytokine suppression, while females exhibited altered thymocyte development.
- Liver transcriptomics revealed disrupted lipid metabolism and PPAR signaling pathways.

## Abstract

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.

•PFOA and PFOS show distinct toxicokinetics, despite equivalent dosing•Both PFASs induced hepatomegaly and disrupted ALP, ALT, and TGL•PFOS and PFOA exposure caused pancreatic atrophy•Immune effects may be sex-specific: males altered cytokines, females altered thymocytes

PFOA and PFOS show distinct toxicokinetics, despite equivalent dosing

Both PFASs induced hepatomegaly and disrupted ALP, ALT, and TGL

PFOS and PFOA exposure caused pancreatic atrophy

Immune effects may be sex-specific: males altered cytokines, females altered thymocytes

Environmental toxicology; molecular toxicology; toxic injury