Tissue accumulation and hepatotoxicity of 8:2 chlorinated polyfluoroalkyl ether sulfonate: A multi-omics analysis deciphering hepatic amino acid metabolic dysregulation in mice.

8:2 Chlorinated polyfluoroalkyl ether sulfonate (8:2 Cl-PFESA) is a substitute for perfluorooctane sulfonate and an emerging environmental pollutant, yet its bioaccumulation and health risks are poorly understood. We established a subchronic exposure model in mice (0.04, 0.2, and 1 mg/kg/d) to evaluate its adverse effects. Our findings show extensive distribution of 8:2 Cl-PFESA in various tissues (plasma, liver, kidney, brain, heart, lung, testis, ovary, spleen, thymus, thyroid, uterus, large intestine, small intestine, muscle, and fat), with the highest accumulation in the liver, identified as the primary storage organ. Liver histopathology revealed elevated alanine aminotransferase levels, reduced triglycerides, and ballooning degeneration. Proteomics analysis indicated significant involvement of amino acid metabolism in 8:2 Cl-PFESA-induced hepatotoxicity. Metabolomics analysis further highlighted pronounced alterations in amino acid interconversion. Multi-omics integration revealed disruptions in amino acid metabolism, particularly with alanine, histidine, and tryptophan, identifying key proteins EHHADH, HAL, MAO-A, ALDH3A2, and TDO2 as crucial connectors in these metabolic processes, validated by Western blot experiments. This study provides a comprehensive analysis of 8:2 Cl-PFESA accumulation and distribution in biological systems, demonstrating that hepatotoxicity is primarily mediated through amino acid metabolism disruption, offering insights for pollution mitigation strategies and future toxicological research.