6:2 Cl-PFESA has the potential to cause liver damage and induce lipid metabolism disorders in female mice through the action of PPAR-γ.

6:2 Cl-PFESA is a polyfluoroalkyl ether with high environmental persistence that has been confirmed to have significant adverse effects on animals. In this study, 6-week-old female C57BL/6 mice were exposed to 0, 1, 3 and 10 μg/L 6:2 Cl-PFESA for 10 weeks to estimate the hepatotoxicity of 6:2 Cl-PFESA and explore its underlying molecular mechanism. The results indicated that 6:2 Cl-PFESA preferentially bioaccumulated in the liver and induced hepatic cytoplasmic vacuolation and hepatomegaly in mice. In addition, serum metabolic profiling showed that 6:2 Cl-PFESA exposure caused an abnormal increase in amino acids and an abnormal decrease in acyl-carnitine, which interfered with fatty acid transport and increased the risk of metabolic diseases. Further experiments showed that 6:2 Cl-PFESA formed more hydrogen bonds with PPAR-γ than PFOS, Rosi and GW9662, and the binding affinity of 6:2 Cl-PFESA toward PPAR-γ was the highest among the ligands. 6:2 Cl-PFESA promoted the differentiation of 3T3-L1 cells by increasing PPAR-γ expression. Therefore, our results showed that 6:2 Cl-PFESA has the potential to induce liver damage and dysfunction in female mice, and this effect was achieved through PPAR-γ. This study is the first to reveal the hepatic toxicity of 6:2 Cl-PFESA in female mammals and provides new insights for subsequent in-depth research.