Exposure to GenX and its novel analogs disrupts fatty acid metabolism in male mice

Perfluoroalkyl ether carboxylic acids (PFECAs), including hexafluoropropylene oxide dimer acid (HFPO-DA, GenX), have been widely used as alternatives to perfluorooctanoic acid (PFOA) and subsequently detected in various environmental matrices. Despite this, public information regarding their hepatotoxicity remains limited. Here, to compare the hepatotoxicity of PFECAs and identify better alternatives for GenX, adult male mice were exposed to different concentrations (0.4, 2, and 10 mg/kg/d) of PFOA, GenX, and its analogs (PFMO2HpA and PFMO3NA) for 28 d. Results demonstrated increased hepatomegaly and disturbed fatty acid metabolism with increasing treatment doses. After dimensionality reduction analysis, significant differences were observed in the relative liver weights and liver and serum biochemical parameters among the four clusters. Furthermore, when chemical concentrations in the liver were similar, no differences in the indicators of liver injury associated with fatty acid metabolism were observed among groups in the same clusters. Our results suggest that dimensionality reduction analysis is a useful strategy for analyzing samples exposed to multiple compounds at different doses. Furthermore, PFECAs exhibit similar hepatotoxicities at the same cumulative hepatic concentration in mice with constant body weight, while PFMO2HpA exhibits lower hepatotoxicity compared to GenX at the same dose.