Exposure to GenX and Its Novel Analogs Disrupts Hepatic Bile Acid Metabolism in Male Mice

Due to its wide usage and recent detection inenvironmental matrices, hexafluoropropylene oxide dimer acid(HFPO-DA, commercial name GenX) has attracted considerableattention. Here, we explored and compared the toxicity of GenXand its novel analogs with that of perfluorooctanoic acid (PFOA)to provide guidance on the structural design and optimization ofnovel alternatives to poly- and perfluoroalkyl substances (PFASs).Adult male BALB/c mice were continuously exposed to PFOA,GenX, perfluoro-2-methyl-3,6-dioxo-heptanoic acid (PFMO2H-pA), and perfluoro-2-methyl-3,6,8-trioxo-nonanoic acid (PFMO3-NA; 0, 0.4, 2, or 10 mg/kg/d) via oral gavage for 28 days. ThePFOA, GenX, and PFMO3NA treatment groups showed anincrease in relative liver weight, and bile acid metabolism was the most significantly affected pathway in all treatment groups, asshown via weighted gene coexpression network analysis. The highest total bile acid levels were observed in the 2 and 10 mg/kg/dPFMO3NA groups. The ratios of primary bile acids to all bile acids increased in the high-dose groups, while the ratios of secondarybile acids showed a downward trend. Thus, bile acid metabolism disorder may be a prominent adverse effect induced by exposure toGenX, its analogs, and PFOA. Results also showed that the hepatotoxicity of PFMO2HpA was lower than that of GenX, whereas thehepatotoxicity of PFMO3NA was stronger, suggesting that PFMO2HpA may be a potential alternative to GenX.

Automated summary

This study investigated the toxicity of GenX and its novel analogs compared to PFOA, and found that bile acid metabolism disorder may be a prominent adverse effect induced by exposure to these substances. Additionally, the results showed that PFMO2HpA may be a potential alternative to GenX.