Impact of per- and polyfluoroalkyl substances structure on oxidative stress and lipid metabolism disruption in HepG2 cells

Abstract

Per- and polyfluoroalkyl substances (PFASs) are bioaccumulative pollutants that pose risks to ecosystems and human health, with oxidative stress and lipid metabolism disorder playing key roles in their hepatotoxicity. However, the toxicological differences between PFASs with varying chain lengths and functional groups remain unclear. This study exposed HepG2 cells to different concentrations (50, 100, 200, and 400 μM) of PFOA, PFOS, PFBA, and PFBS for 24 h to investigate their cytotoxicity and underlying mechanisms. Results indicated that all four PFASs reduced cell viability in a dose-dependent manner. Long-chain PFASs in particular, induced oxidative stress, as evidenced by elevated ROS and MDA levels. Metabolomics revealed significant alterations in lipid and amino acid metabolisms, with lipid metabolism being the most disrupted. Further analysis showed up-regulation of lipid metabolism-related genes and increased TG content, confirming these findings. Correlation analysis revealed that PFASs exacerbate oxidative stress and lipid accumulation through lipid metabolism disorders, resulting in reduced cell viability. Notably, long-chain PFASs (PFOA and PFOS) were more toxic than short-chain PFASs (PFBA and PFBS), and sulfonate-based PFASs (PFOS, PFBS) were more toxic than carboxylate-based ones (PFOA, PFBA) of similar chain length. This study provides insights into the differential toxicity of PFASs, offering a theoretical foundation for improved risk assessment and management of these compounds.