Comparative Cytotoxicity and Toxicological Mechanisms of 6:2 Cl-PFAES and PFOS on Pancreatic β Cells: Implications for Glucose Metabolism Disruption

Previous studies have indicated that 6:2 chlorinated polyfluoroalkyl ether sulfonate (6:2 Cl-PFAES), a substitute for perfluorooctane sulfonate (PFOS), caused disruptions in glucose metabolism, but its toxicological mechanisms remain unclear. Pancreatic β cells are responsible for regulating glucose metabolism. This study used mouse insulinoma β cells (β-TC-6) to study the toxic effects of 6:2 Cl-PFAES and elucidate its potential mechanisms. Through cell counting kit-8, trypan blue staining, and apoptosis assays, we found that 6:2 Cl-PFAES showed toxicity to β-TC-6 cells, even surpassing that of PFOS. Mechanistic studies demonstrated that 6:2 Cl-PFAES induced oxidative stress by ascendant levels of reactive oxygen species (ROS) and malondialdehyde (MDA), alongside increased superoxide dismutase (SOD) activity. The oxidative stress-inducing capability of 6:2 Cl-PFAES was stronger than PFOS. Co-exposure with N-acetyl-L-cysteine (NAC), as the ROS scavenger, which obviously reduced the degree of cell apoptosis and the production of ROS, highlighting oxidative stress as a crucial mechanism of 6:2 Cl-PFAES-induced cell death. Transcriptomic analysis further revealed that 6:2 Cl-PFAES affected genes association with the oxidative phosphorylation pathway, confirming the oxidative stress effect, and altered diabetes-related genes expression, suggesting a heightened risk of diabetes. This study provides insights into the toxicity of 6:2 Cl-PFAES on β cells and its potential risks on glucose metabolism disruption.