Comparative cytotoxicity and toxicological mechanisms of 6:2 Cl-PFAES and PFOS in pancreatic β cells: implications for glucose metabolism disruption.

Abstract

Previous studies have indicated that 6:2 chlorinated polyfluoroalkyl ether sulfonate (6:2 Cl-PFAES), a substitute for perfluorooctane sulfonate (PFOS), causes 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 toward β-TC-6 cells, even surpassing that showed by PFOS. Mechanistic studies demonstrated that 6:2 Cl-PFAES induced oxidative stress by increasing the 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 that of PFOS. Co-exposure with N-acetyl-L-cysteine (NAC) as the ROS scavenger evidently reduced the degree of cell apoptosis and the production of ROS, highlighting that oxidative stress is a crucial mechanism involved in 6:2 Cl-PFAES-induced cell death. Transcriptomic analysis further revealed that 6:2 Cl-PFAES affected gene expression via the oxidative phosphorylation pathway, confirming the oxidative stress effect, and altered diabetes-related gene 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.