Perfluorohexane sulfonate (PFHxS) induces liver cytotoxicity by activating autophagy and endoplasmic reticulum stress-regulated mitochondrial pathway apoptosis.

Perfluorohexane sulfonate (PFHxS), a common alternative to perfluorootane sulfonate, is extensively used in various industrial products. As PFHxS contamination becomes more prevalent, it has been detected in human umbilical cord blood, serum, and breast milk, among other samples. In humans, the elimination half-life of PFHxS is at least 8.5 years. Although PFHxS shows the highest tissue-plasma partition coefficients in the liver and is known to cause liver hypertrophy, the mechanisms underlying PFHxS-induced hepatotoxicity remain unclear. In present study, the impacts of PFHxS on human liver L02 cells were evaluated by examining cell viability, apoptotic rates, reactive oxygen species (ROS) levels, Ca2+ levels, and protein expressions. Results revealed that a 24-h exposure to PFHxS at concentrations of 80-320 μM, particularly at 320 μM, triggered autophagy and endoplasmic reticulum stress (ERS)-regulated mitochondrial pathway apoptosis. This was characterized by increased ROS and Ca2+ levels and upregulation of proteins such as LC3B-II, ATG3, ATG5, ATG7, p-Beclin-1, p62, ATF6, GRP78, CHOP, Bax, CYPD, and Cyt-C. Conversely, the protein expressions of Sigma-1 receptor (Sig-1R), p-mTOR, and Bcl-2 were inhibited. In conclusion, PFHxS induces liver cytotoxicity by activating autophagy and ERS-regulated mitochondrial pathway apoptosis. This study is the first to elucidate the mechanisms underlying PFHxS-induced liver cytotoxicity.