The Regulation of Histone H2A.X and DNA Damage Repair By Environmental PFAS Exposure and the Activation of ER Stress Sensor IRE1?.

Per- and polyfluoroalkyl substances (PFAS) are man-made chemicals found in household cleaning products and packaging. They enter the environment via waste from manufacturing facilities or metabolism in organisms. Thus, they have been accumulating in drinking water, food, and human bodies.

High concentrations of two PFAS chemicals, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), may be linked to cancer by inducing endoplasmic reticulum (ER) stress in cancer cells. In response to this stress, cancer cells utilize cellular survival mechanisms including the unfolded protein response (UPR) and DNA damage repair (DDR) to survive, metastasize, and resist treatment.

One signal protein of the UPR, inositol-requiring enzyme 1 alpha (IRE1α), mediates ER stress via X-box binding protein-1 (XBP1) mRNA splicing and regulated IRE1-dependent decay (RIDD). The DDR mediates genotoxic stress by repairing DNA damage like double stranded breaks (DSBs). An early marker of damage is the phosphorylation of histone H2A.x to γH2A.x. We hypothesized that the activation of the IRE1 pathway by PFOA and PFOS affects the DDR and cellular repair mechanisms.

The results have shown an increase in DNA damage repair in response to PFOA and PFOS induced DNA damage. This research is instrumental to understanding health risks caused by PFAS chemicals from the environment.