(27bz) The Effects of Pfas-Induced Activation of ER Stress Sensor IRE1? and Its Downstream Pathways for DNA Damage Repair

Perfluorooctanoic acid and perfluorooctane sulfonate (PFOA and PFOS) are found in many household cleaning products and commercial packaging materials. Once released to the environment, these “forever chemicals” degrade slowly, resulting in detectable levels in drinking water, food, and animals, including humans.

Evidence suggests high concentrations of PFOA and PFOS in liver cells induce endoplasmic reticulum (ER) stress as well as DNA damage. The activation of ER stress sensor proteins is a necessary step in alleviating cellular stresses. Cells adapt to ER stress by activating the unfolded protein response (UPR), an integrated signal transduction pathway mediated by ER stress sensor proteins including inositol-requiring enzyme 1α (IRE1α). Activation of IRE1α, which possesses an RNase domain, catalyzes the unconventional processing of the mRNA encoding X-Box binding protein-1 (XBP1) and other RNA targets that share the XBP1 consensus sequence (known as regulated IRE1-dependent decay or RIDD).

Increasing evidence supports cross-talk between protein homeostasis (ER stress response) and genome integrity (DNA damage response). Thus, we hypothesized that the IRE1α plays an important role in DNA repair in response PFOA/PFOS. To test this hypothesis, we employed wild-type, IRE1α knockout, and IRE1α mutant HepG2 cells and computational approaches to predict and to validate potential RIDD targets upon PFOA/PFOS exposure. Our results demonstrated that the activation of IRE1α contributed to increasing DNA damage repair activity in response to PFOA/PFOS-induced DNA damage.

This research provides important insight to DNA damage repair mediated through IRE1α, under PFOA/PFOS exposure. This is significant because a clear understanding of the molecular mechanism by which these “forever chemicals” induce ER stress and DNA damage will increase our understanding of the long-term health risks associated with these chemicals.