CRISPR screen identified that UGT1A9 was required for bisphenols-induced mitochondria dyshomeostasis.

Abstract Exposure to bisphenols chemicals could cause various adverse health effects, including non-alcoholic fatty liver disease (NAFLD), which have been associated with cellular mitochondria stress. However, the biological mechanism underlying the mitochondria stress-mediated cell death by bisphenols was poorly understood. Here, CRISPR screens were performed to identify the critical genes which were involved in cell death caused by exposure to four bisphenols (BPA, BPB, BPE and BPS). Results of CRISPR screens showed that UGT1A9 was the primary genetic factor facilitating cell death induced by all of the four bisphenols. Systematic toxicological tests demonstrated that UGT1A9 was required for BPA-induced mitochondria dyshomeostasis in vitro and in vivo, and UGT1A9-mediated mitochondria dyshomeostasis was an important cause of facilitating cell death. Liver injury caused by exposure to BPA in wild-type mice was accompanied with suppression of mitophagy and increased expression of C-Caspase 3, but UGT1A9 knockout attenuated these adverse effects induced by BPA. Finally, molecular epidemiology analysis suggested that the five genetic variants of UGT1A9 could be potential genetic risk factors of NAFLD when people were exposed to BPA. The biological mechanism uncovered here provided mechanistic evidence for identification of susceptible populations of liver injury associated with exposure to BPA.