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CRISPR screen identified that UGT1A9 was required for bisphenols-induced mitochondria dyshomeostasis
Mingming Tian1, Pu Xia1, Xiao Gou1
1State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, People's Republic of China.
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.
Insights
Bisphenol exposure can harm liver health. UGT1A9 gene is crucial for bisphenol-induced cell death and liver injury, identifying susceptible populations for non-alcoholic fatty liver disease (NAFLD).
Area of Science:
- Toxicology
- Genetics
- Molecular Biology
Background:
- Bisphenol chemicals are linked to adverse health effects like non-alcoholic fatty liver disease (NAFLD).
- The precise mechanisms of bisphenol-induced cell death, particularly mitochondrial stress, remain unclear.
- Understanding these pathways is crucial for identifying at-risk populations.
Purpose of the Study:
- To identify critical genes involved in cell death induced by bisphenol exposure using CRISPR screening.
- To elucidate the role of UGT1A9 in bisphenol-induced mitochondrial dysfunction and liver injury.
- To investigate the potential of UGT1A9 genetic variants as risk factors for NAFLD in individuals exposed to bisphenols.
Main Methods:
- CRISPR screens were employed to identify genes mediating cell death from four bisphenols (BPA, BPB, BPE, BPS).
- Toxicological tests assessed the role of UGT1A9 in BPA-induced mitochondrial homeostasis disruption in vitro and in vivo.
- Studies in wild-type and UGT1A9 knockout mice examined liver injury, mitophagy, and apoptosis markers following BPA exposure.
- Molecular epidemiology analysis correlated UGT1A9 variants with NAFLD risk in BPA-exposed populations.
Main Results:
- CRISPR screens identified UGT1A9 as a key genetic factor in bisphenol-induced cell death.
- UGT1A9 is essential for BPA-induced mitochondrial dysfunction, leading to cell death.
- BPA exposure suppressed mitophagy and increased apoptosis in wild-type mice, effects attenuated by UGT1A9 knockout.
- UGT1A9 genetic variants emerged as potential risk factors for NAFLD in BPA-exposed individuals.
Conclusions:
- UGT1A9 plays a critical role in mediating cell death and liver injury caused by bisphenol exposure.
- The findings reveal a mechanism of mitochondrial dyshomeostasis driven by UGT1A9.
- This research provides mechanistic insights for identifying populations susceptible to bisphenol-induced liver damage and NAFLD.
