Abstract
Understanding the toxicological mechanisms of chemicals is essential for accurate assessments of environmental health risks. Inflammation could play a critical role in the adverse health outcomes caused by genotoxicants; however, the toxicological mechanisms underlying genotoxicants-induced inflammatory response are still limited. Here, functional genomics CRISPR screens were performed to enhance the mechanistic understanding of the genotoxicants-induced inflammatory response at low doses exposure. Key genes and pathways associated with the activities of immune cells and the production of cytokines were identified by CRISPR screens of 6 model genotoxicants. Gene network analysis revealed that three genes (TLR10, HCAR2 and TRIM6) were involved in the regulation of neutrophil apoptosis and cytokine release, and TLR10 shared a similar functional pattern with HCAR2 and TRIM6. Furthermore, adverse outcome pathway (AOP) network analysis revealed that TLR10 was involved in the molecular initiating events (MIEs) or key events (KEs) in the inflammatory response AOPs of all the 6 genotoxicants, which provided mechanistic links between TLR10 and genotoxicants-induced inflammation and respiratory diseases. Finally, functional validation tests demonstrated that TLR10 exhibited inhibitory effects on genotoxicants-induced inflammatory responses in both epithelial and immune cells. This study highlights the powerful utility of the integration of CRISPR screen and AOP network analysis in illuminating the toxicological causal mechanisms of environmental chemicals.
Original language | English |
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Article number | 137658 |
Number of pages | 10 |
Journal | Chemosphere |
Volume | 314 |
Early online date | 27 Dec 2022 |
DOIs | |
Publication status | Published - Feb 2023 |
Bibliographical note
Funding Information:This work is supported by the National Natural Science Foundation of China (Grant No. 41977206 ), Jiangsu Environmental Protection Research Foundation (Grant No. 2021002 ), and the ‘100 Talent Program’ from Government of Jiangsu Province, China ( SBX2019010069 ). X.W.Z. was supported by the Fundamental Research Funds for the Central Universities.
Publisher Copyright:
© 2022
Keywords
- Adverse outcome pathway
- CRISPR screen
- Genotoxicants
- Inflammatory response
- TLR10
ASJC Scopus subject areas
- Environmental Engineering
- Environmental Chemistry
- General Chemistry
- Pollution
- Public Health, Environmental and Occupational Health
- Health, Toxicology and Mutagenesis