Human functional genomics reveals toxicological mechanism underlying genotoxicants-induced inflammatory responses under low doses exposure

Mingming Tian, Pu Xia, Lu Yan, Xiao Gou, Hongxia Yu, Xiaowei Zhang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Article number137658
Number of pages10
JournalChemosphere
Volume314
Early online date27 Dec 2022
DOIs
Publication statusPublished - 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

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