Toxicological Mechanism of Individual Susceptibility toFormaldehyde-Induced Respiratory Effects

Tian Mingming; Xia Pu; Yan LuGou XiaoGiesy John P.Dai JiayinYu HongxiaZhang Xiaowei

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Toxicological Mechanism of Individual Susceptibility toFormaldehyde-Induced Respiratory Effects

机译：Toxicological Mechanism of Individual Susceptibility toFormaldehyde-Induced Respiratory Effects

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Understanding the mechanisms of individual susceptibility to exposure to environmental pollutants has been achallenge in health risk assessment. Here, an integrated approach combining a CRISPR screen in human cells and epidemiologicalanalysis was developed to identify the individual susceptibility to the adverse health effects of air pollutants by taking formaldehyde(FA) and the associated chronic obstructive pulmonary disease (COPD) as a case study. Among the primary hits of CRISPRscreening of FA in human A549 cells, HTR4 was the only gene genetically associated with COPD susceptibility in globalpopulations. However, the association between HTR4 and FA-induced respiratory toxicity is unknown in the literature. Adverseoutcome pathway (AOP) network analysis of CRISPR screen hits provided a potential mechanistic link between activation of HTR4(molecular initiating event) and FA-induced lung injury (adverse outcome). Systematic toxicology tests (in vitro and animalexperiments) were conducted to reveal the HTR4-involved biological mechanisms underlying the susceptibility to adverse healtheffects of FA. Functionality and enhanced expression of HTR4 were required for susceptibility to FA-induced lung injury, and FA-induced epigenetic changes could result in enhanced expression of HTR4. Specific epigenetic and genetic characteristics of HTR4were associated with the progression and prevalence of COPD, respectively, and these genetic risk factors for COPD could bepotential biomarkers of individual susceptibility to adverse respiratory effects of FA. These biomarkers could be of great significancefor defining subpopulations susceptible to exposure to FA and reducing uncertainty in the next-generation health risk assessment ofair pollutants. Our study delineated a novel toxicological pathway mediated by HTR4 in FA-induced lung injury, which couldprovide a mechanistic understanding of the potential biomarkers of individual susceptibility to adverse respiratory effects of FA.

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《Environmental Science & Technology: ES&T》 |2022年第10期|6511-6524|共14页
作者
Tian Mingming; Xia Pu; Yan LuGou XiaoGiesy John P.Dai JiayinYu HongxiaZhang Xiaowei;
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作者单位

Nanjing Univ;

Univ Saskatchewan Saskatoon;

Univ Saskatchewan SaskatoonMichigan State UnivBaylor UnivChinese Acad Sci;

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收录信息美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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正文语种英语
中图分类环境科学、安全科学;
关键词
CRISPR screen; formaldehyde; lung injury; COPD; genetic susceptibility; air pollutants; AOP network; INDOOR AIR-QUALITY; FORMALDEHYDE EXPOSURE; WIDE ASSOCIATION; OXIDATIVE STRESS; RISK-ASSESSMENT; HEALTH; WORKERS; POLYMORPHISMS; VENTILATION; INDUSTRIES;

Toxicological Mechanism of Individual Susceptibility toFormaldehyde-Induced Respiratory Effects

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