Toxicological Mechanism of Individual Susceptibility to Formaldehyde-Induced Respiratory Effects.

Abstract

Understanding the mechanisms of individual susceptibility to exposure to environmental pollutants has been a challenge in health risk assessment. Here, an integrated approach combining a CRISPR screen in human cells and epidemiological analysis 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 CRISPR screening of FA in human A549 cells, HTR4 was the only gene genetically associated with COPD susceptibility in global populations. However, the association between HTR4 and FA-induced respiratory toxicity is unknown in the literature. Adverse outcome 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 animal experiments) were conducted to reveal the HTR4-involved biological mechanisms underlying the susceptibility to adverse health effects 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 HTR4 were associated with the progression and prevalence of COPD, respectively, and these genetic risk factors for COPD could be potential biomarkers of individual susceptibility to adverse respiratory effects of FA. These biomarkers could be of great significance for defining subpopulations susceptible to exposure to FA and reducing uncertainty in the next-generation health risk assessment of air pollutants. Our study delineated a novel toxicological pathway mediated by HTR4 in FA-induced lung injury, which could provide a mechanistic understanding of the potential biomarkers of individual susceptibility to adverse respiratory effects of FA.