Integrating epidemiology and adverse outcome pathway analysis to assess the risk of childhood asthma associated with di(2-ethylhexyl) phthalate exposure

초록

Di(2-ethylhexyl) phthalate (DEHP) is a high-production-volume plasticizer and hazardous environmental contaminant, however, the mechanistic pathways underlying the risk of DEHP exposure-associated childhood asthma remain insufficiently characterized. Based on data from the Exposome and Child Health with Omics-Cohort for Childhood Asthma and Allergic Diseases (ECHO-COCOA), DEHP exposure was associated with an increased risk of childhood asthma. Herein, urinary DEHP metabolites were measured in 235 children aged 7 years from the ECHO-COCOA study. Children with asthma showed significantly higher urinary levels of DEHP and its metabolites than those of normal healthy children. Moreover, DEHP biomarkers were positively correlated with blood eosinophil counts. To elucidate the biological pathways involved, publicly available toxicogenomic and disease databases (Comparative Toxicogenomics Database, DisGeNET, and MalaCards) were queried to construct an adverse outcome pathway (AOP) framework linking DEHP exposure to key events related to asthma. We then performed in vitro experiments using EA.hy926 endothelial cells and THP-1-derived macrophages to validate critical AOP nodes, focusing on oxidative stress, apoptosis, inflammation, and macrophage activation. The AOP analysis and cell-based assays consistently supported a mechanistic sequence in which DEHP-induced oxidative stress and endothelial injury promote pro-inflammatory and type 2–associated immune responses. A population pharmacokinetic model was additionally applied for risk assessment, suggesting that DEHP exposure may increase susceptibility to asthma and asthma-related allergic outcomes rather than directly causing asthma. Our findings provide an integrated perspective that connects epidemiologic associations with plausible biological mechanisms. Collectively, DEHP exposure contributes to childhood asthma susceptibility and highlights the importance of reducing exposure in children. © 2026

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