Untargeted metabolomic profiling of childhood asthma: An exploratory analysis of anthropogenic chemicals and the serum metabolome

Background: Asthma is the most common chronic disease in children, yet its causes, environmental links, and underlying mechanisms are still not well understood despite extensive research. Methods: We examined the cross-sectional relationship between asthma and metabolic features in 628 serum samples (165 cases, 463 controls) from children aged 8, 12, and 16 years, in the Prevention and Incidence of Asthma and Mite Allergy birth cohort. Metabolic features were assessed using liquid chromatography with high-resolution mass spectrometry. In a single-feature-at-a-time approach, asthma status (i.e., current asthma) was regressed against the measured intensity of each of the features; this approach alone was further extended to age-stratified analyses. Biological pathways were explored using Mummichog. In addition, we assessed the association of exogenous mixtures exhibiting substantial intercorrelations (i.e., for polyfluoroalkyl substances PFAS only) with asthma. Results: Liquid chromatography with high-resolution mass spectrometry detected 55,444 metabolic features, including 38 identified exogenous compounds (15 PFAS, 14 pesticides, 4 phenols, 4 phthalates, and 1 other compound) and 460 identified endogenous metabolites. Overall, we observed limited evidence of robust associations between individual environmental compounds and childhood asthma. Some age-specific signals were observed, including a positive association for monocyclohexyl phthalate and a negative association for monoethyl phosphate in age-stratified analyses, although these findings did not consistently meet multiple-testing thresholds. PFAS as a mixture was not associated with asthma ( P = 0.67, odds ratio = 1.00). Pathway analyses indicated potential involvement of the tyrosine metabolism pathway in relation to asthma and several environmental compounds. Conclusion: In this exploratory metabolomics analysis, we found limited evidence for strong associations between measured environmental compounds and childhood asthma. Nevertheless, several age-specific signals and pathway-level patterns, particularly involving tyrosine metabolism, were observed and may help guide future hypothesis-driven studies.