A State-of-the-Science Review on High-Resolution Metabolomics Application in Air Pollution Health Research: Current Progress, Analytical Challenges, and Recommendations for Future Direction.

backgroundUnderstanding the mechanistic basis of air pollution toxicity is dependent on accurately characterizing both exposure and biological responses. Untargeted metabolomics, an analysis of small-molecule metabolic phenotypes, may offer improved estimation of exposures and corresponding health responses to complex environmental mixtures such as air pollution. The field remains nascent, however, with questions concerning the coherence and generalizability of findings across studies, study designs and analytical platforms.

objectivesWe aimed to review the state of air pollution research from studies using untargeted high-resolution metabolomics (HRM), highlight the areas of concordance and dissimilarity in methodological approaches and reported findings, and discuss a path forward for future use of this analytical platform in air pollution research.

methodsWe conducted a state-of-the-science review to

resultsWe identified 47 articles that applied untargeted metabolomics on serum, plasma, whole blood, urine, saliva, or other biospecimens to investigate the impact of air pollution exposures on the human metabolome. Eight hundred sixteen unique features confirmed with level-1 or -2 evidence were reported to be associated with at least one or more air pollutants. Hypoxanthine, histidine, serine, aspartate, and glutamate were among the 35 metabolites consistently exhibiting associations with multiple air pollutants in at least 5 independent studies. Oxidative stress and inflammation-related pathways-including glycerophospholipid metabolism, pyrimidine metabolism, methionine and cysteine metabolism, tyrosine metabolism, and tryptophan metabolism-were the most commonly perturbed pathways reported in

conclusionsNumerous investigations have demonstrated the feasibility of using untargeted metabolomics as a platform linking exposure to internal dose and biological response. Our review of the 47 existing untargeted HRM-air pollution studies points to an underlying coherence and consistency across a range of sample analytical quantitation methods, extraction algorithms, and statistical modeling approaches. Future directions should focus on validation of these findings via hypothesis-driven protocols and technical advances in metabolic annotation and quantification. https://doi.org/10.1289/EHP11851.