Understanding the mechanistic basis of environmental pollutant toxicity is dependent on accurately characterizing both exposure and biological responses, especially in the era of exposomics and precision environmental health. 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 and persistent organic pollutants (POPs). The field remains nascent, however, with questions concerning the coherence and generalizability of findings across studies, study designs and analytical platforms. In over ten independent panel and cross-sectional cohort studies, we demonstrated the utility of high-resolution metabolomics as a central platform linking environmental exposure to internal dose and biological response where we identified novel metabolites and metabolic pathways related to complex air pollution and POPs mixtures. Specifically, biological perturbations in oxidative stress, systemic inflammation, and DNA damage and repair related pathway and metabolites were associated with exposures to air pollution and POPs, as well as a wide range of adverse health responses, especially among vulnerable population. These results hold great promise for identifying key connections between environmental exposures and corresponding adverse health effects. Future directions should focus on validation of these findings via hypothesis-driven protocols, technical advances in metabolic annotation and quantification, and application of multi-omics integration.
