The exposome concept proposes that people are exposed to multiple exposure groups across the life-course that can affect health. Metabolomics is a technique that enables unbiased measurement of thousands of metabolites in order to understand the underlying molecular basis linking exposures to disease and to generate hypotheses for future targeted toxicological studies. To date, metabolomics has primarily been used to understand metabolic changes to one exposure or exposure class at a time. However, the molecular connections among multiple exposures, metabolites and health outcomes are still unknown. In this study, we explore the concept of ‘molecular gatekeepers’- key metabolites that link single or multiple exposure biomarkers and correlated clusters of endogenous metabolites. This may uncover important targets for toxicological study and future exposome research. We performed untargeted metabolomics on serum from 180 adolescent girls, participants in the Growing Up Healthy Study in New York City, using high-resolution mass spectrometry (HRMS). Using two different chromatographies with HRMS in positive and negative modes, 4984 and 12868 metabolite features were measured. We then performed network analysis to link metabolites to environmental biomarkers including 5 heavy metals (Cd, Mn, Pb, Se, and Hg) and 6 perfluorinated chemicals (PFCs) (n-PFOS, Sm-PFOS, Sm2-PFOS, n-PFOA, PFHxS, PFNA) previously measured by the CDC in the same samples. Network analysis revealed 74 and 191 clusters of correlated metabolites (≥2 metabolites, Pearson correlation coefficient &gt; 0.9) in positive and negative mode, respectively. Within those correlated clusters, 56 features in positive mode and 179 features in negative mode were defined as gatekeeper molecules that were also correlated with a environmental biomarker. Among those gatekeepers, 25 and 80 features, respectively, were associated with multiple exposures (linear model with FDR adjusted p-value &lt; 0.05). Identification by MS/MS revealed that most of the gatekeeper molecules were lipids. Interestingly, gatekeeper 1-palmitoyl-sn-glycero-3-phosphocholine was linked with both Se and PFCs (n-PFOA and n-PFOS), suggesting that this metabolite and related biological pathways may be commonly dysregulated by multiple xenobiotic exposures. Further work to investigate how gatekeeper metabolite discovery may generate hypotheses on important metabolites and pathways linking multiple exposure groups to health effects is warranted.

Molecular gatekeeper discovery for multiple exposure groups in adolescent girls

ACS Spring Meeting 2021

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