Metabolome-wide association study of prenatal exposure to air pollution and adverse birth outcomes in the Atlanta African American Maternal-Child cohort

Background. African Americans (AA) are disproportionately exposed to high air pollution and elevated risks of adverse birth outcomes, while the underlying mechanisms are still largely unknown. We aimed to address the knowledge gaps by investigating the associations between air pollution exposures, perturbations in maternal metabolome, and preterm (PTB) and early term birth (ETB). Methods: In 288 participants from the Atlanta AA Maternal-Child cohort we performed metabolomic profiling using high-resolution mass spectrometry with liquid chromatography in early gestation serum samples. Using spatiotemporally-resolved machine learning models, we estimated individual residential exposures to nitrogen dioxide, fine particulate matters, and ozone during the first trimester and one-year before conception. Using the meet-in-the-middle approach, we investigated whether the maternal metabolic perturbations associated with air pollution are also associated with PTB and/or ETB. Results: After quality control, 13,980 and 11,106 metabolic features were extracted from HILIC and C18 chromatography columns, respectively. In the HILIC column, 95 and 190 metabolic features were associated with at least one air pollutant (false positive discovery corrected q<0.2) during the first trimester and one-year before conception, respectively, while 3 and 4 features were associated with PTB and ETB. From C18, 243 and 48 features were associated with first trimester and one-year before conception exposures, while 5 and 1 were associated with PTB and ETB, respectively. Perturbations in purine metabolism were associated with both air pollution and PTB in pathway enrichment analysis. Using chemical annotation, we confirmed inosine and inosinic acid, which were enriched in purine metabolism and involved in DNA damage and repair. Conclusions: The findings suggested a potentially critical role of purine metabolism in connecting air pollution exposures and PTB, which may support future development of sensitive biomarker and targeted interventions to reduce adverse birth outcomes induced by air pollution exposures. Keywords: Air pollution, preterm birth, metabolomics, meet-in-the-middle, molecular mechanisms