High-resolution metabolomics of exposure to tobacco smoke during pregnancy and adverse birth outcomes in the Atlanta African American Maternal-Child cohort

Abstract

BACKGROUND AND AIM: Exposure to tobacco smoke during pregnancy has been associated with a series of adverse reproductive outcomes; however, the underlying molecular mechanisms are not well-established. In this analysis, we measured urinary cotinine, a widely used biomarker of tobacco exposure, and conducted high-resolution metabolomics (HRM) to identify biological perturbations associated with prenatal tobacco smoke exposures and adverse birth outcomes. METHODS: We collected early and late pregnancy urine samples for cotinine measurement and serum samples for HRM profiling from 105 pregnant women from the Atlanta African American Maternal-Child cohort (2014-2016). Using an untargeted HRM workflow, we investigated how the biological perturbations in maternal metabolome mediate the association between prenatal smoke exposures and adverse birth outcomes (preterm birth, early term birth vs. full term birth; gestational age at birth) using a meet-in-the-middle approach. RESULTS:The median maternal urinary cotinine level was 4.77 ug/g creatinine, with 29 subjects higher than 100 ug/g creatinine. In total, 16,481 and 13,043 metabolic features were extracted from serum samples using hilic and c18 columns, respectively. Thirteen metabolic pathways were found to be associated with cotinine level and adverse birth outcomes during early and late pregnancy, including tryptophan, histidine, urea cycle, arginine, and proline metabolism. We confirmed 47 metabolites associated with cotinine exposure, preterm birth, and shorter gestational length, which include glutamate, serine, choline, and taurine; these metabolites are closely involved in endogenous inflammation, vascular reactivity, and lipid peroxidation processes. CONCLUSIONS:The metabolic perturbations associated with cotinine exposure were closely connected within a metabolic network related to inflammation, oxidative stress, placental vascularization, and insulin action, which could contribute to shorter gestations. The findings support the future development of targeted interventions to reduce adverse birth outcomes associated with tobacco smoke exposure, especially among African American who are disproportionately exposed to high tobacco smoke and experience higher rates of adverse birth outcomes. KEYWORDS: Tobacco Smoke Exposures, Metabolomics, Birth Outcomes, Preterm Birth