Urinary Metals and Maternal Circulating Extracellular Vesicle microRNA in the MADRES Pregnancy Cohort

<i>Background</i>: Exposure to metals increases risk for pregnancy complications. Extracellular vesicle (EV) miRNA contribute to maternal-fetal communication and are dysregulated in pregnancy complications. However, metal impacts on maternal circulating EV miRNA during pregnancy are unknown. Our objective was to investigate the impact of multiple metal exposures on EV miRNA in maternal circulation during pregnancy in the MADRES Study. <i>Methods</i>: Associations between urinary concentrations of nine metals and 106 EV miRNA in maternal plasma during pregnancy were investigated using robust linear regression (N=231). Primary analyses focused on metal-miRNA associations in early pregnancy (median: 12.3 weeks gestation). In secondary analyses, we investigated associations with late pregnancy miRNA counts in a smaller subset of participants (N=184) with paired data in the third trimester (median: 31.8 weeks gestation). MiRNA associated with three or more metals (P_FDR&lt;0.05) were further investigated using Bayesian Kernel Machine Regression (BKMR), an environmental mixture modeling approach. <i>Results</i>: Thirty-five miRNA were associated (P_FDR&lt;0.05) with at least one metal in early pregnancy. Only one association (an inverse association between cobalt and miR-150-5p) remained statistically significant when evaluating late pregnancy miRNA counts. Eight miRNA (miR-302b-3p, miR-199a-5p, miR-188-5p, miR-138-5p, miR-212-3p, miR-608, miR-1272, miR-19b-3p) were associated with three different metals (barium, mercury, and thallium) in early pregnancy, and their predicted target genes were enriched in pathways important for placental development. Results were consistent when using BKMR. <i>Conclusions</i>: Early pregnancy exposure to barium, mercury, and thallium may have short-term impacts on a common set of maternal circulating EV miRNA which target pathways important for placental development.