Urinary metals and maternal circulating extracellular vesicle microRNA in the MADRES pregnancy cohort

Exposure to metals increases risk for pregnancy complications. Extracellular vesicle (EV) miRNA contribute to maternal-foetal 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. 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 (median: 31.8 weeks gestation) in a subset of participants (N = 184) with paired measures. MiRNA associated with three or more metals (PFDR<0.05) were further investigated using Bayesian Kernel Machine Regression (BKMR), an environmental mixture method. Thirty-five miRNA were associated (PFDR<0.05) with at least one metal in early pregnancy. 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 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. Early pregnancy exposure to barium, mercury, and thallium may have short-term impacts on a common set of EV miRNA which target pathways important for placental development.

金属暴露会增加妊娠并发症的发生风险。细胞外囊泡（Extracellular Vesicle, EV）miRNA参与母胎通信，且在妊娠并发症中呈现表达失调状态。然而，目前尚不清楚妊娠期间金属暴露对母体循环EV miRNA的影响。本研究依托MADRES研究，旨在探究妊娠期间多重金属暴露对母体循环EV miRNA的影响。本研究采用稳健线性回归模型，针对231名受试者，分析了妊娠期间母体血浆中9种金属的尿液浓度与106种EV miRNA之间的关联。初步分析聚焦于妊娠早期（中位孕周：12.3周）的金属-miRNA关联情况。在次级分析中，我们针对184名拥有配对检测数据的受试者亚群，分析了妊娠晚期（中位孕周：31.8周）的miRNA水平与金属暴露的关联。针对与3种及以上金属存在关联（PFDR<0.05）的miRNA，本研究进一步采用环境混合物分析方法贝叶斯核机器回归（Bayesian Kernel Machine Regression, BKMR）进行深入探究。在妊娠早期，共有35种miRNA与至少1种金属存在关联（PFDR<0.05）。在分析妊娠晚期miRNA水平时，仅有1组关联（钴与miR-150-5p之间的负相关）仍具有统计学显著性。在妊娠早期，共有8种miRNA（miR-302b-3p、miR-199a-5p、miR-188-5p、miR-138-5p、miR-212-3p、miR-608、miR-1272、miR-19b-3p）与3种金属（钡、汞、铊）存在关联，且其预测靶基因在胎盘发育相关的重要通路中显著富集。采用BKMR分析得到的结果与此一致。妊娠早期暴露于钡、汞、铊，可能会对一组靶向胎盘发育重要通路的共同EV miRNA产生短期影响。