Department of Biostatistics, University of Michigan, Ann Arbor, USA.
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, USA.
Epigenetics. 2022 Mar;17(3):253-268. doi: 10.1080/15592294.2021.1897059. Epub 2021 Apr 2.
The maternal epigenome may be responsive to prenatal metals exposures. We tested whether metals are associated with concurrent differential maternal whole blood DNA methylation. In the Early Autism Risk Longitudinal Investigation cohort, we measured first or second trimester maternal blood metals concentrations (cadmium, lead, mercury, manganese, and selenium) using inductively coupled plasma mass spectrometry. DNA methylation in maternal whole blood was measured on the Illumina 450 K array. A subset sample of 97 women had both measures available for analysis, all of whom did not report smoking during pregnancy. Linear regression was used to test for site-specific associations between individual metals and DNA methylation, adjusting for cell type composition and confounding variables. Discovery gene ontology analysis was conducted on the top 1,000 sites associated with each metal. We observed hypermethylation at 11 DNA methylation sites associated with lead (FDR False Discovery Rate -value <0.1), near the genes , and . Lead-associated sites were enriched (FDR -value <0.1) for the pathways cell adhesion, nervous system development, and calcium ion binding. Manganese was associated with hypermethylation at four DNA methylation sites (FDR -value <0.1), one of which was near the gene . Manganese-associated sites were enriched for cellular metabolism pathways (FDR -value<0.1). Effect estimates for DNA methylation sites associated ( < 0.05) with cadmium, lead, and manganese were highly correlated (Pearson ρ > 0.86). DNA methylation sites associated with lead and manganese may be potential biomarkers of exposure or implicate downstream gene pathways.
母体的表观基因组可能对产前金属暴露有反应。我们检测了金属是否与同时发生的母体全血 DNA 甲基化差异有关。在早期自闭症风险纵向研究队列中，我们使用电感耦合等离子体质谱法测量了第一或第二孕期母体血液中的金属浓度（镉、铅、汞、锰和硒）。使用 Illumina 450K 阵列测量母体全血中的 DNA 甲基化。97 名女性中有一部分样本可同时进行这两项测量，她们都报告在怀孕期间没有吸烟。线性回归用于测试单个金属与 DNA 甲基化之间的特定部位关联，调整细胞类型组成和混杂变量。对与每种金属相关的前 1000 个位点进行了发现基因本体论分析。我们观察到与铅相关的 11 个 DNA 甲基化位点呈超甲基化（FDR False Discovery Rate 值 <0.1），这些位点靠近基因 和 。与铅相关的位点富集（FDR 值 <0.1）与细胞黏附、神经系统发育和钙离子结合途径有关。锰与四个 DNA 甲基化位点的超甲基化有关（FDR 值 <0.1），其中一个位于基因 附近。与锰相关的位点富含细胞代谢途径（FDR 值 <0.1）。与镉、铅和锰相关（<0.05）的 DNA 甲基化位点的效应估计值高度相关（Pearson ρ>0.86）。与铅和锰相关的 DNA 甲基化位点可能是暴露的潜在生物标志物，或暗示下游基因途径。
