Division of Environmental Health Sciences, School of Public Health, University of California Berkeley, 2121 Berkeley Way, Room 5302, Berkeley, CA, 94720, USA.
Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.
Clin Epigenetics. 2021 Nov 19;13(1):208. doi: 10.1186/s13148-021-01198-z.
Prenatal exposure to essential and non-essential metals impacts birth and child health, including fetal growth and neurodevelopment. DNA methylation (DNAm) may be involved in pathways linking prenatal metal exposure and health. In the Project Viva cohort, we analyzed the extent to which metals (As, Ba, Cd, Cr, Cs, Cu, Hg, Mg, Mn, Pb, Se, and Zn) measured in maternal erythrocytes were associated with differentially methylated positions (DMPs) and regions (DMRs) in cord blood and tested if associations persisted in blood collected in mid-childhood. We measured metal concentrations in first-trimester maternal erythrocytes, and DNAm in cord blood (N = 361) and mid-childhood blood (N = 333, 6-10 years) with the Illumina HumanMethylation450 BeadChip. For each metal individually, we tested for DMPs using linear models (considered significant at FDR < 0.05), and for DMRs using comb-p (Sidak p < 0.05). Covariates included biologically relevant variables and estimated cell-type composition. We also performed sex-stratified analyses.
Pb was associated with decreased methylation of cg20608990 (CASP8) (FDR = 0.04), and Mn was associated with increased methylation of cg02042823 (A2BP1) in cord blood (FDR = 9.73 × 10). Both associations remained significant but attenuated in blood DNAm collected at mid-childhood (p < 0.01). Two and nine Mn-associated DMPs were identified in male and female infants, respectively (FDR < 0.05), with two and six persisting in mid-childhood (p < 0.05). All metals except Ba and Pb were associated with ≥ 1 DMR among all infants (Sidak p < 0.05). Overlapping DMRs annotated to genes in the human leukocyte antigen (HLA) region were identified for Cr, Cs, Cu, Hg, Mg, and Mn.
Prenatal metal exposure is associated with DNAm, including DMRs annotated to genes involved in neurodevelopment. Future research is needed to determine if DNAm partially explains the relationship between prenatal metal exposures and health outcomes.
产前暴露于必需和非必需金属会影响出生和儿童健康，包括胎儿生长和神经发育。DNA 甲基化（DNAm）可能参与了将产前金属暴露与健康联系起来的途径。在 Project Viva 队列中，我们分析了在脐带血中测量的母体红细胞中的金属（As、Ba、Cd、Cr、Cs、Cu、Hg、Mg、Mn、Pb、Se 和 Zn）与差异甲基化位置（DMP）和区域（DMR）之间的关联程度，并检验了这些关联在儿童中期采集的血液中是否仍然存在。我们使用 Illumina HumanMethylation450 BeadChip 测量了母亲红细胞中的金属浓度和脐带血（N=361）和儿童中期血（N=333，6-10 岁）中的 DNAm。对于每种金属，我们使用线性模型（在 FDR<0.05 时被认为是显著的）来检测 DMP，并使用 comb-p（Sidak p<0.05）来检测 DMR。协变量包括生物学相关变量和估计的细胞组成。我们还进行了性别分层分析。
Pb 与脐带血中 cg20608990（CASP8）的甲基化降低有关（FDR=0.04），Mn 与 cg02042823（A2BP1）的甲基化增加有关（FDR=9.73×10）。这两种关联在儿童中期的血液 DNAm 中仍然显著，但强度减弱（p<0.01）。在男性和女性婴儿中分别发现了 2 个和 9 个与 Mn 相关的 DMP（FDR<0.05），其中 2 个和 6 个在儿童中期仍然存在（p<0.05）。除了 Ba 和 Pb 之外，所有金属都与所有婴儿中的至少 1 个 DMR 有关（Sidak p<0.05）。在 Cr、Cs、Cu、Hg、Mg 和 Mn 中，鉴定出与人类白细胞抗原（HLA）区域基因注释的重叠 DMR。
产前金属暴露与 DNAm 有关，包括与神经发育有关的基因注释的 DMR。需要进一步研究来确定 DNAm 是否部分解释了产前金属暴露与健康结果之间的关系。
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