Rygiel Christine A, Dolinoy Dana C, Perng Wei, Jones Tamara R, Solano Maritsa, Hu Howard, Téllez-Rojo Martha M, Peterson Karen E, Goodrich Jaclyn M
Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.
Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.
Epigenet Insights. 2020 Jul 20;13:2516865720938669. doi: 10.1177/2516865720938669. eCollection 2020.
Gestational exposure to lead (Pb) adversely impacts offspring health through multiple mechanisms, one of which is the alteration of the epigenome including DNA methylation. This study aims to identify differentially methylated CpG sites associated with trimester-specific maternal Pb exposure in umbilical cord blood (UCB) leukocytes. Eighty-nine mother-child dyads from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) longitudinal birth cohorts with available UCB samples were selected for DNA methylation analysis via the Infinium Methylation EPIC BeadChip, which quantifies methylation at >850 000 CpG sites. Maternal blood lead levels (BLLs) during each trimester (T1: 6.56 ± 5.35 µg/dL; T2: 5.93 ± 5.00 µg/dL; T3: 6.09 ± 4.51 µg/dL), bone Pb (patella: 11.8 ± 9.25 µg/g; tibia: 11.8 ± 6.73 µg/g), a measure of cumulative Pb exposure, and UCB Pb (4.86 ± 3.74 µg/dL) were measured. After quality control screening, data from 786 024 CpG sites were used to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) by Pb biomarkers using separate linear regression models, controlling for sex and estimated UCB cell-type proportions. We identified 3 DMPs associated with maternal T1 BLL, 2 with T3 BLL, and 2 with tibia bone Pb. We identified one DMR within associated with T1 BLL, one located at chr6:30095136-30095295 with T3 BLL, and one within with tibia bone Pb (adjusted -value < .05). Pathway analysis identified 15 overrepresented gene pathways for differential methylation that overlapped among all 3 trimesters with the largest overlap between T1 and T2 (adjusted -value < .05). Pathways of interest include nodal signaling pathway and neurological system processes. These data provide evidence for differential methylation by prenatal Pb exposure that may be trimester-specific.
孕期接触铅（Pb）会通过多种机制对后代健康产生不利影响，其中之一是表观基因组的改变，包括DNA甲基化。本研究旨在确定与脐带血（UCB）白细胞中孕期特异性母体铅暴露相关的差异甲基化CpG位点。从墨西哥早期生命暴露于环境毒物（ELEMENT）纵向出生队列中选取了89对母婴二元组，这些母婴有可用的UCB样本，通过Infinium甲基化EPIC BeadChip进行DNA甲基化分析，该芯片可对超过850,000个CpG位点的甲基化进行定量。测量了孕期各阶段（T1：6.56±5.35μg/dL；T2：5.93±5.00μg/dL；T3：6.09±4.51μg/dL）的母体血铅水平（BLL）、骨铅（髌骨：11.8±9.25μg/g；胫骨：11.8±6.73μg/g，作为累积铅暴露的指标）以及UCB铅（4.86±3.74μg/dL）。经过质量控制筛选后，使用来自786,024个CpG位点的数据，通过单独的线性回归模型，以性别和估计的UCB细胞类型比例为控制变量，利用铅生物标志物来识别差异甲基化位置（DMP）和差异甲基化区域（DMR）。我们确定了3个与母体T1期BLL相关的DMP、2个与T3期BLL相关的DMP以及2个与胫骨骨铅相关的DMP。我们确定了一个与T1期BLL相关的位于 内的DMR、一个位于chr6:30095136 - 30095295且与T3期BLL相关的DMR以及一个与胫骨骨铅相关的位于 内的DMR（校正P值<0.05）。通路分析确定了15个差异甲基化的过度表达基因通路，这些通路在所有三个孕期中都有重叠，其中T1和T2之间的重叠最大（校正P值<0.05）。感兴趣的通路包括节点信号通路和神经系统过程。这些数据为产前铅暴露导致的差异甲基化提供了证据，且这种差异甲基化可能具有孕期特异性。
