“活力计划”中低水平铅暴露与脐带血DNA甲基化：一项全表观基因组关联研究
Exposure to Low Levels of Lead and Umbilical Cord Blood DNA Methylation in Project Viva: An Epigenome-Wide Association Study.
作者信息
Wu Shaowei, Hivert Marie-France, Cardenas Andres, Zhong Jia, Rifas-Shiman Sheryl L, Agha Golareh, Colicino Elena, Just Allan C, Amarasiriwardena Chitra, Lin Xihong, Litonjua Augusto A, DeMeo Dawn L, Gillman Matthew W, Wright Robert O, Oken Emily, Baccarelli Andrea A
机构信息
Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University , Beijing, China.
Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute , Boston, Massachusetts, USA.
出版信息
Environ Health Perspect. 2017 Aug 25;125(8):087019. doi: 10.1289/EHP1246.
BACKGROUND
Early-life exposure to lead is associated with deficits in neurodevelopment and with hematopoietic system toxicity. DNA methylation may be one of the underlying mechanisms for the adverse effects of prenatal lead on the offspring, but epigenome-wide methylation data for low levels of prenatal lead exposure are lacking.
OBJECTIVES
We investigated the association between prenatal maternal lead exposure and epigenome-wide DNA methylation in umbilical cord blood nucleated cells in Project Viva, a prospective U.S.-based prebirth cohort with relatively low levels of lead exposure.
METHODS
Among 268 mother-infant pairs, we measured lead concentrations in red blood cells (RBC) from prenatal maternal blood samples, and using HumanMethylation450 Bead Chips, we measured genome-wide methylation levels at 482,397 CpG loci in umbilical cord blood and retained 394,460 loci after quality control. After adjustment for batch effects, cell types, and covariates, we used robust linear regression models to examine associations of prenatal lead exposure with DNA methylation in cord blood at epigenome-wide significance level [false discovery rate (FDR)<0.05].
RESULTS
The mean [standard deviation (SD)] maternal RBC lead level was 1.22 (0.63) μg/dL. CpG cg10773601 showed an epigenome-wide significant negative association with prenatal lead exposure (-1.4% per doubling increase in lead exposure; p=2.3×10-7) and was annotated to C-Type Lectin Domain Family 11, Member A (), which functions as a growth factor for primitive hematopoietic progenitor cells. In sex-specific analyses, we identified more CpGs with FDR<0.05 among female infants (n=38) than among male infants (n=2). One CpG (cg24637308), which showed a strong negative association with prenatal lead exposure among female infants (-4.3% per doubling increase in lead exposure; p=1.1×10-06), was annotated to Dynein Heavy Chain Domain 1 gene () which is highly expressed in human brain. Interestingly, there were strong correlations between blood and brain methylation for CpG (cg24637308) based on another independent set of samples with a high proportion of female participants.
CONCLUSION
Prenatal low-level lead exposure was associated with newborn DNA methylation, particularly in female infants. https://doi.org/10.1289/EHP1246.
背景
生命早期接触铅与神经发育缺陷及造血系统毒性有关。DNA甲基化可能是产前铅暴露对后代产生不良影响的潜在机制之一，但缺乏低水平产前铅暴露的全基因组甲基化数据。
目的
在“生命项目”（Project Viva）中，我们研究了产前母亲铅暴露与脐带血有核细胞全基因组DNA甲基化之间的关联。“生命项目”是一个位于美国的前瞻性产前队列，铅暴露水平相对较低。
方法
在268对母婴中，我们测量了产前母亲血样中红细胞（RBC）的铅浓度，并使用HumanMethylation450 Bead芯片测量了脐带血中482,397个CpG位点的全基因组甲基化水平，质量控制后保留了394,460个位点。在调整批次效应、细胞类型和协变量后，我们使用稳健线性回归模型，在全基因组显著性水平[错误发现率（FDR）<0.05]下检查产前铅暴露与脐带血DNA甲基化的关联。
结果
母亲红细胞铅水平的平均值[标准差（SD）]为1.22（0.63）μg/dL。CpG位点cg10773601显示出与产前铅暴露存在全基因组显著的负相关（铅暴露每增加一倍，甲基化水平降低1.4%；p = 2.3×10-7），该位点被注释为C型凝集素结构域家族11成员A（C-Type Lectin Domain Family 11, Member A），其作为原始造血祖细胞的生长因子发挥作用。在性别特异性分析中，我们发现女性婴儿（n = 38）中FDR<0.05的CpG位点比男性婴儿（n = 2）更多。一个CpG位点（cg24637308）在女性婴儿中与产前铅暴露呈现出强烈的负相关（铅暴露每增加一倍，甲基化水平降低4.3%；p = 1.1×10-06），该位点被注释为动力蛋白重链结构域1基因（Dynein Heavy Chain Domain 1 gene），在人类大脑中高度表达。有趣的是，基于另一组女性参与者比例较高的独立样本，CpG位点（cg24637308）的血液和大脑甲基化之间存在强相关性。
结论
产前低水平铅暴露与新生儿DNA甲基化有关，尤其是在女性婴儿中。https://doi.org/10.1289/EHP1246
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