a Department of Environmental Health Sciences , Columbia University , New York , NY , USA.
b Department of Population Medicine , Harvard Medical School and Harvard Pilgrim Health Care Institute , Boston , MA , USA.
Epigenetics. 2018;13(9):923-940. doi: 10.1080/15592294.2018.1516453. Epub 2018 Oct 11.
Prenatal arsenic exposure is associated with adverse birth outcomes and disease risk later in life, which could be mediated through epigenetic dysregulation. We evaluated the association between arsenic and gestational age (GA) that was mediated through DNA methylation (DNAm) using data from a Bangladeshi birth cohort. Arsenic exposure was measured in maternal drinking water at ≤16 weeks GA and maternal toenails collected ≤1 month postpartum. Cord blood DNAm was measured using Infinium HumanMethylation450 arrays (n = 44, discovery phase). Top loci identified in the discovery phase were then pyrosequenced in a second group (n = 569, validation phase). Structural equation models (SEM) evaluated the direct and indirect effects of arsenic and DNAm on GA. In the discovery phase, arsenic was associated with differential DNAm of 139 loci that were associated with GA (P < 1.10X10; |β regression|>0.10). Each doubling in water arsenic concentration decreased GA by 2 days, which was fully mediated through the main principal component of the top-ten CpGs (P < 0.001). In the validation phase, there were direct and indirect effects of miR214-3 and MCC DNAm on GA. In an adjusted SEM model, mediation of the association between arsenic and GA by miR124-3 was borderline significant (P = 0.061). This study therefore identified DNAm at specific loci in cord blood that mediated the effect of arsenic exposure on GA. Specifically, prenatal arsenic exposure was associated with lower methylation of miR124-3 that mediated the exposure-response of arsenic on GA. Future research should evaluate if these epigenetic changes are persistent and associated with disease risk.
产前砷暴露与不良出生结局和生命后期的疾病风险有关，这可能是通过表观遗传失调介导的。我们使用来自孟加拉国出生队列的数据，评估了砷暴露与通过 DNA 甲基化 (DNAm) 介导的胎龄 (GA) 之间的关联。在妊娠≤16 周时测量母亲饮用水中的砷暴露，在产后≤1 个月时采集母亲趾甲。使用 Infinium HumanMethylation450 阵列测量脐带血 DNAm（n=44，发现阶段）。在第二个组（n=569，验证阶段）中对发现阶段确定的前 10 个基因座进行焦磷酸测序。结构方程模型 (SEM) 评估了砷和 DNAm 对 GA 的直接和间接影响。在发现阶段，砷与 139 个与 GA 相关的 DNAm 差异相关（P<1.10X10; |β回归|>0.10）。水砷浓度每增加一倍，GA 就会减少 2 天，这完全是通过前 10 个 CpG 的主要主成分介导的（P<0.001）。在验证阶段，miR214-3 和 MCC DNAm 对 GA 有直接和间接的影响。在调整后的 SEM 模型中，miR124-3 介导砷与 GA 之间关联的中介作用具有边缘显著意义（P=0.061）。因此，本研究确定了脐带血中特定基因座的 DNAm，这些 DNAm 介导了砷暴露对 GA 的影响。具体来说，产前砷暴露与 miR124-3 的低甲基化有关，miR124-3 介导了砷暴露与 GA 的暴露反应。未来的研究应该评估这些表观遗传变化是否持久并与疾病风险相关。
