Department of Toxicology, Cinvestav, Ave. IPN 2508, Zacatenco, Mexico City, 07360, Mexico.
National Institute of Public Health-INSP, Ave. Universidad 655, Santa María Ahuacatitlán, Cuernavaca, Morelos, 62100, Mexico.
J Trace Elem Med Biol. 2019 Sep;55:110-120. doi: 10.1016/j.jtemb.2019.06.014. Epub 2019 Jun 18.
The developmental period in utero is a critical window for environmental exposure. Epigenetic fetal programming via DNA methylation is a pathway through which metal exposure influences the risk of developing diseases later in life. Genetic damage repair can be modified by alterations in DNA methylation, which, in turn, may modulate gene expression due to metal exposure. We investigated the impact of prenatal metal exposure on global and gene-specific DNA methylation and mRNA expression in 181 umbilical cord blood samples from newborns in Mexico City. Global (LINE1) and promoter methylation of DNA-repair (OGG1 and PARP1) and antioxidant (Nrf2) genes was evaluated by pyrosequencing. Prenatal metal exposure (As, Cu, Hg, Mn, Mo, Pb, Se, and Zn) was determined by ICP-MS analysis of maternal urine samples. Multiple regression analyses revealed that DNA methylation of LINE1, Nrf2, OGG1, and PARP1 was associated with potentially toxic (As, Hg, Mn, Mo, and Pb) and essential (Cu, Se, and Zn) elements, and with their interactions. We also evaluated the association between gene expression (mRNA levels quantified by p-PCR) and DNA methylation. An increase in OGG1 methylation at all sites and at CpG2, CpG3, and CpG4 sites was associated with reduced mRNA levels; likewise, methylation at the CpG5, CpG8, and CpG11 sites of PARP1 was associated with reduced mRNA expression. In contrast, methylation at the PARP1 CpG7 site was positively associated with its mRNA levels. No associations between Nrf2 expression and CpG site methylation were observed. Our data suggest that DNA methylation can be influenced by prenatal metal exposure, which may contribute to alterations in the expression of repair genes, and therefore, result in a lower capacity for DNA damage repair in newborns.
子宫内的发育阶段是暴露于环境的关键时期。通过 DNA 甲基化进行的胎儿发育编程是金属暴露影响日后发生疾病风险的一种途径。金属暴露可能会通过改变 DNA 甲基化来修饰基因损伤修复，而这又可能会由于基因表达的改变而调节基因表达。我们研究了产前金属暴露对来自墨西哥城新生儿的 181 个脐带血样本的全基因组和特定基因 DNA 甲基化以及 mRNA 表达的影响。通过焦磷酸测序评估了 DNA 修复（OGG1 和 PARP1）和抗氧化剂（Nrf2）基因的全基因组（LINE1）和启动子甲基化。通过 ICP-MS 分析母亲尿液样本来确定产前金属暴露（As、Cu、Hg、Mn、Mo、Pb、Se 和 Zn）。多元回归分析表明，LINE1、Nrf2、OGG1 和 PARP1 的 DNA 甲基化与潜在毒性（As、Hg、Mn、Mo 和 Pb）和必需元素（Cu、Se 和 Zn）及其相互作用有关。我们还评估了基因表达（通过 p-PCR 定量的 mRNA 水平）与 DNA 甲基化之间的关联。所有 OGG1 位点和 CpG2、CpG3 和 CpG4 位点的 OGG1 甲基化增加与 mRNA 水平降低有关；同样，PARP1 的 CpG5、CpG8 和 CpG11 位点的甲基化与 mRNA 表达降低有关。相反，PARP1 的 CpG7 位点的甲基化与它的 mRNA 水平呈正相关。未观察到 Nrf2 表达与 CpG 位点甲基化之间存在关联。我们的数据表明，产前金属暴露会影响 DNA 甲基化，这可能导致修复基因表达的改变，从而导致新生儿的 DNA 损伤修复能力降低。
