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.
Keywords: DNA methylation; DNA repair; Gene expression; Metals.
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