Prenatal lead exposure is associated with decreased cord blood DNA methylation of the glycoprotein VI gene involved in platelet activation and thrombus formation

Abstract

Early-life lead exposure impairs neurodevelopment and later exposure affects the cardiovascular system. Lead has been associated with reduced global 5-methylcytosine DNA methylation, suggesting that lead toxicity acts through epigenetic mechanisms. The objective of this study is to clarify how early-life lead exposure alters DNA methylation of specific genes, using an epigenomic approach. We measured lead concentrations in urine [gestational week (GW), 8] and erythrocytes (GW 14), using inductively coupled plasma mass spectrometry, for 127 pregnant mothers recruited in the MINIMat food and supplementation cohort in rural Bangladesh. Cord blood DNA methylation was analyzed with the Infinium HumanMethylation450K BeadChip, and top sites were validated by methylation-sensitive high-resolution melt curve analysis. Maternal urinary lead concentrations (divided into quartiles) showed significant (after adjustment for false discovery rate) inverse associations with methylation at nine CpGs. Three of these sites were in the 5′-end, including the promoter, of glycoprotein IV (GP6); cg18355337 (q = 0.029, β = −0.30), cg25818583 (q = 0.041, β = −0.18), and cg23796967 (q = 0.047, β = −0.17). The methylation in another CpG site in GP6 was close to significant (cg05374025, q = 0.057, β = − 0.23). The erythrocyte lead concentrations (divided into quartiles) were also inversely associated with CpG methylation in GP6, although this was not statistically significant after false discovery rate adjustments. Eight CpG sites in GP6 constituted a differentially methylated region in relation to urinary lead (P = 0.005, q = 0.48) and erythrocyte lead (P = 0.007, q = 0.46). In conclusion, we found that moderate prenatal lead exposure appears to epigenetically affect GP6, a key component of platelet aggregation and thrombus formation, suggesting a novel link between early lead exposure and cardiovascular disease later in life.

Sex-Dependent Impact of Low-Level Lead Exposure during Prenatal Period on Child Psychomotor Functions

“…These findings are consistent with the result of a research performed in peripheral blood samples from children of both sexes, where lead-associated changes in DNA methylation showed a significant sex dimorphism [ 48 ]. The increasing number of studies showing that developmental exposure to metals influences DNA methylation in exposed children supports the view that the long-term effects of these agents might be mediated by epigenetic changes [ 49 ]. Recently, epigenetic effects of prenatal lead exposure have been also demonstrated in children; however, there have been no marked differences between the sexes—gender was treated as a confounding factor [ 50 ].…”

Exposure to Low Levels of Lead in Utero and Umbilical Cord Blood DNA Methylation in Project Viva: An Epigenome-Wide Association Study

“…We also investigated the top loci identified by a previous EWAS analysis on prenatal lead exposure and cord blood DNA methylation ( Engström et al 2015 ) based on our data set and found that one of the loci (cg05374025) was significantly associated with prenatal lead exposure in our samples ( ; see Table S13).…”

“…A previous study also investigated the epigenome-wide association of prenatal lead exposure with cord blood DNA methylation profiles in a birth cohort in rural Bangladesh ( ) with high environmental lead levels, and the authors identified a set of loci with , among which some were located around the gene glycoprotein VI ( GP6 ) ( Engström et al 2015 ). However, only one of these loci (cg05374025) reached statistical significance in our samples.…”

“…To account for multiple testing, we only report top loci with a false discovery rate (FDR)-corrected , as has commonly been implemented in previous EWAS analyses ( Engström et al 2015 ; Senut et al 2014 ). To facilitate interpretation of the results, we report effect estimates in the main text using the -value scale for top loci with an based on the robust linear regression.…”

“…These studies provide evidence that lead exposure may affect both global and brain genomic methylation. In addition, a recent epidemiological study found that the epigenome-wide DNA methylation profile in umbilical cord blood was associated with high levels of prenatal lead exposure in 127 mother–infant pairs in lead-endemic regions outside the United States ( Engström et al 2015 ).…”