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

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, beta = -0.30), cg25818583 (q = 0.041, beta = -0.18), and cg23796967 (q = 0.047, beta = -0.17). The methylation in another CpG site in GP6 was close to significant (cg05374025, q = 0.057, beta = -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.