Prenatal metal exposure, cord blood DNA methylation and persistence in childhood: epigenome-wide association study of twelve metals

Abstract

BACKGROUND AND AIM: Associations between prenatal metal exposure and birth and child health outcomes, including fetal growth and neurodevelopment, may be mediated by changes in DNA methylation (DNAm). We analyzed associations between maternal blood metal(loid)s (As, Ba, Cd, Cr, Cs, Cu, Hg, Mg, Mn, Pb, Se and Zn) and differential methylated positions (DMPs) at individual CpGs and differentially methylated regions (DMRs) in cord blood, and tested if associations persisted in blood cells collected in middle childhood. METHODS: In the Project Viva cohort, metal(loid) concentrations were measured in first-trimester maternal erythrocytes. DNAm was measured in cord (N=361) and mid-childhood blood cells (N=333, range 6-10 years) using the Illumina HumanMethylation450 BeadChip. DMPs and DMRs were identified using limma and combp, respectively, adjusting for sex, race, gestational age, parity, maternal age, BMI, education, smoking, income, and estimated cell types. Multiple comparisons were adjusted for using a false discovery rate (FDR) correction for DMPs and the Sidak method for DMRs. Sex-stratified analyses were also conducted. RESULTS:Mn was associated with differential methylation of cg02042823 (A2BP1) in cord blood (FDR=9.27x10-6). This association was nominally significant in middle childhood (p=0.009). Mn was associated with 2 and 9 DMPs in male and female infants, respectively (FDR0.05). No other metal(loid)s were associated with cord blood DMPs. All metal(loid)s except Ba and Pb were associated with ≥1 DMR among all infants (Sidak p0.05). Among males, all exposures except Cr, and among females, all exposures except Hg and Pb were associated with ≥1 DMR. DMRs annotated to genes in the chr6 human leukocyte antigen (HLA) region were identified for Cr, Cs, Hg, Mg, and Mn. CONCLUSIONS:Prenatal metal(loid) exposure is associated with DNAm, including DMRs in the HLA region. Future research is needed to assess whether epigenetic associations partially explain the relation of prenatal metal exposures to health outcomes. KEYWORDS: children's environmental health, heavy metals, environmental epidemiology, epigenomics