Prenatal metal exposure, cord blood DNA methylation and persistence in childhood: an epigenome-wide association study of 12 metals

Anne K Bozack,Sheryl L Rifas-Shiman,Chitra Amarasiriwardena,Brent A Coull,Robert O Wright,Andres Cardenas,Emily Oken,Diane R Gold,Andrea A Baccarelli,Marie-France Hivert

doi:10.1186/s13148-021-01198-z

Abstract

BackgroundPrenatal exposure to essential and non-essential metals impacts birth and child health, including fetal growth and neurodevelopment. DNA methylation (DNAm) may be involved in pathways linking prenatal metal exposure and health. In the Project Viva cohort, we analyzed the extent to which metals (As, Ba, Cd, Cr, Cs, Cu, Hg, Mg, Mn, Pb, Se, and Zn) measured in maternal erythrocytes were associated with differentially methylated positions (DMPs) and regions (DMRs) in cord blood and tested if associations persisted in blood collected in mid-childhood. We measured metal concentrations in first-trimester maternal erythrocytes, and DNAm in cord blood (N = 361) and mid-childhood blood (N = 333, 6–10 years) with the Illumina HumanMethylation450 BeadChip. For each metal individually, we tested for DMPs using linear models (considered significant at FDR < 0.05), and for DMRs using comb-p (Sidak p < 0.05). Covariates included biologically relevant variables and estimated cell-type composition. We also performed sex-stratified analyses.ResultsPb was associated with decreased methylation of cg20608990 (CASP8) (FDR = 0.04), and Mn was associated with increased methylation of cg02042823 (A2BP1) in cord blood (FDR = 9.73 × 10–6). Both associations remained significant but attenuated in blood DNAm collected at mid-childhood (p < 0.01). Two and nine Mn-associated DMPs were identified in male and female infants, respectively (FDR < 0.05), with two and six persisting in mid-childhood (p < 0.05). All metals except Ba and Pb were associated with ≥ 1 DMR among all infants (Sidak p < 0.05). Overlapping DMRs annotated to genes in the human leukocyte antigen (HLA) region were identified for Cr, Cs, Cu, Hg, Mg, and Mn.ConclusionsPrenatal metal exposure is associated with DNAm, including DMRs annotated to genes involved in neurodevelopment. Future research is needed to determine if DNAm partially explains the relationship between prenatal metal exposures and health outcomes.

Highlights

Prenatal exposure to essential and non-essential metals impacts birth and child health, including fetal growth and neurodevelopment
We identified nominally significant Gene Ontology (GO) terms with an overrepresentation of differentially methylated genes associated with Cr (N = 18), Cs (N = 20), Cu (N = 17), Se (N = 41), and Zn (N = 18) (p < 0.05); no terms remained significant after false discovery rate (FDR) adjustment
We investigated epigenome-wide associations of prenatal concentrations of 12 metals measured in maternal firsttrimester Red blood cells (RBCs) samples with cord blood DNA methylation (DNAm) and persistence DNAm changes in mid-childhood in the Project Viva pre-birth cohort

Summary

Introduction

Prenatal exposure to essential and non-essential metals impacts birth and child health, including fetal growth and neurodevelopment. In the Project Viva cohort, we analyzed the extent to which metals (As, Ba, Cd, Cr, Cs, Cu, Hg, Mg, Mn, Pb, Se, and Zn) measured in maternal erythrocytes were associated with differentially methylated positions (DMPs) and regions (DMRs) in cord blood and tested if associations persisted in blood collected in mid-childhood. Bozack et al Clinical Epigenetics (2021) 13:208 of essential metals has been associated with adverse birth outcomes including preterm birth [7], decreased birth weight, and growth restriction [4], as well as infant and child health outcomes including neurodevelopment, cognitive function [8,9,10], and increased risk for infections [10]. Sex-specific associations have been reported with early-pregnancy maternal metal concentrations and birth outcomes in the Project Viva cohort [22]

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