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; Brent A Coull; Andrea A Baccarelli; Robert O Wright; Chitra Amarasiriwardena; Diane R Gold; Emily Oken; Marie-France Hivert; Andres Cardenas

doi:10.1186/s13148-021-01198-z

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

Clin Epigenetics. 2021 Nov 19;13(1):208. doi: 10.1186/s13148-021-01198-z.

Authors

Anne K Bozack¹, Sheryl L Rifas-Shiman², Brent A Coull³, Andrea A Baccarelli⁴, Robert O Wright⁵, Chitra Amarasiriwardena⁵, Diane R Gold^{6

7

8}, Emily Oken², Marie-France Hivert^{2

9}, Andres Cardenas^{10

11}

Affiliations

¹ Division of Environmental Health Sciences, School of Public Health, University of California Berkeley, 2121 Berkeley Way, Room 5302, Berkeley, CA, 94720, USA.
² Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.
³ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
⁴ Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York City, NY, USA.
⁵ Department of Environmental Medicine and Public Health and Institute for Exposomic Research, Icahn School of Medicine at Mount Sinai, NY, New York City, USA.
⁶ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁷ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
⁸ Harvard Medical School, Boston, MA, USA.
⁹ Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Division of Environmental Health Sciences, School of Public Health, University of California Berkeley, 2121 Berkeley Way, Room 5302, Berkeley, CA, 94720, USA. andres.cardenas@berkeley.edu.
¹¹ Center for Computational Biology, University of California, Berkeley, CA, USA. andres.cardenas@berkeley.edu.

Abstract

Background: Prenatal 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.

Results: Pb 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.

Conclusions: Prenatal 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.

Keywords: DNA methylation; EWAS; Manganese; Metals; Prenatal exposure.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adult
DNA Methylation / genetics*
DNA Methylation / immunology
Epigenome / genetics
Epigenome / immunology
Female
Fetal Blood / chemistry*
Fetal Blood / immunology
Humans
Infant
Infant, Newborn
Pregnancy
Prenatal Diagnosis / methods
Prenatal Diagnosis / statistics & numerical data
Prenatal Exposure Delayed Effects / genetics

Abstract

Publication types

MeSH terms

Grants and funding