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Environ Health Perspect. 2017 Aug 25;125(8):087019. doi: 10.1289/EHP1246.

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

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Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University , Beijing, China.
Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute , Boston, Massachusetts, USA.
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University , New York, New York, USA.
Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts, USA.
Environmental Influences on Child Health Outcomes (ECHO) Office of the Director, National Institutes of Health, Department of Health and Human Services , Rockville, Maryland, USA.



Early-life exposure to lead is associated with deficits in neurodevelopment and with hematopoietic system toxicity. DNA methylation may be one of the underlying mechanisms for the adverse effects of prenatal lead on the offspring, but epigenome-wide methylation data for low levels of prenatal lead exposure are lacking.


We investigated the association between prenatal maternal lead exposure and epigenome-wide DNA methylation in umbilical cord blood nucleated cells in Project Viva, a prospective U.S.-based prebirth cohort with relatively low levels of lead exposure.


Among 268 mother-infant pairs, we measured lead concentrations in red blood cells (RBC) from prenatal maternal blood samples, and using HumanMethylation450 Bead Chips, we measured genome-wide methylation levels at 482,397 CpG loci in umbilical cord blood and retained 394,460 loci after quality control. After adjustment for batch effects, cell types, and covariates, we used robust linear regression models to examine associations of prenatal lead exposure with DNA methylation in cord blood at epigenome-wide significance level [false discovery rate (FDR)<0.05].


The mean [standard deviation (SD)] maternal RBC lead level was 1.22 (0.63) μg/dL. CpG cg10773601 showed an epigenome-wide significant negative association with prenatal lead exposure (-1.4% per doubling increase in lead exposure; p=2.3×10-7) and was annotated to C-Type Lectin Domain Family 11, Member A (CLEC11A), which functions as a growth factor for primitive hematopoietic progenitor cells. In sex-specific analyses, we identified more CpGs with FDR<0.05 among female infants (n=38) than among male infants (n=2). One CpG (cg24637308), which showed a strong negative association with prenatal lead exposure among female infants (-4.3% per doubling increase in lead exposure; p=1.1×10-06), was annotated to Dynein Heavy Chain Domain 1 gene (DNHD1) which is highly expressed in human brain. Interestingly, there were strong correlations between blood and brain methylation for CpG (cg24637308) based on another independent set of samples with a high proportion of female participants.


Prenatal low-level lead exposure was associated with newborn DNA methylation, particularly in female infants.

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