Maternal Blood Cadmium Concentrations and Whole Blood DNA Methylation during Pregnancy in the Early Autism Risk Longitudinal Investigation (EARLI)

Abstract

Background: During pregnancy, the maternal epigenome may be responsive to environmental exposures. We tested whether maternal exposure to cadmium (Cd) results in differential maternal whole blood DNA methylation (DNAm) in early pregnancy.Methods: Maternal blood samples were collected at the initial study visit (during trimesters one or two of pregnancy) from 232 participants in the Early Autism Risk Longitudinal Investigation (EARLI) pregnancy cohort. We measured maternal blood Cd (n=215) using inductively coupled plasma mass spectrometry, which reflects recent exposure (blood t1/2 ~75 days), and measured maternal blood DNAm (n=201) on the Illumina 450K array; 93 non-smoking women had both measures available for analysis. Linear regression was used to test for site-specific associations between blood Cd and DNAm, adjusting for cell type composition and confounding variables.Results: The distribution of blood Cd was right skewed and log-transformed for statistical analyses. The geometric mean of blood Cd was 0.2 μg/L (Interquartile range = 0.13 μg/L). An interquartile range difference in blood Cd was associated with a 13.1% increase in B-cell proportions (95% CI: 1.0 – 25.2). In multivariable regression, six CpG sites were associated (p-value<10-5) with log blood Cd concentrations. At five of these sites, increasing blood Cd was associated with hypermethylation, and three corresponded to the genes LYN, TESC, and ESD. The CpG site near LYN was closest to genome-wide significance (p-value = 1.9x10-6), and an interquartile range difference in blood Cd was associated with an 8.4% increase in percent methylation at this site (95% CI: 5.1 – 11.6).Conclusion: We report site-specific associations between DNAm and blood Cd in early pregnancy. Future work will consider the persistence of DNAm marks. Identified sites may be potential biomarkers of Cd exposure that can inform future epidemiological studies or implicate downstream gene pathways affected by Cd exposure.