AbstractBackgroundMetals exposures have important health effects in pregnancy. The maternal epigenome may be responsive to these exposures. We tested whether metals are associated with concurrent differential maternal whole blood DNA methylation.MethodsIn the Early Autism Risk Longitudinal Investigation (EARLI) cohort, we measured first or second trimester maternal blood metals concentrations (cadmium, lead, mercury, manganese, and selenium) in 215 participants using inductively coupled plasma mass spectrometry. DNA methylation in maternal whole blood was measured in the same specimens on the Illumina 450K array (201 participants). A subset sample of 97 women had both measures available for analysis, all of whom did not report smoking during pregnancy. Linear regression was used to test for site-specific associations between individual metals and DNA methylation, adjusting for cell type composition and confounding variables. Discovery gene ontology analysis was conducted on the top 1,000 sites associated with each metal to elucidate downstream pathways.ResultsIn multiple linear regression, we observed hypermethylation at 11 DNA methylation sites associated with lead (FDR q-value <0.1), near the genes CYP24A1, ASCL2, FAT1, SNX31, NKX6-2, LRC4C, BMP7, HOXC11, PCDH7, ZSCAN18, and VIPR2. Lead associated sites were enriched (FDR q-value <0.1) for the pathways cell adhesion, nervous system development, and calcium ion binding. Manganese was associated with hypermethylation at four DNA methylation sites (FDR q-value <0.1), one of which was near the gene ARID2. Manganese associated sites were enriched for cellular metabolism pathways (FDR q-value<0.1). Effect estimates for DNA methylation sites associated (p<0.05) with cadmium, lead, and manganese were highly correlated (Pearson ρ >0.86).DiscussionSingle DNA methylation sites associated with lead and manganese may be potential biomarkers of exposure or implicate downstream gene pathways. Future studies should replicate our findings to characterize potential toxicological mechanisms of trace metals through the maternal epigenome.
Maternal blood trace metal concentrations and whole blood DNA methylation during pregnancy in the Early Autism Risk Longitudinal Investigation (EARLI)
