Associations between Maternal Tobacco Smoke Exposure and the Cord Blood [Formula: see text] DNA Methylome.

Abstract

Background:Maternal tobacco smoke exposure has been associated with altered DNA methylation. However, previous studies largely used methylation arrays, which cover a small fraction of CpGs, and focused on whole cord blood.Objectives:The current study examined the impact of in utero exposure to maternal tobacco smoke on the cord blood DNA methylome.Methods:The methylomes of 20 Hispanic white newborns ( exposed to any maternal tobacco smoke in pregnancy; unexposed) from the Maternal and Child Health Study (MACHS) were profiled by whole-genome bisulfite sequencing (median coverage: ). Statistical analyses were conducted using the Regression Analysis of Differential Methylation (RADMeth) program because it performs well on low-coverage data (minimizes false positives and negatives).Results:We found that 10,381 CpGs were differentially methylated by tobacco smoke exposure [neighbor-adjusted p-values that are additionally corrected for multiple testing based on the Benjamini-Hochberg method for controlling the false discovery rate (FDR) ]. From these CpGs, RADMeth identified 557 differentially methylated regions (DMRs) that were overrepresented () in important regulatory regions, including enhancers. Of nine DMRs that could be queried in a reduced representation bisulfite sequencing (RRBS) study of adult cells ( smokers; nonsmokers), four replicated (). Additionally, a CpG in the promoter of SLC7A8 (percent methylation difference: comparing exposed to unexposed) replicated () in an EPIC (Illumina) array study of cord blood cells ( exposed to sustained maternal tobacco smoke; unexposed) and in a study of adult cells across two platforms (EPIC: smokers; nonsmokers; 450K: smokers; nonsmokers).Conclusions:Maternal tobacco smoke exposure in pregnancy is associated with cord blood DNA methylation in key regulatory regions, including enhancers. While we used a method that performs well on low-coverage data, we cannot exclude the possibility that some results may be false positives. However, we identified a differentially methylated CpG in amino acid transporter SLC7A8 that is highly reproducible, which may be sensitive to cigarette smoke in both cord blood and adult cells. https://doi.org/10.1289/EHP3398