Infant sex and DNA methylation: differentially methylated regions and positions across umbilical cord blood, artery, and placenta samples

Abstract

BACKGROUND AND AIM: Environmental exposures during embryogenesis may cause epigenetic dysregulation. Fetal sex may act as an effect modifier of the association between prenatal conditions and changes in DNA methylation (DNAm); therefore, it is important to understand sex-specific DNAm patterns. Autosomal cord blood and placental DNAm at several loci has been consistently associated with sex. However, there is limited research regarding differentially methylated regions (DMRs) and comparing sex-specific DNAm across tissues. This study leverages data from the PRogramming of Intergenerational Stress Mechanisms (PRISM) cohort to identify sex-associated DNAm profiles in cord blood, placenta, and umbilical artery samples. METHODS: DNAm was measured using the Illumina HumanMethylation450 BeadChip in cord blood (N = 179), placenta (N = 229), and umbilical artery samples (N = 229). Sex-associated DMRs were identified using DMRcate and differentially methylated positions (DMPs) were identified using limma. Analyses were replicated in an independent cord blood dataset (GEO Accession GSE129841). RESULTS:A total of 183, 257, and 419 DMRs and 2,119, 2,281, and 3,405 DMPs (pBonferroni 0.05) were identified in cord blood, placenta, and artery samples, respectively. Common DMRs were identified across tissues: 39 DMRs overlapped in all three tissues. The majority of DMRs (cord blood: 61%; placenta: 69%; artery: 67%) were annotated to small nucleolar RNAs (snoRNA) genes. In a cord blood replication analysis, 85% of DMRs overlapped with those identified in PRISM. Overall, female sex was associated with higher methylation of DMRs and DMPs in cord blood and artery samples, but male sex was associated with higher methylation levels in placenta samples. CONCLUSIONS:Common sex-associated DMRs and DMPs were identified in cord blood, placenta, and artery samples. Further research may provide insights to biological mechanisms that contribute to sex-specific DNAm signatures across fetal tissues, as well as the influence of dimorphism in the epigenome on environmental-induced dysregulation. KEYWORDS: children's environmental health, omics technologies, epigenomics, female, male