An epigenome-wide analysis of cord blood DNA methylation reveals sex-specific effect of exposure to bisphenol A

Ryu Miura,Chihiro Miyashita,Toru Matsumura,Reiko Kishi,Kunio Miyake,Mayumi Ishizuka,Atsuko Araki,Mei-Lien Chen,Sumitaka Kobayashi,Machiko Minatoya,Jun Yamamoto,Takeo Kubota

doi:10.1038/s41598-019-48916-5

Abstract

Exposure to bisphenol A (BPA) in utero is associated with adverse health outcome of the offspring. Differential DNA methylation at specific CpG sites may link BPA exposure to health impacts. We examined the association of prenatal BPA exposure with genome-wide DNA methylation changes in cord blood in 277 mother-child pairs in the Hokkaido Study on Environment and Children’s Health, using the Illumina HumanMethylation 450 BeadChip. We observed that a large portion of BPA-associated differentially methylated CpGs with p-value < 0.0001 was hypomethylated among all newborns (91%) and female infants (98%), as opposed to being hypermethylated (88%) among males. We found 27 and 16 CpGs with a false discovery rate (FDR) < 0.05 in the analyses for males and females, respectively. Genes annotated to FDR-corrected CpGs clustered into an interconnected genetic network among males, while they rarely exhibited any interactions in females. In contrast, none of the enrichment for gene ontology (GO) terms with FDR < 0.05 was observed for genes annotated to the male-specific CpGs with p < 0.0001, whereas the female-specific genes were significantly enriched for GO terms related to cell adhesion. Our epigenome-wide analysis of cord blood DNA methylation implies potential sex-specific epigenome responses to BPA exposure.

Highlights

Exposure to endocrine-disrupting chemicals (EDCs) is associated with dysfunctions of hormone-mediated processes, such as metabolism, energy balance, thyroid and reproductive functions, immune functions, and neurodevelopment[1,2,3,4]
Even though Bisphenol A (BPA) levels in this study were relatively lower[20] than those in the previous studies on cord blood BPA levels[19,57,58], we found substantial sex differences in methylation changes associated with BPA exposure
BPA exposure was more frequently associated with hypermethylation than with hypomethylation, whereas it was associated predominantly with hypomethylation among female infants

Summary

Introduction

Exposure to endocrine-disrupting chemicals (EDCs) is associated with dysfunctions of hormone-mediated processes, such as metabolism, energy balance, thyroid and reproductive functions, immune functions, and neurodevelopment[1,2,3,4]. Evidence from experimental studies suggests that DNA methylation changes in the offspring can occur in response to developmental BPA exposure[40,42,43,44]. Previous human cohort studies showed that prenatal BPA exposure associated with DNA methylation profiles of fetal liver genes[45,46,47] and metabolism-related genes of the offspring[48,49]. Genome-wide methylation analysis allows unbiased assessment of epigenetic alterations in relation to the environmental factors[51]; only one cohort study from Germany showed an association between maternal urinary BPA levels (low levels with 15.9 ng/mg creatinine; n = 101) and genome-wide DNA methylation in cord blood samples regardless of infant’s sex[52]. Analyses were performed to determine sex-specific differences in BPA exposure-associated methylation profiles

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