Association between fetal exposure to phthalate endocrine disruptor and genome-wide DNA methylation at birth


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Abstract

BackgroundPhthalic acid esters are ubiquitous and antiandrogenic, and may cause systemic effects in humans, particularly with in utero exposure. Epigenetic modification, such as DNA methylation, has been hypothesized to be an important mechanism that mediates certain biological processes and pathogenic effects of in utero phthalate exposure.ObjectiveThe aim of this study was to examine the association between genome-wide DNA methylation at birth and prenatal exposure to phthalate.MethodsWe studied 64 infant–mother pairs included in TMICS (Taiwan Maternal and Infant Cohort Study), a long-term follow-up birth cohort from the general population. DNA methylation levels at more than 450,000 CpG sites were measured in cord blood samples using Illumina Infinium HumanMethylation450 BeadChips. The concentrations of three metabolites of di-(2-ethylhexyl) phthalate (DEHP) were measured using liquid chromatography tandem–mass spectrometry (LC–MS/MS) in urine samples collected from the pregnant women during 28–36 weeks gestation.ResultsWe identified 25 CpG sites whose methylation levels in cord blood were significantly correlated with prenatal DEHP exposure using a false discovery rate (FDR) of 5% (q-value < 0.05). Via gene-set enrichment analysis (GSEA), we also found that there was significant enrichment of genes involved in the androgen response, estrogen response, and spermatogenesis within those genes showing DNA methylation changes in response to exposure. Specifically, PA2G4, HMGCR, and XRCC6 genes were involved in genes in response to androgen.ConclusionsPhthalate exposure in utero may cause significant alterations in the DNA methylation in cord blood. These changes in DNA methylation might serve as biomarkers of maternal exposure to phthalate in infancy and potential candidates for studying mechanisms via which phthalate may impact on health in later life. Future investigations are warranted.Graphical abstractHighlightsHumans are ubiquitously exposed to phthalates through digestion, inhalation, or dermal absorption.DNA methylation has been hypothesized to be an important mechanism in in utero phthalate exposure.DNA methylation changes are involved in androgen response, estrogen response, protein secretion, and spermatogenesis.Three CpG sites (cg00935782, cg07732421, and cg00764560) are involved in genes of response to androgen.

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