Maternal levels of endocrine disrupting chemicals in the first trimester of pregnancy are associated with infant cord blood DNA methylation

Epigenetics. 2018;13(3):301-309. doi: 10.1080/15592294.2018.1448680. Epub 2018 Apr 18.


Endocrine disrupting chemicals (EDCs) pose a public health risk through disruption of normal biological processes. Identifying toxicoepigenetic mechanisms of developmental exposure-induced effects for EDCs, such as phthalates or bisphenol A (BPA), is essential. Here, we investigate whether maternal exposure to EDCs is predictive of infant DNA methylation at candidate gene regions. In the Michigan Mother-Infant Pairs (MMIP) cohort, DNA was extracted from cord blood leukocytes for methylation analysis by pyrosequencing (n = 116) and methylation changes related to first trimester levels of 9 phthalate metabolites and BPA. Growth and metabolism-related genes selected for methylation analysis included imprinted (IGF2, H19) and non-imprinted (PPARA, ESR1) genes along with LINE-1 repetitive elements. Findings revealed decreases in methylation of LINE-1, IGF2, and PPARA with increasing phthalate concentrations. For example, a log unit increase in ΣDEHP corresponded to a 1.03 [95% confidence interval (CI): -1.83, -0.22] percentage point decrease in PPARA methylation. Changes in DNA methylation were also inversely correlated with PPARA gene expression determined by RT-qPCR (r = -0.34, P = 0.02), thereby providing evidence in support of functional relevance. A sex-stratified analysis of EDCs and DNA methylation showed that some relationships were female-specific. For example, urinary BPA exposure was associated with a 1.35 (95%CI: -2.69, -0.01) percentage point decrease in IGF2 methylation and a 1.22 (95%CI: -2.27, -0.16) percentage point decrease in PPARA methylation in females only. These findings add to a body of evidence suggesting epigenetically labile regions may provide a conduit linking early exposures with disease risk later in life and that toxicoepigenetic susceptibility may be sex specific.

Keywords: BPA; DNA methylation; DOHaD; Toxicoepigenetics; metabolism; phthalate.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Benzhydryl Compounds / urine
  • DNA Methylation / drug effects
  • DNA Methylation / genetics*
  • Endocrine Disruptors / blood*
  • Endocrine Disruptors / toxicity
  • Endocrine Disruptors / urine
  • Environmental Pollutants / toxicity
  • Estrogen Receptor alpha / genetics
  • Female
  • Fetal Blood / drug effects*
  • Gene Expression Regulation, Developmental / drug effects
  • Genomic Imprinting / drug effects*
  • Humans
  • Infant
  • Insulin-Like Growth Factor II / genetics
  • Long Interspersed Nucleotide Elements / genetics
  • Male
  • PPAR alpha / genetics
  • Phenols / urine
  • Pregnancy
  • Pregnancy Trimester, First
  • RNA, Long Noncoding / genetics


  • Benzhydryl Compounds
  • Endocrine Disruptors
  • Environmental Pollutants
  • Estrogen Receptor alpha
  • H19 long non-coding RNA
  • IGF2 protein, human
  • PPAR alpha
  • Phenols
  • RNA, Long Noncoding
  • estrogen receptor alpha, human
  • Insulin-Like Growth Factor II
  • bisphenol A