Association between prenatal bisphenol a exposure and promoter hypermethylation of CAPS2, TNFRSF25, and HKR1 genes in cord blood

Environ Res. 2020 Nov;190:109996. doi: 10.1016/j.envres.2020.109996. Epub 2020 Aug 4.


In utero exposure to bisphenol A (BPA) in early stages of development has been reported to exert adverse health effects on offspring later in life. Epigenetic alterations, particularly DNA methylation, may be one plausible biological mechanism involved. We examined the association between maternal BPA exposure and DNA methylation in cord blood. We randomly selected 96 paired samples of maternal urine and infant cord blood collected from the Shanghai-Minhang Birth Cohort. BPA levels in maternal urine were measured using high-performance liquid chromatography (HPLC). Three cord blood samples with maternal BPA levels >2.0 μg/g Cr and three samples with undetected BPA were randomly selected for genome-wide methylation analysis using methylated DNA binding domain sequencing (MBD-Seq). The genes with hypermethylated promoter regions were chosen for validation using quantitative methylation-specific polymerase chain reaction (Q-MSP). Based on MBD-seq results, we observed that maternal BPA exposure was primarily associated with hypermethylation of genes involved in signal transduction in the nervous system. Using Q-MSP, we further validated the association between maternal BPA exposure and promoter hypermethylation of three genes in multiple linear regression models: a log unit increase in BPA was associated with 12.63% (95%CI: 7.99, 17.26), 11.17%, (95%CI: 3.31, 19.02), and 16.57% (95% CI: 10.59, 22.56) increase in promoter of CAPS2, TNFRSF25, and HKR1 methylation, respectively. Our findings provide evidence that in utero exposure to BPA could alter the offspring's epigenome by altering DNA methylation pattern.

Keywords: BPA; Ca(2+)-dependent activator protein for secretion 2 (CAPS2); DNA methylation; Krueppel-related zinc finger protein 1(HKR1); TNF receptor Superfamily member 25 (TNFRSF25).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzhydryl Compounds / toxicity
  • Calcium-Binding Proteins
  • China
  • DNA Methylation*
  • Female
  • Fetal Blood
  • Humans
  • Infant
  • Phenols
  • Pregnancy
  • Prenatal Exposure Delayed Effects* / chemically induced
  • Prenatal Exposure Delayed Effects* / genetics
  • Promoter Regions, Genetic


  • Benzhydryl Compounds
  • CAPS2 protein, human
  • Calcium-Binding Proteins
  • Phenols
  • bisphenol A