Prostate Cancer Risk and DNA Methylation Signatures in Aging Rats following Developmental BPA Exposure: A Dose-Response Analysis

Environ Health Perspect. 2017 Jul 11;125(7):077007. doi: 10.1289/EHP1050.


Background: Previous studies have uncovered heightened prostatic susceptibility to hormone-induced neoplasia from early-life exposure to low-dose bisphenol A (BPA). However, significant data gaps remain that are essential to address for biological relevance and necessary risk assessment.

Objectives: A complete BPA dose-response analysis of prostate lesions across multiple prostatic lobes was conducted that included internal BPA dosimetry, progression to adenocarcinoma with aging and mechanistic connections to epigenetically reprogramed genes.

Methods: Male neonatal Sprague-Dawley rats were briefly exposed to 0.1 to 5,000 μg BPA/kg BW on postnatal days (PND) 1, 3, and 5. Individual prostate lobes plus periurethral prostatic ducts were evaluated at 7 mo or 1 y of age without or with adult testosterone plus estradiol (T+E) to promote carcinogenesis. DNA methylation of five genes was quantified by bisulfite genomic sequencing in d-200 dorsal prostates across BPA doses. Serum free-BPA and BPA-glucuronide were quantitated in sera of individual PND 3 pups collected 1 hr postexposure utilizing ultra-high-pressure tandem mass spectrometry (UHPLC-MS-MS).

Results: The lowest BPA dose initiated maximal hormonal carcinogenesis in lateral prostates despite undetectable free BPA 1 hr postexposure. Further, prostatic intraepithelial neoplasia (PIN) progressed to carcinoma in rats given neonatal low-dose BPA with adult T+E but not in rats given adult T+E alone. The dorsal and ventral lobes and periurethral prostatic ducts exhibited a nonmonotonic dose response with peak PIN, proliferation and apoptotic values at 10–100 μg/kg BW. This was paralleled by nonmonotonic and dose-specific DNA hypomethylation of genes that confer carcinogenic risk, with greatest hypomethylation at the lowest BPA doses.

Conclusions: Developmental BPA exposures heighten prostate cancer susceptibility in a complex dose- and lobe-specific manner. Importantly, elevated carcinogenic risk is found at doses that yield undetectable serum free BPA. Dose-specific epigenetic modifications of selected genes provide a mechanistic framework that may connect early-life BPA to later-life predisposition to prostate carcinogenesis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging*
  • Animals
  • Benzhydryl Compounds / blood
  • Benzhydryl Compounds / toxicity*
  • Chromatography, High Pressure Liquid
  • DNA Methylation*
  • Dose-Response Relationship, Drug
  • Environmental Pollutants / blood
  • Environmental Pollutants / toxicity*
  • Incidence
  • Male
  • Phenols / blood
  • Phenols / toxicity*
  • Prostatic Neoplasms / chemically induced
  • Prostatic Neoplasms / epidemiology*
  • Rats / growth & development
  • Rats / physiology
  • Rats, Sprague-Dawley
  • Tandem Mass Spectrometry


  • Benzhydryl Compounds
  • Environmental Pollutants
  • Phenols
  • bisphenol A