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

Abstract

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 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 () 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 but not in rats given adult alone. The dorsal and ventral lobes and periurethral prostatic ducts exhibited a nonmonotonic dose response with peak PIN, proliferation and apoptotic values at 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. https://doi.org/10.1289/EHP1050