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 5,000μg 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 10–100μg/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. https://doi.org/10.1289/EHP1050

CLARITY‐BPA academic laboratory studies identify consistent low‐dose Bisphenol A effects on multiple organ systems

“…Prostates were collected at one-year necropsy, coded and analysed for histopathology by Maarten Bosland, DVM, PhD who was blinded to treatments and controls. As previously reported by the Prins laboratory, 86,93 developmental or continuous exposure to BPA alone at any dose did not produce prostate pathology that differed from vehicle controls. However, in response to T+E, rats given developmental EE, 2.5, 250 or 25 000 μg BPA/kg BW/d showed significant increases in lateral prostate prostatic intraepithelial neoplasia (PIN) severity compared to vehicle controls at one year, shifting from low-grade PIN in controls to high-grade PIN in rats developmentally exposed to BPA with the highest PIN score observed at the 2.5 μg BPA/kg BW/d dose.…”

“…[83][84][85] In this context, previous work from the Prins, Ho and Walker laboratories determined that early-life, lowdose BPA exposure reprogrammed the rat prostate epigenome and increased its susceptibility to hormonal carcinogenesis with ageing, a finding that was subsequently confirmed in a humanized prostate model. [86][87][88][89][90][91][92][93] This is germane to human disease since elevated oestrogen levels rise in ageing men 94 and together with androgens, induce prostate cancer in the rat and human epithelium. 95,96 As part of the CLARITY-BPA consortium, the Prins laboratory had two main goals: (a) re-assess whether developmental BPA PRINS ET AL.…”

The effects of different bisphenol derivatives on oxidative stress, DNA damage and DNA repair in RWPE‐1 cells: A comparative study

“…Inappropriate hormone exposure can alter the gland's function, reprogram the gland, and may lead to prostate cancer. In the literature, there are many in vivo and in vitro studies about the effects of BPA on the prostate (Prins et al, ; Prins & Ho, ; Teng et al, ).…”

The Effects of Endocrine Disrupting Chemicals on Prostate Gland

“…36 Bir diğer çalışmada, yenidoğan Sprague-Dawley erkek sıçanlar, doğum sonrası 1, 3 ve 5. günlerinde 0,1-5.000 μg/kg vücut ağırlığı BPA'ya kısa süre maruz bırakıldıktan sonra, en düşük BPA dozunun prostatın lateral bölgelerinde maksimal hormonal karsinogenezi başlattığı bulunmuştur. 37 Yapılan bir in vitro çalışmada, dört farklı prostat kanseri hücre hattında (LNCaP, C4-2, 22Rv1, PC-3) ve iki normal prostat epitel hücre hattında (NPrEC ve RWPE-1) düşük dozda (0,01-100 nM) BPA maruziyeti değerlendirilmiştir. Düşük dozlarda BPA, sentrozom amplifikasyonlu hücrelerin sayısını %2-8 oranında yükseltmiştir.…”