Bisphenol A Promotes Human Prostate Stem-Progenitor Cell Self-Renewal and Increases In Vivo Carcinogenesis in Human Prostate Epithelium

• Published in: Endocrinology (Philadelphia) 2014-03, Vol.155 (3), p.805-817
• Main Authors: Prins, Gail S, Hu, Wen-Yang, Shi, Guang-Bin, Hu, Dan-Ping, Majumdar, Shyama, Li, Guannan, Huang, Ke, Nelles, Jason L, Ho, Shuk-Mei, Walker, Cheryl Lyn, Kajdacsy-Balla, Andre, van Breemen, Richard B
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Adenocarcinoma; Aging; AKT protein; Animal models; Animals; Benzhydryl Compounds - toxicity; Bisphenol A; Body weight; Cancer; Carcinogenesis; Carcinogenicity; Carcinogens; Cell culture; Cell self-renewal; Cells (biology); Cells, Cultured; Chromatography, High Pressure Liquid; Endocrine-Disrupting Chemicals; Epithelium; Epithelium - drug effects; Epithelium - pathology; Estrogens - metabolism; Estrogens, Non-Steroidal - toxicity; Exposure; Flow Cytometry; Grafting; Health risks; Humans; In vivo methods and tests; Kidney transplantation; Male; Mesenchyme; Mice; Mice, Nude; Oral administration; Phenols - toxicity; Progenitor cells; Prostate; Prostate - cytology; Prostate - drug effects; Prostate cancer; Prostatic Neoplasms - chemically induced; Prostatic Neoplasms - pathology; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Sex hormones; Signal Transduction; Stem Cells - cytology; Stem Cells - drug effects; Tandem Mass Spectrometry; Testosterone; Time Factors; Young Adult
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2013-1955

Previous studies in rodent models have shown that early-life exposure to bisphenol A (BPA) reprograms the prostate and enhances its susceptibility to hormonal carcinogenesis with aging. To determine whether the human prostate is similarly sensitive to BPA, the current study used human prostate epithelial stem-like cells cultured from prostates of young, disease-free donors. Similar to estradiol-17β (E2), BPA increased stem-progenitor cell self-renewal and expression of stem-related genes in a dose-dependent manner. Further, 10 nM BPA and E2 possessed equimolar membrane-initiated signaling with robust induction of p-Akt and p-Erk at 15 minutes. To assess in vivo carcinogenicity, human prostate stem-progenitor cells combined with rat mesenchyme were grown as renal grafts in nude mice, forming normal human prostate epithelium at 1 month. Developmental BPA exposure was achieved through oral administration of 100 or 250 μg BPA/kg body weight to hosts for 2 weeks after grafting, producing free BPA levels of 0.39 and 1.35 ng/mL serum, respectively. Carcinogenesis was driven by testosterone plus E2 treatment for 2 to 4 months to model rising E2 levels in aging men. The incidence of high-grade prostate intraepithelial neoplasia and adenocarcinoma markedly increased from 13% in oil-fed controls to 33% to 36% in grafts exposed in vivo to BPA (P < .05). Continuous developmental BPA exposure through in vitro (200 nM) plus in vivo (250 μg/kg body weight) treatments increased high-grade prostate intraepithelial neoplasia/cancer incidence to 45% (P < .01). Together, the present findings demonstrate that human prostate stem-progenitor cells are direct BPA targets and that developmental exposure to BPA at low doses increases hormone-dependent cancer risk in the human prostate epithelium.