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- Title
Evaluation of Bisphenol A (BPA) Exposures on Prostate Stem Cell Homeostasis and Prostate Cancer Risk in the NCTR-Sprague-Dawley Rat: An NIEHS/FDA CLARITY-BPA Consortium Study.
- Authors
Prins, Gail S.; Wen-Yang Hu; Lishi Xie; Guang-Bin Shi; Dan-Ping Hu; Birch, Lynn; Bosland, Maarten C.
- Abstract
BACKGROUND: Previous work determined that early life exposure to low-dose Bisphenol A (BPA) increased rat prostate cancer risk with aging. Herein, we report on prostate-specific results from CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity), which aims to resolve uncertainties regarding BPA toxicity. OBJECTIVES: We sought to a) reassess whether a range of BPA exposures drives prostate pathology and/or alters prostatic susceptibility to hormonal carcinogenesis, and b) test whether chronic low-dose BPA targets prostate epithelial stem and progenitor cells. METHODS: Sprague-Dawley rats were gavaged daily with vehicle, ethinyl estradiol (EE) or 2:5-25,000 lg BPA/kg-BW during development or chronically, and prostate pathology was assessed at one year. One developmentally exposed cohort was given testosterone plus estradiol (T+E) implants at day 90 to promote carcinogenesis with aging. Epithelial stem and progenitor cells were isolated by prostasphere (PS) culture from dorsolateral prostates (DLP) of rats continuously exposed for six months to 2:5-250 lg BPA/kg-BW. Gene expression was analyzed by quantitative real time reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: Exposure to BPA alone at any dose did not drive prostate pathology. However, rats treated with EE, 2.5, 250, or 25,000 lg BPA/kg-BW plus T+E showed greater severity of lateral prostate intraepithelial neoplasia (PIN), and DLP ductal adenocarcinoma multiplicity was markedly elevated in tumor-bearing rats exposed to 2:5 lg BPA=kg-BW. DLP stem cells, assessed by PS number, doubled with chronic EE and 2:5 lg BPA=kg-BW exposures. PS size, reflecting progenitor cell proliferation, was greater at 25 and 250 lg BPA doses, which also shifted lineage commitment toward basal progenitors while reducing luminal progenitor cells. CONCLUSIONS: Together, these results confirm and extend previous evidence using a rat model and human prostate epithelial cells that low-dose BPA augments prostate cancer susceptibility and alters adult prostate stem cell homeostasis. Therefore, we propose that BPA exposures may contribute to the increased carcinogenic risk in humans that occurs with aging.
- Subjects
THERAPEUTIC use of testosterone; ANALYSIS of variance; ANIMAL experimentation; BODY weight; CELL culture; ESTROGEN; FISHER exact test; GENE expression; HOMEOSTASIS; PHENOLS; POLYMERASE chain reaction; PROSTATE; PROSTATE tumors; RATS; RESEARCH funding; STATISTICS; STEM cells; STATISTICAL power analysis; DATA analysis; ENVIRONMENTAL exposure; TREATMENT effectiveness; REVERSE transcriptase polymerase chain reaction; DESCRIPTIVE statistics; TUMOR risk factors
- Publication
Environmental Health Perspectives, 2018, Vol 126, Issue 11, p1
- ISSN
0091-6765
- Publication type
Article
- DOI
10.1289/EHP3953