Abstract IA12: Role of endocrine disruptors in cancer development

Abstract

Abstract Multiple lines of evidence show that brief, early-life exposures to bisphenol A (BPA) can increase the risk of prostate cancer (PCa) with aging. Initial work from our laboratory determined that low-dose BPA exposure during rat development reprograms the prostate and enhances incidence and severity of neoplastic lesions (PIN) in response to elevated adult estrogen levels, as occurs in aging men (Prins et al., Repro Tox 2007). Subsequent BPA dose-response studies revealed that elevated carcinogenic risk is found at doses that yield undetectable serum free-BPA with documented PIN progression to PCa (Prins et al., EHP 2017). Epigenetic modifications (altered DNA and histone methylation) provide a mechanistic framework that may connect early-life BPA to later-life predisposition to prostate carcinogenesis. Our studies within the CLARITY-BPA Consortium, a collaboration with the NIEHS, NTP, and FDA, found that continuous low-dose BPA exposure from fetal life to 6 months altered adult dorsal prostate stem cell homeostasis, increased stem cell numbers and progenitor cell proliferation, and shifted lineage commitment to favor basal progenitor cells (Prins et al., EHP 2018). At 1 year, dorsolateral prostate ducts had heightened multiplicity of estrogen-driven adenocarcinoma as a function of chronic BPA exposure (2.5 μg/kg/day). We propose that the BPA-induced stem cell alterations may underpin increased carcinogenic risk with aging. To provide translational evidence for human exposures, two approaches were used. First, we generated a pioneer in vitro model of directed differentiation of hESC into prostatic organoids. Exposure to 1-10 nM BPA resulted in focal clusters of stem cells within the organoids, a phenotype not observed in controls, which suggests aberrant stem-cell self-renewal (Calderon and Prins, PLOS One 2015). Next, we developed in vitro and in vivo models utilizing primary prostate cells from young, disease-free organ donors. BPA exposure to 3-D human prostasphere cultures increased stem-progenitor cell self-renewal and stem-related gene expression through membrane-initiated ER signaling pathways. Tissue-cell recombination of human prostasphere cells and rat UGM with renal grafting into nude mice was used as an in vivo model to assess carcinogenicity (Prins et al., Endocrinol 2014). Developmental BPA exposure combined with adult estradiol led to a heightened PIN/PCa incidence (33-46%) in the human prostate epithelium of the chimeric prostate tissue compared to oil controls given adult estrogen (13%; P<0.01). Together, these findings indicate that stem and progenitor cells may be direct BPA targets and suggest that humans may be susceptible to endocrine-disrupting chemical (EDC)-imprinted prostate disease in a manner similar to the rodent models. Supported by NIH grants ES015584, ES018748, ES020886, ES027792, CA172220. Citation Format: Gail S. Prins. Role of endocrine disruptors in cancer development [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr IA12.