Prostatic Effects of Chronic Exposure to Bisphenol A in a Rat Model

本申请提出了NTP/FDA 2年双酚A（BPA）毒性的额外终点。 一项特别关注扩展前列腺分析的研究。先前的研究表明， 发育期暴露于低剂量BPA可增强成人前列腺的致癌易感性 腺体的雌激素水平升高。前列腺DNA永久性变化的鉴定 甲基化组表明BPA重编程的分子机制涉及改变的表观遗传学， 记忆拟议项目的目标是扩大前列腺终点后，慢性，口服 BPA暴露包括尿道周围前列腺导管、表观遗传标记和干细胞分析 重新编程，通过提供一种新的方法， 分子框架来理解疾病易感性的增加。以下具体目标是 提出：目的1：扩大前列腺评价范围，包括尿道周围前列腺导管。目标二： 评估慢性BPA暴露大鼠前列腺对激素致癌作用的敏感性。目标3：分析。 慢性BPA暴露后侧前列腺E2/BPA重编程基因的DNA甲基化和表达 暴露以识别前列腺重编程的分子指纹。目的4：检查干/祖细胞 BPA暴露前列腺细胞的自我更新活性，分化潜力和对 雌二醇Sprague-Dawley大鼠将在FDA动物中接受一系列BPA剂量的长期治疗 设施和目标2，作为成人接受T+E治疗1.5年。运送至UIC实验室的组织将 使用组织学方法、DNA甲基化和基因转录的分子分析进行评价， 前列腺干细胞培养使用前列腺球测定。通过检查致癌易感性， 确定长期接触BPA导致终生前列腺紊乱的分子基础， 目前的多学科方法将显著提高NTPFDA的证据权重评估 使用GLP指南研究。

The present application proposes additional endpoints in the NTP/FDA 2-year bisphenol A (BPA) toxicity Study with a specific focus on expanding prostate gland analysis. Prior research has shown that transient developmental exposure to low-dose BPA can enhance the carcinogenic susceptibility of the adult prostate gland to elevated estrogen levels upon aging. Identification of permanent changes in the prostate DNA methylome indicated that the molecular mechanisms of BPA reprogramming involve altered epigenetic memory. The goals of the proposed project are to expand the prostatic endpoints following chronic, oral BPA exposure to include analysis of periurethral prostatic ducts, epigenetic marks and stem cell reprogramming that will together add significant value to the GLP-compliant toxicology studies by providing a molecular framework to understand heightened disease susceptibility. The following Specific Aims are proposed: Aim 1: Expand the prostatic evaluation to include the periurethral prostatic ducts. Aim 2: Evaluate prostatic susceptibility to hormonal carcinogenesis in chronic BPA-exposed rats. Aim 3: Analyze . DNA methylation & expression of E2/ BPA-reprogrammed genes in lateral prostates following chronic BPA exposure to identify molecular fingerprints of prostate reprogramming. Aim 4: Examine the stem/progenitor cells from BPA exposed prostates for self-renewal activity, differentiation potential and responsiveness to estradiol. Sprague-Dawley rats will be chronically treated with a range of BPA doses at the FDA animal facility and for Aim 2, treated with T+E as adults for 1.5 years. Tissues shipped to the UIC laboratory will be evaluated using histologic approaches, molecular analysis of DNA mehylation and gene transcription, and prostate stem cell culture using a prostasphere assay. By examining carcinogenic susceptibility and identifying the molecular underpinnings of life-long prostate perturbations by prolonged BPA exposure, the present multidisciplinary approach will markedly enhance the weight-of-evidence assessment by the NTPFDA using GLP-guideline studies.