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

本申请建议在NTP/FDA两年期双酚A(BPA)毒性中增加终点 研究的重点是前列腺扩大分析。先前的研究表明，瞬变的 发育过程中暴露于低剂量双酚A可增加成人前列腺癌的易感性 随着年龄的增长，腺体的雌激素水平会升高。前列腺癌DNA永久性改变的鉴定 甲基组研究表明，双酚A重编程的分子机制涉及表观遗传学的改变 记忆。拟议项目的目标是扩大慢性、口腔疾病后的前列腺端点。 双酚A暴露，包括分析尿道周围前列腺管、表观遗传标记和干细胞 重新编程，通过提供一个符合GLP的毒理学研究，共同增加重大价值 了解疾病易感性增加的分子框架。以下是具体目标 建议：目的1：将前列腺术前评估范围扩大到包括尿道周围的前列腺管。目标2： 评估慢性双酚A暴露大鼠对激素致癌的易感性。目标3：分析。 慢性BPA后侧方前列腺区DNA甲基化及E2/BPA重编程基因的表达 暴露以识别前列腺重编程的分子指纹。目标4：检查茎/祖细胞 来自双酚A的细胞暴露在前列腺中，具有自我更新活性、分化潜力和对 雌二醇。将在FDA动物中心用一定剂量的双酚A慢性治疗Spraogue-Dawley大鼠 AIM 2，成人T+E治疗1.5年。运往UIC实验室的组织将被 使用组织学方法、DNA甲基化和基因转录的分子分析进行评估，以及 前列腺液培养法培养前列腺干细胞。通过检测致癌敏感度和 通过长期接触双酚A来确定终身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.