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

长期接触双酚 A 对大鼠模型前列腺的影响

基本信息

批准号：
8334568
负责人：
Gail S Prins
金额：
$ 38.68万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-19 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8334568
关键词：
17p Adenocarcinoma Adult Adverse effects Affect Aging Apoptosis Biological Assay Biological Markers Cell Culture Techniques Chronic Complex DNA DNA Methylation Data Defect Development Disease Progression Disease susceptibility Dose Duct (organ) structure Endocrine disruption Epigenetic Process Epithelial Estradiol Estrogens Evaluation Exhibits Exposure to Gene Expression Genes Genetic Transcription Goals Guidelines Health Histologic Histopathology Hormonal Carcinogenesis Human Hyperplasia Implant Incidence Knowledge Laboratories Lateral Lesion Life Lobe Malignant neoplasm of prostate Measures Memory Methylation Modeling Molecular Molecular Analysis Molecular Profiling Oral Pathology Play Population Predisposition Prostate Prostatic Prostatic Diseases Prostatic duct Public Health Rattus Research Role Route Shipping Ships Specimen Sprague-Dawley Rats Stem cells Testing Testosterone Time Tissues Toxic effect Toxicology Urethra Weaning Weight Work animal facility bisphenol A cancer initiation carcinogenesis epigenomics exposed human population human disease improved interdisciplinary approach male men neonatal exposure novel response self-renewal stem

项目摘要

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.

本申请提出了 NTP/FDA 2 年双酚 A (BPA) 毒性的额外终点研究重点是扩大前列腺分析。先前的研究表明，瞬态发育期接触低剂量BPA可增强成人前列腺的致癌易感性腺体在衰老时雌激素水平升高。鉴定前列腺 DNA 的永久性变化甲基化组表明 BPA 重编程的分子机制涉及表观遗传改变记忆。拟议项目的目标是扩大慢性、口腔疾病后的前列腺终点 BPA 暴露包括对尿道周围前列腺管、表观遗传标记和干细胞的分析重新编程将通过提供了解疾病易感性升高的分子框架。以下具体目标是建议：目标 1：扩大前列腺评估范围，将尿道周围前列腺管纳入其中。目标 2：评估慢性 BPA 暴露大鼠前列腺对激素致癌的易感性。目标 3：分析。慢性 BPA 后侧前列腺中 DNA 甲基化和 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/祖细胞来自暴露于 BPA 的前列腺的细胞具有自我更新活性、分化潜力和对雌二醇。 Sprague-Dawley 大鼠将在 FDA 动物实验中接受一系列 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。运送到 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估，以及使用前列腺球测定法培养前列腺干细胞。通过检查致癌物易感性和确定长期接触 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着增强 NTPFDA 的证据权重评估使用 GLP 指南研究。