Project 2: Human Fetal Prostate and Endocrine Disruption

在世界范围内发病率不断上升。前列腺癌是最常见的非皮肤 癌症诊断和美国男性死亡的第二大原因子宫内雌激素 前列腺癌的发生与以后的生活风险有关，这引起了人们的关注， 终生接触干扰内分泌的化学品可能是造成这种疾病负担的原因。 该试验项目使用人胎儿前列腺（胎龄12-22周）的异种移植作为 研究内分泌干扰化学品对发育影响的模型。以下表征 在异种移植物中的成熟序列，雌二醇对该发育序列的失调 将确定有和没有第二次后续曝光的曝光。组织学和生物标志物 评估将确定雌二醇诱导的导管形态发生的癌前改变， 雌二醇暴露的影响，包括前列腺上皮内瘤的发生， 鉴定基于模型的这一基本特征， 环境内分泌干扰物双酚A和染料木黄酮将与雌二醇进行比较， 修改.工作假设是：人胎儿前列腺异种移植物对雌激素受体应答。 内分泌干扰化学品暴露与DNA甲基化改变导致的异常分化。 啮齿类动物是研究前列腺癌发生的有用模型;然而，自发性前列腺癌的发病率很低。 前列腺肿瘤在啮齿动物中是罕见的，而人类是独特的易发生的。因此，该项目提供了 在环境评估中，人类相关性和增强的可验证性的优势非常明显 对胎儿前列腺发育的影响 该试点项目的目标是建立一个以人为本的平台来评估发展起源 与内分泌干扰化学品暴露相关的晚年前列腺疾病，重点关注 控制疾病诱导和进展的潜在表观遗传机制

With an increasing incidence woridwide. prostate adenocarcinoma is the most common non-skin cancer diagnosis and the second leading cause of death in men in the U.S. Estrogenicity during in utero development has been associated with later life risk of prostate adenocarcinoma, raising concern that eariy life exposures to endocrine disrupfing chemicals may be contributing to this disease burden. This pilot project uses xenotransplantafion of human fetal prostate (gestational age 12-22 weeks) as a model to examine the developmental effects of endocrine disrupting chemicals. Following characterization of the maturation sequence in the xenografts, dysregulation of this developmental sequence by estradiol exposure, with and without a second later exposure, will be determined. Histopathological and biomarker assessment will identify estradiol-induced pre-cancerous alterations in ductal morphogenesis, and the longterm effects of estradiol exposure, including the occurrence of prostatic intraepithelial neoplasia, will be identified. Building on this basic characterizafion of the model, early developmental exposures to the environmental endocrine disruptors bisphenol A and genistein will be compared with estradiol for epigenefic modifications. The working hypothesis is: Human fetal prostate xenotransplants respond to estrogenic endocrine disrupting chemical exposure with aberrant differentiation due to altered DNA methylation. Rodents have been useful models for the study of prostate carcinogenesis; however, spontaneous prostate neoplasia in rodents is rare while humans are uniquely suscepfible. Therefore, this project offers the very disfinct advantages of human relevance and enhanced suscepfibility in the evaluafion of environmental impacts on fetal prostate development. The goal of this pilot project is to build a human-based platform to evaluate the developmental origins of later life prostate disease associated with endocrine disrupting chemical exposure, focusing on the underlying epigenefic mechanisms that control disease induction and progression