Project 2: Human Fetal Prostate and Endocrine Disruption

在全球范围内发病率呈上升趋势。前列腺癌是最常见的非皮肤性肿瘤 癌症诊断和美国男性第二大死因--子宫内雌激素 发展与前列腺癌的晚年风险有关，这引起了人们对早期前列腺癌的担忧 生活中暴露于内分泌干扰物可能是造成这种疾病负担的原因之一。 这个试点项目使用了人胎儿前列腺(胎龄12-22周)的异种移植作为 研究内分泌干扰物对发育影响的模型。以下是人物塑造 异种移植物的成熟序列，雌激素对这一发育序列的失调 将确定是否有第二次随后曝光的曝光。组织病理学和生物标志物 评估将确定雌激素诱导的癌前病变的导管形态发生，以及长期的 雌激素暴露的影响，包括前列腺上皮内瘤的发生，将是 已确认身份。基于这一模型的基本特征，早期发育暴露于 环境内分泌干扰物双酚A和染料木素将与雌二醇进行表观遗传学比较 修改。工作假说是：人类胚胎前列腺异种移植对雌激素有反应 内分泌干扰化学暴露，由于DNA甲基化改变而导致异常分化。 啮齿动物一直是研究前列腺癌发生的有用模型；然而，自发的 在啮齿类动物中，前列腺癌是罕见的，而人类是唯一易感的。因此，这个项目提供了 在环境评价中人类相关性和增强的敏感性具有非常明显的优势 对胎儿前列腺发育的影响。 这个试点项目的目标是建立一个以人为本的平台来评估发展的起源 与内分泌干扰性化学物质暴露有关的晚年前列腺疾病，重点是 控制疾病诱发和进展的潜在表观遗传机制。

With an increasing incidence worldwide. 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 early life exposures to endocrine disrupting chemicals may be contributing to this disease burden. This pilot project uses xenotransplantation 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 long-term effects of estradiol exposure, including the occurrence of prostatic intraepithelial neoplasia, will be identified. Building on this basic characterization of the model, early developmental exposures to the environmental endocrine disruptors bisphenol A and genistein will be compared with estradiol for epigenetic 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 susceptible. Therefore, this project offers the very distinct advantages of human relevance and enhanced susceptibility in the evaluation 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 epigenetic mechanisms that control disease induction and progression.