Developmental Exposure to Low-dose Bisphenol A and Human Prostate Cancer Suscepti

发育时期接触低剂量双酚 A 与人类前列腺癌易感性

• 批准号: 7936941
• 负责人: Shuk-Mei Ho
• 金额: $ 89.81万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-21 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936941
• 关键词: 3-Dimensional; Address; Adult; Adverse effects; Aging; Bioinformatics; Biological Markers; Biological Models; Candidate Disease Gene; Cell Differentiation process; Cell Lineage; Cells; Child; Coculture Techniques; Communities; DNA; DNA Methylation; Defect; Development; Differentiation and Growth; Disease; Dose; Drug Kinetics; Endocrine Disruptors; Epigenetic Process; Epithelial; Epithelial Cells; Estrogens; Ethnic Origin; Event; Exposure to; Fetus; Foundations; Future; Genes; Gland; Goals; Health; Histones; Human; In Vitro; Individual; Infant; Kidney; Knowledge; Laboratories; Laboratory Animals; Lead; Life; Longevity; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Medical; Memory; Mesenchyme; Modeling; Modification; Molecular; Mus; National Toxicology Program; Pattern; Predisposition; Prostate; Rattus; Recombinants; Reporting; Research; Rodent Model; Route; Screening procedure; Seeds; Staging; Stem cells; Stromal Cells; Structure; System; Testing; Tissue Microarray; Tissue Model; Tissues; Toxic effect; Urogenital Sinus; Work; base; bisphenol A; body system; capsule; carcinogenesis; chromatin modification; early life exposure; epidemiology study; epigenomics; exposed human population; genome wide association study; genome-wide analysis; gland development; histone modification; in vivo; in vivo Model; innovation; insight; novel; novel strategies; pluripotency; progenitor; promoter; prostate carcinogenesis; public health relevance; response; self-renewal; tumor growth

DESCRIPTION (provided by applicant): Previous studies in rats have provided evidence that brief, early-life exposures to bisphenol A (BPA) at environmentally relevant doses results in developmental reprogramming of the prostate gland via epigenetic modifications that enhance carcinogenic susceptibility later in life. While dose-response profiles, BPA pharmacokinetics and route of exposure studies in rodent models are underway to validate these findings, there is a current and compelling need for research on BPA effects in the developing human prostate gland. The National Toxicology Program 2008 report summarily stated that "studies in laboratory animals provide only limited evidence for adverse effects on development and more research is needed to better understand their implications for human health". In response to this need, novel models have been developed with human prostate progenitor cells that permit a direct examination of the impact of low-dose BPA exposures as they form prostate-like structures in vitro and in vivo. The goals of the proposed studies are to determine if exposure to environmentally relevant levels of BPA during the early stages of human prostate development increases susceptibility to prostate carcinogenesis later in life and to identify the underlying mechanism of this reprogramming event. It is hypothesized that prostate epithelial progenitor cells are the direct targets of BPA action during early gland formation. Further, it is predicted that BPA-induced reprogramming is mediated through a combination of altered DNA methylation and histone modifications that are heritable as progenitor cells self renew, transmitting altered epigenomic information throughout the lifespan of the individual. The proposed research thus represents a new paradigm that human prostate carcinogenesis may begin early in life in response to adverse environmental influences that epigenetically alter progenitor cells. An innovative approach will be exploited to test this hypothesis and directly examine BPA effects on human prostate progenitor cells using two model systems: 1) a 3-D co-culture system with human primary prostate epithelial/stromal cells to form prostaspheres in vitro, and 2) as recombinants with rat urogenital sinus mesenchyme grafted to murine kidney capsules for 1-3 months to form chimeric prostate-like tissues in vivo. These novel approaches will permit an examination of differentiation defects (Aim 1) and carcinogenesis (Aim 2) in the human prostate epithelial cells as a function of developmental BPA exposures. These studies will be informed by genome-wide studies of DNA methylation patterns and heritable chromatin modifications using human gene promoter arrays and Solexa ChIP-seq analysis (Aim 3). Using integrative bioinformatics, it is expected to identify BPA reprogrammed gene candidates that may serve as biomarkers for early-life BPA exposures in human epidemiology studies. To determine the potential relevance of BPA-reprogrammed candidate genes to human prostate cancer, tissue microarrays (TMAs) of human prostate cancer will be utilized to screen for misexpression of gene candidates as a function of disease stage, progression and ethnicity. The information gained from the proposed studies will be of high impact on the scientific, medical and regulatory communities in terms of 1) providing strong and compelling evidence for negative effects of BPA in humans, 2) establishing a mechanistic framework for developmental reprogramming, 3) identifying BPA-reprogrammed candidate genes for use as biomarkers, 4) ascertaining relevance of BPA-genes to human prostate cancer, 5) validating a useful model system for screening other endocrine disrupting chemicals, and 6) establishing a basis for studies on BPA in other organ systems and diseases. PUBLIC HEALTH RELEVANCE: There is increasing evidence in rodent models that brief, early-life exposures to bisphenol A (BPA) at dose levels typically found in humans results in developmental reprogramming of the prostate gland and increases susceptibility to prostate cancer later in life. The present proposal will test for this possibility in human prostate tissue using newly developed model systems with human prostate progenitor cells. Identification of epigenetic marks and BPA-reprogrammed genes may serve as biomarkers for developmental BPA exposures and provide molecular insight into the epigenomic plasticity that predisposes to prostate cancer with aging. The findings will be of high value to the medical and regulatory communities and serve as a model for human exposures to prevalent environmental endocrine disruptors with suspected carcinogenic potential.

描述(申请人提供)：以前在大鼠身上进行的研究已经提供了证据，表明在生命早期短暂地暴露于环境相关剂量的双酚A(BPA)会通过表观遗传修饰提高晚年的致癌易感性，导致前列腺癌的发育重新编程。虽然在啮齿动物模型中进行剂量-反应曲线、双酚A药代动力学和暴露途径研究以验证这些发现，但目前迫切需要研究双酚A对发育中的人类前列腺癌的影响。国家毒理学计划2008年的报告概要地指出，“对实验室动物的研究只能提供有限的证据证明对发育的不利影响，需要更多的研究来更好地了解它们对人类健康的影响”。为了响应这一需求，人们开发了新的人类前列腺祖细胞模型，允许直接检查低剂量双酚A暴露在体外和体内形成前列腺样结构时的影响。拟议研究的目标是确定在人类前列腺发育的早期阶段暴露于环境相关水平的双酚A是否会增加人在晚年发生前列腺癌的易感性，并确定这种重新编程事件的潜在机制。据推测，在腺体形成的早期，前列腺上皮祖细胞是BPA作用的直接靶点。此外，据预测，双酚A诱导的重编程是通过改变的DNA甲基化和组蛋白修饰的组合来介导的，组蛋白修饰可以随着祖细胞的自我更新而遗传，在个体的整个生命周期中传递改变的表观基因组信息。因此，这项拟议的研究代表了一种新的范式，即人类前列腺癌的发生可能在生命的早期就开始，以回应从表观遗传上改变祖细胞的不利环境影响。我们将采用一种创新的方法来验证这一假说，并使用两种模型系统直接检测BPA对人前列腺癌前体细胞的影响：1)三维共培养系统与人原代前列腺上皮/基质细胞在体外形成前列腺球；2)作为重组体与大鼠泌尿生殖窦间充质细胞移植到小鼠肾胶囊中1-3个月，在体内形成嵌合的前列腺样组织。这些新的方法将允许检查人类前列腺上皮细胞的分化缺陷(目标1)和致癌(目标2)作为发育中双酚A暴露的功能。这些研究将通过使用人类基因启动子阵列和Solexa芯片序列分析对DNA甲基化模式和可遗传染色质修饰的全基因组研究(目标3)来提供信息。利用综合生物信息学，它有望识别BPA重新编程的候选基因，这些候选基因可能在人类流行病学研究中作为早期BPA暴露的生物标志物。为了确定BPA重新编程的候选基因与人类前列腺癌的潜在相关性，将利用人类前列腺癌的组织微阵列(TMA)来筛选候选基因的错误表达，作为疾病阶段、进展和种族的函数。从拟议的研究中获得的信息将在以下方面对科学、医学和监管部门产生重大影响：1)为BPA对人类的负面影响提供强有力的令人信服的证据；2)建立发育重新编程的机制框架；3)确定BPA重新编程的候选基因用作生物标志物；4)确定BPA基因与人类前列腺癌的相关性；5)验证用于筛选其他内分泌干扰物的有用模型系统；以及6)为BPA在其他器官系统和疾病中的研究奠定基础。 与公共健康相关：在啮齿动物模型中，越来越多的证据表明，在生命早期短暂暴露于双酚A(BPA)，剂量通常在人类身上，会导致前列腺发育重新编程，并增加晚年前列腺癌的易感性。目前的建议将使用新开发的人类前列腺祖细胞模型系统在人类前列腺组织中测试这种可能性。表观遗传标记和双酚A重编程基因的鉴定可以作为发育中双酚A暴露的生物标记物，并提供对表观基因组可塑性的分子洞察，该可塑性容易随着年龄的增长而易患前列腺癌。这些发现将对医疗和监管部门具有很高的价值，并将作为人类暴露于普遍存在的具有可疑致癌潜力的环境内分泌干扰物的模型。