Fetal alcohol, estrogen-regulated genes and prostate cancer

胎儿酒精、雌激素调节基因和前列腺癌

• 批准号: 8974973
• 负责人: DIPAK KUMAR SARKAR
• 金额: $ 22.28万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-10 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8974973
• 关键词: Address; Adenocarcinoma; Adult; Age; Aging; Alcohol abuse; Alcohol consumption; Alcohols; American; Androgens; Animal Model; Animals; Area; Barker Hypothesis; Benign; Benign Prostatic Hypertrophy; Binding; Biochemical; Cancer Etiology; Castration; Cell Proliferation; Cells; Cessation of life; ChIP-seq; Characteristics; Clinical; Conceptions; Death Rate; Detection; Development; Diet; Disease; Disease susceptibility; ESR1 gene; Epigenetic Process; Epithelial; Epithelial Cells; Estrogen Antagonists; Estrogen Receptor 1; Estrogen Receptor Modulators; Estrogen Receptors; Estrogens; Etiology; Event; Exposure to; Fetal Alcohol Exposure; Gene Expression; Genes; Genomic Imprinting; Gland; Goals; Gonadal Steroid Hormones; Growth; Health; Human; Hyperplasia; In Situ; Incidence; Investigation; Lesion; Life; Life Style; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediating; Molecular; Morphology; Neoplasms; Pathway interactions; Patients; Physiological; Play; Population; Predisposing Factor; Predisposition; Pregnancy; Process; Production; Prostate; Prostate carcinoma; Prostatic; Prostatic Intraepithelial Neoplasias; Prostatic Neoplasms; Prostatic Tissue; Rattus; Research; Risk; Rodent; Role; Serum; Site; Steroids; Structure; Surface; System; Testing; Testosterone; Therapeutic; Tissues; United States; Validation; Western Blotting; Work; alcohol consumption during pregnancy; alcohol exposure; animal data; base; cancer regression; cancer risk; carcinogenesis; drinking; fetal; fetal programming; genome-wide; imprint; innovation; interest; male; malignant phenotype; men; neoplastic; novel; novel therapeutics; offspring; prenatal; programs; prostate carcinogenesis; response; sex; steroid hormone; tool; transcriptome sequencing; tumor; tumor growth; tumorigenesis

 DESCRIPTION (provided by applicant): It is now widely accepted that exposure to adverse environmental conditions and lifestyle choices during pregnancy can result in fetal programming that underlies disease susceptibility in adulthood. One area that is understudied is the impact of maternal alcohol abuse on the offspring's susceptibility to cancer. A rapidly accumulating body of evidence indicates that many diseases must be understood in a life-long perspective, as trajectories that start at conception and surface upon clinical detection decades later. Factors that change sex hormone levels during pregnancy may have long-term health consequences for the offspring, including changes in prostate cancer risk. Several studies now identified alcohol intake positively correlated with the serum estrogen levels during pregnancy. Despite this information, very few studies have conducted to determine the association of alcohol promotion of estrogen level during pregnancy with the subsequent risk of prostate or other cancer risk in offspring. Our recent studies in rodents have provided evidence for higher incidence of prostate cancers in prenatal alcohol exposed animals. In addition, it has been shown that prostate tumors progress more frequently to a malignant phenotype in fetal alcohol-exposed rat offspring. Therefore, the study of the mechanism by which alcohol-induced fetal programming promotes prostate cancer is an important issue that needs investigation. We now have preliminary evidence that developmental reprogramming of the prostate by alcohol may be mediated, in part, through ESR1 activated transcriptional machineries. The objectives of the present application are to characterize in detail the transcriptional alterations in the prostatic tissues that result from early-life alcohol exposures and to determine if they are involved in predisposition to carcinogenesis. Hence, we propose to determine if the estrogen receptor 1-activation will promote while blocking estrogen receptor activity will suppress fetal alcohol-induced transcriptional responses and tumor susceptibility. We propose to use ChIP-seq to identify sites of occupancy for estrogen receptor 1 and RNA-seq to determine changes in gene expression in the prostate induced by fetal alcohol. Additionally, immunocytochemical and histopathological approaches will be employed to measure the growth and progression of prostatic tumors. The proposed studies employ an integrated approach that include the investigation of genome-wide changes in estrogen receptor 1 binding and gene expression caused by fetal alcohol exposure in the effected tissue during carcinogenesis. These studies address an important issue if epigenetic/genomic imprinting of the prostate gland by early ethanol exposure augments the susceptibility to prostate cancer. These studies are highly innovative as they would be the first to identify the molecular pathway in the process of fetal alcohol programming of the prostate that increases the sensitivity to tumorigenesis.

 描述（由申请人提供）：现在人们普遍认为，怀孕期间暴露于不利的环境条件和生活方式选择可能导致胎儿编程，这是成年期疾病易感性的基础。一个研究不足的领域是母亲酗酒对后代癌症易感性的影响。迅速积累的大量证据表明，必须从终身的角度来理解许多疾病，因为这些疾病的轨迹始于概念，并在几十年后的临床检测中浮出水面。怀孕期间改变性激素水平的因素可能会对后代产生长期的健康影响，包括前列腺癌风险的变化。现在有几项研究发现，酒精摄入量与怀孕期间血清雌激素水平呈正相关。尽管有这些信息，但很少有研究确定怀孕期间酒精促进雌激素水平与后代患前列腺或其他癌症风险的关系。我们最近在啮齿动物中的研究提供了产前酒精暴露动物前列腺癌发病率较高的证据。此外，研究表明，在暴露于酒精的胎儿大鼠后代中，前列腺肿瘤更频繁地发展为恶性表型。因此，酒精诱导的胎儿编程促进前列腺癌的机制的研究是一个重要的问题，需要调查。我们现在有初步的证据表明，酒精对前列腺的发育重编程可能部分是通过ESR 1激活的转录机制介导的。本申请的目的是详细表征早期生活酒精暴露导致的前列腺组织中的转录改变，并确定它们是否参与致癌易感性。因此，我们建议确定是否雌激素受体1激活将促进而阻断雌激素受体活性将抑制胎儿酒精诱导的转录反应和肿瘤易感性。我们建议使用ChIP-seq来确定雌激素受体1和RNA-seq的占位位点，以确定胎儿酒精诱导的前列腺基因表达的变化。此外，将采用免疫细胞化学和组织病理学方法来测量前列腺肿瘤的生长和进展。拟议的研究采用了一种综合的方法，包括调查全基因组的变化，雌激素受体1结合和基因表达所造成的胎儿酒精暴露在受影响的组织在致癌过程中。这些研究解决了一个重要的问题，如果前列腺的表观遗传/基因组印记的早期乙醇暴露增加了前列腺癌的易感性。这些研究具有高度创新性，因为它们将是第一个确定前列腺胎儿酒精编程过程中增加肿瘤发生敏感性的分子途径。