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: 9107765
• 负责人: DIPAK KUMAR SARKAR
• 金额: $ 18.41万
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9107765
• 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 alpha; 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 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的选择可能会导致胎儿编程，从而成为成年后疾病易感性的基础。其中一个尚未得到充分研究的领域是母亲酗酒对后代的影响。迅速积累的证据表明，许多疾病必须从终生的角度来理解，因为这些疾病从受孕时开始并在数十年后的临床检测中显现出来，这些因素改变了性激素水平。怀孕期间饮酒可能会对后代产生长期健康影响，包括前列腺癌风险的变化，目前有几项研究发现，怀孕期间饮酒与血清雌激素水平呈正相关，但很少有研究来确定这种关系。我们最近对啮齿类动物的研究提供了证据，证明产前接触酒精的动物前列腺癌的发病率较高。暴露于酒精的胎儿更容易发展为恶性表型因此，研究酒精诱导的胎儿编程促进前列腺癌的机制是一个需要研究的重要问题，我们现在有初步证据表明，酒精对前列腺的发育重编程可能部分是通过ESR1介导的。本申请的目的是详细表征早期酒精暴露引起的前列腺组织中的转录改变，并确定它们是否涉及致癌倾向。雌激素受体1-激活将促进雌激素受体活性，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 来鉴定雌激素受体 1 的占据位点，并使用 RNA-seq 来确定雌激素受体 1 中基因表达的变化。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，其中包括研究前列腺受体 1 结合和的全基因组变化。这些研究解决了一个重要问题，即早期乙醇暴露对前列腺的表观遗传/基因组印记会增加前列腺癌的易感性。首先确定胎儿酒精编程前列腺过程中增加肿瘤发生敏感性的分子途径。