In utero availability of the essential nutrient, choline, and mammary cancer risk

这项研究的目的是检验产前胆碱的可利用性调节胎儿发育的假设。 患乳腺癌的风险。这一概念是基于证据表明，产前可用性 胆碱具有持久的生物效应，持续到成年和老年。胆碱是一种必需的 对人类的营养。由于胎儿发育构成了对胆碱需求增加的时期， 膳食指南要求妇女在怀孕期间增加胆碱摄入量。在我们之前的研究中， 专注于产前胆碱对大脑发育和认知功能的影响，我们 发现在妊娠后半期补充胆碱的大鼠在以下方面表现出改善： 这段记忆贯穿了他们的一生。这些影响与分子，生物化学， 和大脑结构的变化。在成年大鼠中，饮食中缺乏胆碱会导致肝癌，并且是唯一的原因。 在没有任何已知致癌物质的情况下导致癌症的营养缺乏。我们发现胆碱 成年期缺乏胆碱会增加大鼠患乳腺癌的风险，而补充胆碱则会降低风险 用甲基苄肼作为致癌物治疗。目的1是为了检验产前胆碱 可用性（不足、充足和补充）调节乳腺的发育 在雌性大鼠中，通过组织学技术监测， 微阵列为了评估后一种变化的机制，我们将检验产前 胆碱的可用性改变了基因调控元件的DMA甲基化， 胆碱通过其作为甲基供体的作用，可以改变DNA甲基化和基因表达， vivo.我们将研究受此过程调控的选定基因的DNA甲基化， 我们发现表达受胆碱（例如胰岛素样生长因子II， Igf2）。目的2旨在检验产前胆碱可利用性调节乳腺癌的假设， 用7，12-二甲基苯并[a]蒽处理的Sprague道利大鼠作为模型的致癌作用 （DMBA），一种致癌物质，导致类似于人类乳腺癌的肿瘤。肿瘤发病率和肿瘤 发展将被确定。这些乳腺组织的癌前病变和恶性病变 使用组织学和微阵列技术评价动物。在这类试点研究中， 在产前补充胆碱的大鼠中观察到疾病进展减缓的趋势， 由于产前胆碱缺乏而加速肿瘤生长。产前胆碱导致的乳腺肿瘤- 补充组大鼠细胞周期蛋白D1、STATS和催乳素受体表达增加， 与对照组和产前胆碱缺乏受试者的肿瘤相比，STATS mRNA的表达。这 一项针对NIH计划公告的提案，使用R21探索性 发展补助金机制旨在为研究发展的早期阶段提供支持 例如评估新研究领域可行性的项目。我们研究的最终目的是 将我们的研究结果与人类联系起来，并制定围产期营养策略，使人们受益。

The goal of the proposed studies is to test the hypothesis that prenatal availability of choline modulates the risk of development of mammary carcinoma. This notion is based on evidence that prenatal availability of choline has long-lasting biological effects persisting into adulthood and old age. Choline is an essential nutrient for humans. Because fetal development constitutes a period of increased demand for choline, US dietary guidelines call for increased choline intake by women during pregnancy. In our previous studies, that focused on the effects of prenatal availability of choline on brain development and cognitive functions, we found that rats supplemented with choline during the second half of gestation exhibited improvements in memory which lasted throughout their entire lifespan. These effects correlated with molecular, biochemical, and structural changes in brain. In adult rats, lack of dietary choline causes hepatocarcinoma and is the only nutritional deficiency that leads to cancer in the absence of any known carcinogens. We found that choline deficiency in adulthood increased mammary cancer risk while choline supplementation reduced it in rats treated with procarbazine as a carcinogen. Aim 1 is designed to test the hypothesis that prenatal choline availability (deficiency, sufficiency, and supplementation) modulates the development of the mammary gland in female rats as monitored by histological techniques and patterns of gene expression determined by microarrays. To assess the mechanisms of the latter changes we will test the hypothesis that prenatal availability of choline alters DMA methylation of the regulatory elements of genes, based on the evidence that choline, via its action as a donor of methyl groups, can alter DNA methylation and gene expression in vivo. We will study DNA methylation of selected genes that are regulated by this process and whose expression we found to be modulated by prenatal availability of choline (e.g.insulin-like growth factor II, Igf2). Aim 2 is designed to test the hypothesis that prenatal availability of choline modulates mammary carcinogenesis using as a model Sprague Dawley rats treated with 7,12-dimethylbenz[a]anthracene (DMBA), a carcinogen that causes tumors similar to human breast cancers. Tumor incidence and tumor development will be determined. Premalignant as well as malignant changes in mammary tissues from these animals will be evaluated using histological and microarray techniques. In a pilot study of this kind we observed trends for a slowed disease progression in prenatally choline-supplemented rats and an acceleration of tumor growth by prenatal choline deficiency. The mammary tumors from prenatally choline- supplemented rats had higher expression of cyclin D1, STATS, and prolactin receptor and lower expression of STATS mRNA as compared to the tumors from the control- and prenatally choline-deficient subjects. This proposal, prepared in response to an NIH Program Announcement, uses the R21 Exploratory Developmental grant mechanism designed to provide support for the early stages of research development such as projects to assess the feasibility of a novel area of investigation. The ultimate goal of our studies is to relate our results to humans and to develop perinatal nutritional strategies which could benefit people.