ENVIRONMENTAL TOXINS AND UTERINE GENE EXPRESSION

环境毒素和子宫基因表达

• 批准号: 2018586
• 负责人: SANJOY K. DAS
• 金额: $ 18.81万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2018586
• 关键词: carcinogen testing; chemical carcinogen; chemical carcinogenesis; dichlorodiphenyltrichloroethane; embryo implantation; environmental toxicology; epidermal growth factor; estrogen receptors; gene induction /repression; genetically modified animals; hyperplasia; immunocytochemistry; laboratory mouse; lactoferrin; mirex /kepone; mutagen testing; neoplasm /cancer genetics; ovariectomy; polymerase chain reaction; progesterone receptors; protooncogene; regulatory gene; transcription factor; uterus; uterus neoplasms

DESCRIPTION (Adapted from the Investigator's Abstract): This is a resubmitted R01 application that seeks to test the hypothesis that the reproductive effects of xenobiotics are not limited to the actions of the ER. This hypothesis will be tested by a comparison of the effects of two xenoestrogens, Kepone (chlordecone) and O,P'-DDT and a non-estrogenic analog of DDT (P,P'-DDD) with those of two natural estrogens, estradiol and 4-hydroxy-estradiol, on the expression of several uterine genes in normal animals and those in which the ER is either lacking (transgenic ER knock-out) or inactivated by a pure antiestrogen. The applicant proposes to determine the effect of these agents on: 1. expression of two early response genes, c-fos and c-jun; 2. expression of genes controlling heparin binding-epidermal growth factor like growth factor (HB-EGF) and amphiregulin (AR), two growth factors associated with embryo implantation; 3. expression of two well known estrogen responsive genes for lactoferrin (LF) and progesterone receptor (PR). Studies will also be done to determine the separate and interactive effects of progesterone (P), xenoestrogens and the natural estrogens on the expression of these uterine genes in ovariectomized mice with and without a functional ER (ERKO mice). Morphological and physiological consequences of expression will be tested using: 1. changes in uterine wet and dry weight for protein synthesis; 2. cell specific incorporation of tritiated thymidine to measure DNA synthesis; and 3. immunohistochemical localization of proliferating cell nuclear antigen to indicate cellular hyperplasia. The results are expected to provide the basis for new approaches to understand the mechanisms involved in reproductive toxicity.

描述（改编自研究者的摘要）：这是一个 重新提交 R01 申请，旨在检验以下假设： 外源物质的生殖影响不仅限于 急诊室。 该假设将通过比较两种方法的效果来检验 异雌激素、开蓬（十氯酮）和 O,P'-DDT 以及非雌激素类似物 DDT (P,P'-DDD) 与两种天然雌激素雌二醇和 4-羟基雌二醇，对正常子宫基因表达的影响 动物和缺乏 ER 的动物（转基因 ER 敲除）或被纯抗雌激素灭活。 申请人提议 确定这些药物对以下方面的影响： 1. 两种早期表达 反应基因，c-fos 和 c-jun； 2.控制肝素的基因的表达 结合表皮生长因子样生长因子 (HB-EGF) 和双调蛋白 (AR)，两种与胚胎植入相关的生长因子； 3.表达 两个众所周知的乳铁蛋白 (LF) 雌激素反应基因和 黄体酮受体（PR）。 还将进行研究以确定 黄体酮 (P)、异雌激素和 天然雌激素对卵巢切除患者子宫基因表达的影响 有和没有功能性 ER 的小鼠（ERKO 小鼠）。 形态学和 表达的生理后果将通过以下方式进行测试： 1. 变化 用于蛋白质合成的子宫湿重和干重； 2. 细胞特异性 掺入氚化胸苷以测量 DNA 合成；和 3. 增殖细胞核抗原的免疫组织化学定位 表明细胞增生。 预计结果将提供 为了解相关机制的新方法奠定了基础 生殖毒性。