ENVIRONMENTAL TOXINS AND UTERINE GENE EXPRESSION

描述(改编自《调查者摘要》)：这是一个 重新提交的R01申请，试图测试假设 外源生物的生殖影响并不局限于 呃。这一假设将通过比较两种方法的效果来检验 异种雌激素，Kepone(十氯酮)和O，P‘-DDT和一种非雌激素类似物 滴滴涕(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组织几种基因表达的影响 动物和缺乏内质网的动物(转基因内质网 基因敲除)或被纯抗雌激素灭活。申请人建议： 确定这些药物对以下方面的影响：1.两个早期的表达 反应基因c-fos和c-jun；2.肝素调控基因的表达 结合表皮生长因子样生长因子与两调节素 (AR)，两种与胚胎植入相关的生长因子；3.表达 乳铁蛋白(LF)和乳铁蛋白(Lf)的两个众所周知的雌激素反应基因 孕激素受体(PR)还将进行研究，以确定 孕酮(P)、异种雌激素和雌激素的分离和交互作用 天然雌激素对去卵巢大鼠子宫基因表达的影响 具有和不具有功能性内质网的小鼠(ERKO小鼠)。形态和 表情的生理后果将通过以下方式进行测试：1.变化 子宫湿重和干重对蛋白质合成的影响；2.细胞特异性 氚胸腺嘧啶核苷掺入检测DNA合成； 增殖细胞核抗原的免疫组织化学定位 说明细胞增生。预计结果将提供 新方法的基础，以了解 生殖毒性。

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.