Estrogenic activity of uranium in vitro and in vivo

描述(申请人提供)：铀毒性主要是通过调查其放射性特性来分析的。然而，作为密度最大的自然存在元素，它也像其他重金属一样具有化学毒性。我们一直在研究铀对雌性小鼠的生殖化学毒性。在体内，小鼠暴露于饮用水中的硝酸铀酰，只会选择性地显着减少卵巢中的初级卵泡，并增加子宫重量。这些结果是典型的雌激素反应。为了评估铀的潜在雌激素活性，我们使用了雌激素敏感的Mcf-7乳腺癌细胞E-Screen生物测试，初步数据表明，铀类似于许多其他重金属，具有雌激素样作用。在这里，我们建议进一步描述铀的雌激素样作用。我们的工作假设是铀在体外和体内通过雌激素受体α刺激雌激素反应，这将在两个特定目的进行测试：1)使用Mcf-7细胞E-Screen分析铀的雌激素潜能、受体特异性和有效浓度，培养卵巢膜/间质细胞以检测铀对雄激素产生的影响；2)在完整和去卵巢的小鼠身上进行体内实验，以评估铀对生殖器官和内分泌措施的影响。瑙鲁大学位于纳瓦霍民族的西南部，直到20世纪90年代初S还在那里开采铀。未经修复的矿山和矿石加工厂已用ppb到ppm级别的铀污染饮用水水源。数据非常有限，但数据显示，纳瓦霍十几岁女孩患生殖道癌的几率是年龄匹配的美国青少年的17倍。我们的长期目标是通过在我们的实验室调查铀在体外和体内的假定雌激素活性，来解决是否有可能长期饮用被铀污染的水和/或在子宫内暴露，类似于子宫内暴露的己烯雌酚的影响，导致纳瓦霍青少年生殖器和生殖器癌症的极高发病率。

DESCRIPTION (provided by applicant): Uranium toxicity has been analyzed primarily by investigating its radioactive properties. However as the densest naturally occurring element it also exerts chemical toxicity like other heavy metals. We have been investigating the reproductive chemical toxicity of uranium in female mice. In vivo exposure of mice to uranyl nitrate in their drinking water results in the selective significant reduction in only primary follicles in the ovary and increased uterine weight. These outcomes are typical estrogenic responses. To assess putative estrogenicity of uranium we used the estrogen sensitive Mcf-7 breast cancer cell E-Screen bioassay and preliminary data suggests that uranium, similar to many other heavy metals, is estrogenic. Here we propose to further characterize the putative estrogenicity of uranium. Our working hypothesis is that uranium stimulates estrogenic responses in vitro and in vivo via estrogen receptor alpha, which will be tested in 2 specific aims: 1) Use the Mcf-7 cell E-Screen assay to analyze uranium's estrogenic potency, receptor specificity and effective concentration, culture ovarian theca/interstitial cells to examine the impact of uranium on androgen production; 2) Conduct in vivo experiments in intact and ovariectomized mice to assess uranium's impact on reproductive organs and endocrine measures. NAU is located on the southwest perimeter of the Navajo Nation where until the early1990's there was active uranium mining. Unremediated mines and ore processing sites have contaminated drinking water sources with uranium at ppb to ppm levels. Data is very limited but shows that reproductive cancers in Navajo teenage girls are 17 times more frequent than in age-matched U.S. teenagers. Our long range goal is to address if it is possible that chronic consumption of uranium-contaminated water and/or in utero exposure, similar to the effect of diethylstilbestrol exposure in utero, has contributed to the exceedingly high incidence of genital and reproductive cancers in Navajo teenagers by investigating in our laboratory the putative estrogenicity of uranium in vitro and in vivo.