Estrogenic activity of uranium in vitro and in vivo

描述（由申请人提供）：主要通过研究其放射性特性来分析铀毒性。然而，作为一种天然存在的元素，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。小鼠在体内暴露于饮用水中的硝酸铀酰导致卵巢中仅初级卵泡的选择性显著减少和子宫重量增加。这些结果是典型的雌激素反应。为了评估铀的推定雌激素活性，我们使用雌激素敏感的Mcf-7乳腺癌细胞E-Screen生物测定和初步数据表明，铀，类似于许多其他重金属，是雌激素。在这里，我们建议进一步表征铀的推定雌激素。我们的工作假设是：铀通过雌激素受体α在体内外刺激雌激素反应，具体有两个目的：1）用Mcf-7细胞E-Screen分析铀的雌激素效应、受体特异性和有效浓度，培养卵巢卵泡膜/间质细胞，观察铀对雄激素产生的影响; 2）在完整小鼠和卵巢切除小鼠中进行体内实验，以评估铀对生殖器官和内分泌措施的影响。NAU位于纳瓦霍民族的西南边缘，直到20世纪90年代初，这里一直是活跃的铀矿开采地。未经补救的矿山和矿石加工场已使饮用水源受到ppb至ppm水平的铀污染。数据非常有限，但显示纳瓦霍少女的生殖系统癌症发生率是同龄美国青少年的17倍。我们的长期目标是通过在我们的实验室中调查铀在体外和体内的推定雌激素活性，来解决是否有可能长期饮用铀污染的水和/或子宫内暴露，类似于子宫内己烯雌酚暴露的影响，导致纳瓦霍青少年生殖器和生殖系统癌症的极高发病率。

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.