Estrogenic activity of uranium in vitro and in vivo

描述（由申请人提供）：铀的毒性主要通过研究其放射性特性来分析。然而，作为密度最大的自然元素，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。小鼠体内暴露于饮用水中的硝酸铀酰导致卵巢初级卵泡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。为了评估铀的雌激素敏感性，我们使用雌激素敏感的Mcf-7乳腺癌细胞E-Screen生物测定，初步数据表明，铀与许多其他重金属类似，具有雌激素性。在这里，我们建议进一步表征假定的铀的雌激素性。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，这将在两个特定的目的进行测试：1)使用Mcf-7细胞E-Screen试验分析铀的雌激素效力、受体特异性和有效浓度，培养卵巢内膜/间质细胞研究铀对雄激素产生的影响；2)通过完整和去卵巢小鼠体内实验，评估铀对生殖器官和内分泌指标的影响。NAU位于纳瓦霍族的西南边缘，那里直到20世纪90年代初都有活跃的铀矿开采。未经修复的矿山和矿石加工场所已经用ppb至ppm水平的铀污染了饮用水源。数据非常有限，但表明纳瓦霍族少女的生殖癌症发病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调查体外和体内铀的假定雌激素性，来解决是否可能长期饮用受铀污染的水和/或在子宫内接触铀，类似于在子宫内接触二乙基雌酚的影响，导致纳瓦霍青少年生殖器和生殖癌症的发病率极高。

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.