Estrogenic activity of uranium in vitro and in vivo

描述（由申请人提供）：纳瓦霍族是美国最大的印第安部落所在地。20世纪40年代中期，纳瓦霍族所在的美国西南部四角地区开始了活跃的铀矿开采。铀矿开采持续了40年，直到铀矿市场崩溃。纳瓦霍族有超过1000个未修复的铀矿，由于没有适当关闭这些矿，导致土壤和水受到广泛的铀污染。根据美国环境保护署的数据，纳瓦霍人饮用和家庭使用的水源中有大量的U含量超过了30克/升的安全饮用水限制。众所周知，摄入含铀的水会引起许多健康问题，但迄今为止，所有问题都与铀作为重金属的毒性有关。最近我们发现，U和其他重金属一样，具有雌激素活性。我们发现，与己烯雌酚（DES）等摩尔浓度的U在雌性小鼠的生殖道中引起雌激素反应，在组织培养中刺激人类乳腺癌细胞增殖。在最近的实验中，我们发现，与饮用自来水的幼犬相比，子宫内暴露于DES或U会导致发育中的幼犬卵巢产生过多的雄激素。基于这些新数据，我们提出了一个假设，即子宫内暴露于U会永久性地改变卵巢发育的程序，使其产生更多的雄激素，从而导致卵巢早衰和代谢失调。这一假设将在两个方面得到检验。首先，我们将通过检查卵巢并分析18个月大的小鼠组织培养中雄激素的产生，确定35-38日龄小鼠子宫内暴露于DES或U的卵巢中观察到的高雄激素血症是否是永久性的。我们将确定在发情期黄体生成素激增期间这些小鼠体内的雄激素水平是否升高。在第二个目标，我们将确定是否持续高雄激素有助于加速卵巢功能衰竭的卵泡发生短路。最后，我们将通过分析胰岛素抵抗、高血糖、高甘油三酯血症和躯干脂肪沉积的发病情况来分析终生高雄激素症的整体影响。我们的总体目标是验证这样一种假设，即子宫内暴露于一种扰乱内分泌的雌激素化学物质U，会导致患2型糖尿病和最终心脏病的风险增加。在过去的几十年里，这两种慢性疾病在纳瓦霍人中的发病率急剧上升。越来越多的科学认识表明，子宫环境作为母亲接触环境化学物质的一个功能，可能会导致发育中的儿童产生永久性的差异，从而导致成年后患糖尿病和心脏病的风险增加。

DESCRIPTION (provided by applicant): The Navajo Nation is home to the largest Native American tribe in the U.S. In the mid 1940's active uranium (U) mining began in the Four Corners region of the southwest U.S. where the Navajo Nation is located. U mining continued for 4 decades until the U ore market collapsed. There are over 1000 unremediated U mines on the Navajo Nation and having not closed these properly has led to widespread U contamination of the soil and water. According to the U.S. EPA there are scores of water sources used by Navajo people for drinking and household use that have U levels that exceed the safe drinking water limit of 30 ¿g/L. There are many health problems known to arise from ingesting U containing water but to date all have to do with the toxicity of U as a heavy metal. Recently we discovered that U, much like other heavy metals, has estrogenic activity. We have found that U, at equimolar concentration to diethylstilbestrol (DES), elicits estrogenic responses in the reproductive tract of female mice and in tissue culture stimulates human breast cancer cell proliferation. In recent experiments we have found that in utero exposure to DES or U causes developing pup ovaries to overproduce androgen compared to ovaries from pups whose dams drank tap water. Based on this new data we propose the hypothesis that in utero U exposure permanently alters the programming of the developing ovary so that it produces more androgen that over a lifetime contributes to premature ovarian failure and metabolic dysregulation. This hypothesis will be tested in two aims. First, we will determine if the hyperandrogenism observed in ovaries from 35-38 day old mice exposed in utero to DES or U is permanent by examining ovaries and analyzing production of androgen in tissue culture from mice up to 18 months of age. And, we will determine if androgen blood levels are increased in these mice during the LH surge of the estrus cycle. In the second aim we will determine if persistent hyperandrogenism contributes to accelerated ovarian failure by short circuiting folliculogenesis. Finally, we will analyze the global effects of lifetime hyperandrogenism by analyzing onset of insulin resistance, hyperglycemia, hypertriglyceridemia and deposition of truncal fat. Our overall goal is to test the hypothesis that in utero exposure to an endocrine disrupting estrogenic chemical, U, leads to increased risk of developing type 2 diabetes and ultimately heart disease. The prevalence of these two chronic illnesses has sky rocketed in the Navajo people in the last several decades. Growing scientific understanding has revealed that the uterine environment as a function of the mother's exposure to environmental chemicals can lead to permanent differences in the developing child that leads to as an adult greater risk for developing diabetes and heart disease.