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美洲原住民部落的所在地。20世纪40年代中期，纳瓦霍族所在的美国西南部的四角地区开始了活跃的铀（U）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个未修复的铀地雷，由于没有妥善关闭这些地雷，导致土壤和水受到广泛的铀污染。根据美国环保署的数据，纳瓦霍人饮用和家庭使用的数十种水源的铀含量超过了30微克/升的安全饮用水限值。已知有许多健康问题是由含铀的水引起的，但迄今为止，所有这些问题都与铀作为重金属的毒性有关。最近我们发现，U，很像其他重金属，具有雌激素活性。我们已经发现，U，在等摩尔浓度的己烯雌酚（DES），eleventricular雌激素反应在雌性小鼠的生殖道和组织培养刺激人乳腺癌细胞增殖。在最近的实验中，我们发现子宫内暴露于DES或U会导致发育中的幼鼠卵巢产生过量的雄激素，与那些母鼠喝自来水的幼鼠相比。基于这些新的数据，我们提出了一个假设，即子宫内的U暴露永久地改变了发育中的卵巢的程序，使其产生更多的雄激素，在一生中导致卵巢早衰和代谢失调。这一假设将在两个目标中得到检验。首先，我们将通过检查卵巢和分析18月龄以下小鼠组织培养物中雄激素的产生来确定在子宫内暴露于DES或U的35-38日龄小鼠的卵巢中观察到的高雄激素血症是否是永久性的。并且，我们将确定这些小鼠在发情周期的LH峰期间雄激素血液水平是否增加。第二个目的是确定持续性高雄激素血症是否通过卵泡发生短路而加速卵巢功能衰竭。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生来分析一生中高雄激素血症的总体影响。我们的总体目标是检验子宫内暴露于内分泌干扰雌激素化学物质U会导致2型糖尿病和最终心脏病风险增加的假设。在过去的几十年里，这两种慢性病在纳瓦霍人中的流行率急剧上升。越来越多的科学认识表明，子宫环境作为母亲暴露于环境化学品的函数，可能导致发育中的儿童永久性差异，导致成年后患糖尿病和心脏病的风险更大。

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.