Estrogenic activity of uranium in vitro and in vivo

铀的体外和体内雌激素活性

基本信息

批准号：
7213486
负责人：
CHERYL A DYER
金额：
$ 22.2万
依托单位：
NORTHERN ARIZONA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-15 至 2009-02-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7213486
关键词：
Adult Age Age-Months Androgens Androstenedione Area Blood Body Weight Breast Cancer Cell Cardiovascular Diseases Cell Proliferation Cells Chemicals Child Chronic Disease Count Cytology Data Deposition Diabetes Mellitus Diet Diethylstilbestrol Dyslipidemias Endocrine disruption Energy Metabolism Environment Epidemic Estrus Exposure to Failure Fatty acid glycerol esters Female Glucose Goals Health Heart Diseases Heavy Metals High Density Lipoproteins Histology Home environment Household Human Chorionic Gonadotropin Hyperandrogenism Hyperglycemia Hypertriglyceridemia In Vitro Insulin Insulin Resistance LH Receptors Lead Marketing Measures Metabolic Mining Mothers Mus Native Americans Navajo Non-Insulin-Dependent Diabetes Mellitus Numbers Ovarian Ovary Perinatal Exposure Periodicity Peripheral Physiology Play Population Premature Ovarian Failure Prevalence Production Relative (related person)Research Risk Role SR-BI receptor Score Skiing Soil Source Southwestern United States Staging Staining method Stains Steroids Testing Time Tissues Toxic effect Tribes United States Environmental Protection Agency Uranium Vagina Water Week Weight Gain base corpus luteum day drinking drinking water environmental chemical estrogenic activity feeding folliculogenesis high density lipoprotein receptor in utero in vivo insulin tolerance interstitial cell oil red O programs pup reproductive research study response tissue culture

项目摘要

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.

描述（由适用提供）：Navajo Nation是1940年中期在美国西南部美国西南部的四个角落地区开始的美国最大的美国原住民部落的所在地。 U开采持续了40年，直到U矿石市场崩溃。纳瓦霍（Navajo）国家有超过1000个未散发的U矿，并且没有正确关闭这些矿山，从而导致了土壤和水的污染宽度。根据美国EPA的说法，纳瓦霍人使用的饮酒和家庭用品使用了许多水源，其水平超过了30 g/l的安全饮用水限制。摄入含有水的U摄入的健康问题已知许多健康问题，但迄今为止，这都与U作为重金属的毒性有关。最近，我们发现U与其他重金属一样，U具有雌激素活性。我们发现，在二乙基甲醇（DES）的等摩尔浓度下，u在雌性小鼠的生殖道中引起雌激素反应，在组织培养中会刺激人类乳腺癌细胞的增殖。在最近的实验中，我们发现在子宫内暴露于DES或U导致幼崽与幼犬喝自来水的幼崽相比，幼崽产生过度生产雄激素。基于这些新数据，我们提出了以下假设：在子宫内暴露会永久改变发育中的卵巢的编程，从而产生更多的雄激素，一生中会导致早产卵巢衰竭和代谢失调。该假设将以两个目的进行检验。首先，我们将确定在卵巢中观察到的超雄激素是否是通过检查卵巢和分析卵巢的35-38天大小鼠或U永久性的，并分析了来自18个月大的小鼠组织中雄激素的产生。而且，我们将确定在发情周期的LH激增期间，这些小鼠的雄激素血液水平是否升高。在第二个目的中，我们将确定持续的高狂力主义是否通过短路叉子而导致卵巢衰竭加速。最后，我们将通过分析胰岛素抵抗，高血糖，高甘油三酸酯血症和截短脂肪沉积的开始来分析终生高狂力主义的全球影响。我们的总体目的是检验以下假设：在子宫内暴露于内分泌中的雌激素化学化学，U，导致患上2型糖尿病和最终心脏病的风险增加。在过去的几十年中，这两种慢性疾病的普遍性在纳瓦霍人的天空中散发出来。越来越多的科学理解表明，子宫环境与母亲接触环境化学物质的关系可能会导致发育中的儿童永久差异，这导致成年人患糖尿病和心脏病的更大风险。