Estrogenic activity of uranium in vitro and in vivo

铀的体外和体内雌激素活性

• 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
• 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

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(由申请人提供)：纳瓦霍民族是美国最大的美洲原住民部落的家园。20世纪40年代中期，S活跃的铀(U)开采开始于纳瓦霍民族所在的美国西南部四角地区。铀矿开采持续了40年，直到铀矿市场崩溃。纳瓦霍民族上有1000多个未修复的铀矿，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个水源的铀含量超过了30克/升的安全饮用水限制。已知的许多健康问题是由于摄入含铀的水而引起的，但到目前为止，所有这些都与铀作为一种重金属的毒性有关。最近我们发现，铀和其他重金属一样，也具有雌激素活性。我们发现，在等摩尔浓度的己烯雌酚(DES)中，U在雌性小鼠的生殖道和组织培养中都能诱导雌激素样反应，刺激人乳腺癌细胞的增殖。在最近的实验中，我们发现，在子宫内暴露于DES或U会导致发育中的幼崽卵巢产生过量的雄激素，而不是那些喝自来水的幼崽的卵巢。基于这一新数据，我们提出了一种假设，即子宫内铀暴露永久性地改变了发育中卵巢的编程，从而产生了更多的雄激素，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上得到检验。首先，我们将通过检查卵巢和分析18个月龄小鼠的组织培养中雄激素的产生，来确定从35-38天的小鼠在子宫中暴露到DES或U的卵巢中观察到的高雄激素血症是否是永久性的。并且，我们将确定在发情周期的黄体生成素激增期间，这些小鼠的雄激素水平是否会增加。在第二个目标中，我们将确定持续性高雄激素血症是否通过短路卵泡发生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、高甘油三酯血症和躯干脂肪沉积来分析终生高雄激素血症的全球影响。我们的总体目标是检验这一假设，即在子宫内暴露于一种内分泌干扰性雌激素化学物质U，会增加患2型糖尿病和最终心脏病的风险。在过去的几十年里，这两种慢性病在纳瓦霍人中的流行率直线上升。越来越多的科学认识表明，由于母亲暴露在环境化学物质中，子宫环境可能会导致发育中儿童的永久性差异，从而导致成年后患糖尿病和心脏病的风险更大。