Evaluating the effects of hexavalent chromium on uterine vascular remodeling

项目摘要 美国是世界上主要的铬化合物生产国之一。根据国家 自来水质量数据库和环境工作组的报告显示，美国近7400万人 7，000个社区饮用受六价铬污染的水，Cr（VI），他们倾向于 各种健康问题，包括不孕症、早产、早产流产、宫内胎儿生长 限制和癌症。一项研究使用了新生儿医院记录中公布的数据 和来自Willits，CA的孕妇，暴露于Cr（VI）。这是第一次，有害的生殖影响 在美国报告了人类女性及其婴儿非职业性Cr（VI）暴露的结果。 涉及人胎盘的研究报告称，足月胎盘中的Cr蓄积（从 密歇根州妇女）和增加氧化应激。然而，Cr（VI）如何导致胎盘发育异常， 和妊娠障碍是未知的。子宫螺旋动脉被广泛重塑， 为发育中的胎儿提供母体血液和营养。异常子宫螺旋动脉重构 对怀孕有不良影响。目前的研究假设，铬（VI）破坏子宫螺旋动脉重塑 通过抑制滋养层细胞侵袭和改变生长因子介导的信号通路。第一 同时，我们的初步研究表明Cr（VI）诱导的子宫动脉壁增厚和子宫动脉狭窄， 动脉腔Cr（VI）抑制滋养层细胞侵入子宫-胎儿界面。来传导电流 将8-10周龄的孕鼠随机分为4个实验组：对照组（n=10），Cr（VI）组（n = 10） - 0.1 ppm（n=10）、Cr（VI）-1.0 ppm（n=10）和Cr（VI）-5.0 ppm（n=10），并暴露于相应剂量的 重铬酸钾（Cr（VI））从GD 9.5至12.5，并在GD 18.5处以安乐死。AIM-1将确定 胎盘和胎仔重量、吸收部位、雄性和雌性幼仔数量、胎盘形状以及存活和 死狗Cr（VI）暴露对细胞凋亡调控信号分子时空表达的影响 滋养层浸润AIM-2将确定Cr（VI）对子宫主动脉肌源性反应的机制 动脉及其细胞外基质。将从用以下药物处理的妊娠大鼠解剖子宫主动脉： Cr（VI）。收缩反应、内皮依赖性舒张反应、主动压 将计算响应、内径和外径、壁厚、横截面积和壁应变 使用压力和钢丝肌描记器。在研究2b中，子宫内膜的细胞外基质（ECM）蛋白网络 动脉将被确定。目前的研究是创新的，以填补差距，在理解铬（VI）的作用， 在怀孕期间改变子宫血管适应。这些发现将有助于调节Cr（VI）暴露， 孕妇，因为他们容易受到内分泌干扰物的影响。

PROJECT SUMMARY The United States is one of the world’s leading producers of chromium compounds. According to the National Tap Water quality database and Environmental Working Group report, ~74 million people in the U.S in nearly 7,000 communities drink water contaminated with hexavalent chromium, Cr(VI), and they are predisposed to various health problems including infertility, pre-term labor, pre-mature abortion, intrauterine fetal growth restriction, and cancers. A study was conducted using data released from the hospital records of newborn babies and pregnant women from Willits, CA, exposed to Cr(VI). For the first time, the detrimental reproductive effects from non-occupational Cr(VI) exposure in human females and their infants was reported in the U.S. Our study involving the human placenta reported a positive correlation between Cr accumulation in the term placenta (from Michigan women) and increased oxidative stress. However, how Cr(VI) causes abnormal placental development, and pregnancy disorders is unknown. The uterine spiral artery is extensively remodeled to deliver a sufficient supply of maternal blood and nutrients to the developing fetus. Abnormal uterine spiral artery remodeling adversely affects pregnancy. The current study hypothesizes that Cr(VI) disrupts uterine spiral artery remodeling by inhibiting trophoblast cell invasion and altering growth factor(s)-mediated signaling pathways. For the first time, our preliminary study demonstrates Cr(VI)-induced thickness of uterine artery wall and narrowing of the artery lumen. Cr(VI) inhibited trophoblast cell invasion into the uterine-fetal interface. To conduct the current project, timed pregnant rats (8-10 wk of age) will be divided into four experimental groups: Control (n=10), Cr(VI) - 0.1 ppm (n=10), Cr(VI) - 1.0 ppm (n=10), and Cr(VI) - 5.0 ppm (n=10), and exposed to respective doses of potassium dichromate (Cr(VI)) from GD 9.5 to 12.5 and euthanized on GD18.5. AIM-1 will determine the placental and fetal weight, resorption sites, the number of male and female pups, placentas shape, and live and dead pups. Effects of Cr(VI) exposure on spatio-temporal expression of signaling molecules in regulating trophoblast invasion. AIM-2 will identify the mechanism of Cr(VI) on the myogenic response of the uterine main artery and its extracellular matrix. Uterine main arteries will be dissected from the pregnant rats treated with Cr(VI). The contractile responses, endothelial-dependent relaxation responses, active pressure responses, internal and external diameter, wall thickness, cross-sectional area, and wall strain will be calculated using pressure and wire myographs. In Study 2b, the extracellular matrix (ECM) proteins network of the uterine artery will be determined. The current study is innovative to fill the gap in understanding the role of Cr(VI) in altering uterine vascular adaptation during pregnancy. These findings will help regulate Cr(VI) exposure in pregnant women since they are vulnerable to EDCs’ exposure.