Evaluating the effects of hexavalent chromium on uterine vascular remodeling

评估六价铬对子宫血管重塑的影响

• 批准号: 10581242
• 负责人: Sakhila Banu
• 金额: $ 22.78万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10581242
• 关键词: Actins; Adverse effects; Affect; Age; Apoptosis; Area; Arteries; Birth Rate; Blood; Blood Vessels; Carcinogens; Cells; Chemical Exposure; Child; Chromium Compounds; Clinical Data; Collagen; Communities; Complex; Cytokeratin; Data; Databases; Diameter; Disease; Dose; Elastin; Endocrine Disruptors; Endothelial Cells; Endothelium; Environmental Exposure; Euthanasia; Experimental Designs; Exposure to; Extracellular Matrix; Extracellular Matrix Proteins; Female; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetal Resorption; Fetal Weight; Fetus; Grant; Growth Factor; Health; Heavy Metals; High-Risk Pregnancy; Hospital Records; Human; Individual; Infant; Infertility; Interstitial Collagenase; Invaded; Label; Litter Size; Malignant Neoplasms; Mediating; Michigan; Modeling; Molecular; Newborn Infant; Nutrient; Outcome; Oxidative Stress; PTK2 gene; Pathway interactions; Pattern; Perfusion; Persons; Placenta; Placentation; Potassium; Predisposition; Pregnancy; Pregnancy Outcome; Pregnancy loss; Pregnant Women; Premature Birth; Premature Labor; Proteins; Rattus; Relaxation; Reporting; Role; STAT1 gene; STAT3 gene; Shapes; Signal Pathway; Signaling Molecule; Site; Spiral Artery of the Endometrium; Spontaneous abortion; Stat5 protein; Thick; Time; United States; United States National Institutes of Health; Uterus; Vascular Smooth Muscle; Vascular remodeling; Vulnerable Populations; Woman; abortion; chromium hexavalent ion; contaminated water; early pregnancy; epidemiologic data; experience; experimental group; fetal; human female; immunocytochemistry; indexing; innovation; male; novel; pregnancy disorder; pregnancy health; pregnant; premature; pressure; pup; reproductive; response; spatiotemporal; trophoblast; water quality; working group

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.

项目摘要 美国是世界领先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报告，美国约有7400万人 7,000个社区喝水被六价铬污染的水，CR（VI），它们倾向于 各种健康问题，包括不育症，术前劳动，成熟前流产，内在胎儿生长 限制和癌症。使用从新生婴儿的医院记录中发布的数据进行了一项研究 来自加利福尼亚州威利特的孕妇暴露于CR（VI）。第一次，有害的生殖效应 在美国报告了人类女性及其婴儿的非职业CR（VI）暴露于我们的研究 涉及人papeta报告了术语plapeta中Cr积累之间的正相关（来自 密歇根州妇女）和增加氧化应激。但是，CR（VI）如何引起异常的位置发育， 怀孕疾病是未知的。子宫螺旋动脉被广泛重塑以提供足够的 向发育中的胎儿供应母亲的血液和营养。子宫螺旋动脉重塑异常 不利影响怀孕。当前的研究假设CR（VI）破坏了子宫螺旋动脉重塑 通过抑制滋养细胞的侵袭和改变生长因子（S）介导的信号通路。第一个 时间，我们的初步研究表明，CR（VI）引起的子宫动脉壁的厚度和狭窄 动脉腔。 CR（VI）抑制了滋养细胞侵袭子宫 - 狂热界面。进行电流 项目，定时怀孕大鼠（8-10周龄）将分为四个实验组：对照（n = 10），CR（VI） -0.1 ppm（n = 10），CR（VI）-1.0 ppm（n = 10）和CR（VI）-5.0 ppm（n = 10），并暴露于相对剂量 二分（CR（VI））从GD 9.5到12.5，在GD18.5上进行了安乐死。 AIM-1将确定 胎盘和胎儿体重，分辨率，男幼崽的数量，胎盘形状以及活体 死狗。 CR（VI）暴露对调节信号分子的空间表达的影响 滋养细胞入侵。 AIM-2将确定CR（VI）在子宫主的肌源性反应上的机制 动脉及其细胞外基质。子宫主动脉将从治疗的怀孕大鼠中解剖 CR（VI）。收缩反应，内皮依赖性放松反应，主动压力 将计算响应，内部和外径，壁厚，横截面面积和壁应力 使用压力和电线肌电图。在研究2B中，子宫的细胞外基质（ECM）蛋白网络 将确定动脉。当前的研究具有创新性，以填补了解CR（VI）在 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）的暴露 孕妇很容易受到EDC的暴露。