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.

项目总结 美国是世界上铬化合物的主要生产国之一。根据《国家新闻周刊》 自来水水质数据库和环境工作组报告，美国近7400万人 7000个社区饮用被六价铬，六价铬(VI)污染的水，他们容易患上 各种健康问题，包括不孕症、早产、早产、胎儿宫内发育 限制和癌症。一项研究使用了从新生儿的医院记录中公布的数据 以及来自加利福尼亚州威利茨的孕妇暴露于铬(VI)。这是第一次，有害的生殖影响 我们的研究报告了人类女性及其婴儿的非职业性铬(VI)暴露 涉及人类胎盘的报告称，胎盘中的铬蓄积与术语胎盘中的铬蓄积呈正相关(来自 密歇根州女性)和氧化应激增加。然而，铬(VI)是如何导致胎盘发育异常的， 而妊娠障碍是未知的。子宫螺旋动脉被广泛重塑，以提供足够的 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 对怀孕有不利影响。目前的研究假设，铬(VI)破坏了子宫螺旋动脉重构 通过抑制滋养层细胞侵袭和改变生长因子(S)介导的信号通路。对于第一次 我们的初步研究表明，铬(VI)诱导的子宫动脉壁增厚和狭窄。 动脉管腔。铬(VI)可抑制滋养层细胞侵入子宫-胎儿界面。引导海流 计时妊娠大鼠(8~10wk)随机分为4个试验组：对照组(n=10)、铬(VI)组。 -0.1ppm(n=10)、Cr(VI)-1.0ppm(n=10)和Cr(VI)-5.0ppm(n=10)，并暴露于各自剂量的 重铬酸钾(Cr(VI))从GD 9.5到12.5，并于GD18.5被安乐死。AIM-1将决定 胎盘和胎儿体重，吸收部位，雄性和雌性幼崽的数量，胎盘形状和存活和 死了的小狗。铬(VI)暴露对调控信号分子时空表达的影响 滋养层细胞侵入。AIM-2将确定铬(VI)对子宫主干肌源性反应的机制 动脉及其细胞外基质。子宫主要动脉将从处理过的妊娠大鼠中分离出来。 铬(VI)。收缩反应、内皮依赖性松弛反应、主动压 将计算响应、内径和外径、壁厚、横截面面积和壁应变 使用压力和线状肌电图仪。在研究2b中，子宫的细胞外基质(ECM)蛋白网络 动脉将会被确定。目前的研究是创新的，填补了了解铬(VI)在体内的作用的空白。 妊娠期间子宫血管适应性的改变。这些发现将有助于调节人体内的铬(VI)暴露。 孕妇，因为她们很容易受到EDCs的影响。