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