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.

PROJECT NARRATIVE Women exposed to hexavalent chromium (Cr(VI)) suffer from pre-term labor, pre-mature abortion, and intrauterine fetal growth restriction (IUGR). In humans, exposure to endocrine-disrupting chemicals leads to inadequate uterine spiral artery remodeling in early pregnancy resulting in pregnancy-related disorders. The outcome of the proposed NIH-R21 project will lead to a better understanding of the molecular mechanism of Cr(VI) in causing maladaptation of placental /uterine vasculature, which leads to IUGR and pre-term labor, that in turn might help regulate Cr(VI) exposure in a vulnerable population, such as pregnant women.