Evaluating the effects of hexavalent chromium on uterine vascular remodeling

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.

Grant Number: 5R21ES034905-02
NIH Institute/Center: NIH
Principal Investigator: Sakhila Banu