Increasing numbers of women of child-bearing age are serving in active duty roles in the military. Approximately 10% of these women will have unplanned pregnancies and the numbers are increasing. These young women are serving in foreign countries where environmental exposures could have adverse effects on the developing fetus. For that reason, Defense Department policy prohibits them from serving in roles where they may be exposed to chemicals and fuels that could adversely affect the fetus. The military often serve at high altitudes, for example, the mountains of Afghanistan, which range from 5000-24000 feet in elevation. Because the air is thinner as altitude increases, there is less oxygen in the air, explaining the breathlessness that people experience in the mountains at higher elevations. There are some suggestions that the reduced oxygen at high elevations may adversely affect the pregnancy and the growth of the fetus, but there is little understanding of the effect on the developing fetus of travel to high altitudes. This is especially true early in the pregnancy when the heart and other organs are just forming (8-12 weeks) and the Service member may not yet know or have not verbalized that she is pregnant.

This proposal addresses this question using a novel model in which mice have been engineered to express the firefly luciferase protein -- the protein that in the presence of its substrate luciferin is responsible for the firefly flashing at night. This luciferase has been modified so that it responds to and thus reports on the oxygen concentrations within the cells of the mouse heart and other organs. This is done by measuring the intensity of the flash of light in a test tube or in the intact animal. This is a very accurate assay that will allow us to precisely determine the relationship between reduced oxygen in the air as would be experienced at different altitudes and compromise of oxygen delivery to the developing fetus. By extrapolation of this analysis, we should be able to make recommendations as to safe altitudes for travel at different stages of pregnancy.

The second novel model addresses the question of how might other factors determine the effect of high altitude hypoxia on the developing fetus. One such factor is the placenta, which in development has a function equivalent to that of the lungs of an adult. It provides oxygen and nutrients from the mother to the fetus and removes CO2 and other waste products. We propose to develop a novel mouse of placental insufficiency by inactivating a certain gene specifically in the mother¿s cells. We will then measure how this affects oxygen delivery to the fetal tissues under high altitude hypoxia. In these experiments, we will also test how genetic differences in the fetus might also affect oxygen delivery and the development of congenital heart defects. Overall, these experiments are designed to test maternal-fetal and gene-environment interactions in high altitude hypoxia and the development of congenital heart defects.

Congenital heart defects are one of the most common groups of defects in the United States with an incidence of 0.8% of live births. Some of these are relatively minor such as small ventricular septal defects. Others are severe and life-threatening requiring early surgery and life-long care, a significant emotional and financial burden to the Service members. The cause of the vast majority of congenital heart defects is unknown but thought to be due to a combination of environmental stressors and genetic susceptibility. Defining the risk of high altitude hypoxia and placental insufficiency for congenital heart defects and adverse outcomes of pregnancy is crucial to providing advice to young female Service members, thereby enabling more informed decisions on this important topic.