Fetal brain damage resulting from maternal alcohol abuse is one of the leading causes of mental retardation in the United States and yet the mechanisms by which in utero alcohol exposure adversely affects fetal brain development and function are largely unknown. The investigators have recently demonstrated attenuated hypoxic; cerebral vasodilation in newborn sheep which were exposed to chronic maternal alcohol intoxication in the first trimester. Based on these and other supportive findings, they have developed the hypothesis that in utero alcohol exposure affects the development and function of cerebral blood vessels, and that the consequent vascular abnormalities may contribute to the pathogenesis of brain damage associated with fetal alcohol exposure. The objective of this proposal is to further characterize the cerebrovascular and neuropathological effects of chronic fetal alcohol exposure in sheep, and to evaluate potential mechanisms for and consequences of these effects. They will use in vivo and in vitro physiological methods as well as neuropathology and immunocytochemistry to address the following aims:
Aim #1 : To determine whether chronic maternal alcohol intoxication in the first or second trimester alters fetal cerebrovascular responses to hypoxia in vivo later in pregnancy.
Aim #2 : To compare the neuropathologic effects of repeated hypoxic insults in fetuses previously exposed to either alcohol or saline in utero.
Aim #3 : To determine mechanisms whereby prenatal alcohol exposure alters cerebrovascular reactivity by examining the maturation of the cerebral vascular network and by studying the density and expression of cerebral vasodilatory substances.
Aim #4 : To determine whether prenatal alcohol alters cerebrovascular reactivity in vitro by testing the responses of cannulated, pressurized fetal and adult sheep arterioles to vasoactive substances.
Aim #5 : To determine whether prior prenatal alcohol exposure during pregnancy alters fetal or adult cerebrovascular responses to acute alcohol intoxication. Results from these studies will provide important new information regarding the contribution of fetal cerebrovascular abnormalities to the brain damage associated with fetal alcohol exposure and will lead to the development of perinatal preventive and/or therapeutic strategies for pregnant women who use alcohol.
