OVINE MODEL SYSTEM FOR ALCOHOL RELATED BIRTH DEFECTS

描述（改编自申请人摘要）：总体目的

DESCRIPTION (Adapted from the APPLICANT'S ABSTRACT): The overall purpose of this proposal is to use an ovine (sheep) model system to address FAS questions in conjunction with another of NIAAA's areas of special interest, moderate drinking. Specific Aim 1 will test the hypothesis that maternal alcohol exposure levels during the third trimester that are too low to produce fetal hypoxia will produce substantial brain damage. Second, we will determine if high doses of alcohol that mediate hypoxia result in disproportionate increases in brain injury. We will focus on microencephaly, area measurements of the corpus callosum and on stereo logical cell counts in the cerebellum, neocortex, hippocampal formation, locus coeruleus and the principal sensory nucleus of the trigeminal nerve, structures that include populations of neurons known to exhibit differential sensitivity to both fetal alcohol exposure and hypoxia. Data also will be gathered related to a second popular hypothesis, that heavy maternal alcohol consumption produces altered prostaglandin levels that mediate alcohol related birth defects. Additional dependent variables to be assessed include circulating levels of prostaglandins and hormones, hemodynamic measures, blood gases, gross somatic anomalies and prenatal growth measures. Specific Aim 2 will determine the effects of long-term prenatal alcohol exposure (all three trimesters) on brain development. The design for this experiment is driven by drinking patters reported in moderate and heavy drinkers during pregnancy. Specific Aim 3 will test the hypothesis that brain damage will be qualitatively as well as quantitatively different when comparing alcohol exposure throughout gestation with exposure restricted to third trimester. The questions raised in this proposal have not yet been answered due in part to the lack of a suitable animal model system. The sheep model system has several distinct advantages that will be exploited in the proposed studies. These include: 1) the stages of brain development comparable to that which occurs throughout gestation in humans also occur entirely prenatally in the sheep; 2) a large maternal/fetal unit tolerant of chronic indwelling cannulae; and 3) a long gestation making it much easier to evaluate critical periods, threshold doses, and patterns of alcohol exposure. The most compelling reason for developing the ovine model system is that these advantages are particularly valuable for evaluating mechanisms of damage. Together, these studies will provide new, important data related to fetal alcohol exposure and brain damage that have not been addressed adequately with other animal model systems.