In utero growth retardation resulting from maternal ethanol consumption during pregnancy is a common birth defect observed in both human neonates and animal models. A significant deficiency in brain tissue associated with the growth retardation is correlated with a high incidence of mental retardation among the offspring of chronic alcoholic mothers. A variety of alcohol-induced alterations in maternal, placental, and fetal physiology have been proposed as the basis of this retarded growth, but the molecular mechanisms remain obscure. Using the embryonic chick as a model, which eliminates ethanol-induced changes in maternal and placental function, it is proposed to study the molecular mechanisms of ethanmol-induced inhibition of brain growth. Ongoing research on this model suggests that before day 9 of incubation and in the absence of measurable alcohol dehydrogenase activity, ethanol suppresses the rate of brain cell growth in a dose related manner. This retarded rate of cell division results in fewer brain cells for a given time of incubation. Preliminary data suggest that ethanol induced fetal brain hypoplasia is inversely correlated with ethanol mediated increases in fetal brain cycle AMP levels. Further, these preliminary studies suggest that pharmacological inhibition of prostaglandin biosynthesis reverses the ethanol induced growth suppression. Using biochemical assays, radioimmune assays and pharmacological dosing with chemical analogues or synthesis inhibitors, the proposed research will attempt to verify these observations and to determine if they represent part of the molecular mechanism underlying brain growth suppression. It is proposed that a knowledge of the molecular mechanism involved in the growth retardation will allow a scientific determination of whether there exists a safe time period or safe level for the consumption of ethanol during pregnancy. Further, because certain children will remain at risk for ethanol exposure due to maternal addiction, prevention of mental retardation in these individuals must depend on an understanding of the molecular mechanism(s) responsible for this condition.
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