Ethanol consumption during pregnancy is the single, most common known cause of congenital mental retardation. The mechanism of variance observed in fetal outcome may include variation in the enzymes responsible for maternal or fetal ethanol metabolism. Alcohol is metabolized by alcohol dehydrogenase (ADH) and by Cytochrome P450IIE1 to acetaldehyde which is metabolized by aldehyde dehydrogenase (ALDH) to acetate. For each enzyme, genetic and environmental influences are known. Genetic polymorphism at the ADH2 locus is critical because the resulting isoenzymes are over 30 fold different in their kinetic constants. Variation in the induction of Cytochrome P450IIE1 by chronic ethanol ingestion also appears important. In this project, we will test the hypotheses that maternal or offspring intersubject variation in ethanol metabolizing ability is a determinant of alcohol-related neurobehavioral birth defects. We hypothesize that presence of the ADH3 allele, in either the mother or the offspring, in combination with heavy alcohol intake, leads to an increased rate of ethanol elimination and an increased formation of acetaldehyde which may be more fetotoxic than ethanol. Women of known alcohol intake and ADH genotype will be selectively recruited to an ethanol/acetaldehyde kinetic study. Mothers will be recruited through the antenatal clinic on the basis of alcohol intake during pregnancy using epidemiologic screening tools tested by Sokol and in place as part of the WSU alcohol research center. Maternal and offspring ADH2 genotype will be determined by Li, who is internationally recognized for developing this methodology. The analytical methods for determination of ethanol and acetaldehyde concentrations have been developed by May, who has tested the proposed kinetic protocol in multiple subjects. Neurobehavioral infant outcome will be determined by Bayley scores at 12 months. The ability to identify high risk mother-infant pairs and the responsible mechanism(s) may lead to successful prevention strategies.
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