Alcohol abuse during pregnancy is one of the most prevalent and preventable known causes of mental retardation in the United States. Neuroteratogenic effects of alcohol appear to occur during the first trimester of pregnancy, at a time when neuronal generation, migration and process formation formation are most dynamic. These observations imply that alcohol influences the interaction of developing neurons with cellular and cellular matrices of growth. The hypothesis to be tested in the present proposal is that some of the neuroteratogenic effects of alcohol can be explained by influences on molecular species that subserve the interaction of neurons with their environment in early development. The molecular basis of ethanol effects on developing neurons is beginning to be elucidated. In the presence of ethanol neurons produce less substrate-attached neurite promoting activity (SANPA). Some of this reduced activity can be accounted for by quantitative changes in a 170 kDa species. This neurite promoting factor will be further characterized by 2 D gel electrophoresis, lectin binding, and amino terminal sequencing. The possibility that neuronal synthesis and release of proteoglycans is influenced by ethanol will be investigated both by biochemical methods (eg. cellulose acetate electrophoresis and HPLC) and by bioassay. Experiments to analyze the influence of ethanol on the expression of neuronal receptors for diffusible (NGF) and immobilized (laminin) neurite promoting factors are planned. The effects of ethanol on neuronal cytoskeletal changes will be studied directly with specific antibodies and ELISA systems. The parameters that determine reversibility of adverse effects of ethanol and the molecular basis of the reversible effects will be explored. Further manipulation of the culture environment may provide clues as to how the developing nervous system might be protected from the effects of maternal alcohol consumption. As increased knowledge of the mechanisms of ethanol neuroteratogenesis is acquired, public awareness of the problem should be heightened and increased awareness may itself be an important aspect of prevention.
