Ethanol inhibits cell adhesion mediated by the L1 cell adhesion molecule in neural cells and fibroblasts transfected with human L1. Because the brains of children with L1 mutations resemble those of children with fetal alcohol syndrome, it is possible that inhibition of L1-mediated cell adhesion contributes to the teratogenic effects of ETOH. Structure activity analysis of a series of straight and branch-chain alcohols demonstrates remarkable structural specificity for alcohol inhibition of cell-cell adhesion. Moreover, we have identified a series of compounds that antagonize the effects of ethanol on L1-mediated cell-cell adhesion, on BMP morphogenesis in cultured neural cells, and on the development of mouse whole embryo cultures. The underlying hypothesis of this proposal is that compounds that antagonize ethanol inhibition of L1-mediated cell-cell adhesion will also antagonize ethanol teratogenesis. The proposed research has three specific aims: 1. To identify the structural determinants of alcohols and related compounds that are required for inhibition of cell-cell adhesion in L1-expressing cells and for antagonism of this inhibition; 2. To characterize regions of L1 that are necessary for alcohol inhibition and for antagonism of ethanol inhibition; 3. To evaluate selective ethanol antagonists for their ability to prevent the teratogenic effects of ethanol in mouse whole embryo culture and during early embryogenesis in C57BL/6J mice. Techniques employed in these studies will include mammalian cell transfection, cell-aggregation assays, mutagenesis of the L1 molecule, mouse whole embryo culture, and macroscopic and microscopic analysis of mice exposed to ethanol in utero. These experiments may lead to a better understanding of how ethanol interacts with neural proteins and may reveal mechanisms whereby ethanol causes birth defects. A major goal of the proposed research is to identify compounds that reduce the teratogenic effects of ethanol.
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