Intrauterine growth retardation and diminished brain growth with mental retardation are hallmarks of fetal alcohol syndrome. While ethanol may be directly toxic to the fetus, it may also be placento-toxic. The placenta is critical to normal fetal growth and development. Ethanol-induced placental toxicity would restrict the fetal supply of essential nutrients, thereby contributing to the pathophysiology of alcohol related fetal injury. We postulate that: (1) ethanol interferes with hormone-stimulated placental amino acid uptake, (2) in drinking women, chronic alcohol use impairs both hormone-stimulated and non-stimulated placental amino acid transport; (3) ethanol-induced inhibition of amino acid uptake in the human placenta results from decreased cAMP production and/or enhanced protein kinase C activity. Utilizing cultured human trophoblasts, the effect of ethanol exposure duration and dose on hormone-stimulated amino acid uptake will be evaluated. In addition, changes in hormone-stimulated uptake kinetics, hormone-receptor interaction, Na+, K+-ATPase activity and Na+/H+ exchange will be assessed in cultured trophoblasts and membrane vesicles prepared from the placentae of women who have ingested ethanol throughout pregnancy, but did not smoke. Hormone-stimulated and non-stimulated amino acid uptake will be measured. The third objective is to evaluate two potential mechanisms for ethanol effects on hormone-stimulated amino acid uptake: cAMP production and PKC translocation and activity. The results of the proposed studies should enhance our understanding of the role of ethanol-induced placental toxicity in the pathophysiology of ethanol- associated fetal injury.
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