FETAL ALCOHOL SYNDROME ROLE OF PLACENTAL DYSFUNCTION

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Clinical studies and those in experimental animals have shown that maternal ethanol consumption, especially in large amounts, may exert toxic effects on the fetus and neonate. In man these toxic effects of ethanol are manifested in the Fetal Alcohol Syndrome (FAS), while in animals a spectrum of growth and developmental abnormalities may be seens. The mechanism(s) of these fetotoxic effects of ethanol is still uncertain. Likewise, the possible roles of acetaldehyde (ethanol metabolite) and of caffeine and nicotine are unknown. It is well appreciated, however, that alcoholics (including pregnant ones) tend to consume much coffee and smoke heavily and that both caffeine and nicotine per se may have deleterious effects on the fetus. The general aims of this application are to assess the individual and combined effects of ethanol, acetaldehyde, caffeine and nicotine on the viability, growth and development of the fetus. More specifically we wish to test the hypothesis (derived from extensive studies in our unit and those of others) that ethanol and/or acetaldehyde and perhaps caffeing and nicotine may impair placental transport of vital nutrients. This, if documented further may explain at least partly, fetal dysfunction with alcoholism and may apply also to nutrient uptake by other, especially fetal, tissues. To investigate this hypothesis we will assess the uptake of selected amino acids by rat and human placenta after various types of exposure to ethanol, acetaldehyde, cafeine and nicotine alone and in combination. In the rat placenta studies, pregnant rats will be given ethanol acutely or chronically with or without caffeine or nicotine and placental amino acid transport will be studied in vivo after injection of the labelled nutrient or subsequent in vitro after removal of the placenta. In both the rat and human placental studies, the tissue also will be exposed in vitro to ethanol, acetaldehyde, caffine and nicotine (singly and in combination) and amino acid transport will be determined. The mechanism(s) of any observed changes will be studied in terms of Na-dependence, energy requirements, structural changes and/or alterations of membrane lipid composition, fluidity and Na+-K+ ATPase activity. Similar studies will be carried out with fetal tissues. We hope to establish thus one mechanisms contributing to enthanol-induced fetal dysfunction, to assess the role(s) of acetaldehyde, caffeine and nicotine in this, and perhaps to define a more general effect of enthanol on tissue membrane transport.