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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA005814-04
Application #
3109100
Study Section
(SRC)
Project Start
1982-07-01
Project End
1987-04-30
Budget Start
1985-05-01
Budget End
1986-04-30
Support Year
4
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Henderson, G I; Frosto, T A; Heitman, D W et al. (1989) Ethanol stimulates leucine uptake by rat fetal hepatocytes via trans-stimulation. Am J Physiol 256:G384-9
Henderson, G I; Baskin, G S; Horbach, J et al. (1989) Arrest of epidermal growth factor-dependent growth in fetal hepatocytes after ethanol exposure. J Clin Invest 84:1287-94
Schenker, S; Johnson, R F; Hays, S E et al. (1989) Effects of nicotine and nicotine/ethanol on human placental amino acids transfer. Alcohol 6:289-96
McCall, D; Henderson, G I; Gray, P et al. (1989) Ethanol effects on active Na+ and K+ transport in cultured fetal rat hepatocytes. Biochem Pharmacol 38:2593-600
Schenker, S; Dicke, J M; Johnson, R F et al. (1989) Effect of ethanol on human placental transport of model amino acids and glucose. Alcohol Clin Exp Res 13:112-9
Muhoberac, B B; Hanew, T; Halter, S et al. (1989) A model of cytochrome P-450-centered hepatic dysfunction in drug metabolism induced by cobalt-protoporphyrin administration. Biochem Pharmacol 38:4103-13
Heitman, D W; Frosto, T A; Schenker, S et al. (1987) Stimulatory effects of ethanol on amino acid transport by rat fetal hepatocytes. Hepatology 7:307-14
Schenker, S; Dicke, J; Johnson, R F et al. (1987) Human placental transport of cimetidine. J Clin Invest 80:1428-34
Henderson, G I; Heitman, D W; Schenker, S (1987) Effects of ethanol on rat placental and fetal hepatocyte transport of amino acids. Ann N Y Acad Sci 492:224-32
Henderson, G; Secor, J; Heitman, D et al. (1986) Effects of age and sex on the hepatic monoxygenase system: a correlative approach. Dev Pharmacol Ther 9:201-16

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