The key general objective of this proposal is a better understanding of the pathogenesis of the fetal alcohol syndrome (FAS). We will examine three aspects of this problem. First, we will determine whether ethanol inhibits the transfer of 2 key nutrients-zinc and biotin-across the human placenta. Deficiency of each of these nutrients in experimental animals is known to produce growth impairment and fetal malformation, hence, deficiency of either could contribute to FAS. There are virtually no data on normal transport of these substances by the human placenta and none on the effect of alcohol on this. Initially, we will define the normal characteristics of placental transport of these 2 substances. This will be done using the single perfused human placental cotyledon, isolated apical and basal human placental membrane vesicles, and cultured human placental trophoblast. The latter system permits longer (5 days) study. Having described normal transport, we will assess the effects of alcohol on transport of zinc and biotin. Second, cocaine ingestion too often accompanies ethanol consumption by pregnant women, and cocaine may impair fetal growth and development. To assess the potential for interaction between alcohol and cocaine in FAS we will study 3 aspects of cocaine handling in pregnancy. 1) We will initially determine the mechanism(s) by which cocaine crosses the human placenta and examine whether the tissue metabolizes this drug. 2) In as much as cocaine can suppress fetal liver growth, we will examine a possible mechanism: focusing on binding and processing of epidermal growth factor, an obligatory factor in the replication of these cells. The processing (internalization) of this factor is known to be impaired by ethanol. Now we will examine the role of cocaine and norcocaine (a known toxic metabolite) alone, as well as with ethanol, on EGF processing. These studies will be carried out in cultured rat fetal hepatocytes. 3) Cocaine commonly impairs adult cardiac function, but little is known about its effects on fetal heart. In rat fetal/neonatal cardiac myocytes in tissue culture we will correlate the effects of cocaine/norcocaine alone and with ethanol on heart contractility and 2 key processes-Ca++ influx and Na++ pump turnover. Finally, in pregnant monkeys we will assess, with Doppler ultrasound, the possibility that account may cause FAS by decreasing uterine/placental/fetal blood flow with resulting fetal hypoxia. These 3 approaches should contribute to better understanding of pathogenesis of FAS and the impact on the fetus of concomitant cocaine intake. FAS is a complex process, hence, the need for a comprehensive, multifactorial approach to its study.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA007514-07
Application #
3111240
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1987-05-01
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
7
Fiscal Year
1993
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
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Hamby-Mason, R; Chen, J J; Schenker, S et al. (1997) Catalase mediates acetaldehyde formation from ethanol in fetal and neonatal rat brain. Alcohol Clin Exp Res 21:1063-72
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Henderson, G I; Devi, B G; Perez, A et al. (1995) In utero ethanol exposure elicits oxidative stress in the rat fetus. Alcohol Clin Exp Res 19:714-20
Devi, B G; Henderson, G I; Frosto, T A et al. (1994) Effect of acute ethanol exposure on cultured fetal rat hepatocytes: relation to mitochondrial function. Alcohol Clin Exp Res 18:1436-42
Schenker, S; Bay, M (1994) Drug disposition and hepatotoxicity in the elderly. J Clin Gastroenterol 18:232-7
Hu, Z Q; Henderson, G I; Mock, D M et al. (1994) Biotin uptake by basolateral membrane vesicles of human placenta: normal characteristics and role of ethanol. Proc Soc Exp Biol Med 206:404-8
Schenker, S; Yang, Y; Johnson, R F et al. (1993) The transfer of cocaine and its metabolites across the term human placenta. Clin Pharmacol Ther 53:329-39
Schenker, S; Halff, G A (1993) Nutritional therapy in alcoholic liver disease. Semin Liver Dis 13:196-209
Devi, B G; Henderson, G I; Frosto, T A et al. (1993) Effect of ethanol on rat fetal hepatocytes: studies on cell replication, lipid peroxidation and glutathione. Hepatology 18:648-59

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