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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA007284-08
Application #
2043791
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1987-08-01
Project End
1995-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
8
Fiscal Year
1994
Total Cost
Indirect Cost
Name
North Shore University Hospital
Department
Type
DUNS #
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Divald, A; Karl, P I; Fisher, S E (2002) Regulation of phospholipase D in human placental trophoblasts by the P(2) purinergic receptor. Placenta 23:584-93
Karl, P I; Fisher, S E (1994) Chronic ethanol exposure inhibits insulin and IGF-1 stimulated amino acid uptake in cultured human placental trophoblasts. Alcohol Clin Exp Res 18:942-6
Karl, P I; Divald, A; Fisher, S E (1994) Ethanol enhancement of ligand-stimulated cAMP production by cultured human placental trophoblasts. Biochem Pharmacol 48:1493-500
Karl, P I; Fisher, S E (1993) Ethanol alters hormone production in cultured human placental trophoblasts. Alcohol Clin Exp Res 17:816-21
Karl, P I; Fisher, S E (1992) Biotin transport in microvillous membrane vesicles, cultured trophoblasts, and isolated perfused human placenta. Am J Physiol 262:C302-8
Karl, P I; Alpy, K L; Fisher, S E (1992) Amino acid transport by the cultured human placental trophoblast: effect of insulin on AIB transport. Am J Physiol 262:C834-9
Karl, P I; Alpy, K L; Fisher, S E (1992) Serial enzymatic digestion method for isolation of human placental trophoblasts. Placenta 13:385-7
Karl, P I; Teichberg, S; Fisher, S E (1991) Na(+)-dependent amino acid uptake by human placental microvillous membrane vesicles: importance of storage conditions and preservation of cytoskeletal elements. Placenta 12:239-50
Fisher, S E; Karl, P I (1990) Histidine transfer across the human placenta: characteristics in the isolated perfused human placenta and the effect of ethanol. Placenta 11:157-65
Karl, P I; Fisher, S E (1990) Taurine transport by microvillous membrane vesicles and the perfused cotyledon of the human placenta. Am J Physiol 258:C443-51

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