Ethanol can cause serious fetal abnormalities, including intrauterine growth retardation (IUGR), microcephaly and mental retardation. While ethanol may be directly toxic to the fetus, it may also injure the placenta. The placenta is the sole conduit for fetus' supply of nutrients critical to normal growth and development. It is postulated that the placenta plays an important role in ethanol- related fetal injury through: (1) ethanol-associated impairment of placental function, thereby restricting placental transfer of nutrients and production of hormones essential to fetal growth and (2) placental production and transfer of acetaldehyde, thereby exposing both the fetus and the placenta to additional injury. One objective is to characterize the effects of ethanol or ethanol plus acetaldehyde upon human placental transport of nutrients: amino acids, glucose, vitamins (thiamine, riboflavin), zinc. The influence of ethanol upon placental stimulation of fetal growth and maintenance of an adequate maternal supply of glucose and amino acids will be assessed by measuring placental synthesis of growth hormone releasing factor and human placental lactogen. Models for studying ethanol-related impairment of placental function will include the human isolated perfused placental cotyledon and human placental membrane vesicles. Nutrient transport, hormone synthesis and membrane fluidity changes will be studied with respect to different ethanol doses, at levels achievable in humans. Animals will be used to study chronic effects under controlled conditions, although placentae from chronic alcoholic humans will be obtained for evaluation. The second objective is to identify the extent to which the placenta produces the toxic metabolite of ethanol, acetaldehyde, and the extent to which it transfers maternal blood acetaldehyde to the fetal circulation. Placental metabolism of ethanol will be assessed under intact organ conditions (perfused placenta) and by biochemical analysis. Placental production of acetaldehyde may be a compounding factor in the pathogenesis of ethanol-induced placento-toxicity as well as feto-toxicity. With improved definition of the effects of ethanol upon several parameters of placental function, it should be possible to better understand the pathophysiology of some of the clinical manifestations of ethanol upon several parameters of placental function, it should be possible to better understand the pathophysiology of some of the clinics manifestations of ethanol- related injury, such as IUGR and mental retardation. The use of modest and high physiologic ethanol levels in the experiments, plus the extensive use of human tissue should make the findings more pertinent to the human circumstance.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA007284-03
Application #
3111029
Study Section
Alcohol Biomedical Research Review Committee (ALCB)
Project Start
1987-08-01
Project End
1990-07-31
Budget Start
1989-08-01
Budget End
1990-07-31
Support Year
3
Fiscal Year
1989
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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