Effects of buthionine sulfoximine on the outcome of the in utero administration of alcohol on fetal development.
The adverse effects of the maternal consumption of alcohol on the fetus have been recognized for centuries. Fetal alcohol syndrome is characterized by pre- and postnatal growth retardation, mental retardation, behavioral deficits, and facial deformities. Despite numerous animal studies, the biochemical mechanism(s) by which alcohol produces teratogenic effects on the developing fetus are not well understood. Several studies have shown that administration of alcohol to adult rats produces a decrease in hepatic levels of glutathione (GSH). In utero administration of alcohol has also been shown to produce a decrease in GSH levels, as well as prenatal growth retardation and intrauterine death. In an effort to determine if GSH may have a vital role in protecting the fetus against the teratogenic effects of alcohol, buthionine (SR)-sulfoximine (BSO) was used to deplete GSH levels in the mother and fetus. Timed pregnant Sprague-Dawley rats were placed on a liquid BioServ diet containing either 0%, 11%, 23%, 29%, 31%, 33%, or 35% ethanol-derived calories, with or without BSO (888 mg/kg/24 hr), starting on day 1 of pregnancy. Another set of mothers were fed lab chow and water as a control group for the liquid diet. The mothers were maintained on the diet until gestation day 21 when they were anesthetized with sodium pentobarbital and the pups delivered by cesarean section. The offspring were counted, weighed, killed, and the brain and liver weighed. The effects of BSO on the alcohol dose-response curves (body weights, brain weights, and litter number) were then determined to ascertain if a depletion in GSH potentiated the effects of alcohol. In utero administration of BSO, aside from the depletion of GSH in the liver and brain in the developing fetus, produced a shift to the left in the alcohol dose-response curve.
Department of Pharmacology, University of New Mexico, School of Medicine, Albuquerque 87131-5316, USA.
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D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D002531:Cerebellum / Q000196:embryology; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D000431:Ethanol / Q000493:pharmacokinetics; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000196:embryology*; D005978:Glutathione / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D000963:Antimetabolites; D000431:Ethanol; D019328:Buthionine Sulfoximine; D010751:Phosphopyruvate Hydratase; D005978:Glutathione