Maternal antioxidant supplementation does not reduce the incidence of phenytoin-induced cleft lip and related malformations in rats

There is considerable evidence that phenytoin‐induced birth defects in the rat are a consequence of a period of bradycardia and hypoxia in the embryos. Experiments were designed to test the hypothesis that phenytoin‐induced birth defects result from free‐radical damage to the embryos during the reox...

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Published in:	Birth defects research. Part B. Developmental and reproductive toxicology Vol. 74; no. 2; pp. 201 - 206
Main Authors:	Abela, Dominique, Howe, Andrew M., Oakes, Diana A., Webster, William S.
Format:	Journal Article
Language:	English
Published:	Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-04-2005 Wiley-Liss
Subjects:	Abnormalities, Drug-Induced - prevention & control Animals Anticonvulsants - toxicity antioxidants Antioxidants - administration & dosage Ascorbic Acid - administration & dosage Biological and medical sciences Body Weight - drug effects cleft lip Cleft Lip - chemically induced Cleft Lip - pathology Cleft Lip - prevention & control Coenzymes Diet Eating - drug effects Embryology: invertebrates and vertebrates. Teratology Female free radicals Fundamental and applied biological sciences. Psychology hypoxia Male Maxilla - abnormalities Maxilla - drug effects phenytoin Phenytoin - toxicity Pregnancy Rats Rats, Sprague-Dawley reoxygenation Teratogens - toxicity Teratology. Teratogens Ubiquinone - administration & dosage Ubiquinone - analogs & derivatives Vitamin E - administration & dosage Oxygen free radicals Cleft lip Rat Stomatology antioxidants Rodentia Anticonvulsant Congenital cleft Antioxidant reoxygenation Congenital disease Free radical Incidence Vertebrata Mammalia Mother Malformation Animal Hypoxia Oral cavity disease Supplementation Phenytoin
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Summary:	There is considerable evidence that phenytoin‐induced birth defects in the rat are a consequence of a period of bradycardia and hypoxia in the embryos. Experiments were designed to test the hypothesis that phenytoin‐induced birth defects result from free‐radical damage to the embryos during the reoxygenation period posthypoxia. Female rats (>9 per group) were fed either a control diet or a diet high in antioxidants (vitamins C and E and coenzyme Q10) both before and during pregnancy and were then given a teratogenic dose of phenytoin (180 mg/kg) on GD 11. The rats were killed on GD 20 and the fetuses were examined for malformations. The initial results showed that the antioxidant diet had a significant protective effect, with far fewer antioxidant‐group fetuses showing cleft lip or maxillary hypoplasia compared with the control group. However, this result was confounded by reduced food intake by the rats fed the antioxidant diet and a significantly lower maternal body weight at the time of phenytoin administration. Since the phenytoin was administered by intraperitoneal injection (i.p.) the control rats received higher absolute doses of phenytoin and it is speculated that this results in higher fetal exposure. A second experiment, in which the rats were pair‐fed, failed to demonstrate any protective effect of the high antioxidant diet. These results do not support the reoxygenation hypothesis for phenytoin teratogenesis. An alternative explanation would be hypoxia‐induced transcription‐related changes resulting in cell cycle arrest and apoptosis. Birth Defects Res B 74:201–206, 2005. © 2005 Wiley‐Liss, Inc.
Bibliography:	Australian Dental Research Foundation ark:/67375/WNG-STCJBPJM-R istex:27A135F0E07676B14A8DDE0A3178ADE98CBD1F10 ArticleID:BDRB20037 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1542-9733 1542-9741
DOI:	10.1002/bdrb.20037