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Aspirin-alcohol interaction in the production of cleft palate and limb malformations in the TO mouse.

Our objective in the present study was to determine the effects of alcohol on stages when the limb buds and renal primordia develop in the TO mouse and to see if aspirin pretreatment would prevent these organ systems from being malformed as was shown by Randall et al. ('91) in the C57 mice. On one of days 9-12 of gestation, groups of TO mice were injected intraperitoneally (IP) with a single dose of 200 mg/kg of aspirin, or a proportionate volume of physiological saline. An hour later, half of the aspirin-treated animals received a single dose of 0.03 ml/g of freshly prepared 25% (v/v) solution of absolute alcohol and the other half received a proportionate volume of saline. Half of the saline-treated animals received a single dose of 0.03 ml/g of saline or a proportionate volume of alcohol solution. All animals were killed on day 18 of gestation. Alcohol significantly increased embryonic resorption and caused remarkable intrauterine growth retardation (IUGR). It also induced arched palate, cleft palate and deformities of the digits with haematomas in a modest number of embryos. Aspirin alone did not have any teratogenic effects. Pretreatment with aspirin significantly augmented alcohol-induced resorption, IUGR, cleft palate and digital malformations associated with haematomas. Chronological observations on the development of the treated limbs showed the occurrence of vascular stasis, haematomas, edema and cell death at early stages. Subsequently, digital rays were either destroyed (ectrodactyly) or remained hypoplastic (brachydactyly). It appears that limb development in the aspirin- and alcohol-treated TO mouse embryos is largely affected by vascular disruption. These data provide further evidence to our earlier observation that alcohol and aspirin interact in the production of malformations and that the teratogenic effects of alcohol in the TO mouse are possibly not mediated via treatment related prostaglandin elevation.