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 alc ohol on stages when the limb buds and renal primordia develop in the T O mouse and to see if aspirin pretreatment would prevent these organ s ystems from being malformed as was shown by Randall et al. ('91) in th e C57 mice. On one of days 9-12 of gestation, groups of TO mice were i njected intraperitoneally (IP) with a single dose of 200 mg/kg of aspi rin, 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 sali ne-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 d ay 18 of gestation. Alcohol significantly increased embryonic resorpti on and caused remarkable intrauterine growth retardation (IUGR). It al so induced arched palate, cleft palate and deformities of the digits w ith haematomas in a modest number of embryos. Aspirin alone did not ha ve any teratogenic effects. Pretreatment with aspirin significantly au gmented alcohol-induced resorption, IUGR, cleft palate and digital mal formations associated with haematomas. Chronological observations on t he 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 hypopl astic (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 observ ation that alcohol and aspirin interact in the production of malformat ions and that the teratogenic effects of alcohol in the TO mouse are p ossibly not mediated via treatment related prostaglandin elevation. (C ) 1995 Wiley-Liss, Inc.