SODIUM VALPROATE-INDUCED CARDIOVASCULAR-ABNORMALITIES IN THE JCL ICR MOUSE FETUS - PEAK SENSITIVITY OF GESTATIONAL DAY AND DOSE-DEPENDENT EFFECT

Sodium valproate was administered to Jcl:ICR mice in order to determin e its effect on cardiovascular development. A single dose of 600 mg/kg of sodium valproate was injected intraperitoneally on gestational day s 6, 7, 8, or 9. In same animals, a single dose of 300, 400, 500, or 7 00 mg/kg was injected on gestational day 7. On day 18 of gestation, da ms were laparotomized to observe number of live, dead and resorbed fet uses. In addition, live fetuses were examined for cardiovascular abnor malities. Although cardiovascular abnormalities were noted in 3% of li ve fetuses and in 26% of litters in the group treated on day 6 (600 mg /kg), there was no significant difference from the control group, sugg ests that there may have been a biologically significant increase, alt hough not a statistically significant increase. Cardiovascular abnorma lities were found in 30%, 11%, and 8% of live fetuses in the groups tr eated with 600 mg/kg on days 7, 8, and 9, respectively. These represen ted a statistically significant increase in effects as opposed to the control groups. Among the varying dosages administered on day 7 of ges tation, cardiovascular abnormalities occurred in 2%, 6%, 16%, and 36% of live fetuses in groups treated with 300, 400, 500, and 700 mg/kg, r espectively, showing a significant dose-dependent increase. These card iovascular abnormalities observed were divided into the following grou ps: ventricular septal defect, endocardial cushion defect, transpositi on of the great arteries, double outlet right ventricle, tricuspid atr esia, and hypoplastic left heart syndrome. Maternal death did not occu r at any treatment level. (C) 1993 Wiley-Liss, Inc.