Modification of Radiation Effects on Fetal Mice: III. Reduction of Postnatal Mortality by Application of Sodium Orthovanadate and A Pan-Caspase Inhibitor After A High Dose (6.5Gy) of In Utero Exposure

Exploration of new mitigators, which could be effective if administered after accidental irradiation exposure before the appearance of overt biological consequences, is useful to improve the prognosis of victims as well as to develop more effective and safe clinical therapy. As the cell killing effect plays an important role in the postnatal death (bone marrow death) induced by a high dose fetal exposures (6.5Gy) in the very late fetal period of gestation, in this study combined post-irradiation application of anti-apoptosis reagents was tested as a strategy aiming at reduction of the postnatal mortality.<BR> Pregnant ICR mice were exposed to whole body X-irradiations on E18 at a dose of 6.5Gy and a dose rate of 1.8Gy/min, which could result in about 40% of death in the neonates before weaning. Sodium orthovanadate (Na₃VO₄, VD) at a dose of 15 mg/kg, or its combination with a pan-caspase inhibitor (Z-VAD) at a dose of 1 mg/mouse was intraperitoneally administrated to the pregnant mice 5 minutes after the irradiation. The dams were left for delivery and the neonates were monitored for postnatal survival and development (body weight). The hemogram of peripheral blood and bone marrow of femora in the young offspring (7 weeks old mice) were analyzed respectively with a blood cell differential automatic analyzer and the micronucleus test. Administration of VD alone significantly reduced the detrimental effect on postnatal survival and development, and combined application (VD+Z-VAD) showed a more statistically remarkable efficacy for some endpoints. These findings indicate that administration of combined anti-apoptosis agents would have a great possibility for clinical application in the future as a therapeutic treatment for high dose radiation exposure.<BR> This work was supported in part by a grant for a project of the Radiation Emergency Medical Preparedness by the NIRS.