Zidovudine-associated embryonic toxicity in mice

A novel toxicity associated with zidovudine (AZT), the standard antiviral therapy for infection with human immunodeficiency virus, is described. When AZT was administered to mice to evaluate its safety during gestation, the animals failed to complete pregnancy successfully. Mice receiving AZT during gestation yielded fewer fetuses (P = .003) and greater numbers of resorptions (P = .003) per pregnant mouse compared with untreated animals. Drug effects on adult mice were assessed to determine if toxicity could account for the pregnancy failures. However, adult animals receiving AZT demonstrated no adverse effects with regard to growth, food consumption, activity, or ovarian histology. A direct toxic effect of AZT on the mouse embryo was tested by cultivating single-cell fertilized oocytes in vitro in the presence of increasing concentrations of drug. Exposure to AZT was highly correlated with failure to develop to the blastocyst stage (P less than .001). These data indicate that AZT has a direct toxic effect on the developing mouse embryo. Further analysis of the nature of this toxicity may be important in designing less toxic antiretroviral agents and in planning future uses of AZT.