Cyclophosphamide Teratogenesis: Evidence for Compensatory Responses to InducedCellular Toxicity

摘要

Cyclophosphamide (CP) administered ip to pregnant mice on day 10 of gestationcauses severe malformations at 20 mg/kg and is embryolethal at higher doses. In the present study, CP was administered at 1, 5, 10 or 20 mg/kg. Embryos were removed at 8 and 28 hrs post dosing for immediate staining with Nile Blue sulfate to identify areas of cell death. Forelimb buds of other embryos were removed for flow cytometric analyses. Additional litters were examined at term for malformations. Although only the highest dose produced malformations, a dose-related increase in the percentage of limb bud cells in S phase block was detectable at all doses at 8 hours post exposure and persisted through 28 hours for doses equal to or > 10 mg/kg. Nile Blue sulfate staining showed increased cell death in the limb buds 28 hours after exposure to 10 mg/kg CP, or higher. The cell death was most pronounced in areas of rapid cell proliferation. The absence of an obvious teratogenic response at dose levels that produced significant cellular toxicity indicates that a measure of embryonic damage can be repaired and/or compensated. The implications of these findings for the existence of thresholds in developmental toxicity are discussed.