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CYCLOPHOSPHAMIDE TERATOGENESIS: EVIDENCE FOR COMPENSATORY RESPONSES TO INDUCED CELLULAR TOXICITY
Citation:
Francis, B., J. Rogers, K. Sulik, A. Alles, K. Elstein, R. Zucker, E. Massaro, M. Rosen, AND N. Chernoff. CYCLOPHOSPHAMIDE TERATOGENESIS: EVIDENCE FOR COMPENSATORY RESPONSES TO INDUCED CELLULAR TOXICITY. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-90/352 (NTIS PB91163667).
Description:
Cyclophosphamide (CP) administered ip to pregnant mice on day 10 og gestation causes severe malformations at 20 mg/kg and is embryolethal at higher doses. n the present study, CP was administered at 1, 5, 10 or 20 mg/kg. mbryos were removed at 8 and 28 hrs post dosing for immediate staining with Nile Blue sulfate to identify areas of cell death. orelimb buds of other embryos were removed for low cytometric analyses. dditional litters were examined at term for malformations. lthough 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 > 10 mg/kg. ile Blue sulfate staining showed increased cell death in the limb buds 28 hours after exposure to 10 mg/kg CP, or higher. he cell death was most pronounced in areas of rapid cell proliferation. he 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. he implications of these findings for the existence of thresholds in developmental toxicity are discussed.