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FETAL ANEMIA FOLLOWING MATERNAL EXPOSURE TO 5-FLUOROURACIL IN THE RAT
Citation:
Shuey, D., R. Zucker, K. Elstein, AND J. Rogers. FETAL ANEMIA FOLLOWING MATERNAL EXPOSURE TO 5-FLUOROURACIL IN THE RAT. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-95/043.
Description:
This study examined dose-dependent changes in fetal hematology after maternal 5-FU exposure (0, 20, 30, 40 mg/kg on GD14) to assess 1) hematopoiesis as a potential target for its developmental toxicity, and 2) the significance of the resultant fetal anemia to developmental outcome. tandard clinical hematological parameters, including hematocrit, hemoglobin content, and erythrocyte counts were measured. ose-related deficits were observed in all of these parameters within 48 hr of 5-FU administration. alculation of various red cell indices revealed a concomitant increase in mean cell volume and mean cell hemoglobin. hese changes were preceded by depletion of hepatic precursor populations at 24 hr after exposure to 30 or 40 mg/kg. t doses of 20 and 30 mg/kg there was full to moderate recovery, respectively, in these endpoints by 72 hr after dosing, but persistent deficits were observed at 40 mg/kg. luorescence microscopy revealed that at both 48 and 72 hr after dosing, the proportion of nucleated yolk sac-derived erythrocytes was increased relative to control. hese data suggest that inhibition of proliferation of hepatic erythroid precursors by 5-FU results in depletion of these populations and subsequent deficiency of liver-derived reticulocytes in the fetal circulation, leading to fetal anemia. Since morphological changes are detectable within embryonal target tissues (e.g., hindlimb buds) prior to the onset of significant hematological changes, fetal anemia is probably not involved in the pathogenesis of 5-FU induced malformations. owever, the persistence of hematological deficits at 40 mg/kg was cot elated with fetal growth retardation during late gestation, suggesting that fetal anemia is an important factor contributing to the developmental toxicity of 5-FU.