FETAL ANEMIA FOLLOWING MATERNAL EXPOSURE TO 5-FLUOROURACIL IN THE RAT

Previous studies from our laboratory have shown that maternal 5-fluoro uracil (5-FU) exposure on day 14 of gestation (GD14) in the rat result s in dose-dependent retardation of both cell cycle progression and gro wth of embryonic liver. At this developmental stage, hepatic erythropo iesis is the primary source of new circulating fetal erythrocytes. Thi s study examined dose-dependent hematological changes in the fetus aft er maternal 5-FU exposure (0, 20, 30, 40 mg/kg on GD14) to assess 1) h ematopoiesis as a potential target for 5-FU developmental toxicity and 2) the role of the observed 5-FU-induced fetal anemia in adverse deve lopmental outcome. Standard clinical hematological parameters, includi ng hematocrit, hemoglobin content, and erythrocyte counts, were measur ed in fetal blood drawn by cardiac puncture. Dose-related deficits wer e observed in all of these parameters within 48 hr of 5-FU administrat ion. Calculation of various red cell indices revealed a concomitant in crease in mean cell volume and mean cell hemoglobin. These changes wer e preceded by depletion of hepatic precursor populations which was evi dent by 24 hr after maternal exposure to 30 or 40 mg/kg. At doses of 2 0 and 30 mg/kg there was full and moderate recovery, respectively, in these endpoints by 72 hr after dosing, but persistent deficits were ob served at 40 mg/kg. Fluorescence microscopy of Hoechst-stained fetal b lood smears revealed that at both 48 and 72 hr after dosing, the propo rtion of nucleated yolk sacderived erythrocytes was increased relative to control. These data suggest that inhibition of proliferation of he patic erythroid precursors by 5-FU results in depletion of these popul ations and subsequent deficiency of liver-derived reticulocytes in the fetal circulation, leading to fetal anemia. Since morphological chang es are detectable within embryonal target tissues (e.g., hind limb bud s) prior to the onset of significant hematological changes, fetal anem ia is not involved in the pathogenesis of 5-FU-induced malformations. However, the persistence of hematological deficits at 40 mg/kg was cor related with fetal growth retardation during late gestation, suggestin g that fetal anemia may be an important factor contributing to the dev elopmental toxicity of 5-FU. (C) 1994 Wiley-Liss, Inc.