Fetal anemia following maternal exposure to 5-fluorouracil in the rat

Previous studies from our laboratory have shown that maternal 5‐fluorouracil (5‐FU) exposure on day 14 of gestation (GD14) in the rat results in dose‐dependent retardation of both cell cycle progression and growth of embryonic liver. At this developmental stage, hepatic erythropoiesis is the primary source of new circulating fetal erythrocytes. This study examined dose‐dependent hematological changes in the fetus after maternal 5‐FU exposure (0, 20, 30, 40 mg/kg on GD14) to assess 1) hematopoiesis as a potential target for 5‐FU developmental toxicity and 2) the role of the observed 5‐FU‐induced fetal anemia in adverse developmental outcome. Standard clinical hematological parameters, including hematocrit, hemoglobin content, and erythrocyte counts, were measured in fetal blood drawn by cardiac puncture. Dose‐related deficits were observed in all of these parameters within 48 hr of 5‐FU administration. Calculation of various red cell indices revealed a concomitant increase in mean cell volume and mean cell hemoglobin. These changes were preceded by depletion of hepatic precursor populations which was evident by 24 hr after maternal exposure to 30 or 40 mg/kg. At doses of 20 and 30 mg/kg there was full and moderate recovery, respectively, in these endpoints by 72 hr after dosing, but persistent deficits were observed at 40 mg/kg. Fluorescence microscopy of Hoechst‐stained fetal blood smears revealed that at both 48 and 72 hr after dosing, the proportion of nucleated yolk sac‐derived erythrocytes was increased relative to control. These 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., hind limb buds) prior to the onset of significant hematological changes, fetal anemia is not involved in the pathogenesis of 5‐FU‐induced malformations. However, the persistence of hematological deficits at 40 mg/kg was correlated with fetal growth retardation during late gestation, suggesting that fetal anemia may be an important factor contributing to the developmental toxicity of 5‐FU. c 1994 Wiley‐Liss, Inc. This article is a US Government work and, as such, is in the public domain in the United States of America.