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 Höechst-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.(ABSTRACT TRUNCATED AT 250 WORDS)
Shuey
D L
DL
Curriculum in Toxicology, University of North Carolina, Chapel Hill.
Zucker
R M
RM
Elstein
K H
KH
Rogers
J M
JM
D000740:Anemia / Q000139:chemically induced* / Q000196:embryology; D000818:Animals; D005314:Embryonic and Fetal Development / Q000187:drug effects; D004920:Erythropoiesis / Q000187:drug effects; D005260:Female; D005315:Fetal Diseases / Q000139:chemically induced*; D005472:Fluorouracil / Q000633:toxicity*; D006411:Hematopoiesis, Extramedullary / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000473:pathology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens / Q000633:toxicity*
D013723:Teratogens; D005472:Fluorouracil