The in vitro embryotoxicity of 5-fluorouracil in rat embryos

The fluorinated pyrimidine 5-fluorouracil (5-FU) is an effective chemotherapeutic agent that is teratogenic in a number of species. The mechanism for the embryopathic effect of the drug is unknown. We examined the effects of this compound on gestation day 10.5 rat embryos cultured for 48 hours in a rodent whole embryo culture system. Embryos were exposed for 1-4 hours to various doses of 5-FU. Embryolethality was minimal in all treatment groups. The malformation frequency increased with higher doses; within a dose, the malformation frequency increased with longer exposure to the drug. The tail and hindlimb bud were the most commonly affected structures in vitro; tail and leg defects are produced in several species by exposure to the drug in vivo. The embryopathic drug concentration in the culture media (2-8 micrograms/ml) is similar to the plasma level of 2-17 micrograms/ml, which is associated with embryopathy in vivo. Results from this study suggest that the whole embryo culture system is an appropriate model for developmental toxicity studies of 5-FU.