Early events following maternal exposure to 5-fluorouracil lead to dysmorphology in cultured embryonic tissues.

The chemotherapeutic agent 5-fluorouracil (5-FU) is teratogenic in a number of species, yet the mechanism(s) of its developmental toxicity are not fully understood. Administration of 5-FU to the pregnant CD rat on day 14 of gestation results in dose-dependent growth retardation and numerous malformations in near-term fetuses, including hindlimb defects and cleft palate. Following treatment, a number of rapid biochemical and cellular alterations are detectable in embryonic hindlimbs, craniofacial and other tissues, which include thymidylate synthetase (TS) inhibition and altered cell cycle progression. In order to assess the importance of these early events in 5-FU-induced dysmorphogenesis, embryonic mid-facial tissues and hindlimbs were dissected 3 or 6 hr after administration of 5-FU to the dam and placed in explant culture. After 5 days in culture, craniofacial explants were evaluated morphologically for palatal closure and growth was assessed by measuring total protein and DNA content. Hindlimb explants were stained for cartilage using alcian blue to evaluate development of the digits. Craniofacial explants cultured at either 3 or 6 hr after exposure exhibited dose-dependent growth retardation and defects of palatal fusion at the end of the culture period. Deficits in protein and DNA content were similar to those in craniofacial tissues that continued to develop in utero after treatment, although morphological defects in cultured explants did not correlate well with the incidence of cleft palate in vivo. Dose-dependent deficits in metatarsal and phalanx development were observed in hindlimb explants dissected either 3 or 6 hr after maternal treatment.(ABSTRACT TRUNCATED AT 250 WORDS)