Fluorodeoxyuridine-induced malformations in mice. Studies on the early stages of teratogenesis.

At different stages of gestation, 104 mice were treated with fluorodeoxyuridine (FUDR). 34 pregnant mice served as controls. The experimental mice were examined at varying intervals after the FUDR injection. At term, the young exhibited the malformations of the limbs and skull so well-known after administration of FUDR. In addition, there was an increased number of resorptions. 24 hours after the injection on the 9th—12th day of gestation, vascular dilatations and fresh haemorrhages were found at the sites of predilection of malformations. Foetuses removed 2 or more days after the injections showed characteristic, saccular haematomas in the limbs and tail as well as flat, widespread haematomas in the skull. At increasing intervals after the injections, the haematomas decreased in number and were rarely present in foetuses at term. As the number of haematomas decreased, the number of malformations increased. Daily laparotomies, from the 12th to the 18th day, on 5 mice treated on the 11th day with FUDR revealed extremity haematomas which disappeared on the 13th—18th day. Electron microscopic pilot studies of 2 foetal limbs showed, 24 hours after the injection of FUDR, red blood cells in an extra-vascular situation. The control mice had 354 normal foetuses and 8 per cent spontaneous resorptions. This study, which was a screening experiment, showed that FUDR induces vascular injury with haemorrhages and formation of haematomas, resulting in congenital malformations. The vascular injuries are interpreted as the primary action of FUDR on the cellular level.