Effects of cyclophosphamide on embryonic development in the rabbit

Abstract

Groups of pregnant rabbits were given cyclophasphamide (Endoxan Asta^®) in single intravenous doses of 30 mg/kg on different days from the 6th day to the 14th day of gestation. On the 28th day (shortly before term) the foetuses were removed by caesarean section. Administration of cyclophosphamide about the time of implantation led to an increase in the number of early embryonic deaths. Injection of cyclophosphamide at the later stages resulted in an increased number of foetal deaths. About 10% of the foetuses from dams treated on the 7th day of pregnancy exhibited malformations, in particular disturbances of ventral closure. When cyclophosphamide was administered on the 11th day of pregnancy more than 30% of the foetuses were found to have median cleft palates and other malformations of jaws and lips. All the foetuses from dams treated on the 12th day showed oligodactylia and brachydactylia. The latter type of malformation was also present when treatment was given on the 13th day. The embryotoxic effect of cyclophosphamide administration was particularly evident in the early periods of embryonic development. In contrast, the teratogenic action was more confined to the later periods of organogenesis. Teratogenicity occurred in two peaks corresponding to characteristic ‘phaenocritical’ phases of development. The first and lower peak coincided with the period of histiotrophic nutrition and the second and higher peak corresponded to the heamotrophic phase. It is concluded that embryotoxicity and teratogenicity are largely independent phenomena.