Cyclophosphamide in the male rat: cerebral biochemical changes in progeny.

Adult male Wistar rats were treated with cyclophosphamide either alone or with both cyclophosphamide and vinblastine. They were then mated with virgin non-treated females. Examination of their offspring showed an increased post-natal mortality rate; and diminished learning capacity and spontaneous activity in the adults. These disorders were also found in the second generation, resulting from mating between animals of the first generation. Biochemical analyses of the brains of the offspring of treated males in the first and second generations showed a diminished activity of hippocampal choline acetyl-transferase. Moreover, the second generation showed a diminution of fronto-parietal cortex norepinephrine. These biochemical results may correspond to the observed behavioral deficits. Furthermore, by studying experimental mutation, they add to our knowledge of the consequences of certain cytostatic treatments.

Cyclophosphamide in the male rat: new pattern of anomalies in the third generation.

Several abnormalities, such as postnatal deaths and behavioral impairments, have been previously reported in the progeny of male rats exposed to the cytostatic drug cyclophosphamide 60 days prior to mating. The anomalies were transmitted to the second generation (F2). The present results concern the third generation. Two experimental groups have been studied: a hybrid group, resulting from crosses between control subjects and either experimental F2 males or females, and a nonhybrid group, obtained by mating experimental F2 subjects together. Significant abnormalities were found in all experimental groups, whether the F2 subjects were male or female. F2 females had smaller litters whether they were mated with control or experimental males. Body weight was significantly increased in both hybrid and nonhybrid males. Increased postnatal mortality and learning deficit were also observed in the hybrid group. Such complex phenotypic changes confirm that frequent mutations probably have been inherited from the treated males but also suggest that genetic rearrangements have occurred from one generation to the next.

Antimitotic drugs (cyclophosphamide and vinblastine) in the male rat. Deaths and behavioral abnormalities in the offspring.

The spermatogenesis and the offspring of male rats treated either with cyclophosphamide alone, or with both cyclophosphamide and vinblastine were investigated. The offspring were evaluated for the mean number of pups per litter, sex ratio, the frequency of apparent external malformations and, within the first 4 months of life, growth and mortality. When they reached adulthood and were between 12 and 16 weeks of age, the offspring were also examined for spontaneous activity and learning capacity. Treatment with cyclophosphamide or cyclophosphamide and vinblastine resulted in a decrease in the number of both primary spermatocytes and spermatids; the effect, however, lasted longer for the combined drug regimen. At birth, the animals sired by the treated males did not show any apparent malformations. However, compared with the control population the mortality rate of the offspring was significantly higher within the first 40 days of life; at adult age, the proportion of animals that failed in the learning ability test was significantly increased and those that did succeed showed impaired learning capacity. The difference, however, was significant only in the male offspring. Finally, the offspring's spontaneous activity was significantly decreased. No difference was found in mortality or behavior between the animals born of the cyclophosphamide or cyclophosphamide plus vinblastine-treated males. The behavioral disorders shown in the adult offspring confirm the existence of a long-term risk of paternal origin. This risk, essentially functional and independent of any morphologic pathology, should be taken into account in the context of environmental genotoxicity.