Circadian system and teratogenicity of cytostatic drugs.

Pregnant mice were injected once with cyclophosphamide (20 mg/kg) or Th-R (N-mustard, 2 mg/kg) at one of four different day-times (07.00, 13.00, 19.00, 01.00) on the 12th day of gestation. In a therapeutic dose both alkylating neoplastic agents induced teratogenic effects relative to the maternal circadian cycle. The highest incidence of malformations due to maternal treatment with cyclophosphamide was found to be associated with the dark to light transition (07.00), whereas the lowest occurred at 01.00. In contrast, the teratogenic action of Th-R was strongest at the onset of darkness (19.00) and lowest at 07.00. The mean embryotoxicity of both compounds was subjected to seasonal modifications, being highest during spring and summer and lowest during winter. - The observations indicate that for the evaluation of the teratogenic potentialities of drugs, rhythms cannot be neglected.