Abstract:

OBJECTIVE: Two procedures were chosen to study cyclophosphamide (CP) as a positive control in teratogenicity test of rats. One procedure was dosing CP 4.8 mg/kg from gestation day 6 (GD6) to GD15 continuously (group A). The other procedure was single dosing of CP 12 mg/kg on gestation day 12 (GD12) (group B). METHODS：The successfully mated SD rats were divided into three groups randomly，namely group A (dosing CP 4.8 mg/kg from GD6 to GD15 continuously)，group B (single dosing CP 12 mg/kg on GD12) and group C (the saline negative control group). The general condition of the treated rats was observed and the body weight was recorded every three days. Pregnant rats were euthanized by CO2 on GD20 for autopsy and reproductive organs were weighed. Fetal appearance， internal organs and skeletal malformations were checked and recorded. RESULTS：General conditions in group A and B were normal when compared with group C . Weights of uterus with placentas，placentas and uterus in group B were statistically lower than group C (P<0.05). Fetal appearance in group A showed no significant difference when compared with group C ，while in group B there were obvious deformities，including meningocele，microcephaly， brain exposed，club-foot，etc. Fetal internal organs examination in group A showed only the lateral cerebral ventricle enlarged or congested. However in group B internal organs malformations were found including the third and lateral cerebral ventricles enlarged or congested，and abnormal cardiac atrium or cardiac ventricle. Fetal skeletal examination showed little malformation in group A，with no significant difference when compared with group C. In group B，skeletal deformities incidence was higher in most bones than group C，mainly in the head and thorax，such as basisphenoid abnormalities，abnormal number of ribs，etc. CONCLUSION：In this experiment，dosing CP 12 mg/kg on GD12 induced more severe and more types of fetal malformation than dosing CP 4.8 mg/kg from GD6 to GD15 continuously. Therefore，dosing CP 12 mg/kg on GD12 was recommended as an effective positive control procedure in teratogenicity test of rats.

Key words: cyclophosphamide, positive control, rat, developmental toxicity, teratogenicity