Transplacental teratogenesis and mutagenesis in mouse fetuses treated with cyclophosphamide

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Abstract
We studied transplacental fetotoxicity, teratogenicity, and mutagenicity in Swiss Webster mice following different doses of cyclophosphamide (CP; 0, 5, 10, 15, or 20 mg/kg), a well‐known mutagen/teratogen, on day 12 of gestation. The fetal survival and weight on day 18 of gestation decreased significantly with increasing CP dose (P < 0.01). The CP‐treated fetuses were also dysmorphic (e.g., shortened limbs, digital defects, cleft palate, open eyes, and hydrocephaly) and the percentage of dysmorphology increased with increasing CP doses (P < 0.01). To evaluate mutagenesis, a separate group of females received 5‐bromodeoxyuridine tablet (50‐mg) implants on day 12 of gestation and a CP treatment 8 h later. Fetal liver cells were harvested 24 h post‐BrdU implant to analyze sister chromatid exchange (SCE) frequency and micronuclei. CP caused a significant increase in the SCEs per fetal liver cell from 3.4 ± 0.02 (control) to 90.0 ± 0.04 (20 mg/kg CP) (P < 0.01). The increasing CP dose was also related to an increase in micronuclei. The data suggest that CP is transplacentally toxic, teratogenic, and mutagenic. Further analyses of the data suggest that the mutagenic effects of CP may in fact contribute indirectly to the CP‐related teratogenic effects. Such conclusions are based on path analysis with directional causations associated with SCEs per cell and the dysmorphic features studied.