Ethylenethiourea-induced hindpaw deformities in mice and effects of metabolic modifiers on their occurrence

Time-mated Swiss-Webster mice were pretreated in separate experiments with phenobarbital (60 mg/kg X d sc on d 7-10 of pregnancy), SKF-525A (40 mg/kg ip on d 12 of pregnancy) or 3-methylcholanthrene (20 mg/kg X d on d 10-12 of pregnancy). On the d 12 of pregnancy (1 h after SKF-525A or 3-methylcholanthrene treatment), one group each of pretreated mice was given a single oral dose of 1600, 2000, or 2400 mg/kg of ethylenethiourea (ETU) as a 5% concentrate in a 1.5% aqueous gelatin solution, which as a vehicle was given to other pretreated groups. The respective volume doses were 3.2, 4.0, or 4.8 ml/100 g body weight with the controls given 4.8 ml/100 g body weight of vehicle alone. Maternal toxicity was observed in all groups given ETU, whether pretreated with metabolic modifiers or not. In the three experiments, treatment with ETU alone reduced fetal weight by 15% at 2400 mg/kg and 8% with the remaining 2 doses, and increased the incidence of resorptions (19-62% with the 2400 mg/kg dose, 8-59% at 2000 mg/kg, and 7-32% at the 1600 mg/kg dose). The significant defects with incidence ranges in three experiments were: hindpaw ectrodactyly, 2-6% at 1600 mg/kg, 4-20% at 2000, and 20-29% at 2400 mg/kg; and hindpaw syndactyle, 3% at 16 mg/kg, 6-14% at 2000, and 2-12% at 2400 mg/kg doses. Minor incidences of cleft palate and hindpaw polydactyly were also observed. Phenobarbital pretreatment did not change the ETU-induced maternal or fetal effects. SKF-525A enhanced the resorptions and reduced the litter-size but had no effect on fetal malformations. The 3-methylcholanthrene pretreatment reduced the ETU-induced incidences of hindpaw ectrodactyly, hindpaw syndactyly, and cleft palate at the 2000 and 2400 mg/kg doses. Previous studies with rats and hamsters revealed that SKF-525A enhanced the ETU-induced fetal malformations but phenobarbital and 3-methyl-cholanthrene had no effect in these two species.