Effects of pretreatment with skf‐525a, n‐methyl‐2‐thioimidazole, sodium phenobarbital, or 3‐methylcholanthrene on ethylenethiourea‐induced teratogenicity in hamsters

Abstract

Teratogenicity of ethylenethiourea (ETU) was studied in the hamster to define the organ most vulnerable to its teratogenic action. A single intragastric dose of 600, 1200, 1800 or 2400 mg ETU/kg was given in 1.5% aqueous gelatin on d 11 of pregnancy. None of these dose levels produced any apparent maternal toxicity. However, fetal toxicity was apparent in the form of deaths, reduced body weight at the 2400 mg/kg dose, and dose‐related incidences of hydrocephalus, hypoplastic cerebellum, cleft palate, delayed calvarial ossification, and ectrodactyly. The ventricular system of the brain and the cerebellum were among the most sensitive sites for malformations. Effects of metabolic modifiers on the teratogenicity of ETU were studied in separate experiments. Doses of ETU were administered by gastric intubation on d 11 of pregnancy either immediately after an intragastric dose of 200 or 400 mg N‐methyl‐2‐thioimidazole/kg, or 1 h after an ip 40‐mg/kg dose of SKF‐525A. The SKF‐525A pretreatment significantly increased the incidence of several anomalies at the high doses of ETU, but H‐methyl‐2‐thioimidazole pretreatment showed no significant effect at any dose. Pretreatment with 40 or 60 mg phenobarbital/kg, given sc twice a day for 4 consecutive days or 20 mg/kg of 3‐methylcholanthreen given ip once a day for 3 d prior to ETU dosing, failed to show any significant change in the teratogenic activity of 1200 or 1800 mg ETU/kg administered intragastrically on d 11 of pregnancy.