Teratogenicity of arotinoid ethyl ester (RO 13-6298) in mice

Arotinoid ethyl ester (RO 13-6298) is a new and very potent retinoid that exerts a profound influence on epithelial and mesenchymal differentiation in doses 500 times lower than those of compounds of the first and second retinoid generation. In the present study the teratogenicity of arotinoid ethyl ester was investigated in NMRI mice employing different treatment schedules. Recording of abnormalities was performed on day 18 (day 0 = day of conception) according to Wilson and with cleared skeletal preparations. Intraperitoneal application of the drug at a dosage of 10 micrograms/kg/day for three consecutive days (days 9-11 or 12-14) caused severe malformations, particularly in the skeletal system and the cavernous organs. Skeletal elements were reduced in number, shortened, or abnormally shaped. Ossification was diminished. Atresia of anus and urethra were frequent. Single application of 200 micrograms/kg between days 8 and 14 also caused multiple and severe malformations. However, no stage-specific pattern of abnormalities was detectable. Some skeletal malformations indicated more or less vulnerable stages that were in concordance with special developmental steps. Others, however, seemed to be equally susceptible over a longer period, eg, rays 1 and 5 of the hand or foot and the development of the mandibular joints. The pattern of abnormalities caused by these very low doses of RO 13-6298 is comparable to that obtained with other retinoids and is achieved within the same relative dose-response range. Preconceptional treatment of the animals did not induce any malformations.