Teratogenic dose-response relationships of etretinate in the golden hamster

Abstract

Etretinate (Ro 10-9359; Tigason; 4-methoxy-2,3,6-trimethylphenyl analog of retinoic acid, ethyl ester) was evaluated for teratogenic activity in the Syrian golden hamster, Groups of pregnant hamsters were given a single oral dose of 2.8–88 mg/kg etretinate during the early primitive streak stage of gestation. No signs of maternal intoxication were observed in any of the hamsters given the retinoid and maternal body weight changes throughout gestation were not significantly different from those of the vehicle-treated group. Etretinate administration was associated with a dose-dependent increase in the incidence and severity of malformations. The average fetal body weight was significantly less in litters recovered from dams given 44 or 88 mg/kg of etretinate when compared to the average body weight of fetuses recovered from dams given an equivalent volume of the vehicle. The average crown-rump lengths also were significantly shorter in fetuses taken from the dams given 44 or 88 mg/kg etretinate as compared to the control group. The malformations induced by etretinate administration were similar to those noted following an oral dose of all- trans-retinoic acid ( Willhite and Shealy, 1984). A comparison of the dose-response curves for induction of terata following treatment with etretinate or all- trans-retinoic acid revealed that etretinate was twice as potent as a teratogen in the hamster as all- trans-retinoic acid. Teratogenic activity of etretinate in the hamster was achieved at doses (mg/kg body wt) used in patients at current clinical therapeutic levels.