Retinoic Acid Induces Malformations Related to Cell Death in the Developing Mouse Embryo.

Abstract

Intraperitoneal administration of all-trans retinoic acid (RA) to pregnant mice on 8.5 or 10.5 days post coitum (dpc) resulted in malformed fetuses in all litters in a dose-dependent and developmental stage-specific manner. The pregnant mice were injected with RA dissolved in dimethyl sulfoxide, at a dose of 25 or 50 mg/kg of body weight on 8.5 or 10.5 dpc. In the 8.5 dpc-50 mg/kg treatment group, all fetuses had tail anomalies and vertebral malformations, and some fetuses showed craniofacial anomalies such as exencephaly, spina bifida, micrognathia and agenesis of auricles. Excessive cell death was seen in the tail bud 24 h after RA injection. In the 8.5 dpc-25 mg/kg treatment group, however, fetuses showed palliation of these defects. In the 10.5 dpc-50 mg/kg treatment group, limb disorders were induced, but the tail showed normal morphology. The present results indicate that RA-inducible malformation in mouse embryos is dose-dependent and developmental stage-specific, and these teratogenicity may correlate with excessive cell death. RA is considered to affect rapidly growing parts of embryonic tissues and causes disorders in normal pattern formation of embryonic tissues.