Developmental anomalies induced by all-trans retinoic acid in fetal mice: I. Macroscopic findings

The administration of a single dose of all-trans retinoic acid on day 8 of gestation to pregnant mice, ICR strain, led to malformed fetuses in all of the litters. All-trans retinoic acid (RA) was dissolved in olive oil and given in doses of 60 or 40 mg/kg of body weight. The control mice were given vehicle alone. Examination on day 18 of gestation of the fetuses exposed to 60 mg/kg showed various malformations, such as exencephaly, exophthalmus, micrognathia, agnathia, cleft palate, cleft lower lip, spina bifida, atresia ani, tail anomalies, agenesis of the kidneys, or hydronephrosis. In the fetuses exposed to 40 mg/kg, isolated cleft palate was much more common than in those exposed to 60 mg/kg. Double-stained preparations of bone and cartilage showed cranio-facial anomalies and axial skeletal anomalies: a- or hypogenesis of palatine or maxillary bones, tympanic ring, squamosal temporal bone or otic ossicles in cartilage, and fusion of basioccipital to basisphenoid and maxilla, zygomatic and mandibular bones; a- or hypogenesis of caudal vertebrae and supernumerary thoracic and lumbar vertebrae. These results indicate that anomalies comparable to those seen in the infants of mothers treated with isotretinoin, 13-cis retinoic acid, during pregnancy can also be induced in mice and suggest that the site affected by RA may be neural crest cells, including those in the cephalic and caudal regions, and cells committed to somitic mesoderm in the trunk region.