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

Abstract

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.

Spatial and temporal pattern of expression of the cellular retinoic acid-binding protein and the cellular retinol-binding protein during mouse embryogenesis.

“…The tissue distribution of CRABP and CRBP transcripts that we have found are in good correlation with the spectrum of tissues affected teratogenically by retinoic acid and retinol in embryos of different species (1,(12)(13)(14)(15)(30)(31)(32)(33)(34). CRABP and CRBP transcripts were found in the limb, spinal cord, brain, and facial structures, which all are well-known teratogenic targets of retinoic acid and retinol.…”

“…In mouse embryos, it has been reported that hypervitaminosis A causes alterations in the cell cycle of neuroepithelial cells and prevents the closure of the neural tube, producing brain deformities (12,13). Excess vitamin A also alters the pattern of migration of cranial neural crest cells, producing facial skeleton deformities (cleft palate) (14,15). Alterations in the cephalic mesoderm, the axial nonsegmented mesoderm, and finally the segmented mesoderm, especially the somites (rib defects and vertebral malformations), are also caused by administration of excess vitamin A (16,17).…”

Maternal diabetes in the rat impairs the formation of neural-crest derived cranial nerve ganglia in the offspring

“…In mice, retinoic acid gave craniofacial malformations similar to those seen in rats subjected to maternal diabetes [11,33]. Of note, neuroepithelial cell death and aberrant neural crest-cell migration has been shown to contribute to facial malformations induced by ethanol [34,35] and retinoic acid [36,37].…”

The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse.

“…It has been shown that the diverse teratogenic effects on embryos by RA exposure depend on the developmental stage when RA is administered and the dosage of RA (Yasuda 1986;Kessel and Gruss 1991;Kessel 1992). We chose to use a low dose (10 mg of all-trans RA/kg of body weight) to treat E8.5 embryos because under this condition RA almost exclusively affects the patterning of the vertebrae without any effect on the development of the heart, lung, and other visceral organs as well as craniofacial bones.…”