Pattern of retinoid-induced teratogenic effects: Possible relationship with relative selectivity for nuclear retinoid receptors RARα, RARβ, and RARγ
✍ Scribed by Elmazar, M. M. A.; Reichert, U.; Shroot, B.; Nau, H.
- Publisher
- John Wiley and Sons
- Year
- 1996
- Tongue
- English
- Weight
- 958 KB
- Volume
- 53
- Category
- Article
- ISSN
- 0040-3709
No coin nor oath required. For personal study only.
✦ Synopsis
Retinoic acid, an oxidative metabolite of vitamin A, is involved in the control of many biological processes including embryonic development. Excess as well as deficiency of retinoids were found to be teratogenic. The effects of retinoids in normal as well as abnormal development may be mediated by two members of retinoid receptors, the RARs and RXR' s, which exhibit a specific temporal and spatial expression during development. The significance of the retinoid receptors was investigated here by studying the teratogenic effects of retinoid ligands with relative selectivity for binding and transactivation of the retinoic acid receptors RARa, RARp and RARy. Pregnant NMRl mice were administered 5 or 15 mg/kg of CD 336 (Am 580) (a-ligand), CD 2019 (pligand), CD 437 (y-ligand) or 37.5 mg/kg all-trunsretinoic acid in 25% Cremophor EL on day 8.25 or day 11 of gestation by gastric intubation. External, visceral and skeletal malformations were observed on day 18 of gestation. The order of teratogenic potency was: a-ligand>p-ligand>y-ligand. In addition, these retinoids also produced a different spectrum of defects. The a-ligand induced the most varied defects including severe ear, mandible, and limb malformations. The p-ligand induced defects of the urinary system and liver in greater frequency than expected from its relative potency. The y-ligand preferentially induced ossification deficiencies and defects of the sternebrae and vertebral body. Our results show that these three retinoids, which were previously demonstrated to exhibit retinoidlike activities in several systems, exert differing teratogenic activities, in regard to both potency and regioselectivity: we hypothesize that the relative selectivity for binding and transactivation of the three retinoic acid receptors could possibly be related to the differences of teratogenic effects observed in this study. The low potency of the y-ligand may lead the way to interesting new retinoids with improved therapeutic ratio. o 1996 WiIey-Liss, Inc.
'86; Nau et al., '94). The hypothesis that retinoic acid receptors and their ligands may be involved in normal as well as abnormal embryonic development has recently been supported by a number of studies (Chambon, '93). All-trans-retinoic acid is present endogenously in the embryo and shows a specific distribution within certain areas such as the floor plate of the neural tube (Wagner et al., 'go), in Hensen's node (Chen et al., '92), and in the developing limb bud (Thaller and Eichele, '87; Durston et al., '89; Satre and Kochhar, '89;