PATTERN OF RETINOID-INDUCED TERATOGENIC EFFECTS - POSSIBLE RELATIONSHIP WITH RELATIVE SELECTIVITY FOR NUCLEAR RETINOID RECEPTORS RAR-ALPHA,RAR-BETA, AND RAR-GAMMA

Retinoic acid, an oxidative metabolite of vitamin A, is involved in th e control of many biological processes including embryonic development . Excess as well as deficiency of retinoids were found to be teratogen ic. The effects of retinoids in normal as well as abnormal development may be mediated by two members of retinoid receptors, the RAR's and R XR's, which exhibit a specific temporal and spatial expression during development. The significance of the retinoid receptors was investigat ed here by studying the teratogenic effects of retinoid ligands with r elative selectivity for binding and transactivation of the retinoic ac id receptors RAR alpha, RAR beta and RAR gamma. Pregnant NMRI mice wer e administered 5 or 15 mg/kg of CD 336 (Am 580) (alpha-ligand), CD 201 9 (beta-ligand), CD 437 (gamma-ligand) or 37.5 mg/kg all-trans-retinoi c acid in 25% Cremophor EL on day 8.25 or day 11 of gestation by gastr ic intubation. External, visceral and skeletal malformations were obse rved on day 18 of gestation. The order of teratogenic potency was: alp ha-ligand>beta-ligand>gamma-ligand. In addition, these retinoids also produced a different spectrum of defects. The alpha-ligand induced the most varied defects including severe ear, mandible, and limb malforma tions. The beta-ligand induced defects of the urinary system and liver in greater frequency than expected from its relative potency. The gam ma-ligand preferentially induced ossification deficiencies and defects of the sternebrae and vertebral body. Our results show that these thr ee retinoids, which were previously demonstrated to exhibit retinoid-l ike activities in several systems, exert differing teratogenic activit ies, in regard to both potency and regioselectivity: we hypothesize th at the relative selectivity for binding and transactivation of the thr ee retinoic acid receptors could possibly be related to the difference s of teratogenic effects ob served in this study. The low potency of t he gamma-ligand may lead the way to interesting new retinoids with imp roved therapeutic ratio. (C) 1996 Wiiey-Liss, Inc.