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 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 RAR's 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 RAR alpha, RAR beta and RAR gamma. Pregnant NMRI mice were administered 5 or 15 mg/kg of CD 336 (Am 580) (alpha-ligand), CD 2019 (beta-ligand), CD 437 (gamma-ligand) or 37.5 mg/kg all-trans-retinoic 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: alpha-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 malformations. The beta-ligand induced defects of the urinary system and liver in greater frequency than expected from its relative potency. The gamma-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 retinoid-like 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 gamma-ligand may lead the way to interesting new retinoids with improved therapeutic ratio.
Elmazar
M M
MM
Institute of Toxicology and Embryopharmacology, Free University, Berlin, Germany.
Reichert
U
U
Shroot
B
B
Nau
H
H
D000014:Abnormalities, Drug-Induced; D000015:Abnormalities, Multiple / Q000139:chemically induced; D000284:Administration, Oral; D000818:Animals; D001565:Benzoates / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D001842:Bone and Bones / Q000002:abnormalities; D002490:Central Nervous System / Q000002:abnormalities; D004065:Digestive System Abnormalities; D005260:Female; D051379:Mice; D009281:Naphthalenes / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D011247:Pregnancy; D011256:Pregnancy Outcome; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012176:Retinoids / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D014212:Tretinoin / Q000633:toxicity*; D014564:Urogenital Abnormalities
D001565:Benzoates; C101407:CD 2019; C099555:CD 437; D009281:Naphthalenes; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D013764:Tetrahydronaphthalenes; C068073:Am 580; D014212:Tretinoin