A retinoic acid receptor alpha antagonist counteracts retinoid teratogenicity in vitro and reduced incidence and/or severity of malformations in vivo.
The role of retinoic acid receptors (RAR) in retinoid-induced teratogenesis is mainly unknown. The aim of the present studies was to demonstrate the effect of a RAR alpha antagonist on retinoid-induced teratogenic effects in vitro and in vivo. In micromass cultures of rat limb bud cells a RAR alpha antagonist was able to counteract differentiation inhibiting effects of a RAR alpha agonist. In mouse studies, the selective RAR alpha antagonist reduced frequency and/or severity of major malformations. Our observations indicate the potentiality of selective RAR agonists and antagonists in dissecting the function of nuclear receptors and in particular cases of retinoid teratogenesis, to assign to the different receptors a primary role in determining one or another of the multiple malformations.
Eckhardt
K
K
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Schmitt
G
G
D000014:Abnormalities, Drug-Induced; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D002972:Cleft Palate / Q000139:chemically induced; D004431:Ear, External / Q000002:abnormalities; D005121:Extremities / Q000196:embryology*; D005260:Female; D051379:Mice; D011247:Pregnancy; D051381:Rats; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors*; D012176:Retinoids / Q000633:toxicity*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D001565:Benzoates; D002839:Chromans; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D013764:Tetrahydronaphthalenes; C068073:Am 580; C084904:Ro 41-5253