Induction of RAR-beta 2 gene expression in embryos and RAR-beta 2 transactivation by the synthetic retinoid Ro 13-6307 correlates with its high teratogenic potency.
Vitamin A (retinol), its metabolite all-trans retinoic acid (RA), and many synthetic analogs (retinoids) express variable potencies as teratogens. Although biological activities of retinoids are mediated by nuclear RA receptors (RARs) and retinoid X receptors (RXRs), it is not known if any of these receptors mediate teratogenicity, and if the potency also depends on the nature of the ligand-receptor interactions. Previous evidence has implicated that one specific isoform, RAR-beta 2, does play a role in mediating retinoid teratogenicity. Here, we employed an aromatic retinoid with a triene side chain, Ro 13-6307, to study its interactions with RAR-beta 2 since its teratogenicity is much higher and its accessibility to the embryo is much lower than RA. A fully teratogenic dose of Ro 13-6307 (10 mg-kg) given to pregnant mice preferentially elevated the level of RAR-beta 2 mRNA in susceptible embryonic regions (maximal induction, 10- to 12-fold above control in limb buds) in a manner comparable to a fully teratogenic dose of all-trans RA (100 mg-kg). Using the RAR-beta 2 promoter linked to a reporter gene in cotransfection experiments, the efficacy of Ro 13-6307 and RAR-beta 2 in transcription transactivation was found to be 30-40 times greater than all-trans RA. Since the teratogenic potency of Ro 13-6307 is estimated from a previous study to be 44-fold greater than all-trans RA, we suggest that the teratogenicity of this synthetic retinoid is generally proportional to its ability to enhance receptor function.
Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.
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Tairis
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Gyda
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Jiang
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D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000633:toxicity; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D051379:Mice; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid; D013237:Stereoisomerism; D013723:Teratogens / Q000633:toxicity*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*; D014212:Tretinoin
D002352:Carrier Proteins; D005231:Fatty Acids, Unsaturated; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D013723:Teratogens; D014212:Tretinoin; C077135:Ro 13-6307