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.
Soprano
D R
DR
Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.
Tairis
N
N
Gyda
M
M
Harnish
D C
DC
Jiang
H
H
Soprano
K J
KJ
Kochhar
D M
DM
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