RAR-ALPHA-MEDIATED TERATOGENICITY IN MICE IS POTENTIATED BY AN RXR AGONIST AND REDUCED BY AN RAR ANTAGONIST - DISSECTION OF RETINOID RECEPTOR-INDUCED PATHWAYS

To dissect the complex pattern cif retinoid-induced developmental defe cts, an RXR-selective agonist (AGN191701, an aryl-propenyl-thiophene-c arboxylic acid derivative) was coadministered with an RAR alpha-select ive agonist (Am580, an arylcarboxamidobenzoic acid derivative) to NMRI mice on Day 8.25 of gestation. AGN191701 was neither fetotoxic nor te ratogenic at the doses used, but potentiated AM580-induced resorptions , spina bifida aperta, micrognathia, kidney hypoplasia, dilated bladde r, undescended testis, atresia ani, tail malformations, fused ribs, an d fetal weight retardation, These effects were generally reduced by co administration of an RAR-selective antagonist (CD2366, an adamantyl-me thoxyphenyl-heptatrienoic acid derivative). The incidence of other def ects induced by an RAR alpha-selective agonist such as exencephaly or cleft palate was neither greatly affected by the RXR-selective agonist nor by the antagonist. These results suggest that some malformations such as the posterior neural tube defect spina bifida as well as uroge nital defects may be mediated via liganded RAR alpha-RXR heterodimeriz ation, while other defects such as the anterior neural tube defect exe ncephaly as well as cleft palate are induced by different mechanisms. (C) 1997 Academic Press.