Elmazar M M, Rühl R, Reichert U, Shroot B, Nau H
Institut für Toxikologie und Embryopharmakologie, Freie Universität Berlin, Berlin, D-14195, Germany.
Toxicol Appl Pharmacol. 1997 Sep;146(1):21-8. doi: 10.1006/taap.1997.8221.
To dissect the complex pattern of retinoid-induced developmental defects, an RXR-selective agonist (AGN191701, an arylpropenyl-thiophene-carboxylic acid derivative) was coadministered with an RARalpha-selective agonist (Am580, an arylcarboxamidobenzoic acid derivative) to NMRI mice on Day 8.25 of gestation. AGN191701 was neither fetotoxic nor teratogenic at the doses used, but potentiated Am580-induced resorptions, spina bifida aperta, micrognathia, kidney hypoplasia, dilated bladder, undescended testis, atresia ani, tail malformations, fused ribs, and fetal weight retardation. These effects were generally reduced by coadministration of an RAR-selective antagonist (CD2366, an adamantyl-methoxyphenyl-heptatrienoic acid derivative). The incidence of other defects induced by an RARalpha-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 urogenital defects may be mediated via liganded RARalpha-RXR heterodimerization, while other defects such as the anterior neural tube defect exencephaly as well as cleft palate are induced by different mechanisms.
为剖析类视黄醇诱导的发育缺陷的复杂模式，在妊娠第8.25天，将一种RXR选择性激动剂（AGN191701，一种芳基丙烯基噻吩羧酸衍生物）与一种RARα选择性激动剂（Am580，一种芳基羧酰胺苯甲酸衍生物）共同给予NMRI小鼠。在所使用的剂量下，AGN191701既无胚胎毒性也无致畸性，但增强了Am580诱导的吸收、开放性脊柱裂、小颌畸形、肾发育不全、膀胱扩张、隐睾、肛门闭锁、尾部畸形、肋骨融合以及胎儿体重发育迟缓。通过共同给予一种RAR选择性拮抗剂（CD2366，一种金刚烷基甲氧基苯基庚三烯酸衍生物），这些效应通常会减弱。由RARα选择性激动剂诱导的其他缺陷，如无脑儿或腭裂的发生率，既未受到RXR选择性激动剂的显著影响，也未受到拮抗剂的显著影响。这些结果表明，一些畸形，如神经管后段缺陷开放性脊柱裂以及泌尿生殖系统缺陷，可能是通过配体结合的RARα-RXR异二聚体化介导的，而其他缺陷，如神经管前段缺陷无脑儿以及腭裂，则是由不同机制诱导的。
