Synergistic teratogenic effects induced by retinoids in mice by coadministration of a RARalpha- or RARgamma-selective agonist with a RXR-selective agonist.
Synergistic teratogenic effects induced by retinoids in mice by coadministration of a RARalpha- or RARgamma-selective agonist with a RXR-selective agonist.
复制标题
通过将 RARα 或 RARgamma 选择性激动剂与 RXR 选择性激动剂共同给药，类视黄醇在小鼠中诱导协同致畸作用。
DOI：
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发表时间：
2001
影响因子：
3.8
通讯作者：
H. Nau
中科院分区：
文献类型：
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作者：
M. Elmazar;R. Rühl;H. Nau
为了研究妊娠第 11 天时视黄醇诱发的肢体缺陷和腭裂的相互作用，将 RXR 选择性激动剂（AGN191701，一种芳基丙烯基噻吩羧酸衍生物，口服 20 mg/kg）与 RARα 激动剂（Am580，一种芳基酰胺苯甲酸衍生物，口服 5 mg/kg）共同给予 NMRI 小鼠。 AGN191701 在所用剂量下既无胎儿毒性，也无致畸性，但可增强 Am580 诱导的肢体缺陷和腭裂，并防止 Am580 诱导的胎儿体重迟缓。这些结果表明，妊娠第 11 天时 Am580 诱导的肢体缺陷和可能的腭裂可能是通过 RARα-RXR 异二聚化介导的，特别是在没有毒代动力学相互作用的情况下。 AGN191701 还在妊娠第 8 天和第 11 天与 RARgamma 激动剂（CD437，一种金刚烷基羟苯基萘甲酸衍生物，口服 15 mg/kg）共同给药，以研究哪些 CD437 诱导的缺陷是通过 RARgamma-RXR 异二聚化介导的。在妊娠第 8 天，AGN191701 增强了 CD437 诱导的胚胎致死性、外脑畸形、脊柱裂、腭裂和尾部缺陷，以及内脏和骨骼缺陷，但不增强小颌畸形。妊娠第 11 天，与 RXR 激动剂合用时，CD437 诱导的腭裂和肢体缺陷的发生率也会增加。这些结果表明，两种受体选择性类维生素A的共同给药可以诱导协同致畸作用，表明RARα-RXR和RARγ-RXR异二聚体在器官发生过程中产生结构缺陷中的重要性。
To study the interaction of retinoid-induced limb defects and cleft palate on day 11 of gestation, a RXR-selective agonist (AGN191701, an arylpropenyl-thiophene-carboxylic acid derivative, 20 mg/kg orally) was coadministered with a RARalpha-agonist (Am580, an arylcarboxamidobenzoic acid derivative, 5 mg/kg orally) to NMRI mice. AGN191701 was neither fetotoxic nor teratogenic at the dose used but potentiated Am580-induced limb defects and cleft palate and prevented Am580-induced fetal weight retardation. These results suggest that Am580-induced limb defects and probably cleft palate on day 11 of gestation may be mediated via RARalpha-RXR heterodimerization, particularly in the absence of toxicokinetic interactions. AGN191701 was also coadministered with a RARgamma-agonist (CD437, an adamantyl-hydroxyphenyl naphthoic acid derivative, 15 mg/kg orally) on days 8 and 11 of gestation to investigate which CD437-induced defects are mediated via RARgamma-RXR heterodimerization. On day 8 of gestation, AGN191701 potentiated CD437-induced embryolethality, exencephaly, spina bifida aperta, cleft palate, and tail defects, as well as visceral and skeletal defects, but not micrognathia. On day 11 of gestation, the incidence of CD437-induced cleft palate and limb defects was also potentiated when coadministered with the RXR agonist. These results suggest that synergistic teratogenic effects can be induced by coadministration of two receptor-selective retinoids, indicating the importance of RARalpha-RXR and RARgamma-RXR heterodimers in producing structural defects during organogenesis.