Synergistic teratogenic effects induced by retinoids in mice by coadministration of a RARα- or RARγ-selective agonist with a RXR-selective agonist
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 RARαagonist (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 RARα-RXR heterodimerization, particularly in the absence of toxicokinetic interactions. AGN191701 was also coadministered with a RARγ-agonist (CD437, an adamantyi-hydroxyphenyl naphthoic acid derivative, 15 mg/kg orally) on days 8 and 11 of gestation to investigate which CD437-induced defects are mediated via RARγ-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 receptorselective retinoids, indicating the importance of RARα-RXR and RARγ-RXR heterodimers in producing structural defects during organogenesis. © 2001 Academic Press.
Elmazar, Mohamed M.; Rühl, Ralph; and Nau, Heinz, "Synergistic teratogenic effects induced by retinoids in mice by coadministration of a RARα- or RARγ-selective agonist with a RXR-selective agonist" (2001). Pharmacy. 222.