Synergistic teratogenic effects induced by retinoids in mice by coadministration of a RAR alpha- or RAR gamma-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 RAR alpha -agonist (Am580, an arylcarboxamidobenzoic acid derivative , 5 mg/kg orally) to NMRI mice. AGN191701 was neither fetotoxic nor teratog enic 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 RAR alpha -RXR heterodimerization, partic ularly in the absence of toxicokinetic interactions. AGN191701 was also coa dministered with a RAR gamma -agonist (CD437, an adamantyl-hydroxyphenyl na phthoic acid derivative, 15 mg/kg orally) on days 8 and 11 of gestation to investigate which CD437-induced defects are mediated via RAR gamma -RXR het erodimerization. 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. Thes e results suggest that synergistic teratogenic effects can be induced by co administration of two receptor-selective retinoids, indicating the importan ce of RAR alpha -RXR and RAR gamma -RXR heterodimers in producing structura l defects during organogenesis. (C) 2001 Academic Press.