Synergistic teratogenic effects induced by retinoids in mice by coadministration of a RARalpha- or RARgamma-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 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.
Elmazar
M M
MM
Department of Food Toxicology, School of Veterinary Medicine Hannover, Bischofsholer Damm 15, Hannover, D-30173, Germany.
Rühl
R
R
Nau
H
H
D000014:Abnormalities, Drug-Induced / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000633:toxicity; D001565:Benzoates / Q000493:pharmacokinetics / Q000633:toxicity; D004357:Drug Synergism; D005333:Fetus / Q000473:pathology; D008297:Male; D051379:Mice; D008934:Mitogens / Q000633:toxicity; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids / Q000493:pharmacokinetics / Q000633:toxicity*; D013723:Teratogens / Q000493:pharmacokinetics / Q000633:toxicity*; D013764:Tetrahydronaphthalenes / Q000493:pharmacokinetics / Q000633:toxicity; D013876:Thiophenes / Q000633:toxicity; D014157:Transcription Factors / Q000819:agonists*; D000097768:Retinoic Acid Receptor gamma
D000970:Antineoplastic Agents; D001565:Benzoates; D008934:Mitogens; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids; D013723:Teratogens; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; D014157:Transcription Factors; D000097768:Retinoic Acid Receptor gamma; C099555:CD 437; C000607072:Rara protein, mouse; C068073:Am 580; C108491:AGN 191701