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Potentiation of the teratogenic effects induced by coadministration of retinoic acid or phytanic acid/phytol with synthetic retinoid receptor ligands.

Abstract

Previous studies in our laboratory identified retinoid-induced defects that are mediated by RAR-RXR heterodimerization using interaction of synthetic ligands selective for the retinoid receptors RAR and RXR in mice (Elmazar et al. 1997, Toxicol Appl Pharmacol 146:21-28; Elmazar et al. 2001, Toxicol Appl Pharmacol 170:2-9; Nau and Elmazar 1999, Handbook of experimental pharmacology, vol 139, Retinoids, Springer-Verlag, pp 465-487). The present study was designed to investigate whether these RAR-RXR heterodimer-mediated defects can be also induced by interactions of natural and synthetic ligands for retinoid receptors. A non-teratogenic dose of the natural RXR agonist phytanic acid (100 mg/kg orally) or its precursor phytol (500 mg/kg orally) was coadministered with a synthetic RARalpha-agonist (Am580; 5 mg/kg orally) to NMRI mice on day 8.25 of gestation (GD8.25). Furthermore, a non-teratogenic dose of the synthetic RXR agonist LGD1069 (20 mg/kg orally) was also coadministered with the natural RAR agonist, all- trans-retinoic acid (atRA, 20 mg/kg orally) or its precursor retinol (ROH, 50 mg/kg orally) to NMRI mice on GD8.25. The teratogenic outcome was scored in day-18 fetuses. The incidence of Am580-induced resorptions, spina bifida aperta, micrognathia, anotia, kidney hypoplasia, dilated bladder, undescended testis, atresia ani, short and absent tail, fused ribs and fetal weight retardation were potentiated by coadministration of phytanic acid or its precursor phytol. Am580-induced exencephaly and cleft palate, which were not potentiated by coadministration with the synthetic RXR agonists, were also not potentiated by coadministration with either phytanic acid or its precursor phytol. LGD1069 potentiated atRA- and ROH-induced resorption, exencephaly, spina bifida, aperta, ear anotia and microtia, macroglossia, kidney hypoplasia, undescended testis, atresia ani, tail defects and fetal weight retardation, but not cleft palate. These results suggest that synergistic teratogenesis can be induced by coadministration of a natural RXR ligand (phytanic acid) with a synthetic RAR agonist (Am580). Thus, certain potentially useful therapeutic agents or nutritional factors such as phytanic acid should be tested for teratogenic risk by coadministration with other retinoid receptor agonists.

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  • Authors+Show Affiliations

    ,

    Department of Food Toxicology, School of Veterinary Medicine, Bischofsholer Damm 15, 30173 Hannover, Germany.

    Source

    Archives of toxicology 78:11 2004 Nov pg 660-8

    MeSH

    Abnormalities, Drug-Induced
    Administration, Oral
    Animals
    Benzoates
    Bexarotene
    Dose-Response Relationship, Drug
    Drug Synergism
    Female
    Gestational Age
    Ligands
    Mice
    Mice, Inbred Strains
    Phytanic Acid
    Phytol
    Pregnancy
    Prenatal Exposure Delayed Effects
    Receptors, Retinoic Acid
    Retinoic Acid Receptor alpha
    Retinoid X Receptors
    Teratogens
    Tetrahydronaphthalenes
    Tretinoin
    Vitamin A

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    15558240

    Citation

    Elmazar, M M A., and H Nau. "Potentiation of the Teratogenic Effects Induced By Coadministration of Retinoic Acid or Phytanic Acid/phytol With Synthetic Retinoid Receptor Ligands." Archives of Toxicology, vol. 78, no. 11, 2004, pp. 660-8.
    Elmazar MM, Nau H. Potentiation of the teratogenic effects induced by coadministration of retinoic acid or phytanic acid/phytol with synthetic retinoid receptor ligands. Arch Toxicol. 2004;78(11):660-8.
    Elmazar, M. M., & Nau, H. (2004). Potentiation of the teratogenic effects induced by coadministration of retinoic acid or phytanic acid/phytol with synthetic retinoid receptor ligands. Archives of Toxicology, 78(11), pp. 660-8.
    Elmazar MM, Nau H. Potentiation of the Teratogenic Effects Induced By Coadministration of Retinoic Acid or Phytanic Acid/phytol With Synthetic Retinoid Receptor Ligands. Arch Toxicol. 2004;78(11):660-8. PubMed PMID: 15558240.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Potentiation of the teratogenic effects induced by coadministration of retinoic acid or phytanic acid/phytol with synthetic retinoid receptor ligands. AU - Elmazar,M M A, AU - Nau,H, Y1 - 2004/07/29/ PY - 2004/03/11/received PY - 2004/06/03/accepted PY - 2004/11/24/pubmed PY - 2005/5/3/medline PY - 2004/11/24/entrez SP - 660 EP - 8 JF - Archives of toxicology JO - Arch. Toxicol. VL - 78 IS - 11 N2 - Previous studies in our laboratory identified retinoid-induced defects that are mediated by RAR-RXR heterodimerization using interaction of synthetic ligands selective for the retinoid receptors RAR and RXR in mice (Elmazar et al. 1997, Toxicol Appl Pharmacol 146:21-28; Elmazar et al. 2001, Toxicol Appl Pharmacol 170:2-9; Nau and Elmazar 1999, Handbook of experimental pharmacology, vol 139, Retinoids, Springer-Verlag, pp 465-487). The present study was designed to investigate whether these RAR-RXR heterodimer-mediated defects can be also induced by interactions of natural and synthetic ligands for retinoid receptors. A non-teratogenic dose of the natural RXR agonist phytanic acid (100 mg/kg orally) or its precursor phytol (500 mg/kg orally) was coadministered with a synthetic RARalpha-agonist (Am580; 5 mg/kg orally) to NMRI mice on day 8.25 of gestation (GD8.25). Furthermore, a non-teratogenic dose of the synthetic RXR agonist LGD1069 (20 mg/kg orally) was also coadministered with the natural RAR agonist, all- trans-retinoic acid (atRA, 20 mg/kg orally) or its precursor retinol (ROH, 50 mg/kg orally) to NMRI mice on GD8.25. The teratogenic outcome was scored in day-18 fetuses. The incidence of Am580-induced resorptions, spina bifida aperta, micrognathia, anotia, kidney hypoplasia, dilated bladder, undescended testis, atresia ani, short and absent tail, fused ribs and fetal weight retardation were potentiated by coadministration of phytanic acid or its precursor phytol. Am580-induced exencephaly and cleft palate, which were not potentiated by coadministration with the synthetic RXR agonists, were also not potentiated by coadministration with either phytanic acid or its precursor phytol. LGD1069 potentiated atRA- and ROH-induced resorption, exencephaly, spina bifida, aperta, ear anotia and microtia, macroglossia, kidney hypoplasia, undescended testis, atresia ani, tail defects and fetal weight retardation, but not cleft palate. These results suggest that synergistic teratogenesis can be induced by coadministration of a natural RXR ligand (phytanic acid) with a synthetic RAR agonist (Am580). Thus, certain potentially useful therapeutic agents or nutritional factors such as phytanic acid should be tested for teratogenic risk by coadministration with other retinoid receptor agonists. SN - 0340-5761 UR - https://www.unboundmedicine.com/medline/citation/15558240/Potentiation_of_the_teratogenic_effects_induced_by_coadministration_of_retinoic_acid_or_phytanic_acid/phytol_with_synthetic_retinoid_receptor_ligands_ L2 - https://dx.doi.org/10.1007/s00204-004-0586-8 DB - PRIME DP - Unbound Medicine ER -