Archives of Toxicology

, Volume 64, Issue 8, pp 616–622 | Cite as

Teratogenicity of arotinoids (retinoids) in vivo and in vitro

  • Andreas Kistler
  • Toshie Tsuchiya
  • Masahiko Tsuchiya
  • Michael Klaus
Original Investigations

Abstract

The effect of structural modifications on the arotinoid molecule, a new class of retinoids, on their teratogenicity in mice was studied. Animals were treated on days 8 and 9 of gestation, the most susceptible stages to retinoid-induced malformations in rodents. The teratogenic potency of the 13 arotinoids tested varied over a dose range of more than five orders of magnitude. Next, we tested whether the quantitative differences in the teratogenicity of these arotinoids correlates with their activity in high density (micromass) cultures of rat embryonic limb bud and midbrain cells. There was a good quantitative correlation between the in vivo teratogenicity and the in vitro activity in limb bud cells but no correlation was found in midbrain cells. Thus, the limb bud cell culture system may be useful for a preliminary testing to select non-teratogenic retinoids. For the risk assessment in humans, however, the in vitro results should be verified in animals studies.

Key words

Teratogenicity in vivo Teratogenicity in vitro Retinoids Arotinoids Micromass culture 

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References

  1. Creech Kraft J, Kochhar DM, Scott WJ, Nau H (1987) Low teratogenicity of 13-cis-retinoic acid (isotretinoin) in the mouse corresponds to low embryo concentrations during organogenesis: comparison to the all-trans isomer. Toxicol Appl Pharmacol 87: 474–482CrossRefPubMedGoogle Scholar
  2. Creech Kraft J, Löfberg B, Chahoud I, Bochert G, Nau H (1989) Teratogenicity and placental transfer of all-trans-, 13-cis-, 4-oxo-all-trans-, and 4-oxo-13-cis-retinoic acid after administration of a low oral dose during organogenesis in mice. Toxicol Appl Pharmacol 100: 162–176CrossRefPubMedGoogle Scholar
  3. Flint OP (1987) An in vitro test for teratogens using cultures of rat embryo cells. In: Atterwill CK, Steele CE (eds) In vitro methods in toxicology. Cambridge University Press, Cambridge pp 339–363Google Scholar
  4. Flint OP, Orton TC (1984) An in vitro assay for teratogens with cultures of rat embryo midbrain and limb bud cells. Toxicol Appl Pharmacol 76: 383–395CrossRefPubMedGoogle Scholar
  5. Guntakatta M, Matthews EJ, Rundell JO (1984) Development of a mouse embryo limb bud cell culture system for the estimation of chemical teratogenic potential. Teratogen Carcinogen Mutagen 4: 349–364Google Scholar
  6. Hassell JR, Horigan EA (1982) Chondrogenesis: a model developmental system for measuring teratogenic potential of compounds. Teratogen Carcinogen Mutagen 2: 325–331Google Scholar
  7. Kamm JJ (1982) Toxicology, carcinogenicity, and teratogenicity of some orally administered retinoids. J Am Acad Dermatol 6: 652–659PubMedGoogle Scholar
  8. Kamm JJ, Ashenfelter KO, Ehmann CW (1984) Preclinical and clinical toxicology of selected retinoids. In: Sporn MB, Roberts AB, Goodman DS (eds) The retinoids, vol. 2. Academic Press, New York, pp 287–326Google Scholar
  9. Kistler A (1981a) Structure-activity relationship of retinoids in fetal rat bone cultures. Calcif Tissue Int 33: 249–254PubMedGoogle Scholar
  10. Kistler A (1981b) Teratogenesis of retinoic acid in rats. Susceptible stages and suppression of retinoid acid-induced limb malformations by cycloheximide. Teratology 23: 25–31CrossRefPubMedGoogle Scholar
  11. Kistler A (1984) Structure-activity relationship of retinoids on the differentiation of cultured chick foot skin. Roux's Arch Dev Biol 194: 9–17CrossRefGoogle Scholar
  12. Kistler A (1985) Inhibition of chondrogenesis by retinoids. Limb bud cell cultures as a test system to measure the teratogenic potential of compounds? In: Homburger F. Goldberg AM (eds) In vitro embryotoxicity and teratogenicity tests. Concepts Toxicol, vol 3. Karger, Basel, pp 86–100Google Scholar
  13. Kistler A (1986) Structure-activity relationship of retinoids on lobuloalveolar differentiation of cultured mouse mammary glands. Carcinogenesis 7: 1175–1182PubMedGoogle Scholar
  14. Kistler A (1987) Limb bud cell cultures for estimating the teratogenic potential of compounds. Validation of the test system with retinoids. Arch Toxicol 60: 403–414CrossRefPubMedGoogle Scholar
  15. Kistler A, Howard WB (1990) Testing of retinoids for teratogenicity in vivo. In: Packer L (ed) Retinoids. Methods in enzymology (in press)Google Scholar
  16. Kistler A, Mislin M, Gehrig A (1985) Chondrogenesis of limb bud cells. Improved method and the effect of the potent teratogen retinoic acid. Xenobiotica 15: 673–679PubMedGoogle Scholar
  17. Kistler A, Galli B, Howard WB (1990) Comparative teratogenicity of three retinoids: the arotinoids Ro 13-7410, Ro 13-6298 and Ro 15-1570. Arch Toxicol 64: 43–48PubMedGoogle Scholar
  18. Kochhar DM (1967) Teratogenic acitvity of retinoic acid. Acta Pathol Microbiol Scand 70: 398–404PubMedGoogle Scholar
  19. Lammer EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ, Braun JT, Curry CJ, Fernhoff PM, Grix AW, Lott IT, Richard JM, Sun SC (1985) Retinoic acid embryopathy. N Engl J Med 313: 837–841PubMedGoogle Scholar
  20. Loeliger P, Bollag W, Mayer H (1980) Arotinoids, a new class of highly active retinoids. Eur J Med Chem 15: 9–15Google Scholar
  21. Renault JY, Malcion C, Cordier A (1989) Limb bud cell culture for in vitro teratogen screening: validation of an improved assessment method using 51 compounds. Teratogen Carcinogen Mutagen 9: 83–96Google Scholar
  22. Tsuchiya T, Sekita S, Koyama K, Natori S, Takahashi A (1987) Effect of chaetochromin A, chaetochromin D and ustilaginoidin A, bis (naphtho-γ-pyrone) derivatives, on the mouse embryo limb bud and midbrain cells in culture. Cong Anom 27: 245–250Google Scholar
  23. Wilk AL, Greenberg JH, Horigan EA, Pratt RM, Martin GR (1980) Detection of teratogenic compounds using differentiating embryonic cells in culture. In Vitro 16: 269–276PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • Andreas Kistler
    • 1
  • Toshie Tsuchiya
    • 2
  • Masahiko Tsuchiya
    • 1
  • Michael Klaus
    • 1
  1. 1.Phamaceutical ResearchF. Hoffmann-La Roche LtdBasel
  2. 2.Faculty of Veterinary MedicineUniversity of BerneBernSwitzerland

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