Titre du document / Document title

Interactive dysmorphogenic effects of all-trans-retinol and ethanol on cultured whole rat embryos during organogenesis

Auteur(s) / Author(s)

CHEN H. ⁽¹⁾ ; YANG H.-Y. L. ⁽¹⁾ ; NAMKUNG M. J. ⁽¹⁾ ; JUCHAU M. R. ⁽¹⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Department of Pharmacology, School of Medicine, University of Washington, Seattle, Washington 98165, ETATS-UNIS

Résumé / Abstract

Whole rat conceptuses (10.5 gestational days) were explanted into a culture medium containing all-trans-retinol (t-retinol, vitamin A₁), ethanol, or combinations of the two alcohols at various concentrations, and were cultured at 37°C for 24 he. Parameters emphasized in morphological analyses were branchial arch development, closure of neural tube, axial rotation, and development of otic vesicles and of optic cup. Additions of t-retinol alone to the culture medium resulted in significant decreases in viability at concentrations of 7.0 μM and above. A primary target site affected by t-retinol was the second branchial arch. With initial culture medium concentrations of 3.5 μM, 28% of embryos exhibited an underdeveloped second branchial arch, and the effect was concentration dependent. Incubations with t-retinol alone also caused failure of closure of neural tubes, underdevelopment/absence of otic and optic vesicles, and failure of normal axial rotation, but these effects were statistically significant only at the higher concentrations (10.5-14.0 μM). Incubations of conceptuses with ethanol alone resulted in statistically significant decreases in viability and increases of incidence of embryonic abnormalities at 50 mM but not at 10- or 20-mM concentrations. The embryotoxicity of ethanol appeared less site-specific than that of t-retinol. However, ethanol-elicited developmental abnormalities included underdevelopment of the first and second branchial arches, abnormally open neural tubes, abnormally small or absent otic and optic vesicles, and incomplete axial rotation in common with effects elicited by t-retinol. In general, embryos incubated with combinations of t-retinol and ethanol showed lower survival rates and higher incidences of developmental abnormalities when compared to the calculated values expected for simple additive effects ; i.e., interactive effects were most frequently greater than additive and probably synergistic but not antagonistic. To assist in the elucidation of possible mechanism(s) for the greater than additive/synergistic dysmorphogenic effects observed, concentrations of all-trans-retinoic acid (t-RA) and all-trans-retinal (t-retinal) in cultured conceptal tissues were determined by high-performance liquid chromatography (HPLC). HPLC analysis showed increases in conceptal tissue levels of both t-RA and t-retinal after conceptuses were exposed to t-retinol (10.5 μM) plus various quantities of ethanol for 24 he. These observations, in combination with those of previous studies, suggested that the observed greater-than-additive/synergistic dysmorphogenic effects were not due to the inhibition by ethanol of conceptal biosynthesis oft- RA. Whether the increased levels of t-RA and t-retinal caused the observed greater than additive/synergistic dysmorphogenic effects remains to be elucidated.

Revue / Journal Title

Teratology   ISSN 0040-3709   CODEN TJADAB 

Source / Source

1996, vol. 54, n^o1, pp. 12-19 (26 ref.)

Langue / Language

Anglais

Editeur / Publisher

Wiley-Liss, New York, NY, ETATS-UNIS  (1968-2002) (Revue)

Mots-clés anglais / English Keywords

Ethanol ; Retinol ; Drug poison interaction ; Teratogen ; Dysmorphism ; Embryonic development ; Rat ; Animal ; Toxicity ; In vitro ; Explant ; Tretinoin ; Retinoic acid ; Organogenesis ; Retinoids ; Vitamin ; Mechanism of action ; Rodentia ; Mammalia ; Vertebrata ;

Mots-clés français / French Keywords

Ethanol ; Rétinol ; Interaction toxique médicament ; Tératogène ; Dysmorphie ; Développement embryonnaire ; Rat ; Animal ; Toxicité ; In vitro ; Explant ; Trétinoïne ; Rétinoïque acide ; Organogenèse ; Rétinoïde ; Vitamine ; Mécanisme action ; Vitamine A1 ; t-Rétinal ; Rodentia ; Mammalia ; Vertebrata ;

Mots-clés espagnols / Spanish Keywords

Etanol ; Retinol ; Interacción sustancia tóxica medicamento ; Teratogeno ; Dismorfia ; Desarrollo embrionario ; Rata ; Animal ; Toxicidad ; In vitro ; Explante ; Tretinoína ; Retinoico ácido ; Organogénesis ; Retinoide ; Vitamina ; Mecanismo acción ; Rodentia ; Mammalia ; Vertebrata ;

Localisation / Location

INIST-CNRS, Cote INIST : 14237, 35400006700364.0020