RESUMO
Retinoids are involved in several physiological processes and are used in the treatment of various skin disorders. Therapy with retinoids during pregnancy may induce severe embryotoxic effects like craniofacial and cardiovascular malformations in the developing embryo. We investigated the effects of all-trans-retinoic acid (ATRA) and all-trans-retinoyl-beta-D-glucuronide (ATRAG) in an amphibian embryotoxicity assay with Ambystoma mexicanum (axolotl) as an alternative in vitro method. Embryos were exposed to various concentrations of ATRA or ATRAG for 48 h beginning with the blastula stage. Kinetic investigations in the embryonic tissue were performed during the exposure period. Both retinoids interfered with the development of the axolotl embryos. Dose-dependent effects observed included growth retardation, craniofacial and cardiovascular malformations, as well as neural tube defects. In the axolotl, ATRA induced slightly more pronounced embryotoxic effects than ATRAG. All-trans-retinal was shown to be a major endogenous retinoid in this species. Endogenous levels of all-trans-retinaldehyde were increased during exposure to both ATRA and ATRAG. The glucuronide, however, was only detected in small amounts after ATRAG exposure. The embryotoxic potential of ATRAG could be explained by deglucuronidation to ATRA.
Assuntos
Anormalidades Induzidas por Medicamentos , Ambystoma/embriologia , Embrião não Mamífero/efeitos dos fármacos , Tretinoína/análogos & derivados , Tretinoína/toxicidade , Alternativas aos Testes com Animais , Animais , Técnicas de Cultura , Relação Dose-Resposta a Droga , Embrião não Mamífero/anormalidades , Feminino , Masculino , Tretinoína/metabolismoRESUMO
In the amphibian Ambystoma mexicanum, valproic acid (VPA) causes retarded development and malformations including neural tube defects. Some of the observed abnormalities resemble exencephaly. We present the light microscopic characteristics of VPA-induced effects on the developing central nervous system (CNS) as well as on other developing tissues of this species. To induce malformations, various concentrations of VPA were applied to embryos from blastula stage on, either as 24-h pulse or as continuous exposure. In treated embryos the abnormal development of the CNS was indicated by retarded neurulation and disturbed closure of the neural folds. Furthermore, the neural epithelium was disorganized and its cells were less elongated than normal. Two ventricle lumina of various shapes arose in the neural tube and the neural epithelium extended laterally, whereas in the control animals the neural tube was small and overlaid the notochord only. In treated embryos intercellular spaces in neural epithelium as well as in connective tissue were enlarged and cell adhesion seemed disturbed in both tissues. The notochord underlying the neural plate appeared to be normally organized but oversized somites appeared, which periodically filled the space between notochord and notoplate. VPA also affected neural crest cells. Additional effects occurring were edema and liver damage. A high concentration of VPA even stopped development in early gastrulation. Characteristics of induced effects indicate an interaction between the drug and components of the extracellular matrix and the cytoskeleton.