Xenopus laevis: a model system for the study of embryonic retinoid metabolism. III. Isomerization and metabolism of all-trans-retinoic acid and 9-cis-retinoic acid and their dysmorphogenic effects in embryos during neurulation.

These investigations provide data pertaining to the metabolism and disposition of exogenous 9-cis-retinoic acid and all-trans-retinoic acid during neurulation in Xenopus embryos. Each isomer elicited malformations of the heart, eye, and brain, but approximately 2-fold higher concentrations of all-trans-retinoic acid than 9-cis-retinoic acid were required to produce qualitatively and quantitatively similar dysmorphogenic effects. The dymorphogenic effects of all-trans-retinoic acid could not be attributed to the isomerization of all-trans-retinoic acid to 9-cis-retinoic acid. Evidence is provided that all-trans-retinoic acid and 9-cis-retinoic acid are both direct-acting dysmorphogens. After Xenopus embryos were exposed to all-trans-retinoic acid, elevated levels of 4-oxo-all-trans-retinoic acid, 4-oxo-13-cis-retinoic acid, all-trans-retinoyl-beta-glucuronide, and 13-cis-retinoic acid were detected in the embryos, whereas embryonic levels of 9-cis-retinoic acid were actually slightly lower than endogenous levels during early neurulation. After embryos were exposed to 9-cis-retinoic acid during neurulation, elevated levels of 4-oxo metabolites, glucuronides and 9,13-di-cis-retinoic acid were observed in the embryos. At equivalent concentrations, 4-oxo-13-cis-retinoic acid and 13-cis-retinoic acid elicited fewer severe multiple malformations than all-trans isomers 9,13-di-cis isomers, or 9-cis isomers. The dysmorphogenic effect of 9,13-di-cis-retinoic acid may be caused by its isomerization to 9-cis-retinoic acid. All-trans retinoyl-beta-glucuronide was only marginally teratogenic at the highest concentrations tested.