STRUCTURE-ACTIVITY AND DOSE-RESPONSE RELATIONSHIPS IN THE NEURAL AND BEHAVIORAL TERATOGENESIS OF RETINOIDS

The therapeutic use in the human teratogenic range of retinoid compounds (Accutane; Tigason) for the treatment of dermatologic disorders has refocused attention on the teratogenicity of vitamin A-related compounds. This article reviews rodent data on three retinoids: vitamin A (retinol), all-trans retinoic acid (tretinoin), and 13-cis retinoic acid (isotretinoin) with respect to effects on central nervous system (CNS) malformations and postnatal death, growth reduction, and behavioral dysfunction. All three retinoids have been shown to effect these endpoints in a dose-dependent manner whereby smaller doses are necessary to produce each consecutive endpoint at the same stage of gestation. Whereas gestation days (GD) 8-10 are the most sensitive for the induction of gross CNS malformation, GD 11-13 appear most sensitive in effecting postnatal endpoints in rats with normal gross morphology. With respect to structure-activity relationships, retinol appears to have less than 1/4 the potency of all-trans retinoic acid, and isotretinoin may have much less than 1/8 the potency of all-trans retinoic acid in disrupting development with respect to all endpoints. The systematic relationships across endpoints argue for common controlling variables. For these retinoids, all-trans retinoic acid and its metabolites are proposed as the active agents of developmental toxicity.