Thalidomide-induced limb malformations: an update and reevaluation.

Historically, thalidomide-induced congenital malformations have served as an important example of the enhanced susceptibility of developing embryos to chemical perturbation. The compound produced a wide variety of congenital malformations in humans, which were initially detected by an association with a relatively rare limb defect labeled phocomelia. Although true phocomelia in the most severe form is a transverse defect with intercalary absence of limb regions, it is proposed that thalidomide produces a longitudinal limb phenotype in humans under usual circumstances that can become transverse in severe cases with a preferential sensitivity of forelimb over hindlimb, preaxial over postaxial, and left more impacted than the corresponding non-autopod limb bones on the right. The thalidomide-induced limb phenotype in humans is described and followed by a hierarchical comparison with various laboratory animal species. Mechanistic studies have been hampered by the fact that only non-human primates and rabbits have malformations that are anatomically similar to humans. Included in this review are unpublished data on limb malformations produced by thalidomide in rhesus monkeys from experiments performed more than 50 years ago. The critical period in gestation for the induction of phocomelia may initiate prior to the development of the embryonic limb bud, which contrasts with other chemical and physical agents that are known to produce this phenotype. The importance of toxicokinetic parameters is reviewed including dose, enantiomers, absorption, distribution, and both non-enzymatic and enzymatic biotransformations. The limb embryopathy mechanism that provides a partial explanation of the limb phenotype is that cereblon binds to thalidomide creating a protein complex that ubiquitinates protein substrates (CRL4