the most thoroughly studied of all teratogens. Because natural retinoids are signaling molecules, critical to many developmental processes, exogenous retinoids or vitamin A deficiencies are teratogenic in all animals studied, including humans (for review, see Collins and Mao 1999).

In higher animals, vitamin A is an essential vitamin, requiring absorption from the diet or synthesis from dietary retinyl esters, β-carotene, or other carotenoids. The all-trans form of retinol is most abundant, but there are a number of isomers, which generate the corresponding active retinoid isomers, including 9-cis and 11-cis, following metabolism. The absorption and distribution of retinol involves serum (RBP) and cellular (CRBP-I and CRBP-II) binding proteins. A number of enzymes are capable of converting retinol to retinoic acid, including CYP monooxygenases, alcohol dehydrogenases, and aldehyde dehydrogenases. Mutation of the mouse NAD-dependent retinaldehyde dehydrogenase-2 (ALDH2) (Niederreither et al. 1999) causes severe developmental defects, a result that shows this enzyme to be essential for embryonic RA synthesis. Further metabolism of RA is complex, involving multiple oxidation and conjugation pathways, some also CYP dependent (e.g., CYP26) (Kraft and Juchua 1993; Kraft et al. 1993; Nau et al. 1994; Trofimova-Griffin et al. 2000). Cellular binding proteins (CRABP-I and -II) are thought to influence intracellular levels of RA, but their exact role is unclear. The mouse knockout of CRABP-I is without phenotype, and CRABP-II null mice have polydactyly (Lampron et al. 1995). This phenotype is also the phenotype of the double-knockout mice, which do not, however, differ from wild-type animals in sensitivity to RA teratogenicity (Lampron et al. 1995).

Although there are some strain and species variations in developmental sensitivity and responses to exogenous retinoids, they are usually not profound. The effective oral dose of all-trans-RA in all mammals tested is broadly similar. In contrast, the potency of 13-cis-RA varies by two orders of magnitude. The explanation for this difference lies in species differences in metabolism, coupled with metabolite-specific placental transfer (see Collins and Mao 1999), and is a good illustration of the importance of toxicokinetics.

Some of the dysmorphogenic effects of retinoids are very well conserved across species. For example, RA-induced truncation of the forebrain, with posteriorization in the hindbrain, has been observed in mammals, birds, amphibia, and fish. In addition to CNS and craniofacial malformations, RA also affects the limbs, cardiovascular system, gut, and thymus; the predominant defects depend upon the phase of organogenesis exposed (Collins and Mao 1999). In mice, preorganogenesis RA treatment around the time of implantation induces body axis duplication and supernumerary limbs (Rutledge et al. 1994), whereas fetal exposures can cause functional and behavioral abnormalities (Nolen 1986). Human exposure to the pharmaceutical retinoids 13-cis-RA (isotretinoin) or etretinate predominantly affect CNS and cranial neural-crest development (Coberly et al. 1996).



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