PLACENTAL-TRANSFER AND DEVELOPMENTAL EFFECTS OF 9-CIS RETINOIC ACID IN MICE

9-cis retinoic acid (RA) is a naturally occurring isomer of all-trans RA. While both isomers can bind with high affinity and activate RA rec eptors, only 9-cis RA is the specific ligand for the retinoid X recept ors. 9-cis RA has also been shown to be much more potent than all-tran s RA in inducing digit duplication in the chick embryo wing bud. To ga in further insight into its mechanisms, here we investigated the terat ogenic activity in pregnant mice of 9-cis RA and compared it with thos e of all-trans RA and 13-cis RA. Using frequency and severity of limb reduction defects as well as palatal clefts in the resultant fetuses a s indicators, we found that orally administered 9-cis RA was one-half as potent a teratogen as all-trans RA. That 9-cis RA was intrinsically less active than all-trans RA was deduced by comparing the inhibitory activities of the two retinoids in the limb bud mesenchymal cell micr omass cultures using chondrogenesis as an end-point. Since placental t ransfer of cis isomers of RA is generally poor, we monitored the ident ities and amounts of retinoids in the embryo after administration of 9 -cis RA to the mother. We found that 9-cis RA undergoes extensive meta bolism and isomerization during absorption resulting in a number of me tabolites in the maternal circulation within 30 min after administrati on. Although some of these metabolites remain to be identified, the mo st abundant RA isomers in the plasma coeluted with 13-cis RA. The majo r isomer in the embryo, however, was all-trans RA, which exceeded the embryonic levels of 9-cis RA and other retinoids in the 13-cis RA frac tion during the 3 hr period of monitoring. We conclude that orally adm inistered 9-cis RA is a weaker teratogen in mice than all-trans RA and suggest that its isomerization may be an important contributory facto r to its teratogenicity. The individual role played by either of the r eceptor pathways in teratogenesis is unclear and needs further study.