Placental transfer and developmental effects of 9‐cisretinoic acid in mice

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Abstract
9‐cisretinoic acid (RA) is a naturally occurring isomer of all‐transRA. While both isomers can bind with high affinity and activate RA receptors, only 9‐cisRA is the specific ligand for the retinoid X receptors. 9cisRA has also been shown to be much more potent than all‐transRA in inducing digit duplication in the chick embryo wing bud. To gain further insight into its mechanisms, here we investigated the teratogenic activity in pregnant mice of 9‐cisRA and compared it with those of all‐transRA and 13‐cisRA. Using frequency and severity of limb reduction defects as well as palatal clefts in the resultant fetuses as indicators, we found that orally administered 9‐cisRA was one‐half as potent a teratogen as all‐transRA. That 9‐cisRA 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 micromass cultures using chondrogenesis as an end‐point. Since placental transfer ofcisisomers of RA is generally poor, we monitored the identities and amounts of retinoids in the embryo after administration of 9‐cisRA to the mother. We found that 9‐cisRA undergoes extensive metabolism and isomerization during absorption resulting in a number of metabolites in the maternal circulation within 30 min after administration. Although some of these metabolites remain to be identified, the most abundant RA isomers in the plasma coeluted with 13‐cisRA. The major isomer in the embryo, however, was all‐transRA, which exceeded the embryonic levels of 9‐cisRA and other retinoids in the 13‐cisRA fraction during the 3 hr period of monitoring. We conclude that orally administered 9‐cisRA is a weaker teratogen in mice than all‐transRA and suggest that its isomerization may be an important contributory factor to its teratogenicity. The individual role played by either of the receptor pathways in teratogenesis is unclear and needs further study.