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.