{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T18:37:46Z","timestamp":1791225466671,"version":"4.1.0"},"reference-count":32,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2005,6,3]],"date-time":"2005-06-03T00:00:00Z","timestamp":1117756800000},"content-version":"vor","delay-in-days":3716,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Teratology"],"published-print":{"date-parts":[[1995,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>9\u2010<jats:italic>cis<\/jats:italic>retinoic acid (RA) is a naturally occurring isomer of all\u2010<jats:italic>trans<\/jats:italic>RA. While both isomers can bind with high affinity and activate RA receptors, only 9\u2010<jats:italic>cis<\/jats:italic>RA is the specific ligand for the retinoid X receptors. 9<jats:italic>cis<\/jats:italic>RA has also been shown to be much more potent than all\u2010<jats:italic>trans<\/jats:italic>RA 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\u2010<jats:italic>cis<\/jats:italic>RA and compared it with those of all\u2010<jats:italic>trans<\/jats:italic>RA and 13\u2010<jats:italic>cis<\/jats:italic>RA. 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\u2010<jats:italic>cis<\/jats:italic>RA was one\u2010half as potent a teratogen as all\u2010<jats:italic>trans<\/jats:italic>RA. That 9\u2010<jats:italic>cis<\/jats:italic>RA was intrinsically less active than all\u2010<jats:italic>trans<\/jats:italic>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\u2010point. Since placental transfer of<jats:italic>cis<\/jats:italic>isomers of RA is generally poor, we monitored the identities and amounts of retinoids in the embryo after administration of 9\u2010<jats:italic>cis<\/jats:italic>RA to the mother. We found that 9\u2010<jats:italic>cis<\/jats:italic>RA 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\u2010<jats:italic>cis<\/jats:italic>RA. The major isomer in the embryo, however, was all\u2010<jats:italic>trans<\/jats:italic>RA, which exceeded the embryonic levels of 9\u2010<jats:italic>cis<\/jats:italic>RA and other retinoids in the 13\u2010<jats:italic>cis<\/jats:italic>RA fraction during the 3 hr period of monitoring. We conclude that orally administered 9\u2010<jats:italic>cis<\/jats:italic>RA is a weaker teratogen in mice than all\u2010<jats:italic>trans<\/jats:italic>RA 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. \u00a9 1995 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/tera.1420510411","type":"journal-article","created":{"date-parts":[[2005,6,11]],"date-time":"2005-06-11T16:09:07Z","timestamp":1118506147000},"page":"257-265","source":"Crossref","is-referenced-by-count":25,"title":["Placental transfer and developmental effects of 9\u2010<i>cis<\/i>retinoic acid in mice"],"prefix":"10.1002","volume":"51","author":[{"given":"Devendra M.","family":"Kochhar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Penner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Heyman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2005,6,3]]},"reference":[{"key":"e_1_2_1_2_1","first-page":"451","article-title":"Differences in the pharmacokinetic properties of orally administered all\u2010trans\u2013retinoic acid and 9\u2013cis\u2013retinoic acid in the plasma of nude mice","volume":"22","author":"Achkar C. 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