title: Relative developmental toxicity potencies of retinoids in the embryonic stem cell test compared with their relative potencies in in vivo and two other in vitro assays for developmental toxicity.
abstract: The present study determines the relative developmental toxicity potencies of retinoids in the embryonic stem (ES)-D3 cell differentiation assay of the embryonic stem cell test, and compares the outcomes with their relative potencies in in vivo and two other in vitro assays for developmental toxicity. The results reveal that the potency ranking obtained in the ES-D3 cell differentiation assay is similar to the reported potency rankings in the two other in vitro assays for developmental toxicity. TTNPB ((E)-4[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid) was the most potent retinoid, whereas etretinate and retinol had the lowest potency. All-trans-retinoic acid, 13-cis-retinoic acid, 9-cis-retinoic acid and acitretin showed an intermediate potency. In vivo potency rankings of the developmental toxicity of retinoids appear to be dependent on the species and/or exposure regimens used. The obtained in vitro potency ranking does not completely correspond with the in vivo potency rankings, although TTNPB is correctly predicted to be the most potent and retinol the least potent congener. The lack of in vivo kinetic processes in the ES-D3 cell differentiation assay might explain the deviating potency predictions of some retinoids. Therefore, knowledge on the species-dependent in vivo kinetics is essential when using in vitro toxicity data for the estimation of in vivo developmental toxicity potencies within series of related compounds.
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands. jochem.louisse@wur.nl
authors.forename: Jochem
authors.initials: J
authors.lastname: Louisse
authors.forename: Süleyman
authors.initials: S
authors.lastname: Gönen
authors.forename: Ivonne M C M
authors.initials: IM
authors.lastname: Rietjens
authors.forename: Miriam
authors.initials: M
authors.lastname: Verwei
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology* / Q000473:pathology; D000818:Animals; D041702:BALB 3T3 Cells; D002454:Cell Differentiation / Q000187:drug effects*; D002972:Cleft Palate / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D046149:Embryo Culture Techniques; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007700:Kinetics; D018878:Limb Buds / Q000002:abnormalities / Q000187:drug effects; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011817:Rabbits; D051381:Rats; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000378:metabolism; D012176:Retinoids / Q000633:toxicity*; D013045:Species Specificity; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D018168:Receptors, Retinoic Acid; D012176:Retinoids