title: Extended evaluation on the ES-D3 cell differentiation assay combined with the BeWo transport model, to predict relative developmental toxicity of triazole compounds.
abstract: The mouse embryonic stem D3 (ES-D3) cell differentiation assay is based on the morphometric measurement of cardiomyocyte differentiation and is a promising tool to detect developmental toxicity of compounds. The BeWo transport model, consisting of BeWo b30 cells grown on transwell inserts and mimicking the placental barrier, is useful to determine relative placental transport velocities of compounds. We have previously demonstrated the usefulness of the ES-D3 cell differentiation assay in combination with the in vitro BeWo transport model to predict the relative in vivo developmental toxicity potencies of a set of reference azole compounds. To further evaluate this combined in vitro toxicokinetic and toxicodynamic approach, we combined ES-D3 cell differentiation data of six novel triazoles with relative transport rates obtained from the BeWo model and compared the obtained ranking to the developmental toxicity ranking as derived from in vivo data. The data show that the combined in vitro approach provided a correct prediction for in vivo developmental toxicity, whereas the ES-D3 cell differentiation assay as stand-alone did not. In conclusion, we have validated the combined in vitro approach for developmental toxicity, which we have previously developed with a set of reference azoles, for a set of six novel triazoles. We suggest that this combined model, which takes both toxicodynamic and toxicokinetic aspects into account, should be further validated for other chemical classes of developmental toxicants.
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6700 HE, Wageningen, The Netherlands. hequn.li@wur.nl.
authors.forename: Hequn
authors.initials: H
authors.lastname: Li
authors.affiliation: Experimental Toxicology and Ecology, BASF SE, Z 470, 67056, Ludwigshafen, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Flick
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6700 HE, Wageningen, The Netherlands.
authors.forename: Ivonne M C M
authors.initials: IM
authors.lastname: Rietjens
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6700 HE, Wageningen, The Netherlands.
authors.forename: Jochem
authors.initials: J
authors.lastname: Louisse
authors.affiliation: Experimental Toxicology and Ecology, BASF SE, Z 470, 67056, Ludwigshafen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6700 HE, Wageningen, The Netherlands.|Experimental Toxicology and Ecology, BASF SE, Z 470, 67056, Ludwigshafen, Germany.
authors.forename: Bennard
authors.initials: B
authors.lastname: van Ravenzwaay
mesh_terms: D000818:Animals; D001681:Biological Assay / Q000379:methods*; D001692:Biological Transport; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000473:pathology; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000473:pathology; D005865:Gestational Age; D006801:Humans; D007700:Kinetics; D018811:Maternal Exposure; D051379:Mice; D008954:Models, Biological; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D018570:Risk Assessment; D014230:Triazoles / Q000378:metabolism / Q000633:toxicity*; D014327:Trophoblasts / Q000378:metabolism*
chemical_list: D014230:Triazoles
keywords: Alternatives to animal testing; BeWo cells; Developmental toxicity; Embryonic stem cell test; Placental transfer