title: Prediction of in vivo developmental toxicity by combination of Hand1-Luc embryonic stem cell test and metabolic stability test with clarification of metabolically inapplicable candidates.
abstract: Hand1-Luc Embryonic Stem Cell Test (Hand1-Luc EST) is a promising alternative method for evaluation of developmental toxicity. However, the problems of predictivity have remained due to appropriateness of the solubility, metabolic system, and prediction model. Therefore, we assessed the usefulness of rat liver S9 metabolic stability test using LC-MS/MS to develop new prediction model. A total of 71 chemicals were analyzed by measuring cytotoxicity and differentiation toxicity, and highly reproducible (CV=20%) results were obtained. The first prediction model was developed by discriminant analysis performed on a full dataset using Hand1-Luc EST, and 66.2% of the chemicals were correctly classified by the cross-validated classification. A second model was developed with additional descriptors obtained from the metabolic stability test to calculate hepatic availability, and an accuracy of 83.3% was obtained with applicability domain of 50.7% (=36/71) after exclusion of 22 metabolically inapplicable candidates, which potentially have a metabolic activation property. A step-wise prediction scheme with combination of Hand1-Luc EST and metabolic stability test was therefore proposed. The current results provide a promising in vitro test method for accurately predicting in vivo developmental toxicity.
authors.affiliation: Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 1-98, Kasugadenaka 3-chome, Konohana-ku, Osaka, 554-8558, Japan. Electronic address: nagahori@sc.sumitomo-chem.co.jp.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Nagahori
authors.affiliation: Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 1-98, Kasugadenaka 3-chome, Konohana-ku, Osaka, 554-8558, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Suzuki
authors.affiliation: Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 1-98, Kasugadenaka 3-chome, Konohana-ku, Osaka, 554-8558, Japan.
authors.forename: Florian
authors.initials: F
authors.lastname: Le Coz
authors.affiliation: Faculty of Biomedical Sciences, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Omori
authors.affiliation: Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 1-98, Kasugadenaka 3-chome, Konohana-ku, Osaka, 554-8558, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Saito
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D002478:Cells, Cultured; D016002:Discriminant Analysis; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects; D005786:Gene Expression Regulation; D015386:Hazardous Substances / Q000633:toxicity*; D008099:Liver / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015386:Hazardous Substances; D008156:Luciferases; C095572:Hand1 protein, mouse
keywords: Cytotoxicity; In-vitro toxicity; Metabolism; Reproductive toxicity