title: Prediction of developmental chemical toxicity based on gene networks of human embryonic stem cells.
abstract: Predictive toxicology using stem cells or their derived tissues has gained increasing importance in biomedical and pharmaceutical research. Here, we show that toxicity category prediction by support vector machines (SVMs), which uses qRT-PCR data from 20 categorized chemicals based on a human embryonic stem cell (hESC) system, is improved by the adoption of gene networks, in which network edge weights are added as feature vectors when noisy qRT-PCR data fail to make accurate predictions. The accuracies of our system were 97.5-100% for three toxicity categories: neurotoxins (NTs), genotoxic carcinogens (GCs) and non-genotoxic carcinogens (NGCs). For two uncategorized chemicals, bisphenol-A and permethrin, our system yielded reasonable results: bisphenol-A was categorized as an NGC, and permethrin was categorized as an NT; both predictions were supported by recently published papers. Our study has two important features: (i) as the first study to employ gene networks without using conventional quantitative structure-activity relationships (QSARs) as input data for SVMs to analyze toxicogenomics data in an hESC validation system, it uses additional information of gene-to-gene interactions to significantly increase prediction accuracies for noisy gene expression data; and (ii) using only undifferentiated hESCs, our study has considerable potential to predict late-onset chemical toxicities, including abnormalities that occur during embryonic development.
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8654, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Yamane
authors.affiliation: Computational Biology Research Center, Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Aburatani
authors.affiliation: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8654, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Imanishi
authors.affiliation: Research Center for Environmental Risk, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Akanuma
authors.affiliation: Research Center for Environmental Risk, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Nagano
authors.affiliation: Department of Computer Science, Gunma University, 1-5-1 Tenjin-cho, Kiryu, Gunma 376-8515, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kato
authors.affiliation: Research Center for Environmental Risk, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan.
authors.forename: Hideko
authors.initials: H
authors.lastname: Sone
authors.affiliation: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8654, Japan.
authors.forename: Seiichiroh
authors.initials: S
authors.lastname: Ohsako
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan Computational Biology Research Center, Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan fujibuchi-g@cira.kyoto-u.ac.jp.
authors.forename: Wataru
authors.initials: W
authors.lastname: Fujibuchi
mesh_terms: D001559:Benzhydryl Compounds / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D019295:Computational Biology; D004249:DNA Damage / Q000187:drug effects*; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000235:genetics*; D000066449:Human Embryonic Stem Cells / Q000187:drug effects*; D006801:Humans; D009498:Neurotoxins / Q000633:toxicity*; D026023:Permethrin / Q000633:toxicity; D010636:Phenols / Q000633:toxicity; D021281:Quantitative Structure-Activity Relationship; D060388:Support Vector Machine; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D002273:Carcinogens; D009498:Neurotoxins; D026023:Permethrin; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds