StemPanTox: A fast and wide-target drug assessment system for tailor-made safety evaluations using personalized iPS cells.

An alternative model that reliably predicts human-specific toxicity is necessary because the translatability of effects on animal models for human disease is limited to context. Previously, we developed a method that accurately predicts developmental toxicity based on the gene networks of undifferentiated human embryonic stem (ES) cells. Here, we advanced this method to predict adult toxicities of 24 chemicals in six categories (neurotoxins, cardiotoxins, hepatotoxins, two types of nephrotoxins, and non-genotoxic carcinogens) and achieved high predictability (AUC = 0.90-1.00) in all categories. Moreover, we screened for an induced pluripotent stem (iPS) cell line to predict the toxicities based on the gene networks of iPS cells using transfer learning of the gene networks of ES cells, and predicted toxicities in four categories (neurotoxins, hepatotoxins, glomerular nephrotoxins, and non-genotoxic carcinogens) with high performance (AUC = 0.82-0.99). This method holds promise for tailor-made safety evaluations using personalized iPS cells.

Development of novel in vitro photosafety assays focused on the Keap1-Nrf2-ARE pathway.

Although photoallergens require UV energy for antigen formation, the subsequent immune response is considered to be the same as in ordinary skin sensitization. Therefore, in vitro tests for skin sensitization should also be applicable for photoallergy testing. In this study, we examined whether activation of the Keap1 (Kelch-like ECH-associated protein 1)-Nrf2 (nuclear factor-erythroid 2-related factor 2)-ARE (antioxidant response element) pathway could be used to assess the photoallergenic potential of chemicals, using the reporter cell line AREc32 or KeratinoSens(TM) . First, we identified an appropriate UVA irradiation dose [5 J cm(-2) irradiation in phosphate-buffered saline (PBS)] by investigating the effect of UV irradiation on ARE-dependent gene induction using untreated or 6-methylcoumarin (6-MC)-treated cells. Irradiation of well-known photoallergens under this condition increased ARE-dependent gene expression by more than 50% compared with both vehicle and non-irradiated controls. When the cut-off value for detecting photoallergens was set at 50% induction, the accuracy of predicting photoallergenic/phototoxic chemicals was 70% in AREc32 cells and 67% in KeratinoSens(TM) cells, and the specificity was 100% in each case. We designate these assays as a photo-ARE assay and photo-KeratinoSens(TM) , respectively. Our results suggest that activation of the Keap1-Nrf2-ARE pathway is an effective biomarker for evaluating both photoallergenic and phototoxic potentials. Either of the above tests might be a useful component of a battery of in vitro tests/in silico methods for predicting the photoallergenicity and phototoxicity of chemicals. Copyright © 2015 John Wiley & Sons, Ltd.

Prediction of genotoxic potential of cosmetic ingredients by an in silico battery system consisting of a combination of an expert rule-based system and a statistics-based system.

Genotoxicity is the most commonly used endpoint to predict the carcinogenicity of chemicals. The International Conference on Harmonization (ICH) M7 Guideline on Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk offers guidance on (quantitative) structure-activity relationship ((Q)SAR) methodologies that predict the outcome of bacterial mutagenicity assay for actual and potential impurities. We examined the effectiveness of the (Q)SAR approach with the combination of DEREK NEXUS as an expert rule-based system and ADMEWorks as a statistics-based system for the prediction of not only mutagenic potential in the Ames test, but also genotoxic potential in mutagenicity and clastogenicity tests, using a data set of 342 chemicals extracted from the literature. The prediction of mutagenic potential or genotoxic potential by DEREK NEXUS or ADMEWorks showed high values of sensitivity and concordance, while prediction by the combination of DEREK NEXUS and ADMEWorks (battery system) showed the highest values of sensitivity and concordance among the three methods, but the lowest value of specificity. The number of false negatives was reduced with the battery system. We also separately predicted the mutagenic potential and genotoxic potential of 41 cosmetic ingredients listed in the International Nomenclature of Cosmetic Ingredients (INCI) among the 342 chemicals. Although specificity was low with the battery system, sensitivity and concordance were high. These results suggest that the battery system consisting of DEREK NEXUS and ADMEWorks is useful for prediction of genotoxic potential of chemicals, including cosmetic ingredients.