Expanded Tox21 biological assay panel for the prediction of drug-induced liver injury and cardiotoxicity.
| Title: | Expanded Tox21 biological assay panel for the prediction of drug-induced liver injury and cardiotoxicity. |
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| Authors: | Xu T; Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, USA.; Ooka M; Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, USA.; Zhao J; Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, USA.; Sakamuru S; Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, USA.; Ngan DK; Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, USA.; Zhang L; Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, USA.; Yang S; Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, USA.; Travers J; Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, USA.; Xia M; Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, USA.; Zhao T; Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, USA.; Klumpp-Thomas C; Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, USA.; Zhu H; Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, USA.; Hall MD; Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, USA.; Ferguson S; Division of Translational Toxicology, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Research Triangle Park, North Carolina, USA.; Shaw ND; Pediatric Neuroendocrinology Group, Clinical Research Branch, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park (RTP), North Carolina, USA.; Reif DM; Division of Translational Toxicology, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Research Triangle Park, North Carolina, USA.; Simeonov A; Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, USA.; Huang R; Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, USA. |
| Source: | Environmental health perspectives [Environ Health Perspect] 2025 Jun 06. Date of Electronic Publication: 2025 Jun 06. |
| Publication Model: | Ahead of Print |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: National Institute of Environmental Health Sciences Country of Publication: United States NLM ID: 0330411 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-9924 (Electronic) Linking ISSN: 00916765 NLM ISO Abbreviation: Environ Health Perspect Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Research Triangle Park, N. C. National Institute of Environmental Health Sciences. |
| Abstract: | Background: Toxicology in the 21st Century (Tox21) assay data provide a valuable resource for the prediction of in vivo toxicity using machine learning models. However, the performances of these models previously developed using the pre-existing Tox21 assay data were less than ideal, likely due to insufficient coverage of the biological response space by the assay targets.; Objectives: This study aimed to assess whether expanding the Tox21 portfolio with new assays that probe under-represented targets/pathways related to unanticipated adverse drug effects could improve the predictive capacity of in vitro assay data for in vivo toxicity such as drug induced liver injury (DILI) and cardiotoxicity (DICT).; Methods: Models were constructed using data from the pre-existing panel of 36 assay targets and the expanded panel of 49 assay targets. A feature selection approach was used to determine the optimal number of assays needed for each model. The models were then applied to predict the potential hepatotoxicity and cardiotoxicity of compounds in the Tox21 10K compound library.; Results: For both DILI and DICT prediction, the best-performing models developed using the expanded assay panel required a smaller number of assays to achieve the same level of performance compared to those based on the pre-existing assays. Models constructed by combining both assay data (pre-existing + expanded) and chemical structure consistently outperformed those constructed based on assay data alone, but showed similar performance to those constructed based on chemical structure. The compounds predicted to have the highest toxic potential were experimentally verified to demonstrate the effectiveness of our models in identifying new potentially toxic compounds.; Discussion: The expansion of the Tox21 assay panel has significantly enhanced the predictive capacity of assay data for predicting DILI and DICT potential. This improvement underscores the importance of a diverse and comprehensive in vitro assay portfolio in advancing safety assessment. https://doi.org/10.1289/EHP16190. |
| Grant Information: | Z99 TR999999 United States ImNIH Intramural NIH HHS; ZIA TR000040 United States ImNIH Intramural NIH HHS |
| Entry Date(s): | Date Created: 20250606 Latest Revision: 20260317 |
| Update Code: | 20260317 |
| PubMed Central ID: | PMC12990090 |
| DOI: | 10.1289/EHP16190 |
| PMID: | 40478799 |
| Database: | MEDLINE |
Journal Article