Application of the adverse outcome pathway framework to genotoxic modes of action
| Autor: | Steven M. Bryce, Laura Custer, Kerry L. Dearfield, Carole L. Yauk, Giel Hendriks, Ashley Allemang, Sheila M. Galloway, Maik Schuler, Stefan Pfuhler, Patricia A Escobar, Azeddine Elhajouji, Gladys Ouedraogo, Albert J. Fornace, Heng-Hong Li, Jennifer C. Sasaki, Daniel J Roberts, Yasmin Dietz, Ulrike Hemmann, Jan van Benthem, Véronique Thybaud, Roland Froetschl, Lauren Peel, Mirjam Luijten |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Epidemiology
Health Toxicology and Mutagenesis Population Computational biology 010501 environmental sciences 01 natural sciences Tubulin binding 03 medical and health sciences mode of action Adverse Outcome Pathway Animals Humans Mode of action education Genetics (clinical) Organism 030304 developmental biology 0105 earth and related environmental sciences Aurora Kinase A 0303 health sciences education.field_of_study Adverse Outcome Pathways Mutagenicity Tests genotoxicity Chromosome Breakage Aneuploidy adverse outcome pathway Mutation Biological plausibility Chromosome breakage Genetic Toxicology DNA Damage Mutagens |
| Popis: | In May 2017, the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee hosted a workshop to discuss whether mode of action (MOA) investigation is enhanced through the application of the adverse outcome pathway (AOP) framework. As AOPs are a relatively new approach in genetic toxicology, this report describes how AOPs could be harnessed to advance MOA analysis of genotoxicity pathways using five example case studies. Each of these genetic toxicology AOPs proposed for further development includes the relevant molecular initiating events, key events, and adverse outcomes (AOs), identification and/or further development of the appropriate assays to link an agent to these events, and discussion regarding the biological plausibility of the proposed AOP. A key difference between these proposed genetic toxicology AOPs versus traditional AOPs is that the AO is a genetic toxicology endpoint of potential significance in risk characterization, in contrast to an adverse state of an organism or a population. The first two detailed case studies describe provisional AOPs for aurora kinase inhibition and tubulin binding, leading to the common AO of aneuploidy. The remaining three case studies highlight provisional AOPs that lead to chromosome breakage or mutation via indirect DNA interaction (inhibition of topoisomerase II, production of cellular reactive oxygen species, and inhibition of DNA synthesis). These case studies serve as starting points for genotoxicity AOPs that could ultimately be published and utilized by the broader toxicology community and illustrate the practical considerations and evidence required to formalize such AOPs so that they may be applied to genetic toxicity evaluation schemes. Environ. Mol. Mutagen. 61:114-134, 2020. © 2019 Wiley Periodicals, Inc. |
| Databáze: | OpenAIRE |
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