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Combination of Bioinformatics Approaches for Expanding the Biologically Plausible Taxonomic Domain of Applicability for Adverse Outcome Pathways
Citation:
Lalone, C., M. Jensen, S. Mayasich, M. Botz, P. Schumann, K. Mattingly, W. Melendez, A. Wilkinson, AND C. Simmons. Combination of Bioinformatics Approaches for Expanding the Biologically Plausible Taxonomic Domain of Applicability for Adverse Outcome Pathways. SOT, Nashville, TN, March 19 - 23, 2023. https://doi.org/10.23645/epacomptox.24299149
Impact/Purpose:
Presentation to the Society of Toxicology (SOT) 62nd Annual Meeting and ToxExpo March 2023. To make decisions on chemical safety it is useful to understand how chemicals effect biology. The Adverse Outcome Pathway framework does just that, by evaluating the knowledge available and formatting it in a manner that allows decision-makers the ability to understand the evidence that exists to link a chemical to an adverse event. Typically, this biological understanding can only be described for a single or handful of species. There are computer approaches that aid in understanding if knowledge about a biological pathway pertains to other species that have not been tested in the laboratory. Further there is an international effort to bring together experts developing these approaches and decision-makers that need such approaches to integrate them with the AOP framework to broaden the utility of the AOPs. Such approaches allow decision-makers the ability to make decisions on chemical safety considering the diversity of species. This presentation will describe how these computational approaches have been applied in this way and how they are expanding.
Description:
The adverse outcome pathway (AOP) framework is intended to describe the causal linkages from a direct molecular interaction with a stressor to an adverse outcome of regulatory concern. Capturing such existing knowledge across biological levels of organization in this manner allows decision-makers an opportunity to take advantage of data from growing numbers of mechanistic studies that typically do not measure apical outcomes for evaluations of chemical safety. The challenge of applying AOPs in a broader decision-making framework stems from the fact that the majority of AOPs that have been developed lack evidence to extrapolate pathway knowledge beyond the organisms captured in the AOP descriptions during development. To enhance the utility of AOPs and expand the taxonomic coverage, otherwise known as the defined taxonomic domain of applicability (tDOA), bioinformatics approaches can be used in combination to extrapolate knowledge based on conservation of biology (i.e., protein sequences/structures). Bringing together well-developed bioinformatics approaches for this purpose is the primary objective of the International Consortium to Advance Cross Species Extrapolation in Regulation (ICACSER). The ICACSER is currently in the process of vetting tools/databases/approaches to develop guidance and best practices for development and use of bioinformatics tools for extrapolation. Currently there are examples that focus on the usefulness of the Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool alone and in combination with other approaches demonstrating expansion of the biologically plausible tDOA. The capabilities of SeqAPASS to evaluate conservation of proteins involved in early key events of the AOP has been expanded from sequence only based predictions to protein structural evaluations. With the advances in artificial intelligence driving the protein structural prediction field forward at a rapid pace, there are opportunities to evaluate structural comparisons across species to incorporate additional metrics to be used in defining the biologically plausible tDOA. This presentation will highlight case examples demonstrating the application of such approaches for enhancing the utility of AOPs in decision making for the protection of the diversity of species in the environment. This abstract neither constitutes nor necessarily reflects USEPA policy.
URLs/Downloads:
DOI: Combination of Bioinformatics Approaches for Expanding the Biologically Plausible Taxonomic Domain of Applicability for Adverse Outcome Pathways
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