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The potential of AOP networks for reproductive and developmental toxicity assay development
Citation:
Knapen, D., L. Vergauwen, Dan Villeneuve, AND G. Ankley. The potential of AOP networks for reproductive and developmental toxicity assay development. REPRODUCTIVE TOXICOLOGY. Elsevier Science Ltd, New York, NY, 56:52-55, (2015).
Impact/Purpose:
To support the vision for toxicity testing in the 21st century and societal demands in Europe and elsewhere to minimize the use of whole organisms and protected life stages in toxicology research, there is increased emphasis on the development and application of alternative, mechanistically-based, toxicity tests. The adverse outcome pathway (AOP) framework supports the application of mechanistically-based assays by outlining the biologically-plausible and scientifically supported linkages between molecular/biochemical/cellular-level perturbations and adverse outcomes of regulatory concern that they can lead to. Although individual AOPs represent highly simplified views of complex biology, the construction of modular AOP descriptions within the AOP-knowledgebase (AOP-KB) allows for de facto assembly of AOP networks. AOP networks are defined as a set of AOPs sharing one or more elements. By examining the connectivity within an AOP network it is possible to infer the biological points of convergence and divergence between various pathways and conceptualize potential interactions between pathways. The present letter/mini-review discusses and illustrates how the concept of AOP networks can be leveraged to direct and inform assay development. Through a simple example drawing upon AOPs deposited in the AOP-KB, the paper demonstrates how analysis of an AOP network can aid the identification of assays or endpoints, corresponding with key events in one or more AOPs, that represent points of convergence and thus may have predictive utility for multiple outcomes. It also demonstrates the converse, in which analysis of an AOP network can help identify divergenet key events and associated assays or endpoints which would have high diagnostic specificity. These approaches have direct application for both optimizing and prioritizing the design of alternative, fit-for-purpose assays as well as for directing how those assays may be used in an Integrated Approach to Tesing and Assessment (IATA).
Description:
Historically, the prediction of reproductive and early developmental toxicity has largely relied on the use of animals. The Adverse Outcome Pathway (AOP) framework forms a basis for the development of new non-animal test methods. It also provides biological context for mechanistic information from existing assays. However, a single AOP may not capture all events that contribute to any relevant toxic effect, even in single chemical exposure scenarios. AOP networks, defined as sets of AOPs sharing at least one common element, are capable of more realistically representing potential chemical effects. They provide information on interactions between AOPs and have the potential to reveal previously unknown links between biological pathways. Analysis of these AOP networks can aid the prioritization of assay development, whether the goal is to develop a single assay with predictive utility of multiple outcomes, or development of assays that are highly specific for a particular mode of action. This paper provides a brief overview of the AOPs related to reproductive and early developmental toxicity currently available in the AOP Wiki, and gives an example of an AOP network based on five reproductive and early developmental toxicity-related AOPs for fish to illustrate how AOP networks can be used for assay development and refinement.
