Introducing WikiPathways to link molecular pathways to Adverse Outcome Pathways

1. Introduction

In the last decade, omics-based approaches such as transcriptomics and metabolomics have become valuable tools in toxicological research, and are finding their way into regulatory toxicity. (1,2) One promising framework to bridge the gap between the molecular-level measurements and risk assessment is the concept of Adverse Outcome Pathways (AOPs). (3) These pathways comprise mechanistic knowledge and connect biological events from a molecular level towards an adverse effect after exposure to a chemical at higher biological level. However, the implementation of omics-based approaches in the AOPs and acceptance by the risk assessment community is still a challenge. (2) Therefore, tools are required for omics-based data analysis and visualization, and to link the data to the traditional AOPs.

2. Approach

Here we show how WikiPathways (www.wikipathways.org), an open science pathway database, can serve as a viable tool for this purpose. Therefore, an AOP Portal has been created (http://aop.wikipathways.org) with a collection of molecular-level AOPs on which omics datasets can be mapped an analysed. Besides that, we are making WikiPathways more interoperable with aopwiki.org, the main knowledge-base that collects and stores AOPs.

3. Results

Currently, the AOP Portal on WikiPathways consists of a panel of AOPs that are based on various resources such as aopwiki.org, the AOPXplorer application and directly from literature. One example that connects omics data to the concept of AOPs by using WikiPathways is the AOP on pulmonary fibrosis. (4) The collection of AOPs will grow with, for example, the inclusion of the AOPs that are being developed in EU-ToxRisk project, an “Integrated European ‘Flagship’ Programme Driving Mechanism-based Toxicity Testing and Risk Assessment for the 21st century”, in which AOPs play a central role. (5)

4. Discussion

The open and collaborative nature makes WikiPathways a fast growing platform that is applicable in a wide range of biomedical research fields in which omics-based approaches are used. Also, its use of ontologies, OpenAPI documentation and FAIR (Findable, Accessible, Interoperable, Reusable) approaches makes WikiPathways interoperable with many other data sources. By introducing AOPs in WikiPathways and linking these with the AOPs in aopwiki.org, we addressed the interoperability issues and are making WikiPathways a useful tool for the regulatory toxicity community and for toxicological research in general. We aim to make this integration support the determination of biological plausibility and therefore a suitable for decision-making in REACH (Registration, Evaluation, Authorization, and restriction of Chemicals) dossiers for risk assessment of chemicals.

References

1. Quercioli D, Roli A, Morandi E, Perdichizzi S, Polacchini L, Rotondo F, et al. The use of omics-based approaches in regulatory toxicology: an alternative approach to assess the no observed transcriptional effect level. Microchem J [Internet]. 2018;136:143–8. Available from: https://doi.org/10.1016/j.microc.2017.01.029
2. Brockmeier EK, Hodges G, Hutchinson TH, Butler E, Hecker M, Tollefsen KE, et al. The Role of Omics in the Application of Adverse Outcome Pathways for Chemical Risk Assessment. Toxicol Sci. 2017;158(2):252–62.
3. Ankley GT, Bennett RS, Erickson RJ, Hoff DJ, Hornung MW, Johnson RD, et al. Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem [Internet]. 2010 Mar 1 [cited 2018 Jan 23];29(3):730–41. Available from: http://doi.wiley.com/10.1002/etc.34
4. Nymark P, Rieswijk L, Ehrhart F, Jeliazkova N, Tsiliki G, Sarimveis H, et al. A Data Fusion Pipeline for Generating and Enriching Adverse Outcome Pathway Descriptions. Toxicol Sci. 2018;162(1):264–75.
5. EU-ToxRisk - EU-ToxRisk – An Integrated European “Flagship” Programme Driving Mechanism-based Toxicity Testing and Risk Assessment for the 21st century [Internet]. Available from: http://www.eu-toxrisk.eu/