Introducing WikiPathways as a Data-Source to Support Adverse Outcome Pathways for Regulatory Risk Assessment of Chemicals and Nanomaterials

Abstract

A paradigm shift is taking place in risk assessment to replace animal models, reduce the number of economic resources, and refine the methodologies to test the growing number of chemicals and nanomaterials. Therefore, approaches such as transcriptomics, proteomics, and metabolomics have become valuable tools in toxicological research, and are finding their way into regulatory toxicity. One promising framework to bridge the gap between the molecular-level measurements and risk assessment is the concept of adverse outcome pathways (AOPs). These pathways comprise mechanistic knowledge and connect biological events from a molecular level toward an adverse effect outcome after exposure to a chemical. However, the implementation of omics-based approaches in the AOPs and their acceptance by the risk assessment community is still a challenge. Because the existing modules in the main repository for AOPs, the AOP Knowledge Base (AOP-KB), do not currently allow the integration of omics technologies, additional tools are required for omics-based data analysis and visualization. Here we show how WikiPathways can serve as a supportive tool to make omics data interoperable with the AOP-Wiki, part of the AOP-KB. Manual matching of key events (KEs) indicated that 67% could be linked with molecular pathways. Automatic connection through linkage of identifiers between the databases showed that only 30% of AOP-Wiki chemicals were found on WikiPathways. More loose linkage through gene names in KE and Key Event Relationships descriptions gave an overlap of 70 and 71%, respectively. This shows many opportunities to create more direct connections, for example with extended ontology annotations, improving its interoperability. This interoperability allows the needed integration of omics data linked to the molecular pathways with AOPs. A new AOP Portal on WikiPathways is presented to allow the community of AOP developers to collaborate and populate the molecular pathways that underlie the KEs of AOP-Wiki. We conclude that the integration of WikiPathways and AOP-Wiki will improve risk assessment because omics data will be linked directly to KEs and therefore allow the comprehensive understanding and description of AOPs. To make this assessment reproducible and valid, major changes are needed in both WikiPathways and AOP-Wiki.

WikiPathways: connecting communities

“…Since the introduction of Adverse Outcome Pathways (AOPs) to support regulatory decision making for risk assessment of chemicals ( 24 ), the primary focus of AOP research groups has been capturing mechanistic data in written format. However, since the majority of biological processes described in AOPs are biological pathways that exist as pathway models on WikiPathways, the AOP Portal ( http://aop.wikipathways.org ) has been created to capture all pathways relevant to toxicological assessments ( 25 ). These molecular AOPs contribute to the understanding of AOPs and facilitate the use of various omics approaches in risk assessments ( 26 ).…”

“…One challenge lies in the unique rationale behind molecular AOPs, where biological processes are connected in a chain of Key Events (KEs) that make an AOP, rather than presenting one molecular pathway. Second, KEs often describe disturbances or adverse responses already captured in molecular pathways in WikiPathways ( 25 ) and therefore AOPs are modelled as meta-pathways. These combine pathway nodes and KE nodes in one data model, which is linked to the AOP-Wiki, https://aopwiki.org ).…”

Micro- and nano-plastics activation of oxidative and inflammatory adverse outcome pathways

“…The Key Event Relationships are linkages between adverse outcome pathway modules that provide scientific evidence supporting the relationships between examined substance and its toxic effects [ 20 ]. AOP approach for evaluation and assessment of the health risks associated with exposure to a chemical or compound is increasingly used in metadata analysis of existing knowledge [ 22 , 23 ]. Therefore, we used existing AOPs in an effort to synthetize and present information from systematic review of the reported MP/NPs adverse effects with focus on mechanistic relationships.…”

Adverse outcome pathways as a tool for the design of testing strategies to support the safety assessment of emerging advanced materials at the nanoscale

“…Two main advantages of using toxicogenomics data for advancing AOP development are: i) the comprehensive data supports validation of MIEs and KEs by providing molecular level details, and ii) the data enables identification of sensitive biomarkers for targeted measurement of the KEs identified in the AOP [9,44]. Initiatives have been taken to link biological pathway databases, such as WikiPathways, to AOPs, which enables AOP-linked bioinformatics analysis of toxicogenomics data [13,45]. For example, a data fusion pipeline aiming to enrich AOPs with molecular detail was successfully applied to develop an AOP-linked molecular description of lung fibrosis, demonstrating that transcriptomics data captures early effects of exposure before the histological manifestation of an AO.…”