This expanded annotation of AOPs allows computational reasoners to aid in both AOP development and applications. In addition, the incorporation of explicit biological objects will reduce the time required for converting a qualitative AOP description into a conceptual model that can support computational modeling. As high throughput genomics becomes a more important part of the high throughput toxicity testing landscape, the new approaches described here for annotating key events will also promote the visualization and analysis of genomics data in an AOP context.
The Adverse Outcome Pathway (AOP) framework describes the progression of a toxicity pathway from molecular perturbation to population-level outcome in a series of measurable, mechanistic responses. The controlled, computer-readable vocabulary that defines an AOP has the ability to, automatically and on a large scale, integrate AOP knowledge with publically available sources of biological high-throughput data and its derived associations. To support the discovery and development of putative (existing) and potential AOPs, we introduce the AOP-DB, an exploratory database resource that aggregates association relationships between genes and their related chemicals, diseases, pathways, species orthology information, ontologies, and gene interactions. These associations are mined from publically available annotation databases and are integrated with the AOP information centralized in the AOP-Wiki, allowing for the automatic characterization of both putative and potential AOPs in the context of multiple areas of biological information, referred to here as "biological entities". The AOP-DB acts as a hypothesis-generation tool for the expansion of putative AOPs, as well as the characterization of potential AOPs, through the creation of association networks across these biological entities. Finally, the AOP-DB provides a useful interface between the AOP framework and existing chemical screening and prioritization efforts by the US Environmental Protection Agency.
This study was undertaken to evaluate the use of ontology-based semantic mapping (OS-Mapping) in chemical toxicity assessment. Nineteen chemical-species phenotypic profiles (CSPPs) were constructed by ontologically annotating the toxicity responses reported in more than seven hundred published studies of ten chemicals on six vertebrate species. The CSPPs were semantically compared to more than 29000 publicly available phenotypic profiles of genes, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, and diseases based on a cross-species phenotype ontology. OS-Mapping was shown to differentiate chemical toxicities among themselves as well as within and across species. It also revealed cases of chemical by species interactions. In addition to confirming similar MOAs (mechanisms of action) for a few chemicals, OS-Mapping also generated novel insights into the MOAs underlying some seemingly different, yet phenotypically similar, classes of chemicals. The nature of a unified cross-species phenotype ontology and its representation of diverse knowledge domains allowed the construction of a complete phenotypic continuum for the 17α-ethynylestradiol_fathead minnow across the biological levels of organization, which complemented a similar one derived from the Comparative Toxicogenomics Database but based primarily on 17α-ethynylestradiol-induced molecular phenotypes. Overall, OS-Mapping has been demonstrated to offer a powerful approach to help bridge the gap between the molecular and non-molecular phenotypes of chemicals characterized by using high throughput or traditional omics methods and their apical endpoints of greater regulatory relevance, which are typically phenotypes found at the higher levels of biological organization. OS-Mapping also enables comparative toxicity assessment among chemicals, both within and across species. Furthermore, the semantic analysis of phenotypes can reveal additional novel MOAs for some well-known chemicals and discover candidate MOAs for chemicals that are less molecularly characterized. A full phenotypic continuum based on OS-Mapping will also be conducive to the future development of adverse outcome pathways. As phenomics continues to advance and the ontological annotation of literature becomes more automated, the power of OS-Mapping will be further enhanced.
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