Broadening the Definition of the Taxonomic Domain of Applicability of an Adverse Outcome Pathway Through Bioinformatics Approaches

Abstract

For the majority of developed adverse outcome pathways (AOPs), the taxonomic domain of applicability (tDOA) is typically narrowly defined with a single, or a handful of species. Defining the tDOA of an AOP is critical for use in regulatory decision-making, particularly when considering protection of untested species. Structural and functional conservation are two elements that can be considered when defining the tDOA. Publicly accessible bioinformatics approaches, such as the Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool, take advantage of existing and growing databases of protein sequence and structural information to provide lines of evidence toward structural conservation of key events (KEs) and key event relationships (KERs) of an AOP. It is anticipated that SeqAPASS results could readily be combined with data derived from empirical toxicity studies to provide evidence of both structural and functional conservation, which can be used to define the tDOA for KEs, KERs, and AOPs. Such data could be incorporated in the AOP-Wiki as lines of evidence towards biological plausibility for the tDOA. Here, a case study describing the process of using bioinformatics to define the tDOA of an AOP is presented using an AOP linking the activation of the nicotinic acetylcholine receptor to colony death/failure in Apis mellifera. While the AOP was developed to gain a particular biological understanding relative to Apis mellifera health, applicability to other Apis bees, as well as non-Apis bees, has yet to be defined. This work demonstrates how bioinformatics can be utilized to rapidly take advantage of existing protein sequence and structural knowledge to enhance and inform the tDOA of KEs, KERs, and AOPs, focusing on providing evidence of structural conservation across species.