Citation:

Jensen, M., D. Blatz, AND C. Lalone. Defining the Biologically Plausible Taxonomic Domain of Applicability of an Adverse Outcome Pathway: A Case Study Linking Nicotinic Acetylcholine Receptor Activation to Colony Death. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, 42(1):71-87, (2023). https://doi.org/10.1002/etc.5501

Impact/Purpose:

Understanding how broadly biological pathway knowledge can be extrapolated to other species, beyond the model organisms used to study the pathway, can aid in extrapolation of knowledge from tested model organism to other non-tested species. Recently details of a biological pathway describing the linkages from activation of the nicotinic acetylcholine receptor in honey bees to colony death/failure was developed. Typically, such pathway information is collected with knowledge about, and empirical data from, a single, or handful, of species with uncertainty as to how broadly such pathway-based knowledge can be extrapolated to other species. In describing this biological pathway, which primarily focused on honey bees, we begin to evaluate taxonomic relevance in the context of plausible similarity or differences at different levels of biological organization to also consider other bee species. This evaluation of taxonomic relevance considers, where possible, structural, functional, and modulatory conservation across species. Therefore, the U.S. Environmental Protection Agency’s Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool was employed to evaluate structural similarity across bee species where proteins were identified along the pathway, demonstrating a high degree of conservation. Additionally, at each level of biological organization, other non-molecular considerations can be used to inform taxonomic relevance, including as examples thermoregulation or foraging strategies, as well as colony structure (or lack there-of) and should therefore be described as a component of the evaluation. Initial efforts in defining the taxonomic domain of applicability relative to chemical stressor perturbation of this biological pathway may provide useful insights for protecting or monitoring for adverse effects in bees.

Description:

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 KE 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, to define the tDOA for KEs, KERs, and AOPs. Such data could be incorporated in the AOP-Wiki as lines of evidence toward biological plausibility for the tDOA. We present a case study describing the process of using bioinformatics to define the tDOA of an AOP using an AOP linking the activation of the nicotinic acetylcholine receptor to colony death/failure in Apis mellifera. Although the AOP was developed to gain a particular biological understanding relative to A. mellifera health, applicability to other Apis bees, as well as non-Apis bees, has yet to be defined. The present study 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.

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