Defining the Biologically Plausible Taxonomic Domain of Applicability of an Adverse Outcome Pathway: A Case Study Linking Nicotinic Acetylcholine Receptor Activation to Colony Death

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 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. Environ Toxicol Chem 2023;42:71–87. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Deciphering Host–Parasite Interplay in Leishmania Infection through a One Health View of Proteomics Studies on Drug Resistance

“…For the current analysis, the default susceptibility cutoff was employed, which identified the first local minimum and found the next ortholog candidate. 39 Additionally, we observed results from BLASTp on calpain-like cysteine peptidase (A0A6L0WUS2_LEIIN), which was designated as a putative sequence, and identified calpain-like cysteine peptidase from S. culicis (S9UQJ9_9TRYP) as the most similar, nonputative protein. This accession was selected for additional SeqAPASS analysis (Supporting Information S2).…”

“…We further examine the evolutionary conservation of these putative protein targets across species to gauge the potential environmental impacts of these new antiparasitic agents. Specifically, we use SeqAPASS, an online FDA-approved screening tool to examine protein sequence/structural similarity among taxonomic groups and to identify species with heightened sensitivity to specific chemicals. , The liquid chromatography–mass spectrometry (LC–MS)/MS characterization of new mechanisms of parasitic drug resistance stands as a useful effort in disease control, paving the way for the development of new target-based medicinal chemistry programs.…”

Projection of Interspecific Competition (PIC) Matrices: A Conceptual Framework for Inclusion in Population Risk Assessments

“…This information would directly inform PIC‐based population modeling. When there are no empirical comparative data concerning the effects of chemicals on the function of a given MIE, an alternative approach to predicting cross‐species sensitivity is assessment of structural conservation of the MIE (Jensen et al, 2023). Many molecular targets of chemicals (i.e., MIEs) are proteins for which amino acid sequence information exists for thousands of species in publicly accessible databases, such as the National Center for Bioinformatics Information (NCBI, 2024).…”

Towards Precision Ecotoxicology: Leveraging Evolutionary Conservation of Pharmaceutical and Personal Care Product Targets to Understand Adverse Outcomes Across Species and Life Stages

“…This is likely because toxicity and pathway data generated across species are typically relatively sparse and commonly only generated for a few model organisms. However, with advances in informatics, particularly bioinformatics, the possibilities of enhancing our understanding of conservation across species through extrapolation using comparative genomics, proteomics, and transcriptomics are being realized (Jensen et al, 2023).…”

“…Searching the genomes of wildlife species for pharmacological targets (Verbruggen et al, 2018) through simple online applications has become commonplace. Such comparative knowledge can then be used to inform the tDOA of AOPs (Jensen et al, 2023). We can also use the >900 available databases that provide in silico chemical and drug safety information (Pawar et al, 2019), combined with in vitro studies such as those in the USEPA's (2023) ToxCast database and include published historical in vivo experimental data to gather broad knowledge of chemical pathway information across species using combined new approach methodologies (NAMs) for ecotoxicology (Ankley et al, 2024; Brockmeier et al, 2017; Rivetti et al, 2020).…”