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Assessing cross species conservation of ToxCast Assay targets using Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS)
Citation:
LaLone, C., G. Ankley, T. Tal, AND Dan Villeneuve. Assessing cross species conservation of ToxCast Assay targets using Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS). To be Presented at Society of Toxicology, Baltimore, MD, March 12 - 16, 2017.
Impact/Purpose:
Application of EPA’s Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool to evaluate the protein sequence/structural conservation of the 460 protein targets represented in the ToxCast assay suite is presented. Similarity of primary amino acid sequences and sequences from specific functional domains were compared across species to understand conservation of each assay target across taxa, and to probe the question of how broadly the ToxCast data may be extrapolated to other organisms. This work will aid in characterization of the taxa for which a given ToxCast assay may have mechanistic relevance.
Description:
US EPA’s ToxCast program has screened thousands of chemicals in hundreds of mammalian-based HTS assays for biological activity suggestive of potential toxic effects. These data are being used to prioritize toxicity testing to focus on chemicals likely to lead to adverse health effects. The ToxCast assays are primarily mammlian-based, making cross-species extrapolation necessary for utilization of the ToxCast data for predicting adverse effects beyond humans to wildlife. To aid characterization of the taxa for which a given ToxCast assay may have mechanistic relevance, EPA’s Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool was applied to evaluate the protein sequence/structural conservation of the 460 protein targets represented in the ToxCast assay suite. The query species/sequence used for SeqAPASS analysis was selected based on the model organism used in the ToxCast assay (e.g., human, cattle, chimpanzee, guinea pig, rabbit, rat, mouse, pig, or sheep). Similarity of primary amino acid sequences and sequences from specific functional domains were compared across species to understand conservation of each assay target across taxa and to probe the question of how broadly the ToxCast data may be extrapolated to other organisms. To demonstrate the utility of SeqAPASS for informing the extrapolation of ToxCast data across species, a case study involving 30 ToxCast assay targets representative of molecular initiating events in adverse outcome pathways leading to abnormal vascular development was developed. This case study identified suitable model organisms for follow-up or complementary in vivo toxicity tests. SeqAPASS results for all 460 protein targets will be made available through the iCSS dashboard, to help aid and inform appropriate extrapolation of the ToxCast data. The views expressed in this poster are those of the authors and may not reflect U.S. EPA policy.