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Cross-species Extrapolation of an Adverse Outcome Pathway for Ecdysteroid Receptor Activation Carlie A. LaLone University of Minnesota Water Resources Center Define the taxonomic domain of applicability • Adverse outcome pathway development – Ecdysteroid receptor (EcR) activation leading to mortality ? AOP extrapolation across taxa Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) • Sequence based approach to predict relative intrinsic susceptibility • – Receptor/enzyme available for the chemical to act upon Conservation of MIE: Extrapolate MIE across taxa Facilitates a Strategic Approach for Assessing Protein Similarity Across Species ~ Conservation of molecular target: Line-of-evidence that MIE may be relevant SeqAPASS Query Daphnia magna Ecdysteroid Receptor All Protein Sequences in the NCBI protein database SeqAPASS Results Across Taxa • Query Daphnia magna ecdysteroid receptor Primary amino acid sequence Ligand binding domain Key amino acid residues • Collaborators developed homology model to identify key residues SeqAPASS • EcR sequence and structural conservation: MIE likely relevant – – – – – – Branchiopoda Insecta Chilopoda Arachnida Malacostraca Maxillopoda Taxonomic domain of applicability Acknowledgments • U.S. Environmental Protection Agency • – Daniel Villeneuve – Gerald Ankley Computer Sciences Corporation • – Henry Helgen – Steve Walata – Derek Lane Norwegian Institute for Water Research (NIVA) • – Knut Erik Tollefsen – You Song – Tore Høgåsen Universitetet I Tromsø, The Arctic University of Norway – Ingebrigt Sylte – Kurt Kristiansen