cross-species extrapolation of an adverse outcome pathway ......aop extrapolation across taxa ....
TRANSCRIPT
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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
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Define the taxonomic domain of applicability
• Adverse outcome pathway development – Ecdysteroid receptor (EcR) activation leading to mortality
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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
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Facilitates a Strategic Approach for Assessing Protein Similarity Across Species
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Conservation of molecular target: Line-of-evidence that MIE may be relevant
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Daphnia magna
Ecdysteroid Receptor
All Protein Sequences in the NCBI protein database
SeqAPASS Query
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SeqAPASS Results Across Taxa
• Query Daphnia magna ecdysteroid receptor
Primary amino acid sequence Ligand binding domain
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Key amino acid residues
• Collaborators developed homology model to identify key residues
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SeqAPASS
• EcR sequence and structural conservation: MIE likely relevant
– Branchiopoda – Insecta – Chilopoda – Arachnida – Malacostraca – Maxillopoda
Taxonomic domain of applicability
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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