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Cross-species extrapolation of an adverse outcome pathway for ecdysteroid receptor activation
Citation:
LaLone, C., Dan Villeneuve, G. Ankley, I. Sylte, T. Høgåsen, AND K. Tollefsen. Cross-species extrapolation of an adverse outcome pathway for ecdysteroid receptor activation. SETAC, Vancouver, BC, CANADA, November 09 - 13, 2014.
Impact/Purpose:
not applicable
Description:
Different invertebrate nuclear receptors serve as targets for a variety of environmental contaminants. One of these is the ecdysteroid receptor (EcR). Due to the important role of this nuclear receptor in regulating development and reproduction in invertebrates, particularly during the molting process, literature mining and focused toxicity studies are underway to construct an adverse outcome pathway (AOP) for EcR activation leading to developmental and reproductive dysfunction, and mortality using the cladoceran, Daphnia magna, as a model species. A key element of this AOP development activity is defining the taxonomic domain of applicability beyond cladocerans. To efficiently address this component, the Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool allows for a streamlined evaluation of protein conservation across species through examination of primary amino acid sequence (including ortholog detection), the ligand binding domain, and individual residue alignments to predict relative intrinsic susceptibility. The individual amino acid residue alignments for EcR were conducted using information obtained from homology models and molecular docking studies. SeqAPASS results provide evidence of EcR conservation across branchiopoda, insecta, chilopoda, arachnida, malacostraca, and maxillopoda organism classes, therefore aiding in defining the taxonomic domain of the putative AOP.