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Cross-species extrapolation of an adverse outcome pathway for ecdysone receptor activation
Citation:
LaLone, C. AND J. Doering. Cross-species extrapolation of an adverse outcome pathway for ecdysone receptor activation. EDRISK final workshop, Oslo, NORWAY, October 21 - 28, 2017.
Impact/Purpose:
The adverse outcome pathway (AOPs) framework allows us to capture available knowledge concerning the linkages between the disruption of a biological pathway and an adverse outcome of regulatory significance. The work presented here focuses on a AOP describing the activation of an important chemical protein target, the ecdysone receptor, in arthropod species that leads to lethal molting disruption and therefore mortality. We used the U.S. EPA’s Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool to provide an initial line of evidence for the extrapolation of this biological pathway information across species, beyond the model organisms used to develop the AOP. The SeqAPASS tool compares protein similarity between species to predict how broadly we could anticipate extrapolating the knowledge about disruption of the biological pathway across species. The data indicates that the AOP could be extrapolated to other invertebrates.
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, malacostraca, insecta, chilopoda, merostomata, arachnida, and maxillopoda organism classes, therefore aiding in defining the taxonomic domain of the putative AOP.