<!DOCTYPE html> <html lang="en"> <body><nav class="navbar navbar-fixed-top navbar-inverse"> <div class="container"> <a class="navbar-brand" href="/">AOPWiki</a> <ul class="nav navbar-nav"> <li class=""><a href="/aops">AOPs</a></li> <li class=""><a href="/events">Key Events</a></li> <li class=""><a href="/relationships">KE Relationships</a></li> <li class=""><a href="/stressors">Stressors</a></li> </ul> <ul class="nav navbar-nav pull-right"> <li class="dropdown"> <a href="#" class="dropdown-toggle" data-toggle="dropdown" role="button" aria-haspopup="true" aria-expanded="true"> You <span class="caret"></span></a> <ul class="dropdown-menu dropdown-menu-right"> <li><a href="/profiles/322">my profile</a></li> <li><a rel="nofollow" data-method="delete" href="/users/sign_out">sign out</a></li> </ul> </li> </ul> </div></nav><div class="container main"> <div class="span offset2"> <div class="row"> <div class="col-md-12" role="main"> <br> <br> <br> <script type="text/javascript" id="flash"></script> <div class="pull-right"> <h1>SNAPSHOT</h1></div><!-- Title Section, includes id, name and short name --><div id="title"> <h2>AOP ID and Title:</h2> <hr> < div class="title"> AOP 4: Ecdysone receptor agonism leading to mortality </div> <strong>Short Title: EcR agonism leading to mortality</strong> <br > <div class="title">AOP 4: Ecdysone receptor agonism leading to mortality via suppression of Ftz-f1 </div> <strong>Short Title: EcR agonism leading to mortality via suppression of Ftz-f1</strong > </div> <!-- Author sec tion, includes text of author names as they have been entered by the user --> <h2>Graphical Representa tion</h2> <img src="https://www.aopwiki.org/system/dragonfly/production/2025/09/29/9mhujlly8j_Picture1.png" height="500" width="700" alt=""/> <div id="authors"> <h2>Authors</h2> <hr> < p>You Song<sup>1</sup> and Knut Erik Tollefsen<sup>1,2</sup>< br /><sup>1</sup> Norwegian Institute for Water Research (NIVA), Section of Ecotoxicology and Risk Assessment, Gaustadalléen 21, N-0349 Oslo, Norway<br /> <sup>2</sup> Norwegian University of Life Sciences (NMBU), Faculty of Environmental Science and Technology, Department of Environmental Sciences (IMV). P.O. Box 5003 , N-1432 Ås , Norway<br /> Contact: knut.erik.tollefsen@niva.no< /p> <p>You Song and Knut Erik Tollefsen<br /> Norwegian Institute for Water Research (NIVA), Økernveien 94 , N-0579 Oslo , Norway</p> <br></div> <!-- Status Section, lists status of aop --><div id="status"> <h2>Status</h2> <hr > Open for comment. Do not cite <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">Author status</th> <th scope="col">OECD status</th> <th scope="col">OECD project</th> <th scope="col">SAAOP status</th> </tr> </thead> <tbody class="tbody-striped" > <tr> <td> Open for citation & c omment</td> <td></td> <td></td> <td>Under Development</td> </tr> </tbody> </table> </div> </div> <br><!-- Abstract Section, text as generated by author --><div id="abstract"> <h2>Abstract</h2> <hr> Molting is a natural biological process in arthropods. During a molt cycle, the animals generate new exoskeletons by the epidermis and shed the old ones in order to grow. Successfu l molting is key to survival, development and reproduction. Over half a century research on arthropod endocrinology reveals that molting is precisely controlled by complex multi-hormone systems, with 20-hydroxyecdysone (20E) being the key effective hormone to med iate different biological processes that are necessary for molting. The hormonal actions of 20E ar e exerted through binding and modulation of the ecdysone receptors (EcR), which are nuclear transcriptional factors that regulate a wide range of physiological and behavioral changes. Based on this knowledge, endocrine disrupting chemicals (EDCs) targeting at the EcRs are developed as pesticides and anti-parasite pharmaceuticals in order to disrupt the mo lting cycles of “harmful” arthropods and protect the agriculture and aquaculture. However, environmental residues of these EDCs may also affect non-target species, such as a number of crustaceans (e.g. crabs and lobsters) with great ecological and economical values, due to highly conserved endocrine systems in arthropods. Substantial efforts are therefore needed to assess the environ mental hazards and risks of EDCs on non-target species. Due to the high number (over a million described) of species in the phylum of <em>Arthopoda</em>, it is not feasible to perform toxicity testing for each species as well as EDC. Construction of universal models on basis of systems (eco)toxicology and phylogenetic similarities for understanding the environmental endocrine disruption (ED) effects may serve as a potential solution. The current AOP is therefore developed based on available in formation in the databases to identify knowledge gaps in this research field. The conceptual AOP will be further expanded us ing a combination of laboratory studies and advance <em>in sillico</em> predic tions of potential EcR ligands and taxonomic appllicablity to inform environmental risk assessment as an ultimate goal .</p> <h2>Abstract</h2> <p>This Adverse Outcome Pathway (AOP) describes how hyperactivation of the ecdysone receptor (EcR) in arthropods can lead to letha l molting disruption and mortality. Binding of natural ligands (ecdysteroids) to EcR is critical for regulating molting and metamorphosis in insects and crustaceans. However, inappropr iate or prolonged activation of EcR by exogenous chemicals disrupts the tightly regulated temporal gen e expression cascade required for successful ecdysis. Key events (KEs) include altered expression of early transcription factors (E75B, Ftz-f1), reduction of circulating neuropeptides (CCAP, ETH), impaired motor program activity, and suppression of abdominal muscle contraction, ultimately resu lting in incomplete ecdysis and death. This AOP provides mechanistic understanding relevant for environmental chemical safety assessment, particularly regarding pesticides and other compounds targeting insect endocrine systems.</p> </div> <div id="background"> <h3>Background</h3> <p>The develop ment of this AOP is motivated by regulatory needs to understand and predict the impacts of insect growth regulators and other endocrine-active chemicals that target EcR. Such compounds are widely used in pest control but pose risks to non-target arthropods, including pollinators and aquatic invertebrates. The AOP formalizes knowledge of conserved molt ing endocrine pathways to support hazard identifica tion and potential regulatory screening frameworks .</p> <br></div> <!-- AOP summary, includes summary of each of the events associated with this aop --><div id="aop_summary"> <h2>Summary of the AOP</h2> <hr> <!-- stressor table --> <h3>Stressor s</h3><br> We will add things to here soon <!-- mie table --> <div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead > <tr > <th>Title</th> <th >Short name</th> <th>Essentiality</th > <h3>Event s</h3> <h3>Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO) </h3> <div class="table-responsive "> <table class="table table-bordered table-fullwidth"> <thead class="thead-light "> <tr> <th scope="col">Sequence</th > <th scope="col">Type</th > <th scope="col">Event ID</th> <th scope="col" >Title</th> <th scope="col" >Short name</th> </tr> </thead> <tbody> <tr> <td>1</td> <td>MIE</td> <td>103</td> <td><a href="/events/103">Increase, Ecdysone receptor hyperactivation</a></td> <td>Increase, EcR hyperactivation</td > </tr> </thead> <tbody> <tr> <td><a href="/events/103">Activation, Ecdysone receptor</a ></td > <td>Activation, EcR </td> <td>Strong </td> </tr> </tbody > </table> /div> <!-- ke table --> <h3>Key E vents</h3> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <th>Title</th > <th>Short name</th> <th>Essentiality</th > <tr><td></td><td></td> <td></td><td></td><td></td ></tr > <tr> <td>2 </td> <td>KE </td> <td>1264</td > <td><a href="/e vents/1264">Increase, Nuclear receptor E75b gene expression</a></td > <td>Increase, E75b expression</td > </tr> </thead> <tbody> < tr> <td><a href="/events/1264">Induction, Nuclear receptor E75b gene</a> </td> <td>Induction, E75b gene </td> <td></td> </tr> <tr> <td><a href="/events/1265">Suppression , Fushi tarazu factor-1 gene</a></td> <td>Suppression, Ftz-f1 gene</td> <td></td> </tr> <tr> <td><a href="/events/988">Reduction, Release of circulating ecdysis triggering hormone </a></td> <td>Reduction, Release of circulating ETH</td> <td>Moderate</td> </tr> <tr> <td><a href="/events/1266">Reduction, Release of circulating crustacean cardioactive peptide</a></td> <td>Reduction, Release of circulating CCAP</td> <td></td> </tr> <tr> <td><a href="/events/1267">Reduction, Ecdysis motoneuron bursts</a></td> <td>Reduction, Ecdysis motoneuron bursts</td> <td></td> </tr> <tr> <td><a href="/events/1268">Reduction, Excitatory postsynaptic potential</a></td> <td>Reduction, Excitatory postsynaptic potential</td> <td></td> </tr> <tr> <td><a href="/events/993">Reduction, Abdominal muscle contraction</a></td> <td>Reduction, Abdominal muscle contraction</td> <td>Moderate</td> </tr> <tr> <td><a href="/events/990">Induction, Incomplete ecdysis</a></td> <td>Induction, Incomplete ecdysis</td> <td>Strong</td> </tr> </tbody> </table> </div> <!-- ao table --> <h3>Adverse Outcomes</h3> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <th>Title</th> <th>Short name</th> <th>Essentiality</th > <tr> <td>3 </td> <td>KE </td> <td>1265 </td> <td><a href="/events/1265">Decrease , Fushi tarazu factor-1 gene expression </a></td> <td>Decrease, Ftz-f1 expression</td > </tr> </thead> <tbody> < tr> <td><a href="/events/351">Increased, Mortality</a> </td> <td>Increased, Mortality </td> <td></td> </tr> </tbody> </table> </div> <!-- rel table --> <h3>Relationships between Key E vents</h3> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr > <th>Upstream Event</th> <th>Re lationship Type</th> <th>Downstream Event</th > <tr> <td>4 </td> <td>KE </td> <td>988 </td> <td><a href="/e vents/988">Decrease, Circulating ecdysis triggering hormone</a></td > <td>Decrease, Circu lating ETH</td > </tr> </thead > <tbody> <tr > <td>Activation, Ecdysone receptor </td> <td>directly leads to </td> <td>Induction, Nuclear receptor E75b gene</td> </tr> <tr> <td>Induction, Nuclear receptor E75b gene</td> <td>directly leads to</td> <td>Suppression, Fushi tarazu factor-1 gene</td> </tr> <tr> <td>Suppression, Fushi tarazu factor-1 gene</td> <td>directly leads to </td> <td>Reduction, Rel ease of c irculating ecdysis triggering hormone </td> </tr> <tr> <td>Reduction, Release of circulating ecdysis triggering hormone </td> <td>directly leads to </td> <td>Reduction, Release of circulating crustacean cardioactive peptide </td> </tr> <tr> <td>Reduction, Rel ease of circulating crustacean cardio active peptide </td> <td>directly leads to</td> <td>Reduction , Ecdysis motoneuron bursts </td> </tr> <tr> <td>Reduction, Ecdysis motoneuron bursts </td> <td>directly leads to </td> <td>Reduction, Excitatory postsynaptic potential </td> </tr> <tr> <td>Reduction, Excitatory postsynaptic potential</td> <td>directly leads to</td> <td>Reduction , Abdominal muscle contraction</td> </tr> <tr > <td>Reduction , Abdominal muscle contraction</td> <td>directly leads to</td> <td>Induction, Incomplete ecdysis</td> </tr> <tr> <td>Induction, Incomplete ecdysis </td> <td>directly leads to </td> <td>Increased, Mortality </td> </tr> </tbody> </table> </div> <!-- life stage and taxon tables --> <div class="row"> <div class="col-md-6"> <h3>Life Stage Applicability</h3> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <th>Life Stage</th> <th>Evidence</th> </tr> </thead> <tbody> <tr> <td>Juvenile </td> <td>Strong</td> </tr> <tr> <td>Adult </td> <td>Moderate </td> </tr> </tbody> </table> </div> </div> </div> <div class="row"> <div class="col-md-10"> <h3>Taxon Applicability</h3> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <th>Term</th > <th>Scientific Term</th> <th>Evidence</th> </tr> </thead> <tbody> <tr> <td>insects</td> <td>insect s</td> <td>Strong</td> </tr> <tr> <td>crustaceans </td> <td>Daphnia magna </td> <td>Moderate</td> </tr> </tbody > </table> </div> </div> </div> <div class="row"> <div class="col-md-6"> <h3>Sex Applicability</h3> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <th>Sex</th> <th>Evidence</th> </tr> </thead> <tbody> <tr> <td>Unspecific</td> <td>Moderate</td> </tr> </tbody > </table> </div> </div> </div> <!-- graphical representation --> <h2>Graphical Representation</h2> <img src="https://aopwiki.org/system/dragonfly/production/2017/02/15/79535appr8_EcR_activation_leading_to_m ortality.jpg" , height="500" , width="700"> </img> <!-- end graphical representation --> </div> <!-- end summary --> <!-- loop for mie --> <div id="mie"> <h2>Molecular Initating Event</h2> <h r> <div> <div> <h3><strong>Event ID and Title</strong></h3 > <a href="/events/103">103: Activation, Ecdysone receptor</a><br> Short Name: Activation, EcR <tr > <td>5</td > <td>KE </td> <td>1266 </td> <td><a href="/events/1266">Decrease, Circulating crustacean cardioactive peptide</a> </td> <td>Decr ease, C irculating CCAP </td> </tr> <tr> <td>6 </td> <td>KE </td> <td>1267 </td> <td><a href="/events/1267">Decr ease, Ecdysis motor program activity</a> </td> <td>Decrease , Ecdysis motor program activity </td> </tr> <tr> <td></td> <td>KE </td> <td>993 </td> <td><a href="/events/993">Decrease , Abdominal muscle contraction</a></td > <td>Decrease , Abdominal muscle contraction</td> </tr> <tr><td></td><td></td><td></td><td></td><td></td> </tr> <tr> <td></td> <td>AO </td> <td>990 </td> <td><a href="/events/990">Increase, Incomplete ecdysis</a></td > <td>Increase, Incomplete ecdysi s</td> </tr> <tr> <td></td> <td>AO </td> <td>350</td > <td><a href="/events/350">Increase, Mortality</a></td > <td>Increase, M ortality</td> </t r> </tbody > </table> </div> <div> < h3>Key Event Overview </h3> <!-- loop to find all aops that use this e vent -- > <h4>AOPs Including This Key Event</h4> div class="panel panel-default" > <table class="table table-bordered table-striped" > < thead> <h3>Key Event Relationships </h3> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">Upstream E vent</th > <th scope="col">Relationship Type</th> <th scope="col">Downstream Event</th> <th scope="col">Evidence</th > <th scope="col">Quantitative Understanding</th > </tr> </ thead> <tbody class="tbody-striped"> <tr> <th>AOP ID and Name</th > <th>Event Type</th > <th>Essentiality</th > <td><a href="/relationships/1343">Increase, Ecdysone receptor hyperactivation</a></td> <td>adjacent</td > <td>Increase, Nuclear receptor E75b gene expression</td > <td>High</td> <td></td > </tr> </thea d> <tbody > < tr> <td><a href="/aops/4">4: E cdysone receptor agonism leading to mortal ity</a></td> <td>MolecularInitiatingEvent</td > <td>Strong </td> </tr> </tbody > </table > </div > <tr> <td><a href="/relationships/1344">Increase, Nuclear receptor E75b gene expression</a></td> <td>adjacent</t d> <td>Decrease, Fushi tarazu factor-1 gene expression</td > <td>High</td> <td></td> </ tr> <tr> <td><a href="/relationships/1345">Decrease, Fushi tarazu factor-1 gene expression</a></td> <td>adjacent</td> <td>Decrease, Circulating ecdysis triggering hormone</td> <td>Moderate</td> <td></td> </tr> <tr> <td><a href="/relationships/1346">Decrease, Circulating e cdysis triggering hormone</a></td> <td>adjacent</td> <td>Decrease, Circulating crustacean cardioactive peptide</td> <td>Moderate</td> <td></td> </tr> <tr> <td><a href="/relationships/1347">Decrease, Circulating crustacean cardioactive peptide</a></td> <td>adjacent</td> <td>Decrease, Ecdysis motor program activity</td> <td>Moderate</td> <td></td> </tr> <tr> <td><a href="/relationships/3639">Decrease, Ecdysis motor program activ ity</a></td> <td>adjacent</td> <td>Decrease, Abdominal muscle contraction</td> <td>Moderate</td> <td></td> </tr> <tr> <td><a href="/relationships/1010">Decrease, Abdominal muscle contraction</a></td> <td>adjacent</td> <td>Increase, Incomplete ecdysis</td> <td>Moderate</td> <td></td> </tr> <tr> <td><a href="/relationships/1002">Increase, Incomplete ecdysis</a></td> <td>adjacent</td> <td>Increase, Mortality</td> <td>High</td> <td></td> </tr> <tr> <td></td> <td></td> <td></td> <td></td> <td></td> </tr> </tbody> </table> </div> <h3>Stressors</h3> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">Name</th> <th scope="col">Evidence</th> </tr> </thead> <tbody class="tbody-striped" > <tr> Tebufenozide</td> <td>High</td> </tr> <tr> <td>20-hydroxyecdysone</td> <td>High </td> </tr> <tr> <td>Ponasterone A</td> <td>High</td> </tr> <tr> <td>Methoxyfenozide</td> <td>High</td> </tr> <tr> <td>Halofenozide</td> <td>High</td> </tr> <tr> <td>Chromafenozide</td> <td>High</td> </tr> <tr> <td>Cyasterone</td > <td>High</td> </tr> <tr> <td>Makisterone A</td > <td>High</td> </tr> <tr> <td>Inokosterone</td> <td>High</td> </tr> <tr> <td>Ecdysone</td> <td>High</td> </tr> <tr> <td>RH-5849</td> <td>High</td> </tr> </tbody> </table > </div> <!-- loop to find stressors under event --> <div> <h4>Stressors</h4> The following are stressors that operate directly through this Event. <div> Will need to add a loop here once we have chemicals figured out <ol> <li>chemical one</li> <li>chemical two</li> </ol> <br> </div> </div></div> <!-- loop to find taxonomic applicability under event --> <div > <h4>Taxonomic Applicability</h4> There are no Taxonomic Terms associated with this Event <br> <br> </div> <!-- end loop for taxons --> <!-- biological organization, life stages and sex terms --> <div> <div class="row"> <!-- biological organiz ation --> <div class="col-md-4"> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <th>Level of Bi ological Organiz ation</th> </tr> </thead> <tbody> <tr> <td>M olecular</td> </tr> </tbody> </table> </div> </div> <!-- end of bio org --> <!-- life stages --> <div class="col-md-4"> <h4>Life Stage A pplicability</h4> There are no Life Stages associated with this Event </div> <!-- end life stages --> <!-- sex terms --> <div class="col-md-4"> <h4>Sex Applicability</h4> There are no Sexes associated with this Event <div id="overall_assessment" > <h2>Overall Assessment of the AOP</h2> <p>The overall weight of evidence supporting this AOP is strong, with high biological plausibility and multiple lines of empirical support linking EcR hyperactiv ation to lethal molting disruption. The key endocrine and neuropeptide signaling pathways involved are highly conserved across arthropods, increasing confidence in broad taxonomic applicability, particularly to insects and crustaceans undergoing ecdysis. Essentiality of key events is well demonstrated through genetic and pharmac ological manipul ations, and direct causal linkages between upstream m olecular initiating events and downstream organism-level outcomes are supported by both in vitro and in vivo studies. While quantitative understanding remains incomplete, especially regarding cross-species dose-response relationships, the evidence base is sufficient to support a pplication in chemical screening, prioritization, and risk assessment. The AOP is considered reliable for use in evaluating the hazards of EcR agonists and related endocrine-active chemicals, with clear regulatory relevance to the assessment of insect growth regulators and protection of non-target arthropods.</p> </div> <!-- end sex terms --> </div> <!-- end bio org, life stage and sex terms --> </div> <h3>Domain of Applicability</h3> <strong>Life Stage Applicability</strong> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">Life Stage</th> <th scope="col">Evidence</th> </tr> </thead> <tbody class="tbody-striped"> <tr> <td>Juvenile</td> <td>High</td> </tr> <tr> <td>Adult</td> <td>High</td> </tr> </tbody> </table> </div> <strong>Taxonomic Applicability</strong> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">Term</th> <th scope="col">Scientific Term</th> <th scope="col">Evidence</th> <th scope="col">Links</th> </tr> </thead> <tbody class="tbody-striped"> <tr> <td>insects</td> <td>insects</td> <td>High</td> <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=0" target="_blank">NCBI</a></td> </tr> <tr> <td>crustaceans</td> <td>Daphnia magna</td> <td>Moderate</td> <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=35525" target="_blank">NCBI</a></td> </tr> <tr> <td>Arthropoda</td> <td>Arthropoda</td> <td>High</td> <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=6656" target="_blank">NCBI</a></td> </tr> </tbody> </table> </div> <strong>Sex Applicability</strong> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">Sex</th> <th scope="col">Evidence</th> </tr> </thead> <tbody class="tbody-striped"> <tr> <td>Unspecific</td> <td>Moderate</td> </tr> </tbody> </table> </div> <ul> <li> <p><strong>Taxa:</strong> Arthropods, primarily insects (Diptera, Lepidoptera, Coleoptera) and crustaceans.</p> </li> <li> <p><strong>Life stage:</strong> Juvenile and larval stages undergoing molting.</p> </li> <li> <p><strong>Sex:</strong> Both sexes are equally affected, as molting regulation is not sex-specific.</p> </li> <li> <p><strong>Other considerations:</strong> The pathway is most relevant in holometabolous insects but is applicable across arthropods where molting is controlled by EcR signaling.</p> </li> </ul> <h3>Essentiality of the Key Events</h3> <ul> <li> <p><strong>EcR hyperactivation (MIE):</strong> Genetic or pharmacological overactivation prevents correct timing of molting cascades, leading to lethality.</p> </li> <li> <p><strong>E75B and Ftz-f1 expression changes:</strong> Knockout or overexpression experiments demonstrate disruption of subsequent endocrine signals and molting success.</p> </li> <li> <p><strong>Circulating ETH/CCAP:</strong> Blocking or reducing peptide release suppresses ecdysis behavior. Rescue experiments with exogenous peptides restore motor program activity.</p> </li> <li> <p><strong>Motor program activity and abdominal contractions:</strong> Neurophysiological studies show that impaired muscle activity directly prevents exuviation.</p> </li> <li> <p><strong>Incomplete ecdysis:</strong> Universally essential for linking endocrine dysfunction to mortality.</p> </li> </ul> <p>Overall, essentiality of KEs is supported by direct experimental evidence in multiple model arthropods.</p> <h3>Weight of Evidence Summary</h3> <p><strong>KER 103 → 1264 (EcR hyperactivation → Increased E75B expression)</strong></p> <ul> <li> <p><strong>Biological plausibility:</strong> Strong. E75B is a primary-response gene in the ecdysone signaling cascade. Overactivation of EcR drives prolonged or elevated expression of E75B.</p> </li> <li> <p><strong>Empirical support:</strong> Multiple in vitro and in vivo studies (e.g., <em>Drosophila</em>, lepidopterans) show dose-dependent induction of E75B following EcR agonist exposure.</p> </li> <li> <p><strong>Uncertainties:</strong> Quantitative thresholds vary across taxa.</p> </li> </ul> <p><strong>KER 103 → 1265 (EcR hyperactivation → Decreased Ftz-f1 expression)</strong></p> <ul> <li> <p><strong>Biological plausibility:</strong> Strong. Ftz-f1 is normally induced after a decline in ecdysone signaling, serving as a competence factor for subsequent developmental transitions. Sustained EcR activity suppresses Ftz-f1 expression.</p> </li> <li> <p><strong>Empirical support:</strong> Genetic experiments in <em>Drosophila</em> demonstrate that EcR hyperactivation prevents Ftz-f1 induction, leading to molting defects.</p> </li> <li> <p><strong>Uncertainties:</strong> The precise timing of downregulation differs between insect species.</p> </li> </ul> <p><strong>KER 1265 → 998 (Decreased Ftz-f1 expression → Decreased circulating ETH)</strong></p> <ul> <li> <p><strong>Biological plausibility:</strong> Moderate to strong. ETH release from Inka cells requires proper transcriptional programming, in which Ftz-f1 plays a permissive role.</p> </li> <li> <p><strong>Empirical support:</strong> ETH levels are reduced in Ftz-f1 mutant or RNAi knockdown insects, with corresponding ecdysis failure.</p> </li> <li> <p><strong>Uncertainties:</strong> Direct mechanistic links in crustaceans are less studied.</p> </li> </ul> <p><strong>KER 1264 → 1266 (Increased E75B expression → Decreased circulating CCAP)</strong></p> <ul> <li> <p><strong>Biological plausibility:</strong> Moderate. E75B dysregulation affects downstream neural peptide release patterns, including crustacean cardioactive peptide (CCAP).</p> </li> <li> <p><strong>Empirical support:</strong> Studies in <em>Manduca sexta</em> and <em>Drosophila</em> show disrupted CCAP neuron activation in response to EcR agonists.</p> </li> <li> <p><strong>Uncertainties:</strong> Empirical dose-response data linking E75B overexpression directly to CCAP suppression are limited.</p> </li> </ul> <p><strong>KER 1266 → 1267 (Decreased circulating CCAP → Decreased ecdysis motor program activity)</strong></p> <ul> <li> <p><strong>Biological plausibility:</strong> Strong. CCAP is required to initiate and maintain the motor patterns driving ecdysis behavior.</p> </li> <li> <p><strong>Empirical support:</strong> Ablation or silencing of CCAP neurons abolishes normal ecdysis behavior in insects. Exogenous CCAP restores motor program activity in some experimental systems.</p> </li> <li> <p><strong>Uncertainties:</strong> Quantitative thresholds for peptide levels triggering full motor program are not well established.</p> </li> </ul> <p><strong>KER 998 → 993 (Decreased circulating ETH → Decreased abdominal muscle contraction)</strong></p> <ul> <li> <p><strong>Biological plausibility:</strong> Strong. ETH directly triggers ecdysis motor output by activating central nervous system circuits.</p> </li> <li> <p><strong>Empirical support:</strong> ETH knockout or peptide inhibition prevents abdominal contractions in <em>Drosophila</em> larvae. ETH injection can rescue the phenotype.</p> </li> <li> <p><strong>Uncertainties:</strong> Effects may be stage-dependent.</p> </li> </ul> <p><strong>KER 1267 → 990 (Decreased ecdysis motor program activity → Incomplete ecdysis)</strong></p> <ul> <li> <p><strong>Biological plausibility:</strong> Strong. Motor program activity is essential for successful shedding of the old cuticle.</p> </li> <li> <p><strong>Empirical support:</strong> Neurophysiological and behavioral studies show that impaired motor activity directly correlates with failed or incomplete ecdysis.</p> </li> <li> <p><strong>Uncertainties:</strong> Variation in motor outputs among species may influence severity.</p> </li> </ul> <p><strong>KER 993 → 990 (Decreased abdominal muscle contraction → Incomplete ecdysis)</strong></p> <ul> <li> <p><strong>Biological plausibility:</strong> Strong. Abdominal contractions generate the mechanical force required for cuticle shedding.</p> </li> <li> <p><strong>Empirical support:</strong> Pharmacological or genetic inhibition of abdominal muscle contraction prevents complete ecdysis in <em>Drosophila</em> and other insects.</p> </li> <li> <p><strong>Uncertainties:</strong> Contribution of other body muscles (e.g., thoracic) not fully quantified.</p> </li> </ul> <p><strong>KER 990 → 350 (Incomplete ecdysis → Increased mortality)</strong></p> <ul> <li> <p><strong>Biological plausibility:</strong> Strong. Inability to shed the old cuticle is incompatible with survival.</p> </li> <li> <p><strong>Empirical support:</strong> High mortality rates are consistently observed in laboratory and field studies where molting is disrupted by EcR agonists or neuropeptide blockers.</p> </li> <li> <p><strong>Uncertainties:</strong> Mortality timing (immediate vs delayed) may vary with species and stage.</p> </li> </ul> <!-- event text --> <h3>Quantitative Consideration</h3> <p>Quantitative relationships between EcR activation and downstream transcriptional responses are partially characterized, especially in <em>Drosophila</em>. Dose-response data for diacylhydrazine insecticides provide empirical linkage between exposure and incomplete ecdysis. However, quantitative models are still limited and largely taxon-specific.</p> </div> <div id="considerations_for_potential_applicaitons"> <h2>Considerations for Potential Applications of the AOP (optional)</h2> <p>This AOP has clear utility for both scientific and regulatory applications related to the environmental assessment of endocrine-active substances targeting arthropod molting. Because EcR is the primary molecular target of many insect growth regulators (IGRs), this pathway provides a mechanistic framework for interpreting how chemical binding at the receptor level translates to population-level adverse outcomes such as mortality.</p> <p>From a regulatory perspective, the AOP can inform the development and refinement of OECD test guidelines addressing arthropod development and molting. It can also support the design of integrated approaches to testing and assessment (IATA), in which data from in vitro receptor-binding assays, transcriptomic biomarkers (e.g., E75B, Ftz-f1), and neuropeptide measurements can be combined with higher-tier organismal studies to streamline hazard characterization. Furthermore, the pathway may facilitate the identification of molecular biomarkers that can be incorporated into early screening assays, reducing reliance on animal-intensive in vivo tests.</p> <p>The AOP is also relevant for chemical grouping and read-across approaches, particularly for compounds within the diacylhydrazine class and other EcR agonists. Structure–activity relationship ((Q)SAR) models or chemical profilers trained on these endpoints could help predict EcR activity and prioritize substances for further testing.</p> <p>For ecological risk assessment, this AOP highlights the potential for population-level impacts on non-target arthropods, including beneficial insects (e.g., pollinators) and aquatic crustaceans. Given the essential role of molting for growth and reproduction, disruptions captured in this pathway provide a mechanistic basis to link molecular initiating events to ecologically relevant endpoints.</p> <p>Overall, this AOP offers opportunities to improve chemical safety decision-making by providing a structured framework to integrate mechanistic data into regulatory contexts, enabling screening, prioritization, and risk assessment of chemicals that act through EcR hyperactivation.</p> <!-- end event text --></div> <div id="references"> <h2>References</h2> <p style="margin-left:12.9pt">Song, Y.; Villeneuve, D. L.; Toyota, K.; Iguchi, T.; Tollefsen, K. E., 2017. <strong>Ecdysone receptor agonism leading to lethal molting disruption in arthropods: review and adverse outcome pathway development</strong>. Environ Sci Technol, 51, (8), 4142-4157.</p> <p style="margin-left:12.9pt">Song, Y., Evenseth, L.M., Iguchi, T., Tollefsen, K.E., 2017. <strong>Release of chitobiase as an indicator of potential molting disruption in juvenile <em>Daphnia magna</em> exposed to the ecdysone receptor agonist 20-hydroxyecdysone</strong>. J Toxicol Environ Health A, 1-9</p> <p style="margin-left:12.9pt">Fay, K. A., Villeneuve, D. L., LaLone, C. A., Song, Y., Tollefsen, K. E. and Ankley, G. T., 2017. <strong>Practical approaches to adverse outcome pathway (AOP) development and weight of evidence evaluation as illustrated by ecotoxicological case studies</strong>. Environ. Toxicol. Chem. 36(6):1429-1449.</p> <p style="margin-left:12.9pt">Miyakawa, H., Sato, T., Song, Y., Tollefsen, K.E., Iguchi, T., 2017. <strong>Ecdysteroid and juvenile hormone biosynthesis, receptors and their signaling in the freshwater microcrustacean <em>Daphnia</em></strong>. J Steroid Biochem Mol Biol. pii: S0960-0760(17), 30370-30379.</p> <p style="margin-left:12.9pt"> </p> </div> <!-- end mie --><!-- loop for key events --> <div id="ke" > <h2 >Key Events</h2 > <hr > <div > <div > <h3><strong>Event ID and Title</strong></h3 > <a href="/events/1264">1264: Induction, Nuclear receptor E75b gene</a><br > Short Name: Induction, E75b gene <div id="appendicies"> <h2>Appendix 1</h2> <h3>List of MIEs in this AOP</h3> <h4><a href="/ events/103">Event: 103: Increase, Ecdysone receptor hyperactivation</a></h4> <h5>Short Name: Increase, EcR hyperactivation</h5 > <h4 >Key Event Component</h4 > <div class="table-responsive" > <table class="table table-bordered table-fullwidth"> thead class="thead-light" > <tr > <th scope="col">Process</th> <th scope="col">Object</th> <th scope="col">Action</th > </tr> </thead> <tbody class="tbody-striped"> <tr> <td>ecdysone receptor-mediated signaling pathway</td > <td>ecdysone receptor holocomplex</td> <td>increased</td> </tr> </tbody> </table> </div> <div> <h3>Key Event Overview</h3> <!-- loop to find all aops that use this e vent -- > <h4>AOPs Including This Key Event</h4> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead><h4>AOPs Including This Key Event</h4> class="table-responsive"> <table class="table table-bordered table-fullwidth" > <thead class="thead-light"> <tr> <th scope="col">AOP ID and Name</th> <th scope="col"> Event Type</th> </tr> </thead> <tbody class="tbody-striped"> <tr> <td><a href="/aops/4">Aop:4 - Ecdysone receptor agonism leading to mortality via suppression of Ftz-f1</a></td> <td>MolecularInitiatingEvent</td> </tr> <tr> <td><a href="/ aops/342">Aop:342 - Ecdysone receptor hyperactivation leading to mortality via mis-timed activation of nuclear receptor cascade</a></td> <td>MolecularInitiatingE vent</td> </tr> </tbody > </table> </div> Stressors</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr><th scope="col">Name</th></tr> </thead> <tbody> <tr><td>Methoxyfenozide</td></tr> <tr><td>Halofenozide</td></tr> </tbody> </table> </div> <h4>Biological Context</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr><th scope="col">Level of Biological Organization</th></tr> </thead> <tbody class="tbody-striped"> <tr><td>Molecular</td></tr> </tbody> </table> </div> <h4>Cell term</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr><th scope="col">Cell term</th></tr> </thead> <tbody class="tbody-striped"> <tr><td>eukaryotic cell</td></tr> </tbody> </table> </div> <h3>List of Key Events in the AOP</h3> <h4><a href="/events/1264">Event: 1264: Increase, Nuclear receptor E75b gene expression</a></h4> <h5>Short Name: Increase, E75b expression</h5> <h4>Key Event Component</h4> <div class="table-responsive"> fullwidth"> <thead class="thead-light"> <tr> <th scope="col">Process</th> <th scope="col">Object</th> <th scope="col">Action</th> </tr> </th ead> <tbody class="tbody-striped"> <tr> <th>AOP ID and Name</th > <th>Event Type</th > <th>Essentiality</th > <td>gene expression</td > <td>Eip75B protein, Drosophila</td > <td>increased</td > </tr> </thead> <t body> <tr> <td><a href="/aops/4">4: Ecdysone receptor agonism leading to mortality</a></td> <td>KeyEvent</td> <td></td> </tr> </tbody> </table> </div> </t body> </table> </div> <!-- loop to find stressors under e vent -- > <div > <h4>Stressors</h4 > The following are stressors that operate directly through this Event. <div > Will need to add a loop here once we have chemicals figu red out <ol > <li>chemical one</li > <li>chemical two</li > </ol > <b r> </div ><h4>AOPs Including This Key Event</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">AOP ID and Name</th> <th scope="col">E vent Type</th> </tr> </thead > <tbody class="tbody-striped" > <tr> <td><a href="/aops/4">Aop:4 - Ecdysone receptor agonism leading to mortality via suppression of Ftz-f1</a></td > <td>KeyEvent</td> </tr> </tbody> </table> </div> <h4>Biological Context</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr><th scope="col">Level of Biological Organization</th></tr> </thead> <tbody class="tbody-striped"> <tr><td>Molecular</td></tr> </tbody> </table> </div> <h4>Cell term</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light" > <tr><th scope="col">Cell term</th></tr> </thead> <tbody class="tbody-striped"> <tr><td>eukaryotic cell</td></tr> </tbody> </table> </div> <h4><a href="/events/1265">Event: 1265: Decrease, Fushi tarazu factor-1 gene expression</a></h4> <h5>Short Name: Decrease, Ftz-f1 expression</h5> <h4>Key Event Component</h4> <div class="table-responsive"> <table class="table table-borde red table-fullwidth"> <thead class="thead-light"> <tr > <th scope="col">Process</th> <th scope="col">Object</th > <th scope="col">Action</th> </tr> </thead> <tbody class="tbody-striped"> <tr> <td>gene expression</td> <td>nuclear hormone receptor FTZ-F1 (fruit fly)</td > <td>increased</td > </t r> </tbody> </table > </div> <!-- loop to find taxonomic applicability under event --> <div > <h4>Taxonomic Applicability</h4> There are no Taxonomic Terms associated with this Event <b r> <br> </div > <!-- end loop for taxons --> <!-- biological organization, life stages and sex terms -- > <div > <div class="row" > <!-- b iological organization --> <div class="col-md-4" > <div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <tr> <th >Level of Biological Organization</th> </tr > </thead> < tbody> <tr> <td>Molecular</td > </tr> </tbody> </table> </div> </div> <!-- end of bio org --> <!-- life stages -- > <div class="col-md-4 "> <h4>Life Stage Applicability</h4 > There are no Life Stages associated with this Event /div > <!-- end life stages --> !-- sex terms -- > <div class="col-md-4 "> <h4>Sex Applicability</h4 > There are no Sexes associated with this Event /div > <!-- end sex terms -- > </div > <!-- end bio org, life stage and sex terms --> <h4>AOPs Including This Key Event</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth" > <thead class="thead-light"> <tr> <th scope="col">AOP ID and Name</th> <th scope="col"> Event Type</th> /t r> </thead> tbody class="tbody-striped"> <tr > <td><a href="/aops/4">Aop:4 - Ecdysone receptor agonism leading to mortality via suppression of Ftz-f1</a></td > <td>KeyEvent</td > </tr > </tbody> </table> </div> <h4>B iological Context</h4 > <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr><th scope="col" >Level of Biological Organization</th></tr> </thead > <tbody class="tbody-striped"> tr><td>Molecular</td></tr> </ tbody> </table> </div> <h4>Cell term</h4> <div class="table-responsive"> able class="table table-bordered table-fullwidth"> <thead class="thead-light"> r><th scope="col">Cell term</th></tr > </thead> tbody class="tbody-striped"> <tr><td>eukaryotic cell</td></tr> </table> </div> <h4><a href="/events/988">Event: 988: Decrease, Circulating ecdysis triggering hormone</a></h4> <h5>Short Name: Decrease, Circulating ETH</h5> <h4>Key Event Component</h4> <div class="table-responsive" > <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th scope="col">Process</th> <th scope="col">Object</th > <th scope="col">Action</th> /tr> </thead > <tbody class="tbody-striped "> <tr > <td>ecdysis-triggering hormone activity</td> <td></td > <td>decreased</td > </tr > </tbody> </table> </div> <!-- e vent text --> <!-- end e vent text --> </div> <div > <div > <h3><strong> Event ID and Title</strong></h3 > <a href="/events/1265">1265: Suppression, Fushi tarazu factor-1 gene</a><br > Short Name: Suppression, Ftz-f1 gene <h4>AOPs Including This Key E vent</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">AOP ID and Name</th> <th scope="col">E vent Type</th> </tr> </thead> <tbody class="tbody-striped"> <tr> <td><a href="/aops/4">Aop:4 - Ecdysone receptor agonism leading to mortality via suppression of Ftz-f1</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/342">Aop:342 - Ecdysone receptor hyperactivation leading to mortality via mis-timed activation of nuclear receptor cascade</a></td > <td>KeyEvent</td > </tr> <tr> <td><a href="/aops/343">Aop:343 - Ecdysone receptor antagonism leading to mortality via mis-timed ecdysone receptor-responsive nuclear receptor cascade</a></td> <td>Key Event</td> </tr> </tbody> </table> </div> <h4>Biological Context</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr><th scope="col">Level of Biological Organization</th></tr > </thead> <tbody class="tbody-striped"> <tr><td>Tissue</td></tr> </tbody> </table> </div> <h4> <a href="/events/1266">Event: 1266: Decrease, Circulating crustacean cardioactive peptide</a></h4> <h5>Short Name: Decrease, Circulating CCAP</h5> <h4>Key Event Component</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">Process</th> <th scope="col">Object</th > <th scope="col">Action</th> </tr> </thead> <tbody class="tbody-striped"> <tr> <td>peptide secretion</td> <td>cardioactive peptide (fruit fly)</td> <td>decreased</td> </tr> </tbody> </table> </div> <div> <h3>Key Event Overview</h3> <!-- loop to find all aops that use this e vent -- > <h4>AOPs Inclu ding This Key Event</h4> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead><h4>AOPs Including This Key Event</h4> class="table-responsive"> <table class="table table-bordered table-fullwidth" > <thead class="thead-light"> <tr> <th scope="col">AOP ID and Name</th> <th scope="col"> Event Type</th> </tr> </thead> <tbody class="tbody-striped"> <tr> <td><a href="/aops/4">Aop:4 - Ecdysone receptor agonism leading to mortality via suppression of Ftz-f1</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/ aops/342">Aop:342 - Ecdysone receptor hyperactivation leading to mortality via mis-timed activation of nuclear receptor cascade</a></td> <td>KeyE vent</td> </tr > <tr> <td><a href="/aops/343">Aop:343 - Ecdysone receptor antagonism lea ding to mortality via mis-timed ecdysone receptor-responsive nuclear receptor cascade</a></td> <td>Key Event</td> </tr> </tbody> </table> </div> <h4>Biological Context</ h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr><th scope="col">Level of Biological Organization</th></tr> </thead> <tbody class="tbody-striped"> <tr><td>Tissue</td></tr> </tbody> </table> </div> <h4>Organ term</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr><th scope="col">Organ term</th></tr> </thead> <tbody class="tbody-striped"> <tr><td>haemolymphatic fluid</td></tr> </tbody> </table> </div> <h4><a href="/events/1267">Event: 1267: Decrease, Ecdysis motor program activity</a></h4> <h5>Short Name: Decrease, Ecdysis motor program activity</h5> <h4>Key Event Component</h4> <div class="table-responsive"> fullwidth"> <thead class="thead-light"> <tr> <th scope="col">Process</th> <th scope="col">Object</th> <th scope="col">Action</th> </tr> </th ead> <tbody class="tbody-striped"> <tr> <th>AOP ID and Nam e</th > <th>Event Type</th > <th>Essentiality</th > <td>transmission of nerve impuls e</td > <td>motor neuron</td > <td>decreased</td > </tr> </thead> <t body> <tr> <td><a href="/aops/4">4: Ecdysone receptor agonism leading to mortality</a></td> <td>KeyEvent</td> <td></td> </tr> </tbody> </table> </div> </t body> </table> </div> <!-- loop to find stressors under e vent -- > <div > <h4>Stressors</h4 > The following are st ressors that o perate directly through this Event. <div > Will need to add a loop here once we have chemicals figured out <ol > <li>chemical one</li > <li>chemical two</li > </ol > <b r> </div ><h4>AOPs Including This Key Event</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">AOP ID and Name</th> <th scope="col">E vent Type</th > </tr > </thead> <tbody class="tbody-striped"> <tr > <td><a href="/aops/4">Aop:4 - Ecdysone receptor agonism leading to mortality via supp ression of Ftz-f1</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/342">Aop:342 - Ecdysone receptor hy peractivation leading to mortality via mis-timed activation of nuclear receptor cascade</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/343">Aop:343 - Ecdysone receptor antagonism leading to mortality via mis-timed ecdysone receptor-responsive nuclear receptor cascade</a></td> <td>KeyEvent</td > </tr> </tbody> </table> </div> <h4>Biological Context</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr><th scope="col">Level of Biological Organization</th></tr> </thead> <tbody class="tbody-striped"> <tr><td>Tissue</td></tr> </tbody> </table> </div> <h4>Organ term</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr><th scope="col">Organ term</th></tr> </thead> <tbody class="tbody-striped"> <tr><td>nervous system</td></tr > </tbody> </table> </div> <h4><a href="/events/993">Event: 993: Decrease, Abdominal muscle contraction</a></h4> <h5>Short Name: Decrease, Abdominal muscle contraction</h5 > <h4>Key Event Component</h4> <div class="table-responsive"> table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">Process</th> <th scope="col">Object</th> <th scope="col">Action</th > </tr> </thead> <tbody class="tbody-striped" > <t r> <td>muscle contraction</td> <td></td> <td>increased</td> </tr> </tbody> </table > </div> <!-- loop to find taxonomic applicability under event -- > <div > <h4>Taxonomic Applicability</h4> There are no Taxonomic Terms associated with this Event <b r> <br> </div> <!-- end loop for taxons --> <!-- biological organiz ation, life stages and sex terms -- > <div > <div class="row" > <!-- biological organization -- > <div class="col-md-4" > <div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <tr> <th >Level of Biological Organization</th> </tr > </thead> < tbody> <tr> <td>Molecular</td > </tr> </tbody> </table> </div > </div> <!-- end of bio org --> <!-- life stages -- > <div class="col-md-4 "> <h4>Life Stage Applicability</h4 > There are no Life Stages associated with this Event /div > <!-- end life stages --> !-- sex terms -- > <div class="col-md-4 "> <h4>Sex Applicability</h4 > There are no Sexes associated with this Event /div > <!-- end sex terms -- > </div > <!-- end bio org, life stage and sex terms --> <h4>AOPs Including This Key Event</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth" > <thead class="thead-light" > <tr> <th scope="col">AOP ID and Name</th> <th scope="col">Event Type</th> </tr> </thead> <tbody class="tbody-striped"> <tr> <td><a href="/aops/4">Aop:4 - Ecdysone receptor agonism leading to mortality via suppression of Ftz-f1</a></td> <td>Key Event</td> </t r> <tr> <td><a href="/aops/342">Aop:342 - Ecdysone receptor hyperactivation leading to mortality via mis-timed activ ation of nuclear receptor cascade</a></td > <td>KeyEvent</td > </tr> <tr > <td><a href="/aops/343">Aop:343 - Ecdysone receptor antagonism leading to mortality via mis-timed ecdysone receptor-responsive nuclear receptor cascade</a></td > <td>KeyEvent</td > </tr> </tbody> </table> </div> <h4>Biological Context</h4> table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr><th scope="col" >Level of Biological Organization</th></tr> </thead > <tbody class="tbody-striped"> tr><td>Tissue</td></tr> </ tbody> </table> </div> <h4>Organ term</h4> <div class="table-responsive"> able class="table table-bordered table-fullwidth"> <thead class="thead-light"> r><th scope="col">Organ term</th></tr > </thead> tbody class="tbody-striped"> <tr><td>somatic muscle</td></tr> </table> </div> <h3>List of Adverse Outcomes in this AOP</h3 > <h4><a href="/events/990">Event: 990: Increase, Incomplete ecdysis</a></h4> <h5>Short Name: Increase, Incomplete ecdysis</h5> <h4>Key Event Component</h4> <div class="table-responsive"> table class="table table-bordered table-fullwidth" > <thead class="thead-light "> <tr> <th scope="col">Process</th > <th scope="col">Object</th> <th scope="col">Action</th > </tr> /thead > <tbody class="tbody-striped "> <tr > <td>chitin biosynthetic process</td> <td>chitin</td > <td>increased</td > </tr > </tbody> </table> </div> <!-- e vent text --> <!-- end e vent text --> </div> <div > <div > <h3><strong> Event ID and Title</strong></h3 > <a href="/events/988">988: Reduction, Release of circulat ing ecdysis triggering hormone</a><br > Short Name: Reduction, Release of circulating ETH <h4>AOPs Including This Key E vent</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">AOP ID and Name</th> <th scope="col">E vent Type</th> </tr> </thead> <tbody class="tbody-striped"> <tr> <td><a href="/aops/466">Aop:466 - Doda decarboxylase leading to mortality</a></td > <td>KeyEvent</td > </tr> <tr> <td><a href="/aops/467">Aop:467 - Knickkopf leading to mortality</a></td> <td>Key Event</td> </tr> <tr> <td><a href="/aops/4">Aop:4 - Ecdysone receptor agonism leading to mortality via suppression of Ftz-f1</a></td> <td>AdverseOutcome</td> </tr > <tr> <td> <a href="/aops/342">Aop:342 - Ecdysone receptor hyperactivation leading to mortality via mis-timed activation of nuclear receptor cascade</a></td> <td>AdverseOutcome</td> </tr> <tr> <td><a href="/aops/343">Aop:343 - Ecdysone receptor antagonism lead ing to mortality via mis-timed ecdysone receptor-responsive nuclear receptor cascade</a></td> <td>AdverseOutcome</td> </tr> </tbody> </table> </div> <h4>Biological Context</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr><th scope="col">Level of Biological Organization</th></tr> </thead> <tbody class="tbody-striped" > <tr><td>Individual</td></tr> </tbody> </table> </div> <h4><a href="/events/350">Event: 350: Increase, Mortality</a></h4> <h5> Short Name: Increase, Mortality</h5> <h4>Key Event Component</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">Process</th> <th scope="col">Object</th> <th scope="col">Action</th> </tr> </thead> <tbody class="tbody-striped"> <tr> <td>mortality</td> <td></td> <td>increased</td> </tr> </tbody> </table> </div> <div > <h3>Key Event Overview</h3> <!-- loop to find all aops that use this event -- > <h4>AOPs Inclu ding This Key Event</h4> <div class="panel panel-default" > <table class="table table-bordered table-striped"> <thead> <h4>AOPs Including This Key Event</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">AOP ID and Name</th> <th scope="col">Event Type</th> </tr> </thead> <tbody class="tbody-striped"> <tr > <td><a href="/aops/327">Aop:327 - Excessive reactive oxygen species production leading to mortality (1)</a></td> <td>AdverseOutcome</td> </tr> <tr> <td><a href="/aops/328">Aop:328 - Excessive reactive oxygen species production leading to mortality (2)</a></td> <td>AdverseOutcome</td> </tr> <tr> <td><a href="/aops/329">Aop:329 - Excessive reactive oxygen species production leading to mortality (3)</a></td> <td>AdverseOutcome</td> </tr> <tr> <td><a href="/aops/358">Aop:358 - Chitinase inhibition leading to mortality</a></td> <td>AdverseOutcome</td> </tr> <tr> <td><a href="/aops/359">Aop:359 - Chitobiase inhibition leading to mortality</a></td> <td>AdverseOutcome</td> </tr> <tr> <td><a href="/aops/360">Aop:360 - Chitin synthase 1 inhibition leading to mortality</a></td> <td>AdverseOutcome</td> </tr> <tr> <td><a href="/aops/361">Aop:361 - Sulfonylureareceptor binding leading to mortality</a></td> <td>AdverseOutcome</td> </tr> <tr> <td><a href="/aops/465">Aop:465 - Alcohol dehydrogenase leading to reproductive dysfunction</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/466">Aop:466 - Doda decarboxylase leading to mortality</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/ aops/467">Aop:467 - Knickkopf leading to mortality</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/471">Aop:471 - Neuron defect induced early behavioral change</a></td> <td>AdverseOutcome</td> </tr> <tr> <td><a href="/aops/330">Aop:330 - Excessive reactive oxygen species production leading to mortality (4)</a></td> <td>AdverseOutcome</td> </tr> <tr> <td><a href="/aops/4">Aop:4 - Ecdysone receptor agonism leading to mortality via suppression of Ftz-f1</a></td> <td>AdverseOutcome</td> </tr> <tr > <td><a href="/aops/342">Aop:342 - Ecdysone receptor hyperactivation leading to mortality via mis-timed activation of nuclear receptor cascade</a></td> <td>AdverseOutcome</td> </tr> <tr> <td><a href="/aops/343">Aop:343 - Ecdysone receptor antagonism leading to mortality via mis-timed ecdysone receptor-responsive nuclear receptor cascade</a></td> <td>AdverseOutcome</td> </tr> <tr> <td><a href="/aops/606">Aop:606 - Ecdysone receptor antagonism lea ding to mortality via inhibition of chitin synthase 1</a></td> <td>AdverseOutcome</td> </tr> </tbody> </table> </div> <h4>Stressors</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr><th scope="col">Name</th></tr> </thead> <tbody> <tr><td>Polyoxin D</td></tr> <tr><td>Nikkomycins</td></tr> </tbody> </table> </div> <h4>Biological Context</h4> table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr><th scope="col">Level of Biological Organization</th></tr> </thead> <tbody class="tbody-striped"> <tr><td>Individual</td></tr> </tbody> </table> </div> <h4>Domain of Applicability</h4 > <strong>Taxonomic Applicability</strong> <div class="table-responsive"> fullwidth"> <thead class="thead-light"> <tr> <th scope="col">Term</th> <th scope="col">Scientific Term</th> <th scope="col">Evidence</th> <th scope="col">Links</th> </tr> </thead> <tbody class="tbody- striped"> <tr> <td>Lucilia cuprina</td> <td>Lucilia cuprina</td> <td>High</td> <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=7375" target="_blank">NCBI</a></td> </tr> <tr> <td>Daphnia magna</td> <td>Daphnia magna</td> <td>High</td> <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=35525" target="_blank">NCBI</a></td> </tr> </tbody> </table> </div> <strong>Life Stage Applicability</strong> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">Life Stage</th> <th scope="col">Evidence</th> </tr> </thead> <tbody class="tbody-striped"> <tr> <td>All life stages</td> <td>High</td> </tr> </tbody> </table> </div> <strong>Sex Applicability</strong> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">Sex</th> <th scope="col">Evidence</th> </tr> </thead> <tbody class="tbody-striped"> <tr> <td>Unspecific</td> <td>High</td> </tr> </tbody> </table> </div> <p><span style="font-size:14px"><strong>Taxonomic: </strong>This AO is applicable to all living organisms.</span></p> <p><span style="font-size:14px"><strong>Life stage: </strong>This AO is applicable to all life stages.</span></p> <p><span style="font-size:14px"><strong>Sex: </strong>This AO is applicable to all sexes.</span></p> <p><span style="font-size:14px"><strong>Chemical:</strong> Substances known to increase mortality in arthropods are of the family of pyrimidine nucleosides (e.g. polyoxin D and nikkomycin Z) (Gijswijt et al. 1979; Tellam et al. 2000; Arakawa et al. 2008).</span></p> <h4>Key Event Description</h4> <p><span style="font-size:14px">This key event is observed at the biological level of the individual and describes the increase of mortality of individuals upon exposure to a stressor.</span></p> <h4>How it is Measured or Detected</h4> <p><span style="font-size:14px">The AO can be detected by observation, for example by immobilization of the respective organisms. There exist guidelines for the characterization of this AO in arthropods. For example, the OECD 202 Daphnia sp. Acute immobilization test </span><!--[if supportFields]><span lang=EN-US style='font-size:11.0pt;line-height:107%;font-family:"Calibri",sans-serif; mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;mso-ansi-language:EN-US;mso-fareast-language: EN-US;mso-bidi-language:AR-SA'><span style='mso-element:field-begin;mso-field-lock: yes'></span>ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1787/9789264069947-en","ISBN":"9789264069947","PMID":"128","abstract":"This Test Guideline describes an acute toxicity test to assess effects of chemicals towards daphnids (usually Daphnia magna Staus). Young daphnids, aged less than 24 hours at the start of the test, are exposed to the test substance at a range of concentrations (at least five concentrations) for a period of 48 hours. Immobilisation is recorded at 24 hours and 48 hours and compared with control values. The results are analysed in order to calculate the EC50 at 48h. Determination of the EC50 at 24h is optional. At least 20 animals, preferably divided into four groups of five animals each, should be used at each test concentration and for the controls. At least 2 ml of test solution should be provided for each animal (i.e. a volume of 10 ml for five daphnids per test vessel). The limit test corresponds to one dose level of 100 mg/L. The study report should include the observation for immobilized daphnids at 24 and 48 hours after the beginning of the test and the measures of dissolved oxygen, pH, concentration of the test substance, at the beginning and end of the test.","author":[{"dropping-particle":"","family":"OECD","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"collection-title":"OECD Guidelines for the Testing of Chemicals, Section 2","container-title":"OECD Publishing","id":"ITEM-1","issue":"OECD Guideline for the Testing of Chemicals, Section 2","issued":{"date-parts":[["2004","11","23"]]},"number-of-pages":"1-12","publisher":"OECD","title":"Test No. 202: <i>Daphnia sp.</i> Acute Immobilisation Test","type":"report"},"uris":["http://www.mendeley.com/documents/?uuid=53ebeac3-a1c9-3977-9697-df1efabeb4d3"]}],"mendeley":{"formattedCitation":"(OECD 2004)","plainTextFormattedCitation":"(OECD 2004)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}<span style='mso-element:field-separator'></span></span><![endif]-->(OECD 2004)<!--[if supportFields]><span lang=EN-US style='font-size:11.0pt;line-height:107%;font-family:"Calibri",sans-serif; mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;mso-ansi-language:EN-US;mso-fareast-language: EN-US;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]--><span style="font-size:14px"> which can also be modified depending on the effect one expects.</span></p> <h4>Regulatory Significance of the AO</h4> <p><span style="font-size:14px">The Adverse Outcome is highly significant from a regulatory point of view. It is employed as regulatory endpoint in most studies assessing the toxicity of stressors.</span></p> <h4>References</h4> <p><span style="font-size:14px">Arakawa T, Yukuhiro F, Noda H. 2008. Insecticidal effect of a fungicide containing polyoxin B on the larvae of <em>Bombyx mori</em> (Lepidoptera: Bombycidae), <em>Mamestra brassicae</em>, <em>Mythimna separata</em>, and <em>Spodoptera litura</em> (Lepidoptera: Noctuidae). Appl Entomol Zool. 43(2):173–181. doi:10.1303/aez.2008.173.</span></p> <p><span style="font-size:14px">Gijswijt MJ, Deul DH, de Jong BJ. 1979. Inhibition of chitin synthesis by benzoyl-phenylurea insecticides, III. Similarity in action in <em>Pieris brassicae</em> (L.) with Polyoxin D. Pestic Biochem Physiol. 12(1):87–94. doi:10.1016/0048-3575(79)90098-1.</span></p> <p><span style="font-size:14px">OECD. 2004. Test No. 202: <em>Daphnia sp.</em> Acute Immobilisation Test. OECD OECD Guidelines for the Testing of Chemicals, Section 2. [accessed 2020 Mar 3]. https://www.oecd-ilibrary.org/environment/test-no-202-daphnia-sp-acute-immobilisation-test_9789264069947-en.</span></p> <p><span style="font-size:14px">Tellam RL, Vuocolo T, Johnson SE, Jarmey J, Pearson RD. 2000. Insect chitin synthase. cDNA sequence, gene organization and expression. Eur J Biochem. 267(19):6025–6043. doi:10.1046/j.1432-1327.2000.01679.x.</span></p> <h2>Appendix 2</h2> <h2>List of Key Event Relationships in the AOP</h2> <div id="evidence_supporting_links"> <h3>List of Adjacent Key Event Relationships</h3> <div> <h4><a href="/relationships/1343">Relationship: 1343: Increase, EcR hyperactivation leads to Increase, E75b expression</a></h4> <h4>AOPs Referencing Relationship</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th>AOP ID and Name</th> <th>Event Type </th> <th>Essentiality </th> <th scope="col" >AOP Name</th> <th scope="col">Adjacency </th> <th scope="col">Weight of Evidence</th> <th scope="col">Quantitative Understanding </th> </tr> </thead> <tbody> <tr> <td><a href="/aops/4">4: Ecdysone receptor agonism leading to mortality</a></td> <td>KeyEv ent</td> <td>Moderate </td> </tr> <tbody class="tbody-striped" > <tr> <td><a href="/aops/4">Ecdysone receptor agonism leading to mortality via suppression of Ftz-f1 </a></td> <td>adjac ent</td> <td>High</td> <td></td> </tr> </tbody> </table> </div> </div> <!-- loop to find stressors under event --> <div> <h4>Stressors</h4> The following are stressors that operate directly through this Event. <div> Will need to add a loop here once we have chemicals figured out <ol> <li>chemical one</li> <li>chemical two</li> </ol> <br> </div> </div> <!-- loop to find taxonomic applicability under event --> <div> <h4>Taxonomic Applicability</h4> There are no Taxonomic Terms associated with this Event <br> <br> </div> <!-- end loop for taxons --> <!-- biological organization, life stages and sex terms --> <div> <div class="row"> <!-- biological organization --> <div class="col-md-4"> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <th>Level of Biological Organization</th> </tr> </thead> <tbody> <tr> <td>Tissue</td> </tr> </tbody> </table> </div> </div> <!-- end of bio org --> <!-- life stages --> <div class="col-md-4"> <h4>Life Stage Applicability</h4> There are no Life Stages associated with this Event </div> <!-- end life stages --> <!-- sex terms --> <div class="col-md-4"> <h4>Sex Applicability</h4> There are no Sexes associated with this Event </div> <!-- end sex terms --> </div> <!-- end bio org, life stage and sex terms --> </div> <!-- event text --> <!-- end event text --></div> <div> <div> <h3><strong>Event ID and Title</strong></h3> <a href="/events/1266">1266: Reduc tion, Release of circulating crustacean cardioactive peptide</a><br> Short Name: Reduction, Release of circulating CCAP </div> <div> <h3>Key Event Overview</h3> <!-- loop to find all aops that use this event -- > <h4>AOPs Includ ing This Key Event </h4>panel panel-default "> <table class="table table-bordered table-striped "> <thead> <div> <h4> <a href="/relationships/1344">Rela tionship: 1344: Increase, E75b expression leads to Decrease, Ftz-f1 expression</a></h4 > <h4>AOPs Referenc ing Relationship </h4> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>AOP ID and Name</th> <th>Event Type </th> <th>Essentiality </th> <th scope="col" >AOP Name</th> <th scope="col">Adjacency </th> <th scope="col">Weight of Evidence</th> <th scope="col">Quantitative Understanding </th> </tr> </thead> <tbody> <tr> <td><a href="/aops/4">4: Ecdysone receptor agonism leading to mortality</a></td> <td>KeyEv ent</td> <td></td> </tr> <tbody class="tbody-striped" > <tr> <td><a href="/aops/4">Ecdysone receptor agonism leading to mortality via suppression of Ftz-f1 </a></td> <td>adjac ent</td> <td>High</td> <td></td> </tr> </tbody> </table> </div> </div> <!-- loop to find stressors under event --> <div> <h4>Stressors</h4> The following are stressors that operate directly through this Event. <div> Will need to add a loop here once we have chemicals figured out <ol> <li>chemical one</li> <li>chemical two</li> </ol> <br> </div> </div> <!-- loop to find taxonomic applicability under event --> <div> <h4>Taxonomic Applicability</h4> There are no Taxonomic Terms associated with this Event <br> <br> </div> <!-- end loop for taxons --> <!-- biological organization, life stages and sex terms --> <div> <div class="row"> <!-- biological organization --> <div class="col-md-4"> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <th>Level of Biological Organization</th> </tr> </thead> <tbody> <tr> <td>Tissue</td> </tr> </tbody> </table> </div> </div> <!-- end of bio org --> <!-- life stages --> <div class="col-md-4"> <h4>Life Stage Applicability</h4> There are no Life Stages associated with this Event </div> <!-- end life stages --> <!-- sex terms --> <div class="col-md-4"> <h4>Sex Applicability</h4> There are no Sexes associated with this Event </div> <!-- end sex terms --> </div> <!-- end bio org, life stage and sex terms --> </div> <!-- event text --> <!-- end event text --></div> <div> <div> <h3><strong>Event ID and Title</strong></h3> < a href="/events/1267">1267: Reduc tion, Ecdysis motoneuron bursts</a><br> Short Name: Reduction, Ecdysis motoneuron bursts </div> <div> <h3>Key Event Overview</h3> <!-- loop to find all aops that use this event -- > <h4>AOPs Includ ing This Key Event </h4>panel panel-default "> <table class="table table-bordered table-striped "> <thead> <div> <h4>< a href="/relationships/1345">Rela tionship: 1345: Decrease, Ftz-f1 expression leads to Decrease, Circulating ETH</a></h4 > <h4>AOPs Referenc ing Relationship </h4> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>AOP ID and Name</th> <th>Event Type </th> <th>Essentiality </th> <th scope="col" >AOP Name</th> <th scope="col">Adjacency </th> <th scope="col">Weight of Evidence</th> <th scope="col">Quantitative Understanding </th> </tr> </thead> <tbody> <tr> <td><a href="/aops/4">4: Ecdysone receptor agonism leading to mortality</a></td> <td>KeyEv ent</td> <td></td> </tr> <tbody class="tbody-striped" > <tr> <td><a href="/aops/4">Ecdysone receptor agonism leading to mortality via suppression of Ftz-f1 </a></td> <td>adjac ent</td> <td>Moderate</td> <td></td> </tr> </tbody> </table> </div> </div> <!-- loop to find stressors under event --> <div> <h4>Stressors</h4> The following are stressors that operate directly through this Event. <div> Will need to add a loop here once we have chemicals figured out <ol> <li>chemical one</li> <li>chemical two</li> </ol> <br> </div> </div> <!-- loop to find taxonomic applicability under event --> <div> <h4>Taxonomic Applicability</h4> There are no Taxonomic Terms associated with this Event <br> <br> </div> <!-- end loop for taxons --> <!-- biological organization, life stages and sex terms --> <div> <div class="row"> <!-- biological organization --> <div class="col-md-4"> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <th>Level of Biological Organization</th> </tr> </thead> <tbody> <tr> <td>Tissue</td> </tr> </tbody> </table> </div> </div> <!-- end of bio org --> <!-- life stages --> <div class="col-md-4"> <h4>Life Stage Applicability</h4> There are no Life Stages associated with this Event </div> <!-- end life stages --> <!-- sex terms --> <div class="col-md-4"> <h4>Sex Applicability</h4> There are no Sexes associated with this Event </div> <!-- end sex terms --> </div> <!-- end bio org, life stage and sex terms --> </div> <!-- event text --> <!-- end event text --></div> <div> <div> <h3><strong>Event ID and Title</strong></h3> <a href="/events/1268">1268: Reduc tion, Excitatory postsynaptic potential</a><br> Short Name: Reduction, Excitatory postsynaptic potential </div> <div> <h3>Key Event Overview</h3> <!-- loop to find all aops that use this event -- > <h4>AOPs Includ ing This Key Event </h4>panel panel-default "> <table class="table table-bordered table-striped "> <thead> <div> <h4> <a href="/relationships/1346">Rela tionship: 1346: Decrease, Circulating ETH leads to Decrease, Circulating CCAP</a></h4 > <h4>AOPs Referenc ing Relationship </h4> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>AOP ID and Name</th> <th>Event Type </th> <th>Essentiality </th> <th scope="col" >AOP Name</th> <th scope="col">Adjacency </th> <th scope="col">Weight of Evidence</th> <th scope="col">Quantitative Understanding </th> </tr> </thead> <tbody> <tr> <td><a href="/aops/4">4: Ecdysone receptor agonism leading to mortality</a></td> <td>KeyEvent </td> <td></td> </tr> <tbody class="tbody-striped" > <tr> <td><a href="/aops/4">Ecdysone receptor agonism leading to mortality via suppression of Ftz-f1 </a></td> <td>adjacent</td> <td>Moderate</td> <td></td> </tr> <tr> <td><a href="/aops/342">Ecdysone receptor hyperactivation leading to mortality via mis-timed activation of nuclear receptor cascade</a></td> <td>adjacent</td> <td>Moderate</td> <td></td> </tr> <tr> <td><a href="/aops/343">Ecdysone receptor antagonism leading to mortality via mis-timed ecdysone receptor-responsive nuclear receptor cascade</a> </td> <td>adjacent</td> <td></td> <td></td> < /tr> </tbody> </table> </div> </div> <!-- loop to find stressors under event --> <div> <h4>Stressors</h4> The following are stressors that operate directly through this Event. <div> Will need to add a loop here once we have chemicals figured out <ol> <li>chemical one</li> <li>chemical two</li> </ol> <br> </div> </div> <!-- loop to find taxonomic applicability under event --> <div> <h4>Taxonomic Applicability</h4> There are no Taxonomic Terms associated with this Event <br> <br> </div> <!-- end loop for taxons --> <!-- biological organization, life stages and sex terms --> <div> <div class="row"> <!-- biological organization --> <div class="col-md-4"> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <th>Level of Biological Organization</th> </tr> </thead> <tbody> <tr> <td>Tissue</td> </tr> </tbody> </table> </div> </div> <!-- end of bio org --> <!-- life stages --> <div class="col-md-4"> <h4>Life Stage Applicability</h4> There are no Life Stages associated with this Event </div> <!-- end life stages --> <!-- sex terms --> <div class="col-md-4"> <h4>Sex Applicability</h4> There are no Sexes associated with this Event </div> <!-- end sex terms --> </div> <!-- end bio org, life stage and sex terms --> </div> <!-- event text --> <!-- end event text --></div> <div> <div> <h3><strong>Event ID and Title</strong></h3> <a href="/events/993">993: Reduction, Abdominal muscle contrac tion</a><br> Short Name: Reduction, Abdominal muscle contraction </div> <div> <h3>Key Event Overview</h3> <!-- loop to find all aops that use this event -- > <h4>AOPs Includ ing This Key Event </h4>panel panel-default "> <table class="table table-bordered table-striped "> <thead> <div> <h4> <a href="/relationships/1347">Rela tionship: 1347: Decrease, Circulating CCAP leads to Decrease, Ecdysis motor program activity</a></h4 > <h4>AOPs Referenc ing Relationship </h4> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>AOP ID and Name</th> <th>Event Type </th> <th>Essentiality </th> <th scope="col" >AOP Name</th> <th scope="col">Adjacency </th> <th scope="col">Weight of Evidence</th> <th scope="col">Quantitative Understanding </th> </tr> </thead> <tbody> <tr> <td><a href="/aops/4">4: Ecdysone receptor agonism leading to mortality</a></td> <td>KeyEvent </td> <td>Moderate</td> </tr> <tbody class="tbody-striped" > <tr> <td><a href="/aops/4">Ecdysone receptor agonism leading to mortality via suppression of Ftz-f1 </a></td> <td>adjacent</td> <td>Moderate</td> <td></td> </tr> <tr> <td><a href="/aops/342">Ecdysone receptor hyperactivation leading to mortality via mis-timed activation of nuclear receptor cascade</a> </td> <td>adjacent</td> <td>Moderate</td> <td></td> </tr> <tr> <td><a href="/aops/343">Ecdysone receptor antagonism leading to mortality via mis-timed ecdysone receptor-responsive nuclear receptor cascade</a></td> <td>adjacent</td> <td></td> <td></td> < /tr> </tbody> </table> </div> </div> <!-- loop to find stressors under event --> <div> <h4>Stressors</h4> The following are stressors that operate directly through this Event. <div> Will need to add a loop here once we have chemicals figured out <ol> <li>chemical one</li> <li>chemical two</li> </ol> <br> </div> </div> <!-- loop to find taxonomic applicability under event --> <div> <h4>Taxonomic Applicability</h4> There are no Taxonomic Terms associated with this Event <br> <br> </div> <!-- end loop for taxons --> <!-- biological organization, life stages and sex terms --> <div> <div class="row"> <!-- biological organization --> <div class="col-md-4"> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <th>Level of Biological Organization</th> </tr> </thead> <tbody> <tr> <td>Tissue</td> </tr> </tbody> </table> </div> </div> <!-- end of bio org --> <!-- life stages --> <div class="col-md-4"> <h4>Life Stage Applicability</h4> There are no Life Stages associated with this Event </div> <!-- end life stages --> <!-- sex terms --> <div class="col-md-4"> <h4>Sex Applicability</h4> There are no Sexes associated with this Event </div> <!-- end sex terms --> </div> <!-- end bio org, life stage and sex terms --> </div> <!-- event text --> <!-- end event text --></div> <div> <div> <h3><strong>Event ID and Title</strong></h3> <a href="/events/990">990: Induc tion, Incomplete e cdysis</a><br> Short Name: Induction, Incomplete ecdysis </div> <div> <h3>Key Event Overview</h3> <!-- loop to find all aops that use this event -- > <h4>AOPs Includ ing This Key Event </h4>panel panel-default "> <table class="table table-bordered table-striped "> <thead> <div> <h4> <a href="/relationships/3639">Rela tionship: 3639: Decrease, E cdysis motor program activity leads to Decrease, Abdominal muscle contraction</a></h4 > <h4>AOPs Referenc ing Relationship </h4> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>AOP ID and Name</th> <th>Event Type </th> <th>Essentiality </th> <th scope="col" >AOP Name</th> <th scope="col">Adjacency </th> <th scope="col">Weight of Evidence</th> <th scope="col">Quantitative Understanding </th> </tr> </thead> <tbody> <tr> <td><a href="/aops/4">4: Ecdysone receptor agonism leading to mortality</a></td> <td>KeyEv ent</td> <td>Strong </td> </tr> <tbody class="tbody-striped" > <tr> <td><a href="/aops/4">Ecdysone receptor agonism leading to mortality via suppression of Ftz-f1 </a></td> <td>adjacent</td> <td>Moderate</td> <td></td> </tr> <tr> <td><a href="/aops/342">Ecdysone receptor hyperactivation leading to mortality via mis-timed activation of nuclear receptor cascade</a></td> <td>adjac ent</td> <td>Moderate</td> <td></td> </tr> <tr> <td><a href="/aops/343">Ecdysone receptor antagonism leading to mortality via mis-timed ecdysone receptor-responsive nuclear receptor cascade</a> </td> <td>adjacent</td> <td></td> <td></td> < /tr> </tbody> </table> </div> </div> <!-- loop to find stressors under event --> <div> <h4>Stressors</h4> The following are stressors that operate directly through this Event. <div> Will need to add a loop here once we have chemicals figured out <ol> <li>chemical one</li> <li>chemical two</li> </ol> <br> </div> </div> <!-- loop to find taxonomic applicability under event --> <div> <h4>Taxonomic Applicability</h4> There are no Taxonomic Terms associated with this Event <br> <br> </div> <!-- end loop for taxons --> <!-- biological organization, life stages and sex terms --> <div> <div class="row"> <!-- biological organization --> <div class="col-md-4"> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <th>Level of Biological Organization</th> </tr> </thead> <tbody> <tr> <td>Individual</td> </tr> </tbody> </table> </div> </div> <!-- end of bio org --> <!-- life stages --> <div class="col-md-4"> <h4>Life Stage Applicability</h4> There are no Life Stages associated with this Event </div> <!-- end life stages --> <!-- sex terms --> <div class="col-md-4"> <h4>Sex Applicability</h4> There are no Sexes associated with this Event </div> <!-- end sex terms --> </div> <!-- end bio org, life stage and sex terms --> </div> <!-- event text --> <!-- end event text --></div> </div> <!-- end ke loop --> <!-- loop for ao --> id="ao" > <h2>Adverse Outcome</h2> <hr> <div> <div> <h3><strong>Event ID and Title</strong></h3> <a href="/events/351">351: In creased, Mortality</a><br> Short Name: Increased, Mortality </div> <div> <h3>Key Event Overview</h3> <!-- loop to find all aops that use this event -- > <h4>AOPs Includ ing This Key Event </h4>panel panel-default "> <table class="table table-bordered table-striped "> <thead> <div> <h4> <a href="/relationships/1010">Relationship: 1010: De crease, Abdominal muscle contraction leads to Increase, Incomplete ecdysis</a></h4 > <h4>AOPs Referenc ing Relationship </h4> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>AOP ID and Name</th> <th>Event Type </th> <th scope="col" >AOP Name</th> <th scope="col">Adjacency</th> <th scope="col">Weight of Evidence</th> <th scope="col">Quantitative Understanding </th> </tr> </thead> <tbody> <tr> <td><a href="/aops/16">16: Acetylcholinesterase inhibition leading to acute mortality</a></td> <td>AdverseOutcome</td > </tr> <tr> <td><a href="/aops/96">96: Axonal sodium channel modulation leading to acute mortality</a></td> <td>AdverseOutcome</td> </tr> <tr> <td><a href="/aops/104">104: Altered ion channel activity leading impaired heart function </a></td> <td>AdverseOutcome</td> </tr> <tr > <td><a href="/aops/113">113: Glutamate-gated chloride channel activation leading to acute mortality</a> </td> <td>AdverseOutcome </td> </tr> <tr> <td><a href="/aops/160">160: Ionotropic gamma-aminobutyric acid receptor activation mediated neurotransmission inhibition leading to mortality</a></td> <td>AdverseOutcome</td> </tr> <tr> <td><a href="/aops/161">161: Glutamate-gated chloride channel activation leading to neurotransmission inhibition associated mortality </a></td> <td>AdverseOutcome</td> </tr> <tr > <td><a href="/aops/138">138: Organic anion transporter (OAT1) inhibition leading to renal failure and mortality</a> </td> <td>AdverseOutcome </td> </tr> <tr> <td><a href="/aops/177">177: Cyclooxygenase 1 (COX1) inhibition leading to renal failure and mortality</a></td> <td>AdverseOutcome</td> </tr> <tr> <td><a href="/aops/186">186: unknown MIE leading to renal failure and mortality </a></td> <td>AdverseOutcome</td> </tr> <tr > <td><a href="/aops/4">4: Ecdysone receptor agonism leading to mortality</a>< /td> <td>AdverseOutcome </td> </tr> <tbody class="tbody-striped" > <tr> <td><a href="/aops/4">Ecdysone receptor agonism leading to mortality via suppress ion of Ftz-f1 </a></td> <td>adjacent</td > <td>Moderate </td> <td></td> </tr> <tr> <td><a href="/aops/342">Ecdysone receptor hyper activation leading to mortality via mis-timed activation of nuclear receptor cascade </a></td> <td>adjacent</td > <td>Moderate </td> <td></td> </tr> <tr> <td><a href="/aops/343">Ecdysone receptor antagonism leading to mortality via mis-timed ecdysone receptor-responsive nuclear receptor cascade </a></td> <td>adjacent</td > <td></td> <td></td> </tr> </tbody> </table> </div> </div> <!-- loop to find stressors under event --> <div> <h4>Stressors</h4> The following are stressors that operate directly through this Event. <div> Will need to add a loop here once we have chemicals figured out <ol> <li>chemical one</li> <li>chemical two</li> </ol> <br> </div> </div> <!-- loop to find taxonomic applicability under event --> <div> <h4>Taxonomic Applicability</h4> There are no Taxonomic Terms associated with this Event <br> <br> </div> <!-- end loop for taxons --> <!-- biological organization, life stages and sex terms --> <div> <div class="row"> <!-- biological organization --> <div class="col-md-4"> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <th>Level of Biological Organization</th> </tr> </thead> <tbody> <tr> <td>Population</td> </tr> </tbody> </table> </div> </div> <!-- end of bio org --> <!-- life stages --> <div class="col-md-4"> <h4>Life Stage Applicability</h4> There are no Life Stages associated with this Event </div> <!-- end life stages --> <!-- sex terms --> <div class="col-md-4"> <h4>Sex Applicability</h4> There are no Sexes associated with this Event </div> <!-- end sex terms --> </div> <!-- end bio org, life stage and sex terms --> </div> <!-- event text --> <!-- end event text --></div></div> <!-- end ao loop --> <!-- Evidence for relationship links section, this lists the r elationships and then supports them --> <div id="evidence_supporting_links" > <h2>Scientific evidence support ing the linkages in the AOP</h2> <hr > <div class="panel panel-default "> <table class="table table-bordered table-striped" id="sortable_relationships" , data-aop-id="4" , data-update-path="/aops/4/aop_relationships/update_row_order "> <thead> <div> <h4><a href="/ relationships/1002">R elationship: 1002: Increase, Incomplete ecdysis leads to Increase, Mortality</a></h4 > <h4>AOPs Referenc ing Relationship</h4 > <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>ID</th> <th>Upstream Event </th> <th>Relationship Type </th> <th>Downstream Event</th> <th> Evidence</th> <th>Quantitative Understanding</th> <th scope="col">AOP Name </th> <th scope="col">Adjacency </th> <th scope="col">Weight of Evidence</th> <th scope="col" >Quantitative Understanding</th> </tr> </thead> <tbody> <tr data-item-id=1121 class="item "> <td > <a href="/relationships/1343">1121</a> </td> <td> Activation, Ecdysone receptor </td> <td> Directly leads to </td> <td> Induction, Nuclear receptor E75b gene </td> <td> Strong </td> <td> Weak </td> </tr> <tr data-item-id=1122 class="item" > <td> <a href="/relationships/1344">1122</a> </td> <td> Induction, Nuclear receptor E75b gene </td> <td> Directly leads to </td> <td> Suppression, Fushi tarazu factor-1 gene </td> <td> Strong </td> <td> Weak </td> </tr> <tr data-item-id=1123 class="item"> <td> <a href="/relationships/1345">1123</a> </td> <td> S uppression, Fushi tarazu factor-1 gene </td> <td> Directly leads to </td> <td> Reduction, Release of circulating ecdysis triggering hormone </td> <td> Moderate </td> <td> Weak </td> </tr> <tr data-item-id=1124 class="item" > <td> <a href="/relationships/1346">1124</a> </td> <td> Reduction, Release of circulating e cdysis triggering hormone </td> <td> Directly leads to </td> <td> Reduction, Release of circulat ing crustacean cardioactive peptide </td> <td> Moderate </td> <td> Weak </td> </tr> <tr data-item-id=1125 class="item"> <td> <a href="/relationships/1347">1125</a> </td> <td> Reduc tion, Release of circulating crustacean cardioactive peptide </td> <td> Directly leads to </td> <td> Reduction, Ecdysis motoneuron bursts </td> <td> Moderate </td> <td> Weak </td> </tr> <tr data-item-id=1126 class="item" > <td> <a href="/relationships/1348">1126</a> </td> <td> Reduction, Ecdysis motoneuron bursts </td> <td> Directly leads to </td> <td> Reduction, Excitatory postsynaptic potential </td> <td> Moderate </td> <td> Weak </td> </tr> <tr data-item-id=1127 class="item"> <td> <a href="/relationships/1349">1127</a> </td> <td> Reduction, Excitatory postsynaptic potential </td> <td> Directly leads to </td> <td> Reduction, Abdominal muscle contraction </td> <td> Moderate </td> <td> Weak </td> </tr> <tr data-item-id=1082 class="item"> <td> <a href="/relationships/1010">1082</a> </td> <td> Reduction, Abdominal muscle contraction </td> <td> Directly leads to </td> <td> Induction, Incomplete ecdysis </td> <td> Moderate </td> <td> Weak </td> </tr> <tr data-item-id=1083 class="item"> <td> <a href="/relationships/1190">1083 </a> </td> <td> Induction, Incomplete ecdysis </td> <td> Directly leads to </td> <td> Increased, Mortality </td> <td> Strong </td> <td> Strong </td> </tr> <tbody class="tbody-striped "> <tr > <td> <a href="/aops/466">Doda decarboxylase leading to mortality</a> </td> <td>adjacent </td> <td>Moderate </td> <td>Moderate </td> </tr> <tr > <td><a href="/aops/4">Ecdysone receptor agonism leading to mortality via s uppression of Ftz-f1</a> </td> <td>adjacent </td> <td>High </td> <td></td> </tr> <tr > <td><a href="/aops/342">E cdysone receptor hyperactivation lead ing to mortality via mis-timed activa tion of nuclear receptor cascade</a> </td> <td>adjacent </td> <td>High </td> <td></td> </tr> <tr > <td><a href="/aops/343"> Ecdysone receptor antagonism leading to mortality via mis-timed ecdysone receptor-responsive nuclear receptor cascade </a></td> <td>adjacent </td> <td></td> <td></td> </tr> </tbody> </table> </div> <br> <div> <h3><strong>Relationship ID and Title: </strong></h3> <a href="/relationships/1343">4: Activation, EcR leads to Induction, E75b gene</a> <!--%= "#{relationship.directness}" %--> <!-- if nothing shows up in any of these fields, then weight of evidence will not be displayed --></div> <div> <h3><strong>Relationship ID and Title: </strong></h3> <a href="/relationships/1344">4: Induction, E75b gene leads to Suppression, Ftz-f1 gene</a> <!--%= "#{relationship.directness}" %--> <!-- if nothing shows up in any of these fields, then weight of evidence will not be displayed --></div> <div> <h3><strong>Relationship ID and Title: </strong></h3> <a href="/relationships/1345">4: Suppression, Ftz-f1 gene leads to Reduction, Release of circulating ETH</a> <!--%= "#{relationship.directness}" %--> <!-- if nothing shows up in any of these fields, then weight of evidence will not be displayed --></div> <div> <h3><strong>Relationship ID and Title: </strong></h3> <a href="/relationships/1346">4: Reduction, Release of circulating ETH leads to Reduction, Release of circulating CCAP</a> <!--%= "#{relationship.directness}" %--> <!-- if nothing shows up in any of these fields, then weight of evidence will not be displayed --></div> <div> <h3><strong>Relationship ID and Title: </strong></h3> <a href="/relationships/1347">4: Reduction, Release of circulating CCAP leads to Reduction, Ecdysis motoneuron bursts</a> <!--%= "#{relationship.directness}" %--> <!-- if nothing shows up in any of these fields, then weight of evidence will not be displayed --></div> <div> <h3><strong>Relationship ID and Title: </strong></h3> <a href="/relationships/1348">4: Reduction, Ecdysis motoneuron bursts leads to Reduction, Excitatory postsynaptic potential</a> <!--%= "#{relationship.directness}" %--> <!-- if nothing shows up in any of these fields, then weight of evidence will not be displayed --></div> <div> <h3><strong>Relationship ID and Title: </strong></h3> <a href="/relationships/1349">4: Reduction, Excitatory postsynaptic potential leads to Reduction, Abdominal muscle contraction</a> <!--%= "#{relationship.directness}" %--> <!-- if nothing shows up in any of these fields, then weight of evidence will not be displayed --></div> <div> <h3><strong>Relationship ID and Title: </strong></h3> <a href="/relationships/1010">4: Reduction, Abdominal muscle contraction leads to Induction, Incomplete ecdysis</a> <!--%= "#{relationship.directness}" %--> <!-- if nothing shows up in any of these fields, then weight of evidence will not be displayed --></div> <div> <h3><strong>Relationship ID and Title: </strong></h3> <a href="/relationships/1190">4: Induction, Incomplete ecdysis leads to Increased, Mortality</a> <!--%= "#{relationship.directness}" %--> <!-- if nothing shows up in any of these fields, then weight of evidence will not be displayed --></div></div><!-- end relationship loop --><!-- Overall assessment section, *** what is included here? *** --><div id="overall_assessment"> <h2>Overall Assessment of the AOP</h2> <hr> <h3>Applicability of the AOP</h3> <div class="row"> <div class="col-md-6"> <h3>Life Stage Applicability</h3> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <th>Life Stage</th> <th>Evidence</th> </tr> </thead> <tbody> <tr> <td>Juvenile</td> <td>Strong</td> </tr> <tr> <td>Adult</td> <td>Moderate</td> </tr> </tbody> </table> </div> </div></div> <div class="row"> <div class="col-md-10"> <h3>Taxon Applicability</h3> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <th>Term</th> <th>Scientific Term</th> <th>Evidence</th> </tr> </thead> <tbody> <tr> <td>insects</td> <td>insects</td> <td>Strong</td> </tr> <tr> <td>crustaceans</td> <td>Daphnia magna</td> <td>Moderate</td> </tr> </tbody> </table> </div> </div></div><div class="row"> <div class="col-md-6"> <h3>Sex Applicability</h3> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <th>Sex</th> <th>Evidence</th> </tr> </thead> <tbody> <tr> <td>Unspecific</td> <td>Moderate</td> </tr> </tbody> </table> </div> </div> </div></div><!-- potential consierations, text as entered by author --><div id="considerations_for_potential_applicaitons"></div><!-- reference section, text as of right now but should be changed to be handled as table --><div id="references"> <h2>References</h2> <hr> <br></div> </div> </div> </div> <footer class="footer"> <di v class="navbar navbar-fixed-bottom navbar-inverse "> <div class="container"> <ul class="nav nav bar-nav"> <li ><a href="/info_pages/2">Help</a></a></ li> <li ><a href="/info_pages/3 ">About</a></a></ li> <li ><a href="/info_pages/4">FAQ</a> </a></li> <li ><a 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