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Event: 165

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Activation, Long term AHR receptor driven direct and indirect gene expression changes

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Activation, Long term AHR receptor driven direct and indirect gene expression changes

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help
Process Object Action
signaling aryl hydrocarbon receptor increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Sustained AhR Activation leading to Rodent Liver Tumours MolecularInitiatingEvent Allie Always (send email) Open for citation & comment EAGMST Under Review

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
Rattus sp. ABTC 42503 Rattus sp. ABTC 42503 High NCBI
mouse Mus musculus High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

MIE: Macromolecular Interactions and Sustained Ligand-Activation of Transcription

Insight into sustained AHR activation is provided by examining the induction of ethoxyresorufin-O,O-deethylase in liver by three DLCs at three different time points (NTP, 2006a; NTP, 2006b; NTP, 2006c). Plots of the fractional or normalized ethoxyresorufin-O,O- deethylase response from three NTP cancer bioassays are shown in the plots on the left of Fig. 2. Induction of ethoxyresorufin-O,O- deethylase is easily measured and serves as a biomarker of CYP1A1 gene expression. The dose term on the x-axis is the area under the curve (AUC) of liver concentration. The normalized ethoxyresorufin-O,O-deethylase response on the y-axis is similar at 14, 31 and 53 weeks (Left column of Fig. 2). The plots for 31 weeks and 53 weeks are shifted to the right given the dose term on the x-axis is the AUC of hepatic concentration of the three chemicals, TCDD, 4-PeCDF and PCB-126. To obtain a measure of sustained AHR activation, the fractional ethoxyresorufin-O,O- deethylase response is multiplied by the number of weeks. Hence, a fractional response of 50% at 14 weeks would be a sustained AHR activation index of 7. The sustained AHR activation index is plotted versus the AUC of hepatic toxic equivalents (TEQ) for all three chemicals calculated using TEF values of 1.0, 0.3 and 0.1 for TCDD, 4-PeCDF and PCB-126 respectively (Van den Berg et al., 2006) (Fig. 2, right column). The sustained AHR activation index shows a strong relationship to the AUC of hepatic TEQ and thus the sustained AHR activation index reflects the dose, potency and duration of DLCs in the liver.

Dose-response modeling can be performed using the sustained AHR activation index as the dose term and the measures of the various KEs or biomarkers as the response. Fig. 4 shows an example in which the well-known Hill dose-response model was used. One of the model parameters is the ED50 or EC50 value e in other words, the effective dose or concentration sufficient to produce a 50% of the maximal response. This parameter is also called the half- maximal dose. When this measure of sustained AHR activation is used, the ESA50 denotes the level of sustained AHR activation required for a half-maximal response.

Please also see Becker, R.A., Patlewicz, G., Simon, T.W., Rowlands, J.C., Budinsky, R.A. 2015. The adverse outcome pathway for rodent liver tumor promotion by sustained activation of the aryl hydrocarbon receptor. Regul. Toxicol. Pharmacol. 73, 172-190: PMID: 26145830. The file is open access.

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

Dose-response modeling can be performed using the sustained AHR activation index as the dose term and the measures of the various KEs or biomarkers as the response. Figure 3 shows an example in which the well-known Hill dose-response model was used. One of the model parameters is the ED50 or EC50 value e in other words, the effective dose or concentration sufficient to produce a 50% of the maximal response. This parameter is also called the half- maximal dose. When this measure of sustained AHR activation is used, the ESA50 denotes the level of sustained AHR activation required for a half-maximal response.

Figure 2

Figure 2 alt text
Figure 2: Dose-response of CYP1A1 activation measured by EROD as a measure of AHR activation in response to an AUC measure of dose. The AUC is the hepatic concentration multiplied by the time in weeks. The left hand plots show measured EROD from the NTP bioassays in response to chronic dosing of TCDD (top), 4-PeCDF (middle) or PCB-126 (bottom) (NTP, 2006a, 2006b, 2006c). Dose-dependent EROD levels are sustained over time. The right hand plots show the EROD response on normalized to a zero-to-one scale as a measure of AHR activation level.

shows plots of the increase in 7-Ethoxyresorufin-O-deethylase (EROD) versus the area-under-the-curve (AUC) of the hepatic concentration of three dioxin-like chemicals, TCDD, 4-PeCDF and PCB-126 occurring during lifetime dosing. The figure shows corresponding plots of normalized EROD as a measure of AHR activation. In all three cases, the shape of the dose-response remained consistent except that the position along the dose axis increased with increasing time for all three chemicals. This observation indicates that the level of AHR activation remains relatively constant over time with a continuing dose of persistent AHR ligand. A measure of sustained activation (SA) of the AHR can be calculated by multiplying the level of AHR activation observed as fractional CYP1A1 induction by the number of weeks of dosing. SA calculated in this way can be used as a dose surrogate. In order to use the measurements of all three DLCs considered here, their hepatic AUC concentrations were multiplied by their toxic equivalence factors (TEFs) (Van den Berg et al., 2006). SA was plotted against the AUC of hepatic TEQ concentration (Figure 3).

Figure 3 alt text
Figure 3: Sustained AHR activation versus the area-under-the-curve of hepatic TEQ. TEQ was calculated for TCDD, PeCDF and PCB126 using TEF values of 1, 0.3 and 0.1 respectively. Data from all three chemicals at 14 weeks are shown with blue markers, those from 31 weeks with green markers and those from 53 weeks with orange markers. Please see narrative for additional details.

The plot shows a consistent pattern that can be fit with a Hill function. The curve is shallower than a first-order Hill plot shown by the Hill coefficient less than one. This shallowness may be due to differences in potency and efficacy at different times, possibly stemming from hepatic sequestration of ligand by CYP1A2, especially for PeCDF, thus decreasing the effective hepatic concentration relative to the measured concentration.

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

At a number of levels of biological organization, differences exist between the human and rodent AHR. Considering toxicodynamics, the human AHR binding affinity is an order of magnitude or more lower than that in rodents that is generally correlated with reduced sensitivity in human hepatocytes relative to rats (Black et al., 2012; Budinsky et al., 2010; Connor and Aylward, 2006). In addition, these species differences include AHR binding affinity, different recruit- ment of co-regulatory proteins, and different patterns of gene regulation (Black et al., 2012; Budinsky et al., 2010; Carlson et al., 2009; Connor and Aylward, 2006; Dere et al., 2011; Flaveny et al., 2010).

Evidence for Perturbation by Stressor

Overview for Molecular Initiating Event

When a specific MIE can be defined (i.e., the molecular target and nature of interaction is known), in addition to describing the biological state associated with the MIE, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to list stressors known to trigger the MIE and provide evidence supporting that initiation. This will often be a list of prototypical compounds demonstrated to interact with the target molecule in the manner detailed in the MIE description to initiate a given pathway (e.g., 2,3,7,8-TCDD as a prototypical AhR agonist; 17α-ethynyl estradiol as a prototypical ER agonist). Depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). Known stressors should be included in the MIE description, but it is not expected to include a comprehensive list. Rather initially, stressors identified will be exemplary and the stressor list will be expanded over time. For more information on MIE, please see pages 32-33 in the User Handbook.

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

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