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Event: 165

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

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

Short name
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Activation, Long term AHR receptor driven direct and indirect gene expression changes
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Biological Context

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Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.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.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

The location/biological environment in which the event takes place.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.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  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 signaling 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.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
signaling aryl hydrocarbon receptor increased

Key Event Overview

AOPs Including This Key Event

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AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Sustained AhR Activation leading to Rodent Liver Tumours MolecularInitiatingEvent Rick Becker (send email) Open for citation & comment EAGMST Under Review

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.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

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Sex Applicability

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Key Event Description

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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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.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). Do not provide detailed protocols. More help

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

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  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).

References

List of the literature that was cited for this KE description. More help

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NTP, 2006b. NTP toxicology and carcinogenesis studies of 2,3,4,7,8- Pentachlorodibenzofuran (PeCDF) (CAS No. 57117-31-4) in female Harlan Sprague-Dawley rats (Gavage studies). Natl. Toxicol. Program Tech. Rep. Ser. 1e198.

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