Event:165

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Event Title

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

Key Event Overview

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AOPs Including This Key Event

AOP Name Event Type Essentiality
Sustained AhR Activation leading to Rodent Liver Tumours MIE Strong

Chemical Initiators

The following are chemical initiators that operate directly through this Event:

  1. Dioxin and dioxin-like compounds

Taxonomic Applicability

Name Scientific Name Evidence Links
Rattus sp. ABTC 42503 Rattus sp. ABTC 42503 Strong NCBI
mouse Mus musculus Strong NCBI

Level of Biological Organization

Biological Organization
Cellular

How this Key Event works

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

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

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.

Evidence Supporting Taxonomic Applicability

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).

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