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Relationship: 874

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Activation, Long term AHR receptor driven direct and indirect gene expression changes leads to Changes/Inhibition, Cellular Homeostasis and Apoptosis

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

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

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Changes/Inhibition, Cellular Homeostasis and Apoptosis

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Sustained AhR Activation leading to Rodent Liver Tumours	adjacent	High	High	Undefined (send email)	Open for citation & comment	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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Sustained AHR activation inhibits apoptosis in altered hepatic foci (i.e., initiated hepatic cells), and this inhibition affords cells within altered hepatic foci a survival advantage and increases the likelihood that these cells will acquire additional mutations.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

The weight of evidence descriptor for this KER is strong.

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

All the elements in this AOP are strongly associated with the biological steps and elements of carcinogenesis (Hanahan and Weinberg, 2011). First, there is extensive body of mechanistic evidence in support the biological plausibility of this MOA (see recent review by Budinsky et al., 2014). Further, the relationships between sustained AHR activation and changes in cellular growth homeostasis / apoptosis, has been used for many years in initiation-promotion studies to understand early events in tumor formation (Dragan et al. 1992; Dragan and Schrenk, 2000; Luebeck et al. 2000; Maronpot et al. 1993; Teeguarden et al. 1999).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

AHR activation appears to cause inhibition of apoptosis in altered hepatic foci (Luebeck et al., 2000; Paajarvi et al., 2005; Schrenk et al., 1994, 2004; Stinchcombe et al., 1995). For this KE, initiation-promotion studies provide indirect evidence of inhibition of intrafocal apoptosis due to sustained AHR activation and direct evidence of a threshold for the clonal expansion of altered hepatic foci (Dragan and Schrenk, 2000; Teeguarden et al., 1999). Also, changes in cellular growth homeostasis / apoptosis are measured by changes in AHF reflecting changes in the apoptosis/proliferation balance occurs earliest in dose and time, reflected by the measure of SAA shown in the Dose-Time concordance table on the main page of this AOP.

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

There are few, if any, uncertainties or inconsistencies regarding this KER.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Using the measure of SAA that incorporates both dose and time allows understanding of the quantitative relationship between the sustained AHR activation and changes in cellular growth homeostasis / apoptosis. Figure 4 shows a plot of the increase in volume fraction of ATPase-negative AHF versus sustained AHR activation. The Hill model fit to these data had an ESA50 value of 17.6.

Figure 4: Rat liver tumor promotion by persistent AHR ligands. A) Simplified diagram showing changes in both cell proliferation and apoptosis appear to promote tumors. B) Plot of the increase in volume fraction of ATPase-deficient hepatic foci versus sustained AHR activation (SAA) index. Data from Teeguarden et al. (1999).

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Rodents are highly susceptible to the hepatotoxic, proliferative, and carcinogenic effects of sustained AHR activation induced by TCDD and other dioxin-like chemicals (Hailey et al., 2005; Goodman and Sauer, 1992; Kociba et al., 1978). The sustained AHR activation rodent liver tumor promotion AOP appears to be a pathway that very likely requires exceedance of a threshold for sustained AHR activation for liver cancers to occur in rodents.

References

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

Budinsky, R.A., Schrenk, D., Simon, T., Van den Berg, M., Reichard, J.F., Silkworth, J.B., Aylward, L.L., Brix, A., Gasiewicz, T., Kaminski, N., Perdew, G., Starr, T.B., Walker, N.J., Rowlands, J.C., 2014. Mode of action and dose-response framework analysis for receptor-mediated toxicity: the aryl hydrocarbon receptor as a case study. Crit. Rev. Toxicol. 44, 83-119.

Dragan, Y.P., Schrenk, D., 2000. Animal studies addressing the carcinogenicity of TCDD (or related compounds) with an emphasis on tumour promotion. Food. Addit. Contam. 17, 289-302.

Dragan, Y.P., Xu, X.H., Goldsworthy, T.L., Campbell, H.A., Maronpot, R.R., Pitot, H.C., 1992. Characterization of the promotion of altered hepatic foci by 2,3,7,8- tetrachlorodibenzo-p-dioxin in the female rat. Carcinogenesis 13, 1389-1395.

Goodman, D.G., Sauer, R.M., 1992. Hepatotoxicity and carcinogenicity in female Sprague-Dawley rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD): a pathology working group reevaluation. Regul. Toxicol. Pharmacol. 15, 245-252.

Hailey, J.R., Walker, N.J., Sells, D.M., Brix, A.E., Jokinen, M.P., Nyska, A., 2005. Clas- sification of proliferative hepatocellular lesions in harlan sprague-dawley rats chronically exposed to dioxin-like compounds. Toxicol. Pathol. 33, 165-174.

Hanahan, D., Weinberg, R.A., 2011. Hallmarks of cancer: the next generation. Cell 144, 646-674.

Kociba, R.J., Keyes, D.G., Beyer, J.E., Carreon, R.M., Wade, C.E., Dittenber, D.A., Kalnins, R.P., Frauson, L.E., Park, C.N., Barnard, S.D., Hummel, R.A., Humiston, C.G., 1978. Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats. Toxicol. Appl. Pharmacol. 46, 279-303.

Luebeck, E.G., Buchmann, A., Stinchcombe, S., Moolgavkar, S.H., Schwarz, M., 2000. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on initiation and promotion of GST-P-positive foci in rat liver: a quantitative analysis of experimental data using a stochastic model. Toxicol. Appl. Pharmacol. 167, 63-73.

Maronpot, R.R., Foley, J.F., Takahashi, K., Goldsworthy, T., Clark, G., Tritscher, A., Portier, C., Lucier, G., 1993. Dose response for TCDD promotion of hep- atocarcinogenesis in rats initiated with DEN: histologic, biochemical, and cell proliferation endpoints 8. Environ. Heal. Perspect. 101, 634-642.

Paajarvi, G., Viluksela, M., Pohjanvirta, R., Stenius, U., Hogberg, J., 2005. TCDD ac- tivates Mdm2 and attenuates the p53 response to DNA damaging agents. Carcinogenesis 26, 201-208.

Schrenk, D., Buchmann, A., Dietz, K., Lipp, H.P., Brunner, H., Sirma, H., Munzel, P., Hagenmaier, H., Gebhardt, R., Bock, K.W., 1994. Promotion of preneoplastic foci in rat liver with 2,3,7,8-tetrachlorodibenzo-p-dioxin, 1,2,3,4,6,7,8- heptachlorodibenzo-p-dioxin and a defined mixture of 49 polychlorinated dibenzo-p-dioxins. Carcinogenesis 15, 509-515.

Schrenk, D., Schmitz, H.J., Bohnenberger, S., Wagner, B., Worner, W., 2004. Tumor promoters as inhibitors of apoptosis in rat hepatocytes. Toxicol. Lett. 149, 43e50. Teeguarden, J.G., Dragan, Y.P., Singh, J., Vaughan, J., Xu, Y.H., Goldsworthy, T., Pitot, H.C., 1999. Quantitative analysis of dose- and time-dependent promotion of four phenotypes of altered hepatic foci by 2,3,7,8-tetrachlorodibenzo-p- dioxin in female Sprague-Dawley rats. Toxicol. Sci. 51, 211-223.

Stinchcombe, S., Buchmann, A., Bock, K.W., Schwarz, M., 1995. Inhibition of apoptosis during 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated tumour pro- motion in rat liver. Carcinogenesis 16, 1271-1275.

Teeguarden, J.G., Dragan, Y.P., Singh, J., Vaughan, J., Xu, Y.H., Goldsworthy, T., Pitot, H.C., 1999. Quantitative analysis of dose- and time-dependent promotion of four phenotypes of altered hepatic foci by 2,3,7,8-tetrachlorodibenzo-p- dioxin in female Sprague-Dawley rats. Toxicol. Sci. 51, 211-223.