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Event: 853

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

Changes/Inhibition, Cellular Homeostasis and Apoptosis

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
Changes/Inhibition, Cellular Homeostasis and Apoptosis

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
Level of Biological Organization
Cellular

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
Cell term
hepatocyte

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
cellular homeostasis abnormal
apoptotic process decreased

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 KeyEvent Rick Becker (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
rat Rattus norvegicus NCBI
mouse Mus musculus 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

Tumor promotion requires a perturbation in the balance between cell gain via mitosis and cell loss via apoptosis (Roberts et al., 1997). Indirectly, the inhibition of apoptosis in either damaged or initiated cells favors their survival, and inhibition of apoptosis af- fords initiated cells an increased opportunity for clonal expansion and autonomous growth with the chance to acquire additional mutations during the process of tumor progression. AHR activation inhibits apoptosis in altered hepatic foci (i.e., initiated hepatic cells), and this inhibition affords cells within altered hepatic foci a sur- vival advantage and increases the likelihood that these cells will acquire additional mutations.

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). ?

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). Although increases of cell proliferation could contribute to the increase in size and volume fraction of altered hepatic foci, the greater magnitude of inhibition of apoptosis suggests it is the primary factor contributing to clonal expansion of altered hepatic foci, at least early on (Luebeck et al., 2000; Moolgavkar et al., 1996; Stinchcombe et al., 1995). AHR activators inhibit apoptosis produced by UV light exposure of human cell lines and rat primary hepatocytes (Ambolet-Camoit et al., 2010; Chopra et al., 2009, 2010; Schwarz et al., 2000). Inhibition of apoptosis in primary rat hepatocytes was mediated through phosphorylation and inactivation of p53 and modulation of Mdm2, Tfgb1/4, and AGR2; in addition, inhi- bition of apoptosis required protein synthesis (Ambolet-Camoit et al., 2010; Chopra and Schrenk, 2011; Chopra et al., 2009, 2010; Davis et al., 2001; Franc et al., 2008; Paajarvi et al., 2005; Worner and Schrenk, 1996, 1998). Cytotoxicity appears to occur after intrafocal apoptosis inhibition is measured and inflammation-driven cell proliferation is a somewhat later event. What remains unknown is whether a proliferative response in stem and stellate cells occurs earlier or at the same time as intrafocal apoptosis inhibition.

Quantitative stereology is used to quantify the growth of AHF and such studies provide a measure of this KE (Hendrich et al., 1987; Dragan et al., 1997; Teeguarden et al., 1999; Viluksela et al., 2000).

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

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 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

Ambolet-Camoit, A., Bui, L.C., Pierre, S., Chevallier, A., Marchand, A., Coumoul, X., Garlatti, M., Andreau, K., Barouki, R., Aggerbeck, M., 2010. 2,3,7,8- tetrachlorodibenzo-p-dioxin counteracts the p53 response to a genotoxicant by upregulating expression of the metastasis marker agr2 in the hep- atocarcinoma cell line HepG2. Toxicol. Sci. 115, 501-512.

Chopra, M., Dharmarajan, A.M., Meiss, G., Schrenk, D., 2009. Inhibition of UV-C light-induced apoptosis in liver cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol. Sci. 111, 49-63.

Chopra, M., Gahrs, M., Haben, M., Michels, C., Schrenk, D., 2010. Inhibition of apoptosis by 2,3,7,8-tetrachlorodibenzo-p-dioxin depends on protein biosyn- thesis. Cell Biol. Toxicol. 26, 391-401.

Chopra, M., Schrenk, D., 2011. Dioxin toxicity, aryl hydrocarbon receptor signaling, and apoptosis-Persistent pollutants affect programmed cell death. Crit. Rev. Toxicol. 41:292-320.

Davis W., J.W., Lauer, F.T., Burdick, A.D., Hudson, L.G., Burchiel, S.W., 2001. Prevention of apoptosis by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the MCF-10A cell line: correlation with increased transforming growth factor alpha production. Cancer. Res. 61, 3314-3320.

Dragan, Y. P., Campbell, H. A., Xu, X. H., Pitot, H. C., 1997. Quantitative stereological studies of a 'selection' protocol of hepatocarcinogenesis following initiation in neonatal male and female rats. Carcinogenesis. 18, 149-58.

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.

Franc, M.A., Moffat, I.D., Boutros, P.C., Tuomisto, J.T., Tuomisto, J., Pohjanvirta, R., Okey, A.B., 2008. Patterns of dioxin-altered mRNA expression in livers of dioxin- sensitive versus dioxin-resistant rats. Arch. Toxicol. 82, 809-830.

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.

Hendrich, S., Campbell, H. A., Pitot, H. C., 1987. Quantitative stereological evaluation of four histochemical markers of altered foci in multistage hepatocarcinogenesis in the rat. Carcinogenesis. 8, 1245-50.

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.

Moolgavkar, S.H., Luebeck, E.G., Buchmann, A., Bock, K.W., 1996. Quantitative analysis of enzyme-altered liver foci in rats initiated with diethylnitrosamine and promoted with 2,3,7,8-tetrachlorodibenzo-p-dioxin or 1,2,3,4,6,7,8- heptachlorodibenzo-p-dioxin. Toxicol. Appl. Pharmacol. 138, 31-42.

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.

Roberts, R.A., Nebert, D.W., Hickman, J.A., Richburg, J.H., Goldsworthy, T.L., 1997. Perturbation of the mitosis/apoptosis balance: a fundamental mechanism in toxicology. Fundam. Appl. Toxicol. 38, 107-115.

Schwarz, M., Buchmann, A., Stinchcombe, S., Kalkuhl, A., Bock, K., 2000. Ah receptor ligands and tumor promotion: survival of neoplastic cells. Toxicol. Lett. 112e113, 69-77.

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.

Viluksela, M., Bager, Y., Tuomisto, J. T., Scheu, G., Unkila, M., Pohjanvirta, R., Flodstrom, S., Kosma, V. M., Maki-Paakkanen, J., Vartiainen, T., Klimm, C., Schramm, K. W., Warngard, L., Tuomisto, J., 2000. Liver tumor-promoting activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in TCDD-sensitive and TCDD-resistant rat strains 27. Cancer Res. 60, 6911-6920.

Worner, W., Schrenk, D., 1996. Influence of liver tumor promoters on apoptosis in rat hepatocytes induced by 2-acetylaminofluorene, ultraviolet light, or transforming growth factor beta 1. Cancer. Res. 56, 1272-1278.