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Event: 853

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. 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. More help
Changes/Inhibition, Cellular Homeostasis and Apoptosis
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
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
Cell term
hepatocyte

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
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

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
rat Rattus norvegicus NCBI
mouse Mus musculus NCBI

Life Stages

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

Sex Applicability

An indication of the the relevant sex for this KE. 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. 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

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

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

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