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Event: 59

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

Inhibition of Apoptosis in Altered Hepatic Foci, Changes in Cellular Growth Homeostasis

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
Inhibition of Apoptosis in Altered Hepatic Foci, Changes in Cellular Growth Homeostasis

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

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

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


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
Rodentia sp. 09ZR5#43 Rodentia sp. 09ZR5#43 High 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

A large number of quantitative models have mathematically evaluated the increases in the number and volume of phenotypically altered (e.g. GSTP-positive) foci (Andersen et al., 1993, 1995; Andersen and Conolly, 1998; Bock, and Kohle, 2005; Conolly, and Andersen, 1997; Kim et al., 2003; Mills and Andersen, 1993; Moolgavkar et al., 1996; Portier et al., 1993, 1996). Thresholds for tumour promotion have been described for an increase in volume fraction of altered hepatic foci (Maronpot et al., 1993; Pitot et al., 1987; Teeguarden et al., 1999; Viluksela et al., 2000).

However, it should be noted that tumour promotion protocols create artificial circumstances by greatly accelerating the initiation rate of altered hepatic foci. In contrast, with sustained AHR activation, it is the development of altered hepatic foci (AHF) that naturally occur that are a primary target of the AHR-induced tumour promotion. AHF occur spontaneously in rats, albeit at a low rate. AHF may occur from either transformation of hepatocytes or of liver stem cells that have migrated to the liver parenchyma (Kuhlmann and Peschke, 2006). The rate of growth of AHF seems to be increased in TCDD-treated rats thereby demonstrating that sustained AHR activation either suppresses intrafocal apoptosis or increases intrafocal cell proliferation (Schrenk et al., 1994, 2004). The use of a nitrosamine may, or may not, create mutations in genes that dioxins would normally influence in a two-year cancer bioassay. In any case, the initiation-promotion data coupled to the understanding of the otherwise slow rate of emergence and growth of foci suggests that a critical number and volume of foci are necessary for TCDD-induced sustained AHR activation to promote rodent liver tumours. The dependency on the development of sufficient number and volume of altered hepatic foci may be a ModF for when the MIE actually occurs.

The timing of apoptosis inhibition within foci and increased cell proliferation has been discussed above. The results from initiation-promotion studies illustrate that TCDD-mediated reductions in intrafocal apoptosis can occur within months with continuous TCDD administration (Luebeck et al., 2000). Increased cell proliferation, which appears to occur more selectively in non-parenchymal cells, likewise ensues months after continuous TCDD exposure, suggesting that the observed periportal increase in labelling index occurs in hepatoblasts, biliary cells and other non-parenchymal cells such as oval cells (Hailey et al., 2005; Buchmann et al., 1994; Maronpot et al., 1993).

Hepatocellular adenomas may arise from clonal expansion within altered hepatic foci and cholangiolarcarcinomas from spontaneously initiated biliary progenitor cells near the canals of Hering. Prolonged administration of indole-3-carbinol, an AHR agonist found in broccoli, increased the number and volume of GST-P+ altered hepatic foci in a 26 week initiation-promotion study and hepatocellular adenomas were observed in some animals (Yamamoto et al., 2013). In this study, male F-344 rats received a diet containing 0.5% I3C and assuming they consumed 15% of their body weight daily and weighed on average 300 g, the daily dose of I3C is estimated at 750 mg/kg/day whereas in vivo gene expression data indicated a half-maximal dose of about 100 mg/kg for CYP1A2 mRNA (Coe et al., 2006).

At the organ level (next section), the occurrence of toxic hepatopathy and associated hepatocyte damage likely involves the development of a proliferative response by liver stem cells. Normal replacement of hepatocytes occurs by cell division of other, likely younger hepatocytes. However, in the case of extensive liver damage, replacement likely also occurs by stem cell proliferation (Tanaka et al., 2011). Wnt/β-catenin signalling plays a role in liver regeneration in many species (Nekak-Bowen and Monga, 2011) and may be stimulated by sustained AHR-activation. Sustained activation of the AHR by TCDD downregulated Wnt/β-catenin target genes in WB-F344 cells, considered a model for liver stem cells. Cell-to-cell interactions may also contribute to increased stem cell proliferation, The downregulation of β-catenin reduced cell adhesion and E-cadherin-mediated cell-cell junctions (Procházková et al., 2011a). Indirubin is an endogenous compound that can act as a weak AHR agonist. In WB-F344 cells, considered a model for liver stem/progenitor cells, doses of 100 pM indirubin increased gene expression of plakoglobin, a protein related to cadherin-mediated intracellular communication; however, doses of 1 or 10 μM indirubin decreased the expression of plakoglobin to a similar extent as did 5nM TCDD (Procházková et al., 2011b). For example, the regenerative properties of liver stem cells are modulated by stellate cells, which contain up to 80% of the vitamin A in the body (Senoo et al., 2010; Pintilie et al 2010).

The possibility that hepatic stem cells give rise to both tumor types cannot be discounted. Significant liver toxicity with damage to the parenchymal cells occurs prior to tumor formation and therefore, stem cell proliferation leading to development of both hepatic and biliary tumours seems likely. AHR-mediated transformation and associated changes in cell-cell contact and/or intercellular communication could enable stem cells to migrate from the progenitor cell niche to the liver parenchyma and there become an AHF through clonal expansion.

Several different methods have been established for obtain clonal populations of liver stem cells from rodents that are capable of differentiating into both hepatic and biliary cells (Sahin et al., 2008; Yavorkovsky et al., 1995; Fougere-Deschatrette et al., 2006). These cell lines could be used to develop assays for known AHR agonists to determine their potential effects on stem cell proliferation and biology.

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). ?

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?

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


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 ( (OECD, 2015). More help