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Event: 854

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

Alterations, Cellular proliferation / hyperplasia

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
Alterations, Cellular proliferation / hyperplasia

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

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
Organ term

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
cell proliferation Liver cell abnormal
hyperplasia hepatic oval stem cell increased
hyperplasia intrahepatic bile duct epithelial cell increased

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 Allie Always (send email) Open for citation & comment EAGMST Under Review


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 rodentia 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

Over the time period of high levels of sustained AHR activation, DLCs produce a complex pattern of cell proliferative responses. Teeguarden et al. (1999) observed that rats initiated with diethylnitrosamine (DEN) and then dosed with either 0.1 or 1 ng/ kg-d TCDD for one month exhibited a reduced labeling index relative to controls, and reduced BrdU-labeling was also observed following the 0.1 ng/kg-d TCDD dose after three months. Maronpot et al. (1993) observed a reduction in BrdU labeling index in hepatocytes at a low dose of 3.5 ng/kg-d TCDD in DEN-initiated rats after 30 weeks of TCDD administration but, at a dose of 125 ng/kg/d the labeling index was increased.

Both parenchymal calls and liver stem cells are likely involved in the organ-level response to sustained AHR activation. Early acti- vation of the AHR in zone 3 of the liver acinus causes decreased hepatocyte replication and may act as an indirect proliferative stimulus for stem cells and hepatoblasts (Andersen et al., 1997; Conolly and Andersen, 1997; Tritscher et al., 1992). Oval cells in the periportal region likely function as a source of replacement of hepatocytes after inhibition of normal hepatocyte replication- replacement (Paku et al., 2001; Sahin et al., 2008; Tanaka et al., 2011; Wang et al., 2003). While hepatocyte replication is considered the normal means for replacement of liver parenchyma, inhibition of hepatocyte replication in centrilobular regions induced by TCDD may induce normally quiescent liver stem cells to proliferate.

Following longer period of sustained AHR activation, organ- level increases in cell proliferation ensue, demonstrated by an in- crease in BrdU labeling and likely reflecting the regenerative response to organ-wide toxicity (Hailey et al., 2005).

Non-parenchymal cells, including stem cells, hepatoblasts, biliary cells, stellate cells, endothelial cells, and Kuppfer cells, play a role in this AOP. In rodents, TCDD elicits a fibrogenic and bile duct proliferative response that requires pathological alteration of stellate cell function and increased differentiation and growth of hepatoblasts and bile duct cells before 33 weeks of exposure. Retinoid depletion induces stellate cell proliferation, production of extracellular matrix components, and the transition to fibroblast; stellate cells maintain vitamin A homeostasis and respond to liver injury with formation of proliferative cytokines such as TGF-a and EGF (Friedman, 2008; Pintilie et al., 2010; Senoo et al., 2010). TCDD induces loss of retinoid content (presumably from stellate cells) and may disrupt the extensive communication between various liver cell types (Fletcher et al., 2001; Hoegberg et al., 2005; Pierre et al., 2014; Schmidt et al., 2003). Thus, TCDD-induced retinol loss from hepatic stellate cells may contribute to cell proliferation, biliary fibrosis, and cholangiolarcarcinoma (Fattore et al., 2000; Friedman, 2008; Hakansson and Hanberg, 1989; Schmidt et al., 2003).

AHR activation also induces changes in stem/oval cells. All of the rats receiving 100 ng/kg/day TCDD, the highest dose group animals in the 2-year cancer bioassay, developed oval cell hyperplasia with clear statistical increases in this endpoint at 22 ng/kg/day or greater (Hailey et al., 2005). Evidence points to the involvement of TNF-alpha regulation in the proliferative response of hepatic stem cells; this is likely mediated through modulation of the levels of TNF-alpha, altered beta-catenin signaling, and inhibition of cell-to-cell contact (Knight et al., 2000; Umannova et al., 2007; Vondracek et al., 2009; Dietrich et al., 2002; Prochazkova et al.,2011; Weiss et al., 2008). TNF-alpha is an inflammatory cytokine with an important role in liver tumor promotion. More research on how sustained AHR activation dysregulates normal TNF-alpha activity could be very impactful on evolving the AOP.

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). ?

Bile duct hyperplasia and oval cell hyperplasia are measured histopathological observations using frequency of occurrence and a severity index.

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

The proliferative response of the liver appears to occur in rodents but not humans.


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

Andersen, M.E., Birnbaum, L.S., Barton, H.A., Eklund, C.R., 1997. Regional hepatic CYP1A1 and CYP1A2 induction with 2,3,7,8-tetrachlorodibenzo-p-dioxin eval- uated with a multicompartment geometric model of hepatic zonation. Toxicol. Appl. Pharmacol. 144, 145-155.

Conolly, R.B., Andersen, M.E., 1997. Hepatic foci in rats after diethylnitrosamine initiation and 2,3,7,8-tetrachlorodibenzo-p-dioxin promotion: evaluation of a quantitative two-cell model and of CYP 1A1/1A2 as a dosimeter. Toxicol. Appl. Pharmacol. 146, 281-293.

Dietrich, C., Faust, D., Budt, S., Moskwa, M., Kunz, A., Bock, K.W., Oesch, F., 2002. 2,3,7,8-tetrachlorodibenzo-p-dioxin-dependent release from contact inhibition in WB-F344 cells: involvement of cyclin A. Toxicol. Appl. Pharmacol. 183, 117-126.

Fletcher, N., Hanberg, A., Håkansson, H., 2001. Hepatic vitamin a depletion is a sensitive marker of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure in four rodent species. Toxicol. Sci. 62, 166-175.

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.

Hoegberg, P., Schmidt, C.K., Fletcher, N., Nilsson, C.B., Trossvik, C., Gerlienke Schuur, A., Brouwer, A., Nau, H., Ghyselinck, N.B., Chambon, P., Håkansson, H., 2005. Retinoid status and responsiveness to 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD) in mice lacking retinoid binding protein or retinoid receptor forms. Chem. Biol. Interact. 156, 25-39.

Knight, B., Yeoh, G.C., Husk, K.L., Ly, T., Abraham, L.J., Yu, C., Rhim, J.A., Fausto, N., 2000. Impaired preneoplastic changes and liver tumor formation in tumor necrosis factor receptor type 1 knockout mice. J. Exp. Med. 192, 1809-1818.

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.

Paku, S., Schnur, J., Nagy, P., Thorgeirsson, S.S., 2001. Origin and structural evolution of the early proliferating oval cells in rat liver. Am. J. Pathol. 158, 1313-1323.

Pierre, S., Chevallier, A., Teixeira-Clerc, F., Ambolet-Camoit, A., Bui, L.-C., Bats, A.-S., Fournet, J.-C., Fernandez-Salguero, P., Aggerbeck, M., Lotersztajn, S., Barouki, R., Coumoul, X., 2014. Aryl hydrocarbon receptor-dependent induction of liver fibrosis by dioxin. Toxicol. Sci. 137, 114-124.

Pintilie, D.G., Shupe, T.D., Oh, S.-H., Salganik, S.V., Darwiche, H., Petersen, B.E., 2010. Hepatic stellate cells' involvement in progenitor-mediated liver regeneration. Lab. Invest. 90, 1199-1208.

Prochazkova, J., Kabatkova, M., Bryja, V., Umannova, L., Bernatík, O., Kozubík, A., Machala, M., Vondracek, J., 2011. The interplay of the aryl hydrocarbon receptor and b-catenin alters both AhR-dependent transcription and Wnt/b-catenin signaling in liver progenitors. Toxicol. Sci. 122, 349-360.

Sahin, M.B., Schwartz, R.E., Buckley, S.M., Heremans, Y., Chase, L., Hu, W.-S., Verfaillie, C.M., 2008. Isolation and characterization of a novel population of progenitor cells from unmanipulated rat liver. Liver Transpl. 14, 333-345.

Schmidt, C.K., Hoegberg, P., Fletcher, N., Nilsson, C.B., Trossvik, C., Hakansson, H., Nau, H., 2003. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters the endoge- nous metabolism of all-trans-retinoic acid in the rat. Arch. Toxicol. 77, 371-383.

Senoo, H., Yoshikawa, K., Morii, M., Miura, M., Imai, K., Mezaki, Y., 2010. Hepatic stellate cell (vitamin A-storing cell) and its relativeepast, present and future. Cell. Biol. Int. 34, 1247-1272.

Tanaka, M., Itoh, T., Tanimizu, N., Miyajima, A., 2011. Liver stem/progenitor cells: their characteristics and regulatory mechanisms. J. Biochem. 149, 231-239.

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.

Tritscher, A.M., Goldstein, J.A., Portier, C.J., McCoy, Z., Clark, G.C., Lucier, G.W., 1992. Dose-response relationships for chronic exposure to 2,3,7,8- tetrachlorodibenzo-p-dioxin in a rat tumor promotion model: quantification and immunolocalization of CYP1A1 and CYP1A2 in the liver. Cancer. Res. 52, 3436-3442.

Umannova, L., Zatloukalova, J., Machala, M., Krcmar, P., Majkova, Z., Hennig, B., Kozubík, A., Vondracek, J., 2007. Tumor necrosis factor-alpha modulates effects of aryl hydrocarbon receptor ligands on cell proliferation and expression of cytochrome P450 enzymes in rat liver “stem-like” cells. Toxicol. Sci. 99, 79-89.

Vondracek, J., Krcmar, P., Prochazkova, J., Trilecova, L., Gavelova, M., Skalova, L., Szotakova, B., Buncek, M., Radilova, H., Kozubik, A., Machala, M., 2009. The role of aryl hydrocarbon receptor in regulation of enzymes involved in metabolic activation of polycyclic aromatic hydrocarbons in a model of rat liver progenitor cells. Chem. Biol. Interact. 180, 226-237.

Wang, X., Foster, M., Al-Dhalimy, M., Lagasse, E., Finegold, M., Grompe, M., 2003. The origin and liver repopulating capacity of murine oval cells. Proc. Natl. Acad. Sci. U. S. A. 100 (Suppl. 1), 11881-11888.

Weiss, C., Faust, D., Schreck, I., Ruff, A., Farwerck, T., Melenberg, A., Schneider, S., Oesch-Bartlomowicz, B., Zatloukalova, J., Vondracek, J., Oesch, F., Dietrich, C., 2008. TCDD deregulates contact inhibition in rat liver oval cells via Ah receptor, JunD and cyclin A. Oncogene 27, 2198-2207.