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Event: 384

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

Increased, Clonal Expansion / Cell Proliferatin to form Pre-Neoplastic Altered Hepatic Foci

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
Increased, Clonal Expansion / Cell Proliferatin to form Pre-Neoplastic Altered Hepatic Foci

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

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

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

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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

The occurrence of altered hepatic foci (AHF) as precursors to liver tumors in AFB1-treated rats has been recognized for decades. Originally, these foci were observed as histologically different from the surrounding parenchyma. (Harada et al, 1989, 1990; Gil et al., 1988; Bannasch et al., 1985) In addition, enzyme alterations were used to identify AHF foci, most notably, the occurrence of a placental form of glutathione-S-transferase (GSTP+). (Godlewski et al., 1985; Dragan et al., 1994a, 1995; Kirby et al., 1990) The growth and occurrence of foci are expressed as the number of AHF in a volume of liver, possibly the entire liver, and the volume fraction of the liver occupied by AHF. (Dragan et al., 1997) Both of these reflect focal growth because single cell foci are not detectable with the immunohistochemical staining technique. The assumption is that single transformed cells in which apoptosis is blocked by tumor-critical mutations will grow into AHF. (Grassl-Kraupp et al., 1997). A number of agents regarded as tumor promoters appear to enhance the growth of foci, acting to further inhibit apoptosis and also creating an overall proliferative stimulus. (Angsubhakorn et al., 2002; Wyde et al., 2002).

AFB1 appears to be a “complete” carcinogen in that the toxin acts as an initiator through the formation of pro-mutagenic DNA adducts (the MIE) and as a promoter through increasing oxidative stress and inflammation. (Ohnishi et al., 2013; Caballero et al., 2004).

Evidence Supporting Essentiality

Strong

Chemoprevention studies, reviewed in another section of this AOP, suggest a strong relationship between altered hepatic foci (AHF) and HCC tumor formation (Olden and Vulimiri, 2014; Liby et al., 2008; Yates et al., 2007; Yates and Kensler, 2007; Kensler et al., 2004). For example, Johnson et al. (2014) observed background levels of AHF along with a complete absence of tumors in rats treated with a triterpenoid chemoprotectant CDDO-Im, despite maintaining a significant burden of AFB1-induced adducts. (Johnson et al., 2014) Cell proliferation appears to be six- to seven-fold greater in AHF than in surrounding liver parenchyma. (Dragan et al., 1994) However, the measurements were made from liver biopsies, and whether the increased expression was associated with foci is not known.

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). ?

Quantitative stereology has been used to quantify the growth of AHF.(Pitot et al., 1996; Dragan et al., 1995; Xu et al., 1990). Growth of foci appears to follow the Moolgavkar-Venzon-Knudson model of initiation and promotion. (Dewanji et al., 1991; Dragan et al, 1995) Most recently, Johnson et al. (2014) have shown that a chemoprotective agent reduces the occurrence of AHF to background levels and completely protects against tumors, although pro-mutagenic adducts are still present at easily quantifiable levels.

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 occurrence of AHF appears to be universal and has been observed in mammals, including humans, as well as in birds and in fish. (Ribback et al., 2013; Thoolen et al., 2012; Kirby et al., 1990).

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

Angsubhakorn S, Pradermwong A, Phanwichien K, Nguansangiam S (2002) Promotion of aflatoxin B1-induced hepatocarcinogenesis by dichlorodiphenyl trichloroethane (DDT). Southeast Asian J Trop Med Public Health 33: 613-623.

Bannasch P, Benner U, Enzmann H, Hacker HJ (1985) Tigroid cell foci and neoplastic nodules in the liver of rats treated with a single dose of aflatoxin B1. Carcinogenesis 6: 1641-1648.

Caballero F, Meiss R, Gimenez A, Batlle A, Vazquez E (2004) Immunohistochemical analysis of heme oxygenase-1 in preneoplastic and neoplastic lesions during chemical hepatocarcinogenesis. Int J Exp Pathol 85: 213-222.

Dewanji A, Moolgavkar SH, Luebeck EG (1991) Two-mutation model for carcinogenesis: joint analysis of premalignant and malignant lesions. Math Biosci 104: 97-109.

Dragan Y, Teeguarden J, Campbell H, Hsia S, Pitot H (1995) The quantitation of altered hepatic foci during multistage hepatocarcinogenesis in the rat: transforming growth factor alpha expression as a marker for the stage of progression. Cancer Lett 93: 73-83.

Dragan YP, Campbell HA, Baker K, Vaughan J, Mass M, Pitot HC (1994) Focal and non-focal hepatic expression of placental glutathione S-transferase in carcinogen-treated rats. Carcinogenesis 15: 2587-2591.

Dragan YP, Hully J, Baker K, Crow R, Mass MJ, Pitot HC (1995) Comparison of experimental and theoretical parameters of the Moolgavkar-Venzon-Knudson incidence function for the stages of initiation and promotion in rat hepatocarcinogenesis. Toxicology 102: 161-175.

Dragan YP, Campbell HA, Xu XH, Pitot HC (1997) Quantitative stereological studies of a 'selection' protocol of hepatocarcinogenesis following initiation in neonatal male and female rats. Carcinogenesis 18: 149-158.

Gil R, Callaghan R, Boix J, Pellin A, Llombart-Bosch A (1988) Morphometric and cytophotometric nuclear analysis of altered hepatocyte foci induced by N-nitrosomorpholine (NNM) and aflatoxin B1 (AFB1) in liver of Wistar rats. Virchows Arch B Cell Pathol Incl Mol Pathol 54: 341-349.

Godlewski CE, Boyd JN, Sherman WK, Anderson JL, Stoewsand GS (1985) Hepatic glutathione S-transferase activity and aflatoxin B1-induced enzyme altered foci in rats fed fractions of brussels sprouts. Cancer Lett 28: 151-157.

Grasl-Kraupp B, Ruttkay-Nedecky B, Müllauer L, Taper H, Huber W, et al (1997) Inherent increase of apoptosis in liver tumors: implications for carcinogenesis and tumor regression. Hepatology 25: 906-912.

Harada T, Maronpot RR, Morris RW, Boorman GA (1990) Effects of mononuclear cell leukemia on altered hepatocellular foci in Fischer 344 rats. Vet Pathol 27: 110-116.

Harada T, Maronpot RR, Morris RW, Stitzel KA, Boorman GA (1989) Morphological and stereological characterization of hepatic foci of cellular alteration in control Fischer 344 rats. Toxicol Pathol 17: 579-593.

Johnson NM, Egner PA, Baxter VK, Sporn MB, Wible RS, et al (2014) Complete protection against aflatoxin B1-induced liver cancer with triterpenoid: DNA adduct dosimetry, molecular signature and genotoxicity threshold. Cancer Prev Res (Phila) .

Kirby GM, Stalker M, Metcalfe C, Kocal T, Ferguson H, Hayes MA (1990) Expression of immunoreactive glutathione S-transferases in hepatic neoplasms induced by aflatoxin B1 or 1,2-dimethylbenzanthracene in rainbow trout (Oncorhynchus mykiss). Carcinogenesis 11: 2255-2257.

Ohnishi S, Ma N, Thanan R, Pinlaor S, Hammam O, et al (2013) DNA damage in inflammation-related carcinogenesis and cancer stem cells. Oxid Med Cell Longev 2013: 387014.

Pitot HC, Dragan YP, Teeguarden J, Hsia S, Campbell H (1996) Quantitation of multistage carcinogenesis in rat liver. Toxicol Pathol 24: 119-128.

Ribback S, Calvisi DF, Cigliano A, Sailer V, Peters M, et al (2013) Molecular and metabolic changes in human liver clear cell foci resemble the alterations occurring in rat hepatocarcinogenesis. J Hepatol 58: 1147-1156.

Thoolen B, Ten Kate FJ, van Diest PJ, Malarkey DE, Elmore SA, Maronpot RR (2012) Comparative histomorphological review of rat and human hepatocellular proliferative lesions. J Toxicol Pathol 25: 189-199.

Wyde ME, Cambre T, Lebetkin M, Eldridge SR, Walker NJ (2002) Promotion of altered hepatic foci by 2,3,7,8-tetrachlorodibenzo-p-dioxin and 17beta-estradiol in male Sprague-Dawley rats. Toxicol Sci 68: 295-303.

Xu YH, Maronpot R, Pitot HC (1990) Quantitative stereologic study of the effects of varying the time between initiation and promotion on four histochemical markers in rat liver during hepatocarcinogenesis. Carcinogenesis 11: 267-272.

Xu YH, Campbell HA, Sattler GL, Hendrich S, Maronpot R, et al (1990) Quantitative stereological analysis of the effects of age and sex on multistage hepatocarcinogenesis in the rat by use of four cytochemical markers. Cancer Res 50: 472-479.