API

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Relationship: 351

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increased, Induced Mutations in Critical Genes leads to Increased, Clonal Expansion / Cell Proliferatin to form Pre-Neoplastic Altered Hepatic Foci

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Increased, Induced Mutations in Critical Genes
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Increased, Clonal Expansion / Cell Proliferatin to form Pre-Neoplastic Altered Hepatic Foci

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

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

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

There is no direct evidence addressing AFB1 induced critical gene mutations and the subsequent induction of AHF. However, in general the progression from chemical exposure to pre-neoplastic lesions appears to include six general mechanisms: 1) decrease in the activity of the Keap1/Nrf2/ARE pathway; 2) decrease in p53 function leading to increased survival in the presence of genomic instability; 3) changes in the tumor microenvironment within cells; 4) alterations in apoptosis; 5) changes in Wnt/b-catenin signaling, and 6) gene expression changes that may be related to cancer promotion/progression. In addition to these six possible mechanisms, epigenetic changes in DNA methylation may occur and may be related to the progression of cancer.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Map 2.0

ID Experimental Design Species Upstream Observation Downstream Observation Citation (first author, year) Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Title First Author
Biological Plausibility
Dose Concordance
Temporal Concordance
Incidence Concordance
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

There is no direct information as to whether AFB1 induced mutations in critical genes leads to cellular proliferation and clonal expansion of mutant cells. It is known, however that the Hepatitis B virus plays a large role in the development of HCC in many endemic AFB1 regions, and viral infection is thought to interact with AFB1 exposure increasing the possibility that individual cells progress down the pathway to tumor formation. It seems reasonable that this infection may contribute to increased cell proliferation which could contribute to more clonal expansion (and, therefore, an increase in tumor formation) of AFB1-induced critical cancer gene mutant cells. It might also contribute to inflammation and increased cell proliferation which could result in an increased number of spontaneously mutant cells containing mutants in cancer critical genes (such as p53) thus also resulting in HCC (via a non-mutagenic MOA). This interaction between AFB1 and viral infection has motivated much research (Chittmittrapap et al., 2013; Farazi et al., 2006; Gouas et al., 2010; Kew 2003).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

In mammals, the identification of AHF as a pre-neoplastic lesion has been recognized for many years as part of the general etiology of HCC (Beer and Pitot, 1987; Dragan et al., 1995; Goldsworthy et al., 1986; Pitot et al., 1990; Sargent et al., 1989). In rats, the presence of AHF with altered growth characteristics has been observed in a number of studies (Bannasch et al., 1985; Fischer, 1986; Fischer et al., 1987; Gil et al., 1988; Godlewski et al., 1985; Manson et al., 1984; Newberne, 1976; Nishizumi et al., 1977; Roebuck et al., 1991; Youngman and Campbell, 1992). The mechanisms involved in the formation of AHF appear to be generalizable across animals and likely apply to fish and birds as well as mammals.