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Relationship: 343


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, Proliferation/Clonal Expansion of Mutant Cells (Pre-Neoplastic Lesions/Altered H leads to Tumorigenesis, Hepatocellular carcinoma

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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

While there is no direct evidence addressing how AFB1 exposure affects cellular proliferation and the clonal expansion of mutant cells to ultimately form HCC, there are multiple biological processes that are generally involved in tumor development. These are discussed in a previous section and include effects on apoptosis, inflammation, the development of a tumor microenvironment, interference with the anti-oxidant response, and likely others.

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 Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

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; 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. Cell proliferation appears to be six- to seven-fold greater in AHF than in surrounding liver parenchyma (Dragan et al., 1994). In tree shrews, the apoptosis-related genes p53, bcl-2, bax and survivin were expressed to a much greater extent at 30 and 60 weeks in rats treated with AFB1 than in control rats (Duan et al., 2005). However, the measurements were made from liver biopsies, and whether the increased expression was associated with foci is not known. The Nrf2-Keap1 pathway activated by chemoprotectants appears to be a large factor in preventing hepatocellular carcinoma (HCC). Hence, the oxidative environment and resulting cellular stress that are the targets of this pathway likely contribute to tumor development from AHF.

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

A seemingly strong relationship exists between AHF and tumors; AHF have been considered as pre-neoplastic lesions for a number of years (Bannasch et al., 1986; Ikeda et al., 2004; Ribback et al., 2013).

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
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. 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

AHF have been observed essentially universally in AFB1-treated mammals, birds, and fish examined (Pottenger et al., 2014; Kensler et al., 2011; Kimura et al., 2004; Cullen et al., 1900; Kirby et al., 1990).


List of the literature that was cited for this KER description. More help

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

Cullen JM, Marion PL, Sherman GJ, Hong X, Newbold JE. 1990. Hepatic neoplasms in aflatoxin B1-treated, congenital duck hepatitis B virus-infected, and virus-free pekin ducks. Cancer Res 50: 4072-4080.

Dragan YP, Hully J, Crow R, Mass M, Pitot HC. 1994. Incorporation of bromodeoxyuridine in glutathione S-transferase-positive hepatocytes during rat multistage hepatocarcinogenesis. Carcinogenesis 15: 1939-1947.

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.

Duan XX, Ou JS, Li Y, Su JJ, Ou C, et al. 2005. Dynamic expression of apoptosis-related genes during development of laboratory hepatocellular carcinoma and its relation to apoptosis. World J Gastroenterol 11: 4740-4744.

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.

Ikeda H, Nishi S, Sakai M. 2004. Transcription factor Nrf2/MafK regulates rat placental glutathione S-transferase gene during hepatocarcinogenesis. Biochem J 380: 515-521.

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) .

Kensler TW, Egner PA, Wang JB, Zhu YR, Zhang BC, et al. 2004. Chemoprevention of hepatocellular carcinoma in aflatoxin endemic areas. Gastroenterology 127: S310-S318.

Kensler TW, Roebuck BD, Wogan GN, Groopman JD. 2011. Aflatoxin: a 50-year odyssey of mechanistic and translational toxicology. Toxicol Sci 120 Suppl 1: S28-S48.

Kimura M, Lehmann K, Gopalan-Kriczky P, Lotlikar PD. 2004. Effect of diet on aflatoxin B1-DNA binding and aflatoxin B1-induced glutathione S-transferase placental form positive hepatic foci in the rat. Exp Mol Med 36: 351-357.

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.

Liby K, Yore MM, Roebuck BD, Baumgartner KJ, Honda T, et al. 2008. A novel acetylenic tricyclic bis-(cyano enone) potently induces phase 2 cytoprotective pathways and blocks liver carcinogenesis induced by aflatoxin. Cancer Res 68: 6727-6733.

Olden K, Vulimiri SV. 2014. Laboratory to community: chemoprevention is the answer. Cancer Prev Res (Phila) 7: 648-652.

Pitot HC, Dragan Y, Sargent L, Xu YH. 1991. Biochemical markers associated with the stages of promotion and progression during hepatocarcinogenesis in the rat. Environ Health Perspect 93: 181-189.

Pitot HC, Dragan Y, Xu YH, Pyron M, Laufer C, Rizvi T. 1990. Role of altered hepatic foci in the stages of carcinogenesis. Prog Clin Biol Res 340D: 81-95.

Pitot HC. 1990. Altered hepatic foci: their role in murine hepatocarcinogenesis. Annu Rev Pharmacol Toxicol 30: 465-500.

Pottenger LH, Andrews LS, Bachman AN, Boogaard PJ, Cadet J, et al. 2014. An organizational approach for the assessment of DNA adduct data in risk assessment: case studies for aflatoxin B1, tamoxifen and vinyl chloride. Crit Rev Toxicol 44: 348-391.

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. 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.

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.

Yates MS, Tauchi M, Katsuoka F, Flanders KC, Liby KT, et al. 2007. Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. Mol Cancer Ther 6: 154-162.

Yates MS, Kensler TW. 2007. Keap1 eye on the target: chemoprevention of liver cancer. Acta Pharmacol Sin 28: 1331-1342.