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Relationship: 345

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

Formation, Pro-mutagenic DNA Adducts leads to Tumorigenesis, Hepatocellular carcinoma

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Formation, Pro-mutagenic DNA Adducts

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Tumorigenesis, Hepatocellular carcinoma

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

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
AFB1: Mutagenic Mode-of-Action leading to Hepatocellular Carcinoma (HCC)	non-adjacent	Moderate	Moderate	Agnes Aggy (send email)	Open for citation & comment	Under Review

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

Formation of the pro-mutagenic DNA adduct, N7-AFB1-G (or its conversion product, N7-AFB1-FAPy) is the first step in the initiation of a process that may finish in development of hepatocellular carcinoma (HCC). These steps (pro-mutagenic adduct formation and HCC) are indirectly linked through insufficient/mis-repair of DNA and induction of a mutation in a critical gene and clonal expansion/cell proliferation with formation of altered hepatic foci (AHF).

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

While there is no specific information for AFB1, it is widely recognized that pro-mutagenic adducts formed by AFB1 metabolites may be repaired/removed or may result in mutations. The fidelity of the repair processes and probability of mis-repair determine whether mutations arise in tumor-critical genes. The altered hepatic foci (AHF) are believed to result from mutations expressed in cells that demonstrate reduced apoptosis and increased proliferation, likely linked to the mutations. (Alekseyev et al., 2004; Zhang et al., 2003; Giri et al., 2002; Bailey et al., 1996; Lin et al., 2014). The further development of AHF to HCC is believed to be a continuum of these same processes over time. 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.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Formation of AFB1-induced DNA adducts clearly precede tumor formation, thus the necessary temporal pattern exists. The plethora of published chemoprevention studies support a relationship between AFB1-induced DNA adducts and hepatocellular carcinoma (HCC). There are some evaluations that claim (Bechtel et al. 1989) linearity in the dose-response for adduct formation as a function of dose in both rats and trout; but linearity does not seem to apply, however, for adducts and HCC. Recent work of Johnson et al. (2014) showed that HCC incidence was reduced to zero by the chemoprotectant CDDO-Im, while around 30% of the original level of N7-AFB1-G adducts were still present. These authors note that there remained ~15,000 adducts per cell after application of the chemoprotectant, while no HCC tumors were induced. Other chemoprevention data also support the reduction or elimination of HCC, accompanied by a reduction in AFB1-induced DNA adducts, e.g., oltipraz (Kensler et al.,1987 ; Roebuck et al., 1991; Maxuitenko et al., 1993). There are also chemoprevention data from humans demonstrating administration of chlorophyllin results in an increased elimination of urinary AFB1-induced adducts, presumably stemming from a reduced burden of AFB1-induced adducts, and an assumed concomitant reduction in tumor burden (Jubert et al., 2009) (see Chemoprevention section).

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

The direct KER relationships between adducts and mutations (MIE→KE#2) and from mutations to AHF (KE#2→KE#3) and from AHF to HCC (KE#3→AO) determine this indirect relationship. Unfortunately, there is a paucity of data to support quantification of a relationship between adducts and HCC; neither are there data to address an AFB1-related dose-response for both KEs.

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

One might obtain a quantitative understanding of this linkage from studies with AFB1 that reported dose-response data for both AFB1-induced adduct levels and HCC tumor incidence. However, no such data were identified. As mentioned above, some chemoprevention studies report reduced levels of AFB1-induced adducts (or increased urinary elimination of AFB1-induced adducts) but they only used single dose levels, so there are no dose-response data. Most initiation-promotion studies used a highly artificial system with chemical initiation with an alkylating agent and promotion with phenobarbital, TCDD, or some other compound, coupled with partial hepatectomy to further stimulate rapid cell proliferation (Xu et al., 1990a, 1990b). Chemoprotection studies such as Johnson et al. (2014) indicate that a strong relationship likely exists between AFB1-induced adducts and tumors, but insufficient data exist for quantification or definitive dose-response determination.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

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

HCC has 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., 1990; Kirby et al., 1990).

References

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

Alekseyev YO, Hamm ML, Essigmann JM (2004) Aflatoxin B1 formamidopyrimidine adducts are preferentially repaired by the nucleotide excision repair pathway in vivo. Carcinogenesis 25: 1045-1051. Bailey EA, Iyer RS, Stone MP, Harris TM, Essigmann JM (1996) Mutational properties of the primary aflatoxin B1-DNA adduct. Proc Natl Acad Sci U S A 93: 1535-1539.

Bechtel DH (1989) Molecular dosimetry of hepatic aflatoxin B1-DNA adducts: linear correlation with hepatic cancer risk. Regul Toxicol Pharmacol 10: 74-81

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.

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).

Jubert C, Mata J, Bench G, Dashwood R, Pereira C, et al (2009) Effects of chlorophyll and chlorophyllin on low-dose aflatoxin B(1) pharmacokinetics in human volunteers. Cancer Prev Res (Phila) 2: 1015-1022.

Giri I, Johnston DS, Stone MP (2002) Mispairing of the 8,9-dihydro-8-(N7-guanyl)-9-hydroxy-aflatoxin B1 adduct with deoxyadenosine results in extrusion of the mismatched dA toward the major groove. Biochemistry 41: 5462-5472.

Gursoy-Yuzugullu O, Yuzugullu H, Yilmaz M, Ozturk M (2011) Aflatoxin genotoxicity is associated with a defective DNA damage response bypassing p53 activation. Liver Int 31: 561-571.

Kensler TW, Egner PA, Dolan PM, Groopman JD, Roebuck BD (1987) Mechanism of protection against aflatoxin tumorigenicity in rats fed 5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz) and related 1,2-dithiol-3-thiones and 1,2-dithiol-3-ones. Cancer Res 47: 4271-4277.

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.

Lin YC, Li L, Makarova AV, Burgers PM, Stone MP, Lloyd RS (2014) Molecular basis of aflatoxin-induced mutagenesis--role of the aflatoxin B1-formamidopyrimidine adduct. Carcinogenesis .

Maxuitenko YY, MacMillan DL, Kensler TW, Roebuck BD (1993) Evaluation of the post-initiation effects of oltipraz on aflatoxin B1-induced preneoplastic foci in a rat model of hepatic tumorigenesis. Carcinogenesis 14: 2423-2425.

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.

Roebuck BD, Liu YL, Rogers AE, Groopman JD, Kensler TW (1991) Protection against aflatoxin B1-induced hepatocarcinogenesis in F344 rats by 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione (oltipraz): predictive role for short-term molecular dosimetry. Cancer Res 51: 5501-5506.

Sudakin DL (2003) Dietary aflatoxin exposure and chemoprevention of cancer: a clinical review. J Toxicol Clin Toxicol 41: 195-204.

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.

Zhang YJ, Chen Y, Ahsan H, Lunn RM, Lee PH, et al (2003) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B1-DNA adducts and p53 mutation in hepatocellular carcinoma. Int J Cancer 103: 440-444.