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Formation, Pro-mutagenic DNA Adducts leads to Increased, Clonal Expansion / Cell Proliferatin to form Pre-Neoplastic Altered Hepatic Foci
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
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 altered hepatic foci (AHF) which can lead to hepatocellular carcinoma (HCC). These steps (pro-mutagenic adduct formation and formation of AHF) are indirectly linked through insufficient/mis-repair of DNA and induction of a mutation in a critical gene.
Evidence Collection Strategy
Evidence Supporting this KER
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).
Uncertainties and Inconsistencies
The direct KER relationships between adducts and mutations (MIE→KE#2) and from mutations to AHF (KE#2→KE#3) determine this indirect relationship. Unfortunately, there is a paucity of data to support quantification of a relationship between adducts and AHF; neither to address an AFB1 dose-response for both KEs.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The universality of both DNA adducts and AHF in the pathogenesis of liver cancer suggests that the wide taxonomic applicability noted elsewhere in this AOP is likely true for this KER.
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.
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.
Bechtel DH (1989) Molecular dosimetry of hepatic aflatoxin B1-DNA adducts: linear correlation with hepatic cancer risk. Regul Toxicol Pharmacol 10: 74-81.
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.
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.
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) doi:10.1158/1940-6207.CAPR-13-0430
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 doi:10.1093/carcin/bgu003
Popp JA, Scortichini BH, Garvey LK (1985) Quantitative evaluation of hepatic foci of cellular alteration occurring spontaneously in Fischer-344 rats. Fundam Appl Toxicol 5: 314-319.
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.