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Relationship: 547

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, Insufficient repair or mis-repair of pro-mutagenic DNA adducts leads to Increased, Induced Mutations in Critical Genes

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

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) adjacent Moderate Ted Simon (send email) Open for citation & comment EAGMST 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

There is no direct information concerning insufficient or mis-repair of AFB1 promutagenic adducts leading directly to mutations in critical genes. It is well known, however, that in general when the repair of DNA adducts is either done incorrectly or is insufficient to remove the DNA adduct and correct the DNA sequence prior to DNA replication, a mutation at the site of the DNA adduct will result in the daughter cells upon DNA replication.

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

When DNA adducts are not repaired, mutations result if cell replication (and DNA synthesis) takes place.

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

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
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

References

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

1. Bedard LL, and Massey TE. Aflatoxin B1-induced DNA damage and its repair. Cancer Lett. 2006, Sep 28;241(2):174-83.

2. Bedard LL, Alessi M, Davey S, and Massey TE. Susceptibility to aflatoxin B1-induced carcinogenesis correlates with tissue-specific differences in DNA repair activity in mouse and in rat. Cancer Res. 2005, Feb 15;65(4):1265-70.

3. Smith BT, and Walker GC. Mutagenesis and more: umuDC and the Escherichia coli SOS response. Genetics. 1998, Apr;148(4):1599-610.

4. Bailey EA, Iyer RS, Stone MP, Harris TM, and Essigmann JM. Mutational properties of the primary aflatoxin B1-DNA adduct. Proc Natl Acad Sci U S A. 1996, Feb 20;93(4):1535-9.

5. Denissenko MF, Koudriakova TB, Smith L, O'Connor TR, Riggs AD, and Pfeifer GP. The p53 codon 249 mutational hotspot in hepatocellular carcinoma is not related to selective formation or persistence of aflatoxin B1 adducts. Oncogene. 1998, Dec 10;17(23):3007-14.

6. Banerjee S, Brown KL, Egli M, and Stone MP. Bypass of aflatoxin B1 adducts by the Sulfolobus solfataricus DNA polymerase IV. J Am Chem Soc. 2011, Aug 17;133(32):12556-68.

7. Guo Y, Breeden LL, Zarbl H, Preston BD, and Eaton DL. Expression of a human cytochrome p450 in yeast permits analysis of pathways for response to and repair of aflatoxin-induced DNA damage. Mol Cell Biol. 2005, Jul;25(14):5823-33.

8. Alekseyev YO, Hamm ML, and Essigmann JM. Aflatoxin B1 formamidopyrimidine adducts are preferentially repaired by the nucleotide excision repair pathway in vivo. Carcinogenesis. 2004, Jun;25(6):1045-51. 9. Kew MC. Aflatoxins as a cause of hepatocellular carcinoma. J Gastrointestin Liver Dis. 2013, Sep;22(3):305-10.

10. Mulder JE, Bondy GS, Mehta R, and Massey TE. Up-regulation of nucleotide excision repair in mouse lung and liver following chronic exposure to aflatoxin B₁ and its dependence on p53 genotype. Toxicol Appl Pharmacol. 2014, Mar 1;275(2):96-103.

11. Kirk GD, Turner PC, Gong Y, Lesi OA, Mendy M, Goedert JJ, et al. Hepatocellular carcinoma and polymorphisms in carcinogen-metabolizing and DNA repair enzymes in a population with aflatoxin exposure and hepatitis B virus endemicity. Cancer Epidemiol Biomarkers Prev. 2005, Feb;14(2):373-9.

12. Long XD, Ma Y, Wei YP, and Deng ZL. The polymorphisms of GSTM1, GSTT1, HYL1*2, and XRCC1, and aflatoxin B1-related hepatocellular carcinoma in Guangxi population, China. Hepatol Res. 2006, Sep;36(1):48-55.

13. Long XD, Ma Y, Qu de Y, Liu YG, Huang ZQ, Huang YZ, et al. The polymorphism of XRCC3 codon 241 and AFB1-related hepatocellular carcinoma in Guangxi population, China. Ann Epidemiol. 2008, Jul;18(7):572-8.

14. Long XD, Ma Y, Huang HD, Yao JG, Qu de Y, and Lu YL. Polymorphism of XRCC1 and the frequency of mutation in codon 249 of the p53 gene in hepatocellular carcinoma among Guangxi population, China. Mol Carcinog. 2008, Apr;47(4):295-300.

15. Long X-D, Ma Y, and Deng Z-L. GSTM1 and XRCC3 polymorphisms: Effects on levels of aflatoxin B1-DNA adducts. Chinese Journal of Cancer Research. 2009, Sep;21(3):177-184.

16. Besaratinia A, Kim SI, Hainaut P, and Pfeifer GP. In vitro recapitulating of TP53 mutagenesis in hepatocellular carcinoma associated with dietary aflatoxin B1 exposure. Gastroenterology. 2009, Sep;137(3):1127-37, 1137.e1-5.

17. Lin YC, Li L, Makarova AV, Burgers PM, Stone MP, and Lloyd RS. Error-prone Replication Bypass of the Primary Aflatoxin B1 DNA Adduct, AFB1-N7-Gua. J Biol Chem. 2014, May 16;

18. Lin YC, Li L, Makarova AV, Burgers PM, Stone MP, and Lloyd RS. Molecular basis of aflatoxin-induced mutagenesis--role of the aflatoxin B1-formamidopyrimidine adduct. Carcinogenesis. 2014, Feb 7;

19. Leung MC, Goldstone JV, Boyd WA, Freedman JH, and Meyer JN. Caenorhabditis elegans generates biologically relevant levels of genotoxic metabolites from aflatoxin B1 but not benzo[a]pyrene in vivo. Toxicol Sci. 2010, Dec;118(2):444-53.

20. Meier B, Cooke SL, Weiss J, Bailly AP, Alexandrov LB, Marshall J, et al. C. elegans whole genome sequencing reveals mutational signatures related to carcinogens and DNA repair deficiency. Genome Res. 2014, Jul 16;

21. de Carvalho FM, de Almeida Pereira T, Gonçalves PL, Jarske RD, Pereira FE, and Louro ID. Hepatocellular carcinoma and liver cirrhosis TP53 mutation analysis reflects a moderate dietary exposure to aflatoxins in Espírito Santo State, Brazil. Mol Biol Rep. 2013, Aug;40(8):4883-7.

22. Gursoy-Yuzugullu O, Yuzugullu H, Yilmaz M, and Ozturk M. Aflatoxin genotoxicity is associated with a defective DNA damage response bypassing p53 activation. Liver Int. 2011, Apr;31(4):561-71.

23. Szymañska K, Chen JG, Cui Y, Gong YY, Turner PC, Villar S, et al. TP53 R249S mutations, exposure to aflatoxin, and occurrence of hepatocellular carcinoma in a cohort of chronic hepatitis B virus carriers from Qidong, China. Cancer Epidemiol Biomarkers Prev. 2009, May;18(5):1638-43.

24. Villar S, Le Roux-Goglin E, Gouas DA, Plymoth A, Ferro G, Boniol M, et al. Seasonal variation in TP53 R249S-mutated serum DNA with aflatoxin exposure and hepatitis B virus infection. Environ Health Perspect. 2011, Nov;119(11):1635-40.

25. Macé K, Aguilar F, Wang JS, Vautravers P, Gómez-Lechón M, Gonzalez FJ, et al. Aflatoxin B1-induced DNA adduct formation and p53 mutations in CYP450-expressing human liver cell lines. Carcinogenesis. 1997, Jul;18(7):1291-7.

26. Aguilar F, Hussain SP, and Cerutti P. Aflatoxin B1 induces the transversion of G-->T in codon 249 of the p53 tumor suppressor gene in human hepatocytes. Proc Natl Acad Sci U S A. 1993, Sep 15;90(18):8586-90.

27. Preston RJ, Williams GM. (2005). DNA-reactive carcinogens: mode of action and human cancer hazard. Crit Rev Toxicol, 35, 673–83

28. Pottenger, L.H., Andrews LS, Bachman AN, Boogaard PJ, Cadet J, Embry MR, Farmer PB, Himmelstein MW, Jarabek AM, Martin EA, Mauthe RJ, Persaud R, Preston RJ, Schoeny R, Skare J, Swenberg JA, Williams GM, Zeiger E, Zhang F, Kim JH. (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(4):348-391.

29. Puisieux A, Lim S, Groopman J, Ozturk M. (1991). Selective targeting of p53 gene mutational hotspots in human cancers by etiologically defined carcinogens. Cancer Res. 51(22):6185-6189.