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Bulky DNA adducts, increase leads to Increase, Mutations
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
|All life stages|
Key Event Relationship Description
Bulky DNA adducts occur when aromatic compounds are metabolically activated and interact with DNA bases. Not all of these bulky adductsare stable, however some have been found to persist and cause mutations during repair or replication. The specific mutation that occurs variesby bulky DNA adduct and by chemical. Exposure to the benzo(a)pyrene (B(a)P) or its metabolite anti-benzo(a)pyrene diol epoxide (BPDE)leads to (+/-)-trans-anti-BPDE-N-2-dG adducts, these adducts are associated with G→T transversions (Chiapperino et al. 2002; Zhang et al.2000, 2002), the occurrence of these transversions has been observed both in smokers (Anna et al. 2009; Hainaut and Pfeifer 2001) and in non-smokers (DeMarini et al. 2001). Exposure to aristicholic acid (AA) leads to the persistent DNA adduct 7-(deoxyadenosin-N6-yl) aristolactamI (dA–AAI) adducts and leads to AT→TA transversions (Arlt et al., 2002). Exposure to aflatoxin B1 has been leads to 8,9-dihydro-8- (N7-guanyl)-9-hydroxyaflatoxin B1 (AFB1-N7-Gua) adducts, which can lead to the AFB1-formamidopyrimidine (FAPY) adduct and ultimately causeG→T transversions (Bailey et al. 1996; Smela et al. 2002).
Evidence Collection Strategy
Evidence Supporting this KER
There is a large body of evidence that describes the relationship between bulky DNA adducts and mutations (Alexandrov et al. 2002; Chen etal. 2008; Veglia, Matullo, and Vineis 2003; Yagi et al. 2017). The bulky DNA adducts preferentially pair with an erroneous base, resulting in amutation, the mutation that results depends on the specific bulky DNA adduct that occurs.
Aristolochic acid and plants containing aristolochic acid have been found to be carcinogenic to humans due to the specific DNA adducts and theA:T to T:A transversions found in renal tissues of exposed populations (IARC 2011). Exposure to AA leads to the formation of the adduct dA-AAI. In experiments with modified bacteriophage T7 DNA polymerase and with human DNA polymerase α, dA-AAI has been found to pairequally well with adenine or tyrosine (Broschard et al. 1994; Broschard, Wiessler, and Schmeiser 1995). Pairing with tyrosine results in a non-mutagenic event, therefore mutations resulting from dA-AAI are AT→TA transversion (Arlt, Stiborova, and Schmeiser 2002; Kohara et al.2002). Aristolochic acid and plants containing aristolochic acid are considered carcinogenic to humans due to the specific DNA adducts and theA:T to T:A transversions found in renal tissues of exposed populations (IARC, 2011).
B(a)P is a known to be carcinogenic to humans due to extensive experimental evidence in many animal species along with mechanisticevidence to support the biological plausibility of bulky DNA adducts leading to mutations that cause cancer in humans (IARC 2014). Exposureto the B(a)P or its metabolite anti-benzo(a)pyrene diol epoxide (BPDE) leads to (+/-)-trans-anti-BPDE-N-2-dG adducts. Human DNApolymerase eta has been found to insert an A across from the (+/-)-trans-anti-BPDE-N-2-dG adducts, resulting in the above mentioned GvTtransversions (Chiapperino et al. 2002; Zhang et al. 2000, 2002). Polymerase eta has been found to be unlikely to extend past the lesion (Chiapperino et al. 2002)and instead polymerase kappa has been found to work as the second step in the bypass of this lesion (Zhang et al.2002). Another common mutation occurring from the bulky DNA lesion (+)-trans -anti-BPDE-N-2-dG is a G→A transversion. Through molecularmodelling, it has been suggested DNA polymerase may be more likely to insert a T if the bulk of the adduct is in the major groove and an A ifthe bulk of the adduct is in the minor groove (Kozack, Shukla, and Loechler 1999).
Uncertainties and Inconsistencies
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Bulky DNA adducts can occur in any cell type that is able to metabolically activate the stressor. Bulky adducts and resulting mutation frequencyhave been observed in various cell lines in vitro (TK6, HeLa, CHO) as well as various organisms in vivo (yeast, rat, human and mouse). This is unspecific to sex and to life stage.
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Anna, Lívia et al. 2009. “Relationship between TP53 Tumour Suppressor Gene Mutations and Smoking-Related Bulky DNA Adducts in aLung Cancer Study Population from Hungary.” Mutagenesis 24(6): 475–80.
Arlt, Volker M., Marie Stiborova, and Heinz H. Schmeiser. 2002. “Aristolochic Acid as a Probable Human Cancer Hazard in HerbalRemedies: A Review.” Mutagenesis 17(4): 265–77.
Bailey, Elisabeth A. et al. 1996. “Mutational Properties of the Primary Aflatoxin B1-DNA Adduct.” Proceedings of the National Academy of Sciences of the United States of America 93(4): 1535–39.
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Kozack, Richard E., Rajiv Shukla, and Edward L. Loechler. 1999. “A Hypothesis for What Conformation of the Major Adduct of(+)-Anti-B[a]PDE (N2-DG) Causes G→T versus G→A Mutations Based upon a Correlation between Mutagenesis and Molecular Modeling Results.” Carcinogenesis 20(1): 95–102.
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Veglia, Fabrizio, Giuseppe Matullo, and Paolo Vineis. 2003. “Bulky DNA Adducts and Risk of Cancer: A Meta-Analysis.” Cancer Epidemiology Biomarkers and Prevention 12(2): 157–60.
Yagi, Takashi et al. 2017. “Error-Prone and Error-Free Translesion DNA Synthesis over Site-Specifically Created DNA Adducts of Aryl Hydrocarbons (3-Nitrobenzanthrone and 4-Aminobiphenyl).” Toxicological Research 33(4): 265–72.
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