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Aop: 296

AOP Title

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Oxidative DNA damage leading to chromosomal aberrations and mutations

Short name:

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Oxidative DNA damage, chromosomal aberrations and mutations

Graphical Representation

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Authors

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Eunnara Cho1,2, Ashley Allemang3, Marc Audebert4, Vinita Chauhan5, Stephen Dertinger6, Giel Hendriks7, Mirjam Luijten8, Francesco Marchetti1,2, Lauren Peel9, Stefan Pfuhler3, Daniel J. Roberts10, Kristina Trenz11, Carole L. Yauk1,2, *

 

1 Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada

2 Department of Biology, Carleton University, Ottawa, ON, Canada

3 The Procter & Gamble Company, Mason, OH, United States

4 Toxalim, INRA, Toulouse, France

Consumer and Clinical Radiation Protection Bureau, Health Canada, Ottawa, ON, Canada

Litron Laboratories, Rochester, NY, United States

7 Toxys, Leiden, The Netherlands

Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands

Health and Environmental Sciences Institute, Washington, D.C., United States

10 Charles River Laboratories, Skokie, IL, United States

11 Boehringer-Ingelheim, Ingelheim, Germany

*Corresponding author: Carole Yauk (carole.yauk@canada.ca)

Point of Contact

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Carole Yauk   (email point of contact)

Contributors

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  • Carole Yauk

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite


This AOP was last modified on June 06, 2019 20:20

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Revision dates for related pages

Page Revision Date/Time
Increase, Oxidative damage to DNA June 04, 2019 05:16
N/A, Inadequate DNA repair June 06, 2019 20:32
Increase, DNA strand breaks June 04, 2019 08:47
Increase, Mutations September 16, 2017 10:14
Increase, Chromosomal aberrations June 04, 2019 04:04
Increase, Oxidative DNA damage leads to N/A, Inadequate DNA repair June 06, 2019 18:41
Increase, Oxidative DNA damage leads to Increase, DNA strand breaks June 01, 2019 18:10
N/A, Inadequate DNA repair leads to Increase, DNA strand breaks June 04, 2019 05:08
Increase, Oxidative DNA damage leads to Increase, Mutations June 01, 2019 18:49
Increase, DNA strand breaks leads to N/A, Inadequate DNA repair May 19, 2019 16:36
Increase, DNA strand breaks leads to Increase, Mutations June 03, 2019 12:42
N/A, Inadequate DNA repair leads to Increase, Mutations June 04, 2019 10:28
N/A, Inadequate DNA repair leads to Increase, Chromosomal aberrations May 19, 2019 16:37
Increase, DNA strand breaks leads to Increase, Chromosomal aberrations June 03, 2019 16:18
Hydrogen peroxide May 19, 2019 17:21
Potassium bromate May 19, 2019 17:21
Ionizing Radiation May 07, 2019 12:12
Cadmium chloride May 19, 2019 17:23
tert-Butyl hydroperoxide May 19, 2019 17:24
Reactive oxygen species August 15, 2017 10:43

Abstract

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This adverse outcome pathway (AOP) network describes the linkage between oxidative DNA damage and irreversible genomic damage (chromosomal aberrations and mutations). Both endpoints are of regulatory interest because irreversible genomic damage is associated with various adverse health effects such as cancer and heritable disorders.

Mutagens are genotoxic substances that alter the DNA sequence and this includes single base substitutions, deletion or addition of a single base or multiple bases of DNA, and complex multi-site mutations. Mutations can occur in coding and non-coding regions of the genome and can be functional or silent. The site and type of mutation will determine its consequence. Clastogens are genotoxic substances that cause DNA double-strand breaks that can result in deletion, addition, or rearrangement of sections in the chromosomes. As with mutagens, the type and extent of chromosome modification(s) determine cellular consequences.

The molecular initiating event (MIE) of this AOP is increase in oxidative DNA damage, indicated by increases in oxidative DNA lesions. DNA in any cell type is susceptible to oxidative damage due to endogenous (e.g., aerobic respiration) and exogenous (i.e., exposure to oxidants) oxidative insults. Although this is the MIE for this AOP network, we note that there are numerous upstream key events (KE) that can also lead to DNA oxidation. Thus, we expect this AOP to be expanded upstream, and to be incorporated into a variety of AOP networks. Generally, cells are able to tolerate and readily repair oxidative DNA lesions by basal repair mechanisms. However, excessive damage can override the basal repair capacity and lead to inadequate repair of oxidative damage (KE1). Mutations (AO1) can arise from incorrect repair of oxidative lesions (KE1), where incorrect bases are inserted opposite lesions during DNA replication. Insufficiently or incompletely repaired oxidative DNA lesions can also lead to DNA strand breaks (KE2) that, if insufficiently repaired (KE1), may result in chromosome aberrations (AO2) and/or mutations (AO1) following DNA replication.

Support for this AOP is strong based on extensive understanding of the mechanisms involved in this pathway, evidence of essentiality of certain KE (i.e., studies using reactive oxidative species scavengers and modulating DNA repair enzymes), and a robust set of studies providing empirical support for many of the KERs.

We anticipate that this AOP will be of widespread use to the regulatory community as oxidative DNA damage is considered an important contributor to the adverse health effects of many environmental toxicants. Importantly, the AOP points to critical research gaps required to establish the quantitative associations and modulating factors that connect KEs across the AOP, and highlights the utility of novel test methods in understanding and evaluating the implications of oxidative DNA damage.


Background (optional)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
1 MIE 1634 Increase, Oxidative damage to DNA Increase, Oxidative DNA damage
2 KE 155 N/A, Inadequate DNA repair N/A, Inadequate DNA repair
3 KE 1635 Increase, DNA strand breaks Increase, DNA strand breaks
4 AO 185 Increase, Mutations Increase, Mutations
5 AO 1636 Increase, Chromosomal aberrations Increase, Chromosomal aberrations

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Increase, Oxidative DNA damage leads to N/A, Inadequate DNA repair adjacent High Low
N/A, Inadequate DNA repair leads to Increase, DNA strand breaks adjacent High Low
Increase, DNA strand breaks leads to N/A, Inadequate DNA repair adjacent Moderate Low
N/A, Inadequate DNA repair leads to Increase, Mutations adjacent High Low
N/A, Inadequate DNA repair leads to Increase, Chromosomal aberrations adjacent High Low
Increase, Oxidative DNA damage leads to Increase, DNA strand breaks non-adjacent Moderate Low
Increase, Oxidative DNA damage leads to Increase, Mutations non-adjacent Moderate Low
Increase, DNA strand breaks leads to Increase, Mutations non-adjacent Moderate Low
Increase, DNA strand breaks leads to Increase, Chromosomal aberrations non-adjacent High Low

Network View

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Stressors

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Life Stage Applicability

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Life stage Evidence
All life stages

Taxonomic Applicability

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Term Scientific Term Evidence Link
human Homo sapiens NCBI
mice Mus sp. NCBI
rat Rattus norvegicus NCBI

Sex Applicability

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Sex Evidence
Unspecific

Overall Assessment of the AOP

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Domain of Applicability

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Theoretically, this AOP is relevant to any cell type in any organism at any life stage. Regardless of the type of cell or organism, DNA is susceptible to oxidative damage and repair mechanisms exist to protect the cell against permanent chromosomal damage. Generally, DNA repair pathways are highly conserved among eukaryotic organisms (Wirth et al., 2016). Base excision repair (BER), the primary repair mechanism for oxidative DNA lesions, and associated glycosylases are highly conserved across eukaryotes (Jacobs and Schar, 2012). DNA strand break repair pathways such as homologous recombination (HR) and non-homologous end joining (NHEJ) are shared among eukaryotes as well. Induction of chromosomal aberrations and mutations following oxidative DNA damage has been studied in both eukaryotic and prokaryotic cells. Notably, the KEs of this AOP have been measured in rodent models (i.e., rat and mouse) and mammalian cells in culture (e.g., TK6 human lymphoblastoid cells, HepG2 human hepatic cells Chinese hamster ovary cells) (Klungland et al., 1999; Arai et al., 2002; Platel et al., 2009; Platel et al., 2011; Deferme et al., 2013).


Essentiality of the Key Events

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Examples below demonstrate the effect of modulating each KE on the downstream KEs.

Essentiality of Increase, oxidative DNA damage (MIE)

  • GSH depletion increases 8-oxo-dG (MIE), and DNA strand breaks (KE2)
    • HepG2 human hepatocytes were treated with 1 mM buthionine sulphoximine (BSO), a GSH-depleting agent, for 4, 8, and 24 hours. Time-dependent reduction in GSH was observed and the reduction was significant at all time points compared to 0h. The level of 8-oxo-dG lesions was measured at 6 and 24h; at both time points, there was a significant increase in the oxidative lesions, with a larger amount of lesions present at 24h. Strand breaks were also measured concurrently. While there was no observable increase in strand breaks at 6h, the increase at 24h was significant compared to control (p<0.01) (Beddowes et al., 2003).
  • Antioxidant treatment reduces oxidative lesions and downstream strand breaks and MN (AO2)
    • Three-hour exposure of HepG2 cells to increasing concentrations of tetrachlorohydroquinone (TCHQ) with N-acetylcysteine (NAC) pre-treatment reduced the amount of cellular ROS, 8-oxodG, and strand breaks induced by TCHQ measured immediately following exposure. The MN assay at 24h indicated a significant decrease in MN at the highest concentration (Dong et al., 2014).
    • In other study, treatment of HL-60 human leukemia cells with increasing concentrations of NAC and 12 mM H2O2 significantly reduced the amount of ROS produced by H2O2, in a NAC concentration-dependent manner, compared to H2O2-only treatment. The NAC+ 12 mM H2O2 treatment also significantly decreased the amount of 8-oxo-dG lesions in a NAC concentration-dependent manner (Shih et al., 2018).
    • Reduction of 8-oxo-dG levels following NAC treatment was also observed in embryos isolated from C57BL/6Jpun/pun mice treated with NAC via drinking water; NAC significantly reduced the number of 8-oxo-dG in the treatment group (Reliene et al., 2004). In human blood mononuclear cells collected in clinical studies, 72-hour NAC treatment prior to MN assay significantly reduced the number of MN. Together, these data support the correlation between the levels of ROS, 8-oxo-dG, and MN (Federici et al., 2015).

Essentiality of Inadequate DNA repair (KE1)

  • The effect of inadequate DNA repair on lesion accumulation and strand breaks (KE2)
    • Nth1 knock-out - FapyG and FapyA lesions were measured in the liver nuclear extracts from wild type and Nth1-/- mice. A significant increase in FapyG and FapyA was observed in Nth1-/- mice. These results demonstrate insufficient repair leading to accumulation of unrepaired oxidative lesions (Hu et al., 2005).
    • Ogg1 knock-out in vitro - In Ogg1-/- mouse embryonic fibroblasts (MEF) treated with 400 µM hydrogen peroxide for 30 minutes, there were significantly fewer strand breaks measured by comet assay, compared to Ogg1+/+ MEFs. Time series (5 – 90 minutes) immunoblotting of the genomic DNA using anti-8-oxo-dG antibody indicated a larger magnitude of increase in oxidative lesions in Ogg1-/- cells compared to wild type.  The results demonstrate the induction and accumulation of strand breaks as an intermediate in base excision repair initiated by Ogg1 following oxidative stress (Wang et al., 2018).    
  • The effect of inadequate DNA repair on micronucleus (AO2)
    • Ogg1 knock-out in vivo - In Ogg1-deficient mice exposed to silver nanoparticles (AgNPs) for seven days, a significant increase (compared to Ogg1+/+ control) in double strand breaks (indicated by % γ-H2AX positive cells) and 8-oxo-dG lesions was observed on day 7 of the exposure and following seven days of recovery. The magnitude of increase in DSBs after the seven day recovery was smaller in the wild type. Levels of micronucleus were measured in erythrocytes at the same time points. Increases in micronucleus were significant in wild type on day 7; however, following 7 and 14 days of recovery, the increase was no longer significant. In Ogg1-/- mice, the increase in MN was significant on day 7 compared to Ogg1+/+ control and continued to be significant seven and 14 days after the exposure (Nallanthighal et al., 2017).
  • The effect of inadequate DNA repair on mutations (AO1)
    • Suzuki et al. (2010) knocked-down BER-initiating glycosylases (OGG1, NEIL1, MYH, NTH1) in HEK293T human embryonic kidney cells transfected with plasmids that were either positive or negative for 8-oxodG. The resulting changes in mutant frequencies were measured. Compared to the negative control, all knock-downs caused the mutant frequency to increase in 8-oxodG plasmid-containing cells. Moreover, G:C to T:A transversion frequency increased in all analyzed cells. MYH knock-down decreased A:T to C:G transversion frequency of A paired to 8-oxo-dG; this result supports the futile MYH-initiated BER model for the repair of 8-oxo-dG opposite A (Suzuki et al., 2010).

Essentiality of Increase, DNA strand breaks (KE2)

  • Double strand breaks leading to mutations (AO1)
    • Tatsumi-Miyajima et al. (1993) analyzed different mutations arising from the repair of DSBs induced by a restriction endonuclease, AvaI¸ in five different human fibroblast cell lines transfected with plasmids containing the AvaI restriction site in the supF gene. Cells containing non-digested plasmids (negative control) produced spontaneous supF mutation frequencies between 0.197 and 2.49 x10-3. In cells containing Ava1-digested plasmids, the number of supF mutants increased, indicated by the rejoining fidelity ((total colonies-supF mutants)/total colonies) between 0.50-0.86 (Tatsumi-Miyajima et al., 1993).
  • Reduction in strand breaks leads to decrease in micronucleus (AO2)
    • PCCL3 normal differentiated rat thyroid cells were internally irradiated by 131I treatment and externally irradiated by 5 Gy X-rays, with or without NAC pre-treatment. Cellular ROS and strand breaks were measured at different time points after irradiation. NAC pre-treatment prevented the ROS spike induced by both internal and external irradiation at 30 min. The level of ROS was also significantly lower in the NAC-treated cells compared to the non-treated cells at later time points (2, 24, and 48 h). Moreover, the spike in strand breaks at 30 min was also prevented by NAC pre-treatment and there was a reduction in strand breaks compared to the non-treated cells at later time points as well. Finally, the induction of MN measured at 24 and 48 h following irradiation was significantly lower in NAC-treated cells compared to non-treated cells (Kurashige et al., 2017).

Evidence Assessment

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1. Support for biological plausibility

Defining Question

High (Strong)

Moderate

Low (Weak)

Is there a mechanistic relationship between KEup and KEdown consistent with established biological knowledge?

Extensive understanding of the KER based on extensive previous documentation and broad acceptance.

KER is plausible based on analogy to accepted biological relationships, but scientific understanding is incomplete

Empirical support for association between

KEs, but the structural or functional relationship between them is not understood.

MIE → KE1: Increase, oxidative DNA damage leads to inadequate repair

STRONG

The repair mechanisms for oxidative DNA damage have been extensively studied and well-understood. It is generally accepted that there exist limits on the amount of oxidative DNA damage that can be managed by these repair mechanisms.

KE1 → KE2: Inadequate repair leads to Increase, DNA strand breaks

STRONG

It is well-established that unrepaired (i.e., accumulated lesions) and inadequately repaired DNA lesions (e.g., repair intermediates such as abasic sites and SSBs) can lead to increase in DNA strand breaks. The

KE2 →KE1:

Increase, DNA strand breaks leads to Inadequate repair

 

KE1 → AO1: Inadequate repair leads to Increase, mutations

STRONG

Numerous previous studies have demonstrated increase in mutation due to unrepaired lesions (insufficient repair) and incorrect repair (e.g., non-homologous end joining and error-prone lesion bypass), both in vitro and in vivo. The mechanisms by which these events occur are well-understood.

KE1 → AO2: Inadequate repair leads to Increase, chromosomal aberrations

 

 

Non-adjacent:

KE2 →AO1: Increase, DNA strand breaks leads to Increase, mutations

STRONG

Mechanisms of DNA strand break repair have been extensively studied. It is accepted that joining of broken ends can introduce deletions, insertions, or base substitution.   

Non-adjacent

MIE → KE2: Oxidative DNA lesions leads to Increase, DNA strand breaks

MODERATE

Increase in strand breaks due to failed attempted repair of oxidative DNA lesions is an accepted mechanism for clastogenic effects of oxidative damage. Concurrent increase in the two KEs have been observed in previous studies. However, limited data are available that demonstrate a causal relationship.

Non-adjacent

MIE → AO2: Oxidative DNA lesions leads to Increase, mutations

STRONG

Strong empirical evidence exist in literature demonstrating increase in mutations due to increase in oxidative DNA lesions. Notably, mutagenicity of 8-oxodG, the most abundant oxidative DNA lesion, has been extensively studied.

2. Support for Essentiality of KEs

Defining Question

High (Strong)

Moderate

Low (Weak)

Are downstream KEs and/or the AO prevented if an upstream KE is blocked?

Direct evidence from specifically designed experimental studies illustrating essentiality for at least one of the important KEs

Indirect evidence that sufficient modification of an expected modulating factor attenuates or augments a KE

No or contradictory experimental evidence of the essentiality of any of the KEs.

MIE: Increase, oxidative DNA damage

MODERATE

Studies have demonstrated that indirectly reducing or increasing the amount of oxidative DNA lesions by reducing or increasing cellular ROS (via antioxidant addition or depletion) causes concordant changes in the level of strand breaks and MN.

KE1: Inadequate repair

STRONG

Numerous studies have investigated inadequate repair of oxidative DNA lesions by disrupting base excision repair (BER) through generating gene knock-down rodent or mammalian cell models. Modulation of the downstream KEs (i.e., DNA strand breaks, mutation, MN) by dysfunctional repair has been demonstrated in these studies.

KE2: DNA strand breaks

MODERATE

Theoretically, chromosomal aberrations (AO2) cannot occur unless DNA strands break. Mostly indirect evidence exist that support the essentiality of KE2 in leading to mutations (AO1).

3. Empirical Support for KERs

Defining Question

High (Strong)

Moderate

Low (Weak)

Does empirical evidence support that a change in KEup leads to an appropriate change in KEdown?

Does KEup occur at lower doses and earlier time points than KE down and is the incidence of KEup> than that for KEdown?

Inconsistencies?

Multiple studies showing dependent change in both events following exposure to a wide range of specific stressors.

No or few critical data gaps or conflicting data

Demonstrated dependent change in both events following exposure to a small number of stressors.

Some inconsistencies with expected pattern that can be explained by various factors.

Limited or no studies reporting dependent change in both events following exposure to a specific stressor; and/or significant inconsistencies in empirical support across taxa and species that don’t align with hypothesized AOP

MIE → KE1: Increase, oxidative DNA damage leads to inadequate repair

MODERATE

Empirical data are available both in vitro and in vivo that demonstrate increase in oxidative DNA lesions leadings to indications of inadequate repair (i.e., increase in mutation, retention of adducts, increase in lesions despite upregulation of repair enzymes).

KE1 → KE2: Inadequate repair leads to Increase, DNA strand breaks

MODERATE

 Limited in vivo data are available.

 

KE2 →KE1:

Increase, DNA strand breaks leads to Inadequate repair

 

KE1 → AO1: Inadequate repair leads to Increase, mutations

STRONG

Repair deficiency causing increase in mutations has been extensively demonstrated in both in vitro and in vivo models. Overexpression of repair enzymes has been shown to reduce mutation frequency following chemical exposure in vitro; these data furthe support the causal relationship between these two KEs.

 

KE1 → AO2: Inadequate repair leads to Increase, chromosomal aberrations

 

 

Non-adjacent:

KE2 →AO1: Increase, DNA strand breaks leads to Increase, mutations

MODERATE

Non-adjacent

MIE → KE2: Oxidative DNA lesions leads to Increase, DNA strand breaks

MODERATE

Non-adjacent

MIE → AO2: Increase, oxidative DNA lesions leads to Increase, mutations

MODERATE

4. Inconsistencies and Uncertainties

MIE → KE1: Increase, oxidative DNA damage leads to inadequate repair

 

KE1 → KE2: Inadequate repair leads to Increase, DNA strand breaks

 

KE2 →KE1:

Increase, DNA strand breaks leads to Inadequate repair

 

KE1 → AO1: Inadequate repair leads to Increase, mutations

 

KE1 → AO2: Inadequate repair leads to Increase, chromosomal aberrations

 

 

Non-adjacent:

KE2 →AO1: Increase, DNA strand breaks leads to Increase, mutations

 

Non-adjacent

MIE → KE2: Oxidative DNA lesions leads to Increase, DNA strand breaks

 

Non-adjacent

MIE → AO2: Increase, oxidative DNA lesions leads to Increase, mutations

 


Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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Oxidative stress is a well-known genotoxic hazard and, thus, an endpoint to be considered in genotoxicity assessments. Numerous chemicals induce oxidative stress and cause DNA damage consequently (Deavall et al., 2012). Oxidative stress can be induced in various ways by exogenous sources (i.e., depletion of antioxidants, during metabolism, direct oxidation and generation of RONS). There are many instances when the mode of action of a genotoxic chemical is uncertain and oxidative stress is suspected to be the cause. In this AOP, we present evidence linking oxidative DNA lesions to chromosomal aberrations and mutations, two apical endpoints in genotoxicity testing. Observation of oxidative DNA lesions at an early time point can be used to predict permanent DNA damage downstream. While RONS can cause a wide range of DNA lesions, 8-oxodG is the most abundant lesion and serves as a representative marker of oxidative stress-induced DNA damage (Gedik et al., 2002). A list of methods for measuring oxidative DNA lesions is provided in the KE document. The empirical data supporting each of the KERs in this AOP are examples of how data obtained from different endpoints can be integrated to demonstrate the KER.


References

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Arai, T., Kelly, V.P., Minowa, O., Noda, T., Nishimura, S. (2002), High accumulation of oxidative DNA damage, 8-hydroxyguanine, in Mmh/Ogg1 deficient mice by chronic oxidative stress, Carcinogenesis, 23:2005-2010.

Beddowes, E., Faux, S., Chipman, J.K. (2003), Chloroform, carbon tetrachloride and glutathione depletion induce secondary genotoxicity in liver cells via oxidative stress, Toxicol, 187:101-115.

Deavall, D., Martin, E., Hornet, J., Roberts, R. (2012), Drug-Induced Oxidative Stress and Toxicity, J Toxicol, 2012:645460.

Deferme, L., Briede, J.J., Claessen, S.M., Jennen, D.G., Cavill, R., Kleinjans, J.C. (2013), Time series analysis of oxidative stress response patterns in HepG2: A toxicogenomics approach  , Toxicol, 306:24-34.

Dong, H., Xu, D., Hu, L., Li, L., Song, E., Song, Y. (2014), Evaluation of N-acetyl-cysteine against tetrachlorobenzoquinoneinduced genotoxicity and oxidative stress in HepG2 cells, Food Chem Toxicol, 64:291-297.

Federici, C., Drake, K., Rigelsky, C., McNelly, L., Meade, S., Comhair, S., Erzurum, S., Aldred, M. (2015), Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension, Am J Respir Crit Care Med, 192:219-228.

Gedik, C., Boyle, S., Wood, S., Vaughan, N., Collins, A.R. (2002), Oxidative stress in humans: validation of biomarkers of DNA damage, Carcinogenesis, 23:1441-1446.

Hu, J., de Souza-Pinto, N.C., Haraguchi, K., Hogue, B., Jaruga, P., Greenberg, M.M., Dizdaroglu, M., Bohr, V. (2005), Repair of formamidopyrimidines in DNA involves different glycosylases: role of the OGG1, NTH1, and NEIL1 enzymes, J Biol Chem, 280:40544-40551.

Jacobs, A., Schar, P. (2012), DNA glycosylases: in DNA repair and beyond, Chromosoma, 121:1-20.

Klungland, A., Rosewell, I., Hollenbach, S., Larsen, E., Daly, G., Epe, B., Seeberg, E., Lindahl, T., Barnes, D. (1999), Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage, Proc Natl Acad Sci USA, 96:13300-13305.

Kurashige, T., Shimamura, M., Nagayama, Y. (2017), N-Acetyl-l-cysteine protects thyroid cells against DNA damage induced by external and internal irradiation, Radiat Environ Biophys, 56:405-412.

Nallanthighal, S., Chan, C., Murray, T., Mosier, A., Cady, N., Reliene, R. (2017), Differential effects of silver nanoparticles on DNA damage and DNA repair gene expression in Ogg1-deficient and wild type mice, Nanotoxicol, 11:996-1011.

Platel, A., Nesslany, F., Gervais, V., Claude, N., Marzin, D. (2011), Study of oxidative DNA damage in TK6 human lymphoblastoid cells by use of the thymidine kinase gene-mutation assay and the in vitro modified comet assay: Determination of No-Observed-Genotoxic-Effect-Levels, Mutat Res, 726:151-159.

Platel, A., Nesslany, F., Gervais, V., Marzin, D. (2009), Study of oxidative DNA damage in TK6 human lymphoblastoid cells by use of the in vitro micronucleus test: Determination of No-Observed-Effect Levels, Mutat Res, 678:30-37.

Reliene, R., Fischer, E., Schiestl, R. (2004), Effect of N-Acetyl Cysteine on Oxidative DNA Damage and the Frequency of DNA Deletions in Atm-Deficient Mice, Cancer Res, 64:5148-5153.

Shih, W., Chang, C., Chen, H., Fan, K. (2018), Antioxidant activity and leukemia initiation prevention in vitro and in vivo by N‑acetyl‑L‑cysteine, Oncol Lett, 16:2046-2052.

Suzuki, T., Harashima, H., Kamiya, H. (2010), Effects of base excision repair proteins on mutagenesis by 8-oxo-7,8-dihydroguanine (8-hydroxyguanine) paired with cytosine and adenine, DNA Repair, 9:542-550.

Tatsumi-Miyajima, J., Yagi, T., Takebe, H. (1993), Analysis of mutations caused by DNA double-strand breaks produced by a restriction enzyme in shuttle vector plasmids propagated in ataxia telangiectasia cells, Mutat Res, 294:317-323.

Wang, R., Li, C., Qiao, P., Xue, Y., Zheng, X., Chen, H., Zeng, X., Liu, W., Boldogh, I., Ba, X. (2018), OGG1-initiated base excision repair exacerbates oxidative stress-induced parthanatos, Cell Death and Disease, 9:628.

Wirth, N., GrosBuechner, C.N., Kisker, C., Tessmer, I. (2016), Conservation and Divergence in Nucleotide Excision Repair Lesion Recognition, J Biol Chem, 291:18932-18946.