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Relationship: 2810
Title
Oxidative Stress leads to Increase, Oxidative DNA damage
Upstream event
Downstream event
AOPs Referencing Relationship
| AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
|---|---|---|---|---|---|---|
| Deposition of energy leading to occurrence of cataracts | adjacent | Moderate | Low | Arthur Author (send email) | Open for citation & comment |
Taxonomic Applicability
Sex Applicability
| Sex | Evidence |
|---|---|
| Unspecific | Moderate |
Life Stage Applicability
| Term | Evidence |
|---|---|
| All life stages | Moderate |
Oxidative stress refers to a state in which the amount of reactive oxygen (ROS) and nitrogen (RNS) species overwhelms the cell’s antioxidant defense system. This loss in redox homeostasis can lead to oxidative damage to proteins, lipids, and nucleic acids (Schoenfeld et al., 2012; Tangvarasittichai & Tangvarasittichai, 2018; Turner et al., 2002). As energy is deposited in an aqueous solution, the water molecules undergo radiolysis, breaking bonds to produce ROS (Ahmadi et al., 2021; Karimi et al., 2017). ROS are molecules with oxygen as the functional center and at least one unpaired electron in the outer orbits. Although less common than ROS, RNS can also induce oxidative stress (Cadet et al., 2012; Tangvarasittichai & Tangvarasittichai, 2018).
Organisms contain a defense system of antioxidants to help manage ROS levels. Antioxidant measures consist of antioxidant enzymes, vitamins and minerals that catalyze the conversion of ROS to non-toxic molecules such as water and O2. When an antioxidant system is overwhelmed by the amount of ROS, the cell can enter a state of oxidative stress (Balasubramanian, 2000; Ganea & Harding, 2006; Karimi et al., 2017).
Unmanaged oxidative stress can damage vital macromolecules such as DNA leading to oxidative DNA damage. This can be divided into two categories, damage caused by one ROS, and damage caused by at least two ROS associating with the DNA in the space of one to two helix turns. The first scenario initiates DNA-protein cross-links, inter and intrastrand links, and tandem base lesions, while the second scenario produces more complicated lesions, known as oxidatively generated clustered lesions (ODCLs). These can include single and double strand breaks, abasic sites, and oxidized bases (Cadet et al., 2012) which can cause chromosomal aberrations, cytotoxicity, and oncogenic transformations (Stohs, 1995) as well as structural changes to the DNA, such as blocking polymerases (Zhang et al., 2010).
8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG) lesions are the most common and best-studied, as such they are often used as a marker of oxidative DNA damage (Tangvarasitichai & Tangvarasittichai, 2018).
Cells possess DNA repair mechanisms that help repair the damage, but these processes are not perfect (Eaton, 1995; Ainsbury et al., 2016; Markkanen, 2017). Furthermore, certain types of lesions, such as DNA double strand breaks, are more complex to repair (Schoenfeld et al, 2012), leading to increased oxidative DNA damage.
The strategy for collating the evidence to support the relationship is described in Kozbenko et al 2022. Briefly, a scoping review methodology was used to prioritize studies based on a population, exposure, outcome, endpoint statement.
| ID | Experimental Design | Species | Upstream Observation | Downstream Observation | Citation (first author, year) | Notes |
|---|
| Title | First Author | Biological Plausibility |
Dose Concordance |
Temporal Concordance |
Incidence Concordance |
|---|
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
Uncertainties and Inconsistencies
No evidence.
| Modulating Factor (MF) | MF Specification | Effect(s) on the KER | Reference(s) |
|---|---|---|---|
| Age | Increased age | Increased levels of oxidative DNA damage, partly due to decreased antioxidant levels, meaning that the removal of ROS occurs more slowly, increasing the level of oxidative damage. Moreover, in humans, after about forty to fifty years, a barrier forms in the lens of the eye that decreases intracellular antioxidant transportation. Normally, antioxidants circulate via a current in the cytoplasm of lens fiber cells. However, as the age of the organism increases, the cytoplasm of these cells becomes stiffer. Small molecules such as H2O2 and the superoxide anion can diffuse through, but larger molecules, such as glutathione, cannot enter the barrier. As a result, the core of the lens has a decreased antioxidant concentration, making it more vulnerable to oxidative damage. Furthermore, the amount of protein and mRNA corresponding to important mitochondrial BER enzymes decreases with age, causing a decrease in DNA repair ability and therefore an increase in DNA damage in the mitochondria. | Stohs, 1995; Lee et al., 2004; Martinez et al., 2010; Pendergrass et al., 2010; Zhang et al., 2010; Ainsbury et al., 2016; Tangvarasittichai & Tangvarasittichai, 2018 |
| H2 | Increased concentration | Decreased level of oxidative DNA damage. | Schoenfeld et al., 2012 |
| Antioxidants | Increased concentration | Reviews have found that about 50% of studies examined showed a decrease in base oxidation, but the other half show no change. | Turner et al., 2002; Møller & Loft, 2006; Hoelzl et al., 2009 |
| Lipoic acid | Increased concentration | Decreased level of oxidative DNA damage. | Turner et al., 2002 |
| Acetyl carnitine | Increased concentration | Decreased level of oxidative DNA damage. | Turner et al., 2002 |
| Ubiquinone Q-9 | Increased concentration | Decreased level of oxidative DNA damage. | Turner et al., 2002 |
| Hydroquinone | Increased concentration | Decreased level of oxidative DNA damage. | Turner et al., 2002 |
| Folate | Increased concentration | Decreased level of oxidative DNA damage. | Turner et al., 2002 |
| Aged garlic extracts | Increased concentration | Decreased level of oxidative DNA damage. | Turner et al., 2002 |
Available data suggests that increases in oxidative stress leads to increases in oxidative DNA damage. The following tables provide representative examples of the relationship, unless otherwise indicated, all data is significantly significant.
Dose Concordance
|
Reference |
Experiment Description |
Result |
|
Zhang et al., 2010 |
In vivo. 72 male Wistar rats were exposed to 21%, and 60% O2 to induce oxidative stress. Oxidative DNA damage was measured by determining 8-hydroxy-2’-deoxy-guanosine (8-OHdG) via competitive ELISA assays. |
In rats exposed in vivo, a 39% increase in atmospheric O2 concentration (indicative of oxidative stress) resulted in a 1.27x increase in 8-OHdG. |
Time Concordance
|
Reference |
Experiment Description |
Result |
|
Pendergrass et al., 2010 |
In vivo. Female, 3-month-old, C57BL/6 mice had their heads exposed to 11 Gy X-rays at 2 Gy/min to induce oxidative stress. Oxidative DNA damage was measured using antibody staining of fixed eyes and immunofluorescence. |
In mice exposed in vivo to 11 Gy X-rays, oxidative stress increased 4.3x relative to control 6 months post-irradiation. The amount of 8-OH G positive DNA fragments increased to 2.7x control 6.5 months after the increase in oxidative stress. |
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Not identified
This KER is plausible in all life stages, sexes, and organisms with DNA. The majority of the evidence is from in vivo studies conducted in male and female adult mice and rats. No in vitro evidence was found to support the relationship.