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Oxidative Stress leads to Increase, DNA strand breaks
Key Event Relationship Overview
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||Vinita Chauhan (send email)||Under development: Not open for comment. Do not cite|
|Deposition of Energy Leading to Learning and Memory Impairment||adjacent||Vinita Chauhan (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
|All life stages||Low|
Key Event Relationship Description
Oxidative stress is an event that involves both a reduction in free radical scavengers and enzymes, and an increase in free radicals (Brennan et al., 2012). Oxidative stress needs to be maintained within an organism to avoid an excess of damage to biological structures, such as DNA. A redox homeostasis between the radicals and the scavengers is necessary. Between ROS and RNS, collectively known as RONS, ROS is particularly significant to oxidative damage and disease states. Increased ROS-mediated oxidative stress is defined by the state of a cell where ROS production has surpassed the ability of antioxidant/scavenging systems to stabilize the radicals (Kurutas 2016). Free radicals such as superoxide anion (O2•-) and hydroxyl radical (OH • -) are highly reactive molecules that have at least one unpaired electron in an outer ring, causing them to have a strong affinity for electrons in other molecules (Cabrera et al., 2011). A redox reaction occurs when the radical gains an electron from a nearby molecule (Kruk et al., 2016). The oxidation reaction can alter elements of the molecule’s structure. Depending on individual reactivity, RONS can travel varying distances following formation. Radicals such as singlet oxygen and hydroxyl radical are highly unstable and will react with molecules near their generation point, while radicals such as H2O2 are more stable and membrane permeable, meaning they can travel further to find electrons (Spector, 1990). Since DNA is mainly found in nucleus, ROS needs to reach the nucleus to induce breaks. Hydroxyl radicals, in addition to being highly reactive, are capable of causing DNA damage (Halliwell et al., 2021; Engwa et al., 2020). The regulation of these radicals is achieved by the antioxidant defense response (ADR), which includes enzymatic and non-enzymatic processes. The ADR is recruited to manage RONS levels, with antioxidants such as superoxide dismutase (SOD) functioning as the first line of defense (Engwa et al., 2020). These antioxidants act as scavengers to oxidants, reacting with them before reaching other structures within the cell such as DNA strands (Cabrera et al., 2011; Engwa et al., 2020). The backbone of DNA can fragment upon sustained exposure to ROS (Uwineza et al., 2019; Cannan et al., 2016). Due to low oxidation potentials, adenine and guanine are the DNA bases more prone to oxidation, with oxidation potentials (normal hydrogen electrode) at pH 7 of 1.3 eV and 1.42 eV compared to the 1.6 eV and 1.7 eV of cytosine and thymine (Fong, 2016; Halliwell et al., 2021; Poetsch, 2020). In fact, certain radicals even target guanine in a selective fashion, including carbonate anion radical (CO3•-) and singlet oxygen (1O2) (Halliwell et al., 2021).
Evidence Collection Strategy
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.
Evidence Supporting this KER
Overall Weight of Evidence: Moderate
The biological plausibility of the relationship between increased oxidative stress leading to increased DNA double strand breaks (DSBs) is highly supported by the literature. Evidence was collected from studies conducted using in vitro lens epithelial cell models and derived from humans, but also includes bovine and germ line cells (Spector, 1990; Stohs, 1995; Aitken et al., 2001; Spector, 1995). Since most of the evidence is derived from studies using a human cell model it limits the ability to compare between different taxonomies. (Cencer et al., 2018; Liu et al., 2013; Smith et al., 2015; Zhou et al., 2016; Ahmadi et al., 2022; Meng et al., 2021).
ROS that are generated specifically as a result of radiation are highly localized, increasing the likelihood of clustered regions of damage. Naturally generated ROS are more widespread and as a result less capable of generating clusters of damage. ROS will act on DNA bases to oxidize or delete them from the sequence, which create nicks on the strand (Cannan et al., 2016). This damage can occur to any DNA base but bases such as guanine and adenine are most vulnerable due to their low oxidation potentials (Fong, 2016). The mechanism through which the strand break occurs is a result of base excision repair (BER) happening at multiple sites that are too close together, resulting in the spontaneous conversion to DSBs prior to completion of repair. ROS damage to bases clustered together means that multiple sites of BER are happening very close together and while the strand may be able to support the damaged area for one repair, concurrent repairs make surrounding areas more fragile and the strand breaks at the nick sites are under added strain (Cannan et al., 2016). Endogenous damage to DNA as a result of radicals appears over time and mainly as isolated lesions, a pattern understood to be due to the diffusion of the radicals resulting in homogenous distribution patterns. This differs from the specific situations where radiation acts as the stressor to increase oxidative stress, as the radiation track will be highly localized and form radicals within that hit space. This leads to non-homologous lesions and clustered damage to the DNA (Ward et al., 1985).
Uncertainties and Inconsistencies
Known modulating factors
|Modulating Factor (MF)||MF Specification||Effect(s) on the KER||Reference(s)|
|Age||Reduced antioxidant capacities have been linked to aged lenses (in humans >30 years old). The development of a chemical barrier between the cortex and the nucleus is partially responsible, as it prevents GSH from protecting aged lens cells from ROS.||Prevention of RONS-mediated damage is primarily achieved by antioxidants, so a lowered capacity would likely lead to reduced damage mitigation abilities. 78% of lens over 30 had a low level of GSH in the center compared to 14% of lens under 30. Lens epithelial cells have an associated 3-fold increase in γ-H2AX (marker of DNA damage) when GSH-PX decreases by 2-fold.||Taylor & Davies, 1987; Cabrera & Chihuailaf, 2011; Quinlan & Hogg, 2018; Sweeney & Truscott, 1998; Meng & Fang, 2021|
|Free radical scavengers||ROS-scavengers are essential components of the body’s natural defense against oxidative damage. Increased ROS production leads to increased incidence of electron donation by scavengers, thus reducing the overall level of free radical scavengers available to deal with ROS.||Isothiocyanates, such as sulforaphane (SFN), activate the release of more enzymatic scavengers. When SFN was added to in vitro LECs, LDH decreased to near unexposed cell levels and was associated with 3.3x less DNA strand breaks compared to the non-SFN cells following stressor exposure.||Taylor et al., 1987; Cabrera et al., 2011; Liu et al., 2013|
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
This KER is plausible in all life stages, sexes, and organisms with DNA. The majority of the evidence is from human in vitro studies that do not specify the sex. No in vivo evidence was found to support the relationship.
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