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Energy Deposition 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|
|Direct deposition of ionizing energy leading to lung cancer||adjacent||High||High||Vinita Chauhan (send email)||Under development: Not open for comment. Do not cite||EAGMST Under Review|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Direct deposition of ionizing energy refers to imparted energy interacting directly with the DNA double helix and producing randomized damage in the form of strand breaks. Among the different types of damage, the most detrimental type of DNA damage to a cell is the double-strand break (DSB). DSBs are caused by the breaking of the sugar-phosphate backbone on both strands of the DNA double helix molecule, either directly across from each other or several nucleotides apart (Ward, 1988; Iliakis et al., 2015). The number of DSBs produced and the complexity of the breaks is highly dependent on the amount of energy deposited on and absorbed by the cell. This can vary as a function of the dose-rate (Brooks et al., 2016) and the radiation quality which is a function of its linear energy transfer (LET) (Sutherland et al., 2000; Nikjoo et al., 2001; Jorge et al., 2012). LET describes the amount of energy that an ionizing particle transfers to media per unit distance (Smith et al., 2003; Okayasu, 2012a; Christensen et al., 2014). High LET radiation, such as alpha particle radiation, can deposit larger quantities of energy within a single track than low LET radiation, such as gamma-ray radiation (Kadhim et al., 2006; Franken et al., 2012; Frankenberg et al., 1999; Rydberg et al., 2002; Belli et al., 2000; Antonelli et al., 2015). As such, radiation with higher LETs tends to produce more complex, dense structural damage, particularly in the form of clustered damage, in comparison to lower LET radiation (Nikjoo et al., 2001; Terato and Ide, 2005; Hada and Georgakilas, 2008; Okayasu, 2012a; Lorat et al., 2015; Nikitaki et al., 2016). Thus, the complexity and yield of clustered DNA damage increases with ionizing density (Ward, 1988; Goodhead, 2006).
However, clustered damage can also be induced even by a single radiation track through a cell.
Evidence Supporting this KER
The biological rationale linking the direct deposition of energy on DNA with an increase in DSB formation is strongly supported by numerous literature reviews that are available on this topic (J .F. Ward, 1988; Terato & Ide, 2005; Goodhead, 2006; Asaithamby et al., 2008; Hada & Georgakilas, 2008; Okayasu, 2012b; M. E. Lomax et al., 2013; Moore et al., 2014; Desouky et al., 2015; Sage & Shikazono, 2017; Jeggo, 2009). Ionizing radiation can be in the form of high energy particles (such as alpha particles, beta particles, or charged ions) or high energy waves (such as gamma-rays or X-rays). Ionizing radiation can break the DNA within chromosomes both directly and indirectly, as shown through using velocity sedimentation of DNA through neutral and alkaline sucrose gradients. The most direct path entails a collision between a high-energy particle or photon and a strand of DNA. The high-energy subatomic particles can interact with the orbital electrons of the DNA causing ionization (where electrons are ejected from atoms) and excitation (where electrons are raised to higher energy levels) (Joiner, 2009). These processes ultimately break the phosphodiester backbone.
Additionally, excitation of secondary electrons in the DNA allows for a cascade of ionization events to occur, which can lead to the formation of multiple damage sites (Joiner, 2009). As an example, high-speed electrons will traverse a DNA molecule in a mammalian cell within 10-18 s and 10-14 s, resulting in 100,000 ionizing events per 1 Gy dose in a 10 μm cell (Joiner, 2009). The amount of damage can be influenced by factors such as the cell cycle stage and chromatin structure. It has been shown that in more condensed, packed chromatin structures such as those present in intact cells and heterochromatin, it is more difficult for the DNA to be damaged (Radulescu et al., 2006; Agrawala et al., 2008; Falk et al., 2008; Venkatesh et al., 2016). In contrast, DNA damage is more easily induced in lightly-packed chromatin such as euchromatin, nucleoids, and naked genome DNA (Radulescu et al., 2006; Falk et al., 2008; Venkatesh et al., 2016).
DNA damage can be in the form of DSBs, single-strand breaks, base damage, or the crosslinking of DNA to other molecules (Smith et al., 2003; Joiner, 2009; Christensen, 2014; Sage and Shikazono, 2017). Of the possible radiation-induced DNA damage types, DSB is considered to be the most harmful to the cell, as there may be severe consequences if this damage is not adequately repaired (Khanna & Jackson, 2001; Smith et al., 2003; Okayasu, 2012a; M. E. Lomax et al., 2013; Rothkamm et al., 2015).
A considerable fraction of DSBs can also be formed in cells through indirect mechanisms. In this case, deposited energy can split water molecules near DNA, which can generate a significant quantity of reactive oxygen species in the form of hydroxyl free radicals (Ward, 1988; Desouky et al., 2015; Maier et al., 2016). Estimates using models and experimental results suggest that hydroxyl radicals may be present within nanoseconds of energy deposition by radiation (Yamaguchi et al., 2005). These short-lived but highly reactive hydroxyl radicals may react with nearby DNA. This will produce DNA damage, including single-strand breaks and DSBs (Ward, 1988; Desouky et al., 2015; Maier et al., 2016). DNA breaks are especially likely to be produced if the sugar moiety is damaged, and DSBs occur when two single-strand breaks are in close proximity to each other (Ward, 1988).
Uncertainties and Inconsistencies
Uncertainties and inconsistencies in this KER are as follows:
- Studies have shown that dose-rates (Brooks et al., 2016) and radiation quality (Sutherland et al., 2000; Nikjoo et al., 2001; Jorge et al., 2012) are factors that can influence the dose-response relationship.
- Low-dose radiation has been observed to have beneficial effects and may even invoke protection against spontaneous genomic damage (Feinendegen, 2005; Day et al., 2007; Feinendegen et al., 2007; Shah et al., 2012; Nenoi et al., 2015). This protective effect has been documented in in vivo and in vitro, as reviewed by ICRP (2007) and UNSCEAR (2008) and can vary depending on the cell type, the tissue, the organ, or the entire organism (Brooks et al., 2016).
- Depositing ionizing energy is a stochastic event; as such this can influence the location, degree and type of DNA damage imparted on a cell. As an example, studies have shown that mitochondrial DNA may also be an important target for genotoxic effects of ionizing radiation (Wu et al., 1999).
There is evidence of a response-response relationship between the deposition of energy and the frequency of DSBs. In studies encompassing a variety of biological models, radiation types and radiation doses, a positive, linear relationship was found between the radiation dose and the number of DSBs (Sutherland et al., 2000; de Lara et al., 2001; Rothkamm & Lo, 2003; Kuhne et al., 2005; Rube et al., 2008; Grudzenski et al., 2010; Shelke & Das, 2015; Antonelli et al., 2015; Frankenberg et al., 1999). There were, however, two exceptions reported. When human blood lymphocytes were irradiated with X-rays in vitro, a linear relationship was only found for doses ranging from 6 - 500 mGy; at low doses from 0 - 6 mGy, there was a quadratic relationship reported (Beels et al., 2009). Secondly, simulation studies predicted that there would be a non-linear increase in DSBs as energy deposition increased, with a saturation point at higher LETs (Charlton et al., 1989).
Data from temporal response studies suggests that DSBs likely occur within seconds to minutes of energy deposition by ionizing radiation. In a variety of biological models, the presence of DSBs has been well documented within 10 - 30 minutes of radiation exposure (Rogakou et al., 1999; Rube et al., 2008; Beels et al., 2009; Kuefner et al., 2009; Grudzenski et al., 2010; Antonelli et al., 2015); there is also evidence that DSBs may actually be present within 3 - 5 minutes of irradiation (Rogakou et al., 1999; Rothkamm & Lo, 2003; Rube et al., 2008; Grudzenski et al., 2010). Interestingly, one study that focussed on monitoring the cells before, during and after irradiation by taking photos every 5, 10 or 15 seconds found that foci indicative of DSBs were present 25 and 40 seconds after collision of the alpha particles and protons with the cell, respectively. The number of foci were found to increase over time until plateauing at approximately 200 seconds after alpha particle exposure and 800 seconds after proton exposure (Mosconi et al., 2011).
After the 30 minute mark, DSBs have been shown to rapidly decline in number. By 24 hours post-irradiation, DSB numbers had declined substantially in systems exposed to radiation doses between 40 mGy and 80 Gy (Rothkamm & Lo, 2003; Rube et al., 2008; Grudzenski et al., 2010; Russo et al., 2015; Antonelli et al., 2015), with the sharpest decrease documented within the first 5 hours (Rogakou et al., 1999; Rube et al., 2008; Kuefner et al., 2009; Grudzenski et al., 2010; Shelke and Das, 2015). Interestingly, DSBs were found to be more persistent when they were induced by higher LET radiation (Antonelli et al., 2015).
Known modulating factors
Some common clinical radiation modifiers include cisplatin, 5-fluorouracil, thiols, and nitroxides (reviewed in (Citrin and Mitchel, 2014)). Clinical approaches have identified many modulating radiation factors, which are often categorized as either sensitizers or protectors. Sensitizers enhance radiation-induced tumour cell killing, and protectors protect normal tissues from the deleterious effects of ionizing radiation (Citrin & Mitchel, 2014).
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The domain of applicability relates to all eukaryotic species that contain genetic information in the form of a double strand helix of DNA (Parris et al., 2015; Cannan & Pederson, 2016).
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