Upstream eventEnergy Deposition
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Direct deposition of ionizing energy leading to lung cancer||non-adjacent||High||High|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Energy can be deposited on biomolecules from various forms of radiation. Radiation with high linear energy transfer (LET) tends to produce more complex, dense structural damage than low LET radiation; both, however, can lead to detrimental damage within a cell (Hada & Georgakilas, 2008; Okayasu, 2012; Lorat et al., 2015; Nikitaki et al., 2016). The DNA is particularly susceptible to damage which can be in the form of mutations. Mutations may occur in germ cells or somatic cells; mutations in germ stem and progenitor cells are often of the greatest concern, as they may persist and be propagated to offspring. Regardless of the cell type, there are several different categories of mutations including: missense, nonsense, insertion, deletion, duplication, and frame-shift mutations. These mutations can present with different downstream effects which are not predictable but can potentially initiate a path to carcinogenesis.
Evidence Supporting this KER
The biological rationale for linking direct deposition of energy by ionizing radiation to mutation induction is strong. The structural and functional relationships in this KER contribute sufficiently to the overall biological plausibility.
There are numerous studies that demonstrate, using various model systems, an increase in mutation frequency in response to radiation exposure (Russell et al., 1957; Winegar et al., 1994; Gossen et al., 1995; Suzuki & Hei 1996; Albertini et al., 1997; Dubrova et al., 1998; Dubrova, Plumb, et al., 2000; Canova et al., 2002; Dubrova et al., 2002; Dubrova & Plumb, 2002; Masumura et al., 2002; Somers et al., 2004; Burr et al., 2007; Ali et al., 2012; Bolsunovsky et al., 2016; Mcmahon et al., 2016; Matuo et al., 2018; Nagashima et al., 2018; Wu et al., 1999; Hei et al., 1997; Nagasawa and Little, 1999; Barnhart and Cox, 1979; Thacker at al., 1982; Zhu et al., 1982; Metting et al., 1992; Schwartz et al., 1991; Chen et al., 1984; Albertini et al., 1997). The process of mutation induction by radiation is initiated when cells are exposed to ionizing radiation. These high-energy waves or particles interact with the genetic material in the nucleus, damaging the DNA and triggering a cascade of signalling events and activities aimed at repairing the damage. This process, however, may result in not only the repair of the DNA, but also the formation of mutations (Sankaranarayanan & Nikjoo, 2015). Of note, radiation is not likely to impact only one gene; more often than not, the random nature of energy deposition by radiation results in mutations to many genes and genomic sites clustered in the same area (Sankaranarayanan & Nikjoo, 2015; Adewoye et al., 2015). Many of the radiation-induced mutations have been documented as deletions (Gossen et al., 1995; Behjati et al., 2016), often of differing sizes in a number of different genes (Sankaranarayanan & Nikjoo, 2015). The mechanism for radiation-induced mutations is thought to be similar to the process for spontaneously-occurring mutations, as the structure of radiation-induced mutations examined at expanded simple tandem repeat (ESTR) loci was not found to differ from the structure of spontaneous mutations (Dubrova, 2005). Moreover, exposure to radiation may produce specific mutational signatures. Two ionizing radiation-specific mutational signatures were found when 12 radiation-induced secondary tumours across 4 different tumour types underwent whole-genome sequencing and bioinformatics processing. In particular, these radiation-exposed tumours were significantly enriched in small deletions and balanced inversions. These results were validated when the same mutational signatures were observed in radiation-exposed but not radiation-naïve prostate tumours from a previously-published dataset (Behjati et al., 2016). Similarly, another study examining mutations present in radiation-induced tumours of Nf1 heterozygous and wild-type mice revealed three distinctive mutational signatures. Interestingly, these signatures were found in all of the tumours regardless of its histology or of the animal’s genotype. Moreover, these signatures were still present after removal of the 33 most mutated samples from the analysis, after analysis of only the non-synonymous substitutions, and after analysis of only the synonymous substitutions (though the third mutational signature could not be extracted in this last analysis group) (Sherborne et al. 2015). There were also common cellular pathways that were found to be frequently mutated in the tumours of these mice. In sarcomas from mice of both genetic backgrounds (Nf1 heterozygous and wild-type), the top two pathways harbouring mutations were those influencing cellular assembly and organization, and those involved in cellular function and maintenance. Additionally, Ras pathways were commonly mutated in tumours from both genetic backgrounds. Specific to wild-type sarcomas, mutations were also found in cell cycle and cell signalling pathways (Sherborne et al., 2015). Supporting the finding that different genetic backgrounds in mice do not affect mutational signatures in tumours (Sherborne et al., 2015), there also does not appear to be strain-specific differences in ESTR mutational frequencies in response to radiation. One study examined five different strains of male mice that were irradiated and mated to unirradiated females at least 4 weeks post-irradiation. Although there was a difference in doubling doses between strains, the ESTR mutations themselves were not significantly different. Furthermore, there were no significant differences found between strains in terms of germline mutation induction (Dubrova, 2005).
Germline mutations have been further interrogated in studies examining the effects of radiation exposure on germ cells. There is evidence from mouse studies suggesting that the germ cells of radiation-exposed males have elevated ESTR mutations and that the offspring of these irradiated males inherit more ESTR mutations as a result of the germline mutations (Dubrova et al., 1998; Dubrova, Bersimbaev, et al., 2000; Dubrova & Plumb, 2002; Somers et al., 2004; Barber et al., 2009; Ali et al., 2012; T.E. Wilson et al., 2015). This was reviewed by Somers et al. (2006). Interestingly, in utero irradiation of embryos at day 12 resulted in increased ESTR mutations across several tissue types in males and females; however, only the offspring of the irradiated males showed an elevated ESTR mutation rate (Barber et al., 2009). On a genome-wide scale, the offspring of irradiated males were found to have significantly more clustered single nucleotide variants (SNVs) and insertion/deletion events compared to offspring from unirradiated fathers (Adewoye et al., 2015).
Human studies have also shown correlations in radiation exposure and increased germline mutations. This relationship was assessed in families exposed accidently to high doses of ionizing radiation after the Chernobyl accident in Ukraine, and in families living in close proximity to the Semipalatinsk nuclear test site in Kazakhstan. In both cases, germline mutations were evaluated using eight hypervariable minisatellite probes. In the Chernobyl study, the paternal mutation rate in the exposed group was significantly increased by 1.6-fold relative to an unexposed control group; there was, however, no significant difference in the maternal germline mutation rates between the exposed group and the unexposed control group (Dubrova et al., 2002C). In the Semipalatinsk study, analysis of families living in the affected region over three generations found that germline mutations in the first and second generation were significantly increased relative to unexposed families living in a low-radiation area. Overall, the germline mutation rate in the families exposed to radiation from this test site was doubled (Dubrova, Bersimbaev, et al., 2000).
Overall, there is strong supporting evidence that direct deposition of energy increases the frequency of mutations. The evidence presented below is summarized in table 2, here (click link). In general, exposure to ionizing radiation has been documented to elevate mutation frequencies in a number of different studies spanning different models and cell types (Russell et al., 1957; Winegar et al., 1994; Gossen et al., 1995; Suzuki & Hei, 1996; Albertini et al., 1997; Canova et al., 2002; Dubrova & Plumb, 2002; Masumura et al., 2002; Bolsunovsky et al., 2016; Mcmahon et al., 2016; Matuo et al., 2018; Nagashima et al., 2018; Wu et al., 1999; Hei et al., 1997; Nagasawa and Little, 1999; Barnhart and Cox, 1979; Thacker at al., 1982; Zhu et al., 1982; Metting et al., 1992; Schwartz et al., 1991; Chen et al., 1984; Albertini et al., 1997) . Furthermore, several reviews outline evidence of the relationship specifically between radon gas exposure and mutation frequency (Jostes, 1996; Robertson et al., 2013; ICRP, 2005). At low doses (<1 Gy) the induction of mutations in cells has been observed for high-LET radiation such as alpha particles (Wu et al., 1999; Hei et al., 1997; Nagasawa and Little, 1999; Barnhart and Cox, 1979; Thacker at al., 1982; Zhu et al., 1982; Metting et al., 1992; Schwartz et al., 1991; Chen et al., 1984; Albertini et al., 1997).
Figure 1: Plot of example studies (y-axis) against equivalent dose (Sv) used to determine the empircal link between direct deposition of energy and increased cell mutation rates. The z-axis denotes the equivalent dose rate used in each study. The y-axis is ordered from low LET to high LET from top to bottom.
Figure 2: Plot of example studies (y-axis) against time scales used to determine the empircal link between direct deposition of energy and and increased cell mutation rates. The z-axis denotes the equivalent dose rate used in each study. The y-axis is ordered from low LET to high LET from top to bottom.
Dose and Incidence Concordance
It is clear that increasing doses of ionizing radiation is concordant with increased incidence of mutations (see table under Quantitative Understanding of the Linkage). Extensive evidence from in vitro studies using human cells (Suzuki & Hei 1996; Canova et al., 2002), animal cells (Canova et al., 2002; Mcmahon et al., 2016; Nagashima et al., 2018), yeast cells (Matuo et al., 2018), and bacteria (Bolsunovsky et al., 2016) demonstrates this concordance. In vivo studies using mice have also found a dose-dependent increase in mutations across several different types of radiation (Russell et al., 1957; Dubrova & Plumb 2002).
This relationship between radiation exposure and mutation incidence is impacted by several different factors. Higher LET radiation, such as high LET carbon ions and neutrons, were found to induce more mutations in comparison to radiation of a lower LET, including low LET carbon ions, gamma-rays and X-rays (Dubrova & Plumb, 2002; Matuo et al., 2018). Similarly, more mutations were present in the gametes of mice exposed to acute X-rays compared to those exposed to chronic gamma-rays (Russell et al., 1957). The tissue being irradiated may also have a role in determining mutant frequency, as whole body irradiation of mice led to a significant increase in mutations (mostly deletions) of the spleen, liver, lung and kidneys (Gossen et al., 1995; Masumura et al., 2002), but not the testis (Masumura et al., 2002). Furthermore, the specific kind of mutation may be dependent on the type of radiation. In one study, irradiation of the liver with carbon ions resulted in a significant increase in deletion mutations, while irradiation with X-rays or gamma-rays resulted in a significant increase in point mutations (Masumura et al., 2002).
Temporal concordance is well established. As described above, energy deposition happens immediately upon radiation exposure, with an increased incidence of mutations documented days or weeks after irradiation (Russell et al., 1957; Winegar et al., 1994; Gossen et al., 1995; Albertini et al., 1997; Canova et al., 2002; Dubrova & Plumb, 2002; Masumura et al., 2002; Matuo et al., 2018; Nagashima et al., 2018).
Uncertainties and Inconsistencies
Uncertainties and inconsistencies in this KER are as follows:
- In a review paper describing the role ionizing radiation plays in elevating mutation frequency in the germline and therefore genetic risk, Sankaranarayanan & Nikjoo (2015) stated that most radiation-induced mutations tended to be deletions. In contrast, an examination of ESTR loci mutations in offspring and their irradiated fathers found that the ESTR mutations tended to be gains more often than losses (Dubrova ,2005). This may, however, highlight a characteristic specific to ESTR mutations rather than mutations in general.
- In a study examining the long-term of effects of in utero radiation exposure, males irradiated at embryonic day 12 showed significant increases in both somatic and germline ESTR mutations as adults, and produced offspring with significantly elevated ESTR mutations in their sperm (Barber et al., 2009). In contrast, male mice exposed to radiation during their neonatal days (6 - 8 days old) or pubertal stage (18 - 25 days) did not have increased mutations in adult spermatozoa, as mutant frequencies that were present in spermatogenesis stages immediately after radiation returned to normal levels later in the spermatogenesis process (Xu et al., 2008).
- Factors such as dose, dose-rate, tissue type and radiation quality can influence mutation rate induction (Hooker et al., 2004; Rydberg et al., 2005; Day et al., 2007; Okudaira et al., 2010; Brooks et al., 2016).
Quantitative Understanding of the Linkage
Below are representative examples of the mutation frequency rates across different studies. Overall, a quantitative understanding of this linkage suggests that mutation rates can be predicted and are dependent on the type and dose of radiation exposure.
Matuo et al., 2018
Study of impact of high and low LET radiation (high LET: carbon ions, 25 keV/um, low LET: carbon ions, 13 keV/um) in the dose range of 0 - 200 Gy incident on Saccharomyces cerevisiae (yeast cells). Found a 24-fold increase over baseline of mutations from high LET radiation and an 11-fold increase for low LET radiation.
Nagashima et al, 2018
Study of X-rays incident on GM06318-10 hamster cells in the dose range of 0-1 Gy. Found a calculated mutation rate of 19.0 ± 6.1 mutants per 104 survivors per Gy.
Albertini et al., 1997
Study of T-lyphocytes from human peripheral blood exposed to low LET gamma-rays and high LET radon gas. Doses in the range 0.5 - 5 Gy (gamma-rays) and 0 - 1 Gy (radon gas). The calculated mutation rate was as follows: gamma-rays (0-2 Gy): 7.0x10-6 mutants / Gy, gamma-rays (2-4 Gy): 54.0x10-6 mutants / Gy, radon gas (0-1 Gy): 63.0x10-6 mutants / Gy.
Dubrova and Plumb 2002
Study of paternal ESTR mutation rates in CBA/H mice. Mice exposed to acute low LET X-rays, chronic low LET gamma-rays and chronic high LET neutrons. X-rays in the 0 - 1 Gy dose (D) range, gamma-rays: 0 - 1 Gy & neutrons: 0 - 0.5 Gy. Calculated mutation rate (y) (of the form y = a + bD) as follows: X-rays (a, b := 0.111, 0.338), gamma-rays (a,b := 0.110, 0.373 ± 0.082), neutrons (a, b := 0.136, 1.135 ± 0.202).
McMahon et al., 2016
Study across various studies of the HPRT gene in chinese hamster cells exposed to doses in the range of 1 - 6 Gy. Found 0.2 mutations in HPRT gene per 104 cells and 0.1 point mutations per 104 cells (1 Gy). At higher doses (6 Gy) observed 1.5 mutations per 104 cells and 0.4 point mutations per 104 cells.
There is evidence of a positive response-response relationship between the radiation dose and the frequency of mutations (Russell et al., 1957; Suzuki & Hei, 1996; Albertini et al., 1997; Canova et al., 2002; Dubrova & Plumb, 2002; J.W. Wilson et al., 2015; Bolsunovsky et al., 2016; Mcmahon et al., 2016; Nagashima et al., 2018) . Most studies found that the response-response relationship was linear (Russell et al., 1957; Albertini et al., 1997; Canova et al., 2002; Dubrova et al., 2002; Nagashima et al., 2018). There were however, two exceptions. In a study using normal human bronchial epithelial cells irradiated with 1 - 6 Gy of gamma-rays, the relationship between the number of induced HPRT mutants and the radiation dose was described as non-linear (Suzuki & Hei, 1996) Similarly, in a study examining HPRT mutations in isolated peripheral blood T-lymphocytes irradiated with low LET gamma-rays, the slope of the line from 0 - 2 Gy differed from the slope at the 2 - 4 Gy interval; thus this was described as two different linear relationships or an overall linear-quadratic relationship (Albertini et al., 1997).
The time scale relationship between radiation exposure and the frequency of mutations is not well defined. Most studies look for manifestation of mutations days or weeks after irradiation, making it particularly difficult to pinpoint exactly when the mutations first occur. Analysis of various organs from mice after in vivo radiation found that mutations were present at 2 days (Winegar et al., 1994; Masumura et al., 2002) and 3 days (Gossen et al., 1995)(Gossen, 1995) post-exposure. Mutations were still present at 7 days and 14 days (Winegar et al., 1994), and 10 days and 21 days (Gossen, 1995) following irradiation. One study documented a doubling in the number of mutations from 7 to 14 days (Winegar et al., 1994) while the other reported a two-fold decrease from 3 to 21 days (Gossen et al., 1995).
An attempt to better define this time scale relationship was made in a study using Salmonella typhimurium bacteria. This study was designed to determine how mutation frequency was affected by constant cesium-137 gamma-ray radiation exposure at defined dose rates of 67.8 uGy/hour, 3.2 uGy/hour, and 0.6 uGy/hour; these mutation frequencies were compared to a control group exposed to background radiation levels (0.09 uGy/hour). Mutation frequencies were evaluated after 24, 48, 72 and 96 hours of constant exposure. At 24 hours, the 67.8 uGy/hour, 3.2 uGy/hour and 0.6 uGy/hour mutant frequencies were significantly higher than background exposure controls. Interestingly, however, these levels were decreased at 48 hours and continued to decline gradually towards control frequencies over time. This decline was proposed to be due to an elimination of the highly mutated cells, leaving behind an increasing number of cells that had adapted to the radiation and were thus more equipped for survival (Bolsunovsky et al., 2016). Other studies are required to build a more complete understanding of this timeline.
Known modulating factors
There are several factors that have been documented to affect the relationship between direct deposition of energy and increased mutation frequency. The sex, age, and use of adaptive dosing have been demonstrated to affect the radiation-induced mutations present in offspring. In contrast to male mice, female mice that were irradiated in utero (Barber et al., 2009) or as adults (Ali et al., 2012)(Ali, 2012) did not produce offspring with increased ESTR mutations. This suggests that radiation-induced mutations are only heritable through the paternal line. As such, the age of the father may affect the mutant frequency in the offspring, as increased mutations were present in spermatogenic cells of older male mice relative to younger males both at baseline levels and post-irradiation (Xu et al., 2012). Lastly, the use of ‘adaptive’ radiation dosing, or giving a very small dose 24 hours prior to the full radiation dose, may also affect offspring’s mutational frequency. In male mice who received adaptive dosing relative to males who received only the full radiation dose, there were significant decreases in germline mutation frequencies and in the rate of paternal mutations in their offspring (Somers et al., 2004) .
The radiation-mutation relationship may also be impacted by the genetics of the organism, as the genotype appears to play an important role in determining how the biological system responds to radiation. In yeast with inactivated rad50 or rad52, the radiation-induced mutation frequency was significantly increased relative to wild-type yeast (Matuo et al., 2018). Msh2 knock-out mice (Burr et al., 2007) and medaka fish (Otozai et al., 2014) both had significantly increased baseline mutation frequencies relative to wild-type animals. Irradiation, however, did not change this mutation rate from baseline for these Msh2 knock-out animals (Burr et al., 2007; Otozai et al., 2014). Similarly, BRCA2 knock-out embryos had significantly elevated baseline mutation rates relative to wild-type littermates; however, in utero radiation was found to increase the mutation rate of all genotypes. Thus irradiated BRCA2 knock-out embryos also had a significantly increased mutation frequency relative to wild-type embryos by approximately three-fold (Tutt et al., 2002). Finally, baseline mutation levels in p53 knock-out medaka fish did not differ from wild-types; however, p53 knock-out fish exposed to radiation were found to have a 24-fold increase in mutation frequency relative to unirradiated p53 knock-out fish (Otozai et al., 2014). Construction of a dose response curve found the following mutation rates for wild-type, Msh2 knock-out, p53 knockout, and Msh2/p53 double knock-out medaka fish, respectively: 1.1x10-4 mutations/allele/Gy, 1.1x10-4 mutations/allele/Gy, 4.3x10-4 mutations/allele/Gy, and 5.6x10-4 mutations/allele/Gy (Otozai et al., 2014).
Finally, factors such as dose, dose-rate, tissue type and radiation quality can influence mutation rate induction (Suzuki & Hei ,1996; Hooker et al., 2004; Rydberg et al., 2005; Day et al., 2007; Okudaira et al., 2010; Brooks et al., 2016).
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The domain of applicability applies to single-celled organisms such as bacteria and yeast, eukaryotic cells, and multi-cellular organisms such as fish, mice and humans.
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