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Relationship: 1981
Title
Energy Deposition leads to Increase, Mutations
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 lung cancer | non-adjacent | High | High | Brendan Ferreri-Hanberry (send email) | Open for citation & comment | EAGMST Approved |
| Deposition of energy leading to occurrence of cataracts | non-adjacent | High | High | Arthur Author (send email) | Open for citation & comment |
Taxonomic Applicability
Sex Applicability
| Sex | Evidence |
|---|---|
| Unspecific | High |
Life Stage Applicability
| Term | Evidence |
|---|---|
| All life stages | High |
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.
| 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
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).
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).
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.
|
Reference |
Summary |
|
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. |
Response-response Relationship
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; Kraemer et al., 2000; 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). In a study with V79 Chinese hamster cells, a curvilinear response was also seen as a result of x-ray response while a linear response was seen for Am-241 alpha-particle exposure (Schmidt and Keifer, 1998).
Time-scale
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 Feedforward/Feedback loops influencing this KER
Not identified.
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.