Upstream eventEnergy Deposition
Increase, Chromosomal aberrations
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 in a randomized manner. 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 and Georgakilas 2008; Okayasu 2012; Lorat et al. 2015; Nikitaki et al. 2016). The DNA is particularly susceptible to damage in the form of DNA strand breaks. This damaged DNA can lead to aberrations/rearrangements in chromosomes and chromatids. Examples of chromosome-type aberrations include chromosome-type breaks, ring chromosomes, and dicentric chromosomes, while chromatid-type aberrations refer to chromatid-type breaks and chromatid exchanges (Hagmar et al. 2004; Bonassi et al. 2008). Other types of CAs that may occur in response to radiation include micronuclei (MN), nucleoplasmic bridges (NPBs), and copy number variants (CNVs). CAs may also be classified as stable aberrations (translocations, inversions, insertions and deletions) and unstable aberrations (dicentric chromosomes, acentric fragments, centric rings and MN) (Hunter and Muirhead 2009; Qian et al. 2016).
Evidence Supporting this KER
The biological plausibility for this KER is strong, as there is a broad mechanistic understanding of the process CA induction from deposited energy in the form of radiation, which is widely accepted. Many studies have provided clear evidence to support this KER using both in vitro and in vivo models (Schmid et al. 2002; Thomas et al. 2003; Maffei et al. 2004; Tucker et al. 2005b; Tucker et al. 2005a; George et al. 2009; Meenakshi and Mohankumar 2013; Santovito et al. 2013; Arlt et al. 2014; Balajee et al. 2014; George et al. 2014; Han et al. 2014; Vellingiri et al. 2014; Suto et al. 2015; Adewoye et al. 2015; Cheki et al. 2016; Mcmahon et al. 2016; Morishita et al. 2016; Qian et al. 2016; Basheerudeen et al. 2017; Meenakshi et al. 2017; Abe et al. 2018; Jang et al. 2019; Puig et al., 2016; Barquinero et al., 2004; Curwen et al., 2012; Testa et al., 2018; Franken et al., 2012; Cornforth et al., 2002; Loucas et al., 2013; Nagasawa et al., 1990a; Nagasawa et al., 1990b; Edwards et al., 1980; Themis et al., 2013; Schmid et al., 1996; Mestres et al., 2004; Bilbao et al., 1989; Mill et al., 1996; Brooks, 1975; Tawn and Thierens, 2009; Durante et al., 1992; Hamza and Mohankumar, 2009; Takatsuji and Sasaki, 1984; Moquet et al., 2001; Purrott et al., 1980; duFrain et al., 1979).
The process from deposition of energy to CA occurrence has been described in several reviews (Smith et al. 2003; Christensen 2014; Sage and Shikazono 2017). When ionizing radiation comes into contact with a cell, it is able to deposit energy through ionization and excitation of molecules, which results in the freeing of electrons. These electrons have enough energy to break chemical bonds; thus if the high-energy electrons come into contact with DNA, they may break DNA bonds and cause damage in the form of double-strand breaks, single-strand breaks, base damage, or the crosslinking of DNA to other molecules. This damage should trigger DNA repair. If the enzymatic repair, however, is incorrect or incomplete, this could push the cell towards apoptotic pathways. However, the repair processes may lead to asymmetrical exchanges in the chromosomes that are not removed from the cell and can propagate in the form of aberrations. Radiation-damaged cells display accumulated CAs in the form of chromosomal rearrangements, genetic amplifications and/or MN (Smith et al. 2003; Christensen 2014; Sage and Shikazono 2017).
The first incidence of radiation-induced CA was reported by Weissenborn and Streffer (1988). The authors show formation of CAs in neutron and X-irradiated mouse embryos, subsequent studies by numerous laboratories have shown CA formation from different radiation qualities (reviewed by Smith et al, 2003). More recent studies also support this notion. A study using a single particle irradiation system (SPICE) to deliver highly directed and tightly controlled radiation doses to select nuclei of oral squamous cell carcinoma cells was shown to generate 46 mutant monoclonal sublines. Copy number alterations ((CNAs), which are CNVs found in somatic cells rather than germline cells (Li et al. 2009)), were found in 43 (93%) of the sublines generated. Although most of the sublines were found to have multiple CNAs, one subline in particular had 16 documented CNAs. Further genetic analyses of this subline revealed 14 de novo chromosomal rearrangements and 2 detectable translocations in addition to the 16 CNAs, which is suggestive of chromothripsis. This study thus provides strong evidence that direct deposition of energy by ionizing radiation results in CAs, and in some cases, chromothripsis (Morishita et al. 2016).
CNVs may also be generated through deposition of energy by ionizing radiation. Due to the structural similarities between CNVs that are radiation-induced, chemically-induced, and spontaneously-occurring, all CNVs are likely produced by a similar mechanism. The chemicals, aphidicolin and hydroxyurea, are known inducers of DNA replication stress. This suggests that radiation-induced CNVs are also formed through a similar replication-dependent mechanism(Arlt et al. 2014). Additionally, CNVs may affect germline cells. In fact, there was a significant 8-fold increase in de novo CNVs in the progeny of irradiated male mice, regardless of whether the radiation affected post-meiotic sperm or pre-meiotic sperm. The majority of these CNVs were found to be large deletions, often more than 1000 kB (Adewoye et al. 2015).
Evidence supporting the formation of CAs from the direct deposition of energy in the form of ionizing radiation is strong. The evidence presented below is summarized in table 3, here (click link). In general, there is much evidence that deposition of energy by ionizing radiation results in a higher burden of CAs (Schmid et al. 2002; Thomas et al. 2003; Maffei et al. 2004; Tucker et al. 2005A; Tucker et al. 2005B; George et al. 2009; Meenakshi and Mohankumar 2013; Santovito et al. 2013; Arlt et al. 2014; Balajee et al. 2014; Han et al. 2014; Vellingiri et al. 2014; Suto et al. 2015; Adewoye et al. 2015; Cheki et al. 2016; Mcmahon et al. 2016; Morishita et al. 2016; Qian et al. 2016; Basheerudeen et al. 2017; Meenakshi et al. 2017; Abe et al. 2018; Jang et al. 2019; Puig et al., 2016; Barquinero et al., 2004; Curwen et al., 2012; Testa et al., 2018; Franken et al., 2012; Cornforth et al., 2002; Loucas et al., 2013; Nagasawa et al., 1990a; Nagasawa et al., 1990b; Edwards et al., 1980; Themis et al., 2013; Schmid et al., 1996; Mestres et al., 2004; Bilbao et al., 1989; Mill et al., 1996; Brooks, 1975; Tawn and Thierens, 2009; Durante et al., 1992; Hamza and Mohankumar, 2009; Takatsuji and Sasaki, 1984; Moquet et al., 2001; Purrott et al., 1980; duFrain et al., 1979). Reviews have been published that provide details regarding the relationships between radiation of different LETs and the relative effectiveness of CA induction (Hunter and Muirhead 2009), ionizing radiation and genomic instability (Smith et al. 2003), and low-dose ionizing radiation and chromosomal translocations (Tucker 2008).
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 rates of chromosomal aberrations. 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 over which studies were conducted for a temporal response used to determine the empircal link between direct deposition of energy and increased rates of chromosomal aberrations. The y-axis is ordered from low LET to high LET from top to bottom.
Several human epidemiological studies have provided evidence of both dose/incidence and temporal concordance in terms of deposition of energy by ionizing radiation and resultant CAs. In a study involving 34 health professionals occupationally exposed to radiation, there was a significant increase in the number of chromosome breaks and aberrant cells relative to a group of 35 unexposed professionals from the same hospital. Furthermore, when the exposed group was broken into two groups based on the levels of radiation exposure (those with a dose equivalent to whole body of ionizing radiation (Hwb) of less than/equal to 50 mSv and those with an Hwb greater than 50 mSv), there was a dose-dependent increase in aberrant cells, chromosome breaks and chromatid breaks such that the higher exposure group had significantly elevated aberrations relative to controls for all three parameters scored (Maffei et al. 2004). In a similar study involving 1,392 radiation healthcare workers in the city of Tangshan in 2010, there was a significant increase in CA and MN in exposed workers relative to unexposed healthy controls. Furthermore, there were significant, dose-dependent increases in the CA rate and the MN rate when the exposed workers were split into groups according to cumulative radiation dose, ranging from less than 10 mSv up to greater than 50 mSv. There was also a time-dependent increase in CA and MN rate, such that workers with longer exposure times had significantly increased CAs and MNs. Exposure times ranged from less than 10 years to greater than 20 years (Qian et al. 2016).
Dose and Incidence Concordance
There is a clear correlation between radiation dose (i.e., increasing amounts of energy deposition) and different clastogenic endpoints including dose-dependent increases in: dicentric aberrations(Schmid et al. 2002; Thomas et al. 2003; Tucker et al. 2005A; Suto et al. 2015; Mcmahon et al. 2016; Abe et al. 2018; Jang et al. 2019), centric rings (Tucker et al. 2005a) (Schmid et al. 2002; Thomas et al. 2003; Tucker et al. 2005A), acentric fragments (Schmid et al. 2002; Thomas et al. 2003) , translocations (Tucker et al. 2005A; Tucker et al. 2005B; Suto et al. 2015; Abe et al. 2018; Jang et al. 2019), CNVs (Arlt et al. 2014), large deletions (Mcmahon et al. 2016), NPBs (Thomas et al. 2003), MN (Thomas et al. 2003; Balajee et al. 2014), and CAs in general (Mcmahon et al. 2016) (George et al. 2009). Interestingly, MN structural complexity was likewise demonstrated to be dose-dependent between 1 and 10 Gy. MN were found to contain fragments from two or more different chromosomes at and above 2 Gy; between 5 and 10 Gy, MN contained material from 3 - 5 different chromosomes. These results suggest that MN formation appears to become increasingly more complex with higher doses of radiation due to the increasing number of acentric fragments and the resultant fusion of these fragments (Balajee et al. 2014). Of note, the voltage of the radiation has an effect on the relationship between direct deposition of energy and the resulting CAs. Specifically, dicentric aberration frequency in human peripheral blood lymphocytes was observed to change with voltage of the ionizing radiation. As the X-ray voltage decreased from 60 kV to 10 kV, there was an increase in the number of dicentric aberrations (Schmid et al. 2002).
Temporal concordance is well established. Energy deposition happens immediately upon radiation exposure, with an increased incidence of CAs documented minutes, hours or days after irradiation (Schmid et al. 2002; Thomas et al. 2003; Tucker et al. 2005A; Tucker et al. 2005B; George et al. 2009; Meenakshi and Mohankumar 2013; Arlt et al. 2014; Balajee et al. 2014; Suto et al. 2015; Cheki et al. 2016; Mcmahon et al. 2016; Basheerudeen et al. 2017; Meenakshi et al. 2017; Abe et al. 2018; Jang et al. 2019).
Uncertainties and Inconsistencies
Uncertainties and inconsistencies in this KER are as follows:
- (Bender et al. 1988; Suzuki and Hei 1996; Guerrero-Carbajal et al. 2003; Day et al. 2007, Smithe et al. 2003).
Quantitative Understanding of the Linkage
Quantitative understanding of this linkage suggests that CA frequency can be predicted from the radiation, as per the representative examples provided below. When predicting this relationship, the characteristics of the radiation and the model system should be taken into account (Smith et al. 2003; Hunter and Muirhead 2009).
|Suto et al., 2015||Study of human peripheral blood lymphcytes from a healthy donor subjected to gamma-ray radiation in the dose (D) range of 0 - 300 mGy found a calculated CA rate (y) of dicentrics, translocations and dicentrics+translocations (of the quadratic form, y = a + bD + bD^2) found - dicentrics + translocations (a,b,c := 0.0023 ± 0.0003, 0.0015 ± 0.0058, 0.0819 ± 0.0225), dicentrics (a,b,c := 0.0004 ± 0.0001, 0.0008 ± 0.0028, 0.0398 ± 0.0117), translocations (a,b,c := 0.0019 ± 0.0003, 0.0008 ± 0.0028, 0.0398 ± 0.0117).|
|Abe et al., 2018||Study of human mononuclear blood cells from healthy donors; analyzed for dicentric chromosomes. Exposure to gamma-ray doses (D) in the 0 - 1000 mGy range. Quadratic form fit for the CA rate in Giemsa staining and Centrosmere-FISH staining cases (y) (of the form y = a + bD + cD^2) found to be: Giemsa staining: (a,b,c := 0.0013 ± 0.0005, 0.0067 ± 0.0071, 0.0313 ± 0.0091), Centromere-FISH staining (a,b,c := 0.0010 ± 0.0004, 0.0186 ± 0.0081, 0.0329 ± 0.0104).
Study of mononuclear blood cells from healthy donors; analyzed for translocations. Exposure to gamma-ray doses (D) in the 0 - 1000 mGy range. Quadratic form fit for the CA rate (y) before and after donor age adjustment (of the form y = a + bD + cD^2) found to be: before donor age adjustment: (a,b,c := 0.0053 ± 0.0009, 0.259 ± 0.0127, 0.0826 ± 0.0161), after donor age adjustment (a,b,c := 0.0015 ± 0.0009, 0.0049 ± 0.0155, 0.1033 ± 0.0223).
|Jang et al., 2019||Human peripheral blood lymphcytes studied from healthy donors. Lyphocytes irradiated with X-rays in a dose (D) range 0 - 5 Gy. Calculated CA rate from dicentrics or translocations (y) (of the form y = a + bD + cD^2). Dicentrics, (a,b,c := 0.0011 ± 0.0004, 0.0119 ± 0.0032, 0.0617 ± 0.0019). Translocations, (a,b,c := 0.0015 ± 0.0004, 0.0048 ± 0.0024, 0.0237 ± 0.0014).|
|Schmid et al., 2002||Study of various X- and gamma-ray types irradiating peripheral human blood lymphocytes, analyzed dicentrics and acentrics (10, 29, 60, 220 kV X-rays & Cs-137, Co-60 gamma-rays). See Schmid et al. for details on equations.|
|Goerge et al., 2009||Gamma-rays and iron nuclei irradiating HF19 normal primary lung fibroblasts; Ataxia telangiectasia (AT) primary fibroblasts; NSB1-deficient primary fibroblasts (Nijmegen breakage syndrome); M059K glioblastoma cells & M059J glioblastoma cells (lack DNA-dependent protein kinase activity). Dose range of 0 - 3 Gy. See Table 5 & 6 of George et al. for details on equations.|
There is evidence of a positive response-response relationship between the radiation dose and the frequency of CAs (Schmid et al. 2002; Thomas et al. 2003; Tucker et al. 2005a; Tucker et al. 2005b; George et al. 2009; Arlt et al. 2014; Balajee et al. 2014; Suto et al. 2015; Mcmahon et al. 2016; Abe et al. 2018; Jang et al. 2019). Most studies found that the response-response relationship was linear-quadratic (Schmid et al. 2002; Suto et al. 2015; Abe et al. 2018; Jang et al. 2019). One study, however, reported different results when CAs were examined across five cell lines that had been irradiated with either iron nuclei or gamma-rays. For complex aberrations in three types of fibroblasts (two of which were deficient in DNA repair), the best fit was a quadratic relationship for both gamma-rays and iron ions; for simple aberrations induced by iron ions in these cells, there was a linear relationship found. In two tumor cell lines, a linear response was defined for simple aberrations for both types of radiation, while the response for complex aberrations was not well-defined by the models that were evaluated (George et al. 2009).
The time scale relationship between radiation exposure and the frequency of CAs has been examined. Most studies search for CAs hours, days, weeks, or even years after exposure to radiation (Schmid et al. 2002; Thomas et al. 2003; Tucker et al. 2005a; Tucker et al. 2005b; George et al. 2009; Meenakshi and Mohankumar 2013; Arlt et al. 2014; Balajee et al. 2014; Han et al. 2014; Suto et al. 2015; Cheki et al. 2016; Mcmahon et al. 2016; Basheerudeen et al. 2017; Meenakshi et al. 2017; Abe et al. 2018; Jang et al. 2019) ; this makes it particularly difficult to identify CA induction in relation to the deposition of energy by ionizing radiation. There is an account, however, of CAs appearing within 20 minutes of irradiation, with levels peaking at 40 minutes and plateauing for the remainder of the experiment (up to 100 minutes) (Mcmahon et al. 2016). CAs have also been documented 2 - 3 hours after radiation exposure, with frequency being shown to increase slightly at 24 hours (Basheerudeen et al. 2017). A study examining CAs in human blood samples for 2 - 7 days following irradiation with gamma-rays found that CAs were present at the 2-day mark, but had declined by day 7 (Tucker et al. 2005a; Tucker et al. 2005b) to suspected asymptotic minimum levels (Tucker et al. 2005b). For translocations specifically, the relationship between time and translocation frequency was found to be linear at low doses (0 - 0.5 Gy) and linear quadratic at higher doses (0.5 - 4 Gy) (Tucker et al. 2005b). The sharpest decline over the 7 days was found in dicentrics, acentric fragments, and ring chromosomes (Tucker et al. 2005a).
Interestingly, in vivo radiation exposure has been shown to induce long-lasting CAs in a relatively short time-frame. When lymphocytes from patients undergoing an interventional radiology procedure were compared pre-procedure and 2-3 hours post-procedure, there were significant increases in chromatid-type aberrations, chromosome-type aberrations, dicentrics and MN in post-procedure lymphocytes)(Basheerudeen et al. 2017). Similarly, lymphocytes from subjects exposed to radiation 32-41 years prior to blood collection were found to have significantly increased chromosome-type aberrations (acentric fragments, dicentrics and translocations) and MN relative to unexposed controls (Han et al. 2014). Taken together, the results from these two studies suggest that CAs are not only induced within mere hours of radiation exposure, but that these radiation-induced CAs may also endure for several decades.
Known modulating factors
As evidenced in chronic exposure studies, the relationship between CAs and radiation may be affected by sex, age and smoking status. In terms of sex, females were found to have increased aberrant cells and chromosome breaks relative to males (Maffei et al. 2004). Additionally, increases in age were associated with increased CAs, including sister chromatid exchanges per number of metaphases (Santovito et al. 2013) and MN (Vellingiri et al. 2014). Smoking was also found to increase chromosomal damage. Aberrant cells and chromosome breaks were found to be significantly increased in smokers relative to non-smokers (Maffei et al. 2004). Likewise, blood samples from smokers that were exposed to radon gas had lymphocytes with significantly increased dicentric aberrations, acentric fragments, chromatid breaks (Meenakshi and Mohankumar 2013), MN, and NPBs (Meenakshi et al. 2017) relative to lymphocytes from non-smokers also exposed to radon gas.
In vitro studies found that hyperthermia modified the effect of radiation on CA induction. In cells exposed to hyperthermic conditions (41oC for one hour) followed by radiation (4 Gy), there were significant increases in chromosomal translocations and chromosomal fragments at one hour and at 24 hours post-exposure, respectively, as compared to cells exposed only to radiation (Bergs et al. 2016).
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The domain of applicability applies to eukaryotic cells and multi-cellular organisms such as mice and humans.
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