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DNA double-strand breaks induced by low-dose exposure to x-rays used in medical diagnostics

Laurence Beels UGent (2011)
abstract
Ionizing radiation (IR) used in clinical diagnosis contributes to 53% of the radiation burden to the Belgian population. IR, such as x-rays, is known to induce cancer at high doses, but the effect at low doses is less clear. Clarification of low-dose health consequences is needed and is the subject of this PhD research, which fits well with the goals of the High Level and Expert Group on European Low Dose Risk Research. The first part of the PhD dissertation consists of three chapters necessary to understand the whys and wherefores of this PhD research. The use of x-rays in medical diagnostics is discussed in chapter 1. Parameters describing x-ray exposure and related health effects are explained to understand the contribution of x-rays in the medical radiation burden. We go deeper into the paediatric cardiac catheterization and adult contrast computed tomography (CT) procedures as these populations were considered for in vivo evaluation of low-dose effects. In chapter 2, risks from x-ray exposure are discussed. Both deterministic and stochastic effects are defined, but because cancer is the major concern of low-dose x-ray exposure, the estimation of lifetimeattributable risks (LAR) for cancer incidence or mortality is discussed more in detail. Up to now, for radiation protection purposes, the low-dose cancer risk is estimated according to the linear-no-threshold (LNT) hypothesis, which linearly extrapolates high-dose risks down to the low-dose area assuming no threshold. The LNT hypothesis is based on the target theory by which effects are assumed to be produced in cells hit by the ionizing particles. However, radiobiological data suggest that IR targeted cells are able to pass damage signals to non-targeted cells which are in close proximity. Due to these non-targeted observations, the validity of the LNT hypothesis in terms of radiation protection and risk estimation is questioned. Epidemiological studies to investigate low-dose cancer risks are statistical underpowered as low-dose cancer incidences are much lower than the background cancer incidence. Hence, another approach is necessary to evaluate the low-dose cancer risk. A biomarker visualizing early steps in the carcinogenesis process can provide valuable information on the dose effect behaviour in the low-dose area. In chapter 3, DNA damage is discussed. DNA double-strand breaks (DSBs) are internationally recognized as the DNA lesions responsible for the biological effects of IR. Methods to detect DNA damage are reviewed with special attention for a very sensitive biomarker for DNA DSBs, gamma-H2AX foci immunodetection. Histone H2AX, which is involved in packaging of the DNA into chromosomes, is phosphorylated during one of the first steps in the signalling cascade to eliminate DNA DSBs. Once histone H2AX is phosphorylated (gamma-H2AX), it can be detected by a fluorescence immunostaining technique based on an antibody against the phosphorylated form of histone H2AX. One fluorescent gamma-H2AX focus represents one DNA DSB, enabling to determine x-ray-induced DNA DSBs in lymphocytes of both in vivo irradiated patient’s blood or in vitro irradiated samples. The aim and outline of the PhD research are stated in chapter 4 and chapter 5, respectively. The second part of the PhD dissertation consists of three scientific papers resulting from this PhD research. A paediatric population receiving an x-ray guided cardiac catheterization during the diagnosis or treatment of congenital heart diseases is an ideal population to evaluate x-ray-induced DNA DSBs. On the one hand, x-ray doses can rise quickly due to the complexity of the procedures and on the other hand, children are more radiosensitive than adults with respect to radiation-induced malignancies. When the x-ray-induced gamma-H2AX foci were plotted versus the calculated blood dose for each paediatric patient, a low-dose hypersensitivity was found. This low-dose hypersensitive gamma-H2AX foci response might have a big impact on low-dose risk estimations. Therefore, the LAR of cancer mortality was calculated using the LNT hypothesis and the obtained gamma-H2AX foci data. A four time increased risk was found when using the gamma-H2AX data. The paper resulting from this study is presented in chapter 6. Because the biphasic dose response behaviour found in the paediatric population was completely unexpected, this behaviour needed further investigation by in vitro experiments. Dose response and repair kinetics of x- or 60Co gamma-irradiated whole blood or isolated T-lymphocytes were determined. A clear lowdose hypersensitivity was only observed when whole blood was irradiated with x-rays, simulating the in vivo irradiation conditions. Furthermore, a delayed repair was observed for x-ray irradiated whole blood with 40% of gamma-H2AX foci still present at 24 hours post-irradiation. In contrast, irradiation of whole blood or isolated T-lymphocytes with gamma-rays resulted in a linear dose response. The results of these in vitro experiments indicate that the irradiation type and cell environment have a great impact on the gamma-H2AX dose effect behaviour and these results were published in a second paper, presented in chapter 7. An interesting population to validate the obtained in vivo x-ray-induced dose response is an adult population undergoing a contrast CT examination. Especially for CT, there is an increasing concern about possible low-dose cancer risks. Although the risks to an individual CT exposure are quite low, the population undergoing a CT examination has increased over the years and therefore, a bigger number of individuals are at risk for cancer development due to x-ray exposure for a CT examination. The low-dose hypersensitive gamma-H2AX foci response observed in the paediatric study was also found in this adult CT study. In addition, a significantly lower number of CT x-ray-induced gamma-H2AX foci was observed when a CT scanner using lower dose settings was used to perform the examination. The paper resulting from this second in vivo study is presented in chapter 8. The third part of the PhD dissertation is a thorough discussion of the observed low-dose hypersensitivity and its importance in terms of radiation protection. As this PhD research is based on the application of the gamma-H2AX foci scoring technique, its use as low-dose biomarker is first discussed in chapter 9. Both advantages and drawbacks of the technique are treated. Furthermore, the observed in vitro dose response and repair kinetics are discussed. Both the observed in vitro and in vivo dose response behaviour can be explained by the bystander effect. Targeted cells might pass damage signals to their non-targeted neighbouring bystander cells. The mechanism of this bystander effect is not fully understood, but levels of reactive oxygen species and nitrogen oxide seem to be involved and could be transferred by the medium or by gap-junction intercellular communication. The bystander effect is discussed in chapter 10. The observed low-dose hypersensitivity points to the importance of dose-reducing technologies, discussed in chapter 11. For cardiac catheterization procedures, the use of cone-beam CT could reduce the patient dose, but its applications for paediatric procedures should be further investigated. For CT examinations, the introduction of dose-reducing iterative reconstruction could decrease the patient dose. In conclusion (chapter 12), awareness of the physicians regarding the biological effect of low-dose x-rays might help the most to minimize long term health consequences of medical diagnostics. Some future perspectives are addressed in chapter 13. A better understanding of the observed lowdose hypersensitivity with respect to the bystander effect is necessary. To this end, bystander inhibitors and gene expression should be studied in a whole blood environment irradiated with x-ray doses used in clinical diagnostics. Furthermore, single cell irradiation with microbeam x-rays could provide more information about the mechanisms of the bystander effect.
Please use this url to cite or link to this publication:
author
promoter
UGent and UGent
organization
alternative title
DNA dubbelstrengbreuken geïnduceerd door lage dosis blootstelling aan x-stralen gebruikt in de medische diagnostiek
year
type
dissertation (monograph)
subject
keyword
low-dose, gamma-H2AX foci, DNA double-strand breaks, x-rays
pages
XLIII, 157 pages
publisher
Ghent University. Faculty of Medicine and Health Sciences
place of publication
Ghent, Belgium
defense location
Gent : UZ (auditorium C)
defense date
2011-06-15 17:00
language
English
UGent publication?
yes
classification
D1
additional info
dissertation in parts contains copyrighted material
copyright statement
I have transferred the copyright for this publication to the publisher
id
1851140
handle
http://hdl.handle.net/1854/LU-1851140
date created
2011-07-01 14:56:33
date last changed
2011-07-04 09:45:54
@phdthesis{1851140,
  abstract     = {Ionizing radiation (IR) used in clinical diagnosis contributes to 53\% of the radiation burden to the Belgian population. IR, such as x-rays, is known to induce cancer at high doses, but the effect at low doses is less clear. Clarification of low-dose health consequences is needed and is the subject of this PhD research, which fits well with the goals of the High Level and Expert Group on European Low Dose Risk Research.
The first part of the PhD dissertation consists of three chapters necessary to understand the whys and wherefores of this PhD research. The use of x-rays in medical diagnostics is discussed in chapter 1. Parameters describing x-ray exposure and related health effects are explained to understand the contribution of x-rays in the medical radiation burden. We go deeper into the paediatric cardiac catheterization and adult contrast computed tomography (CT) procedures as these populations were considered for in vivo evaluation of low-dose effects. In chapter 2, risks from x-ray exposure are discussed. Both deterministic and stochastic effects are defined, but because cancer is the major concern of low-dose x-ray exposure, the estimation of lifetimeattributable risks (LAR) for cancer incidence or mortality is discussed more in detail. Up to now, for radiation protection purposes, the low-dose cancer risk is estimated according to the linear-no-threshold (LNT) hypothesis, which linearly extrapolates high-dose risks down to the low-dose area assuming no threshold. The LNT hypothesis is based on the target theory by which effects are assumed to be produced in cells hit by the ionizing particles. However, radiobiological data suggest that IR targeted cells are able to pass damage signals to non-targeted cells which are in close proximity. Due to these non-targeted observations, the validity of the LNT hypothesis in terms of radiation protection and risk estimation is questioned. Epidemiological studies to investigate low-dose cancer risks are statistical underpowered as low-dose cancer incidences are much lower than the background cancer incidence. Hence, another approach is necessary to evaluate the low-dose cancer risk. A biomarker visualizing early steps in the carcinogenesis process can provide valuable information on the dose effect behaviour in the low-dose area. In chapter 3, DNA damage is discussed. DNA double-strand breaks (DSBs) are internationally recognized as the DNA lesions responsible for the biological effects of IR. Methods to detect DNA damage are reviewed with special attention for a very sensitive biomarker for DNA DSBs, gamma-H2AX foci immunodetection. Histone H2AX, which is involved in packaging of the DNA into chromosomes, is phosphorylated during one of the first steps in the signalling cascade to eliminate DNA DSBs. Once histone H2AX is phosphorylated (gamma-H2AX), it can be detected by a fluorescence immunostaining technique based on an antibody against the phosphorylated form of histone H2AX. One fluorescent gamma-H2AX focus represents one DNA DSB, enabling to determine x-ray-induced DNA DSBs in lymphocytes of both in vivo irradiated patient{\textquoteright}s blood or in vitro irradiated samples. The aim and outline of the PhD research are stated in chapter 4 and chapter 5, respectively.
The second part of the PhD dissertation consists of three scientific papers resulting from this PhD research. A paediatric population receiving an x-ray guided cardiac catheterization during the diagnosis or treatment of congenital heart diseases is an ideal population to evaluate x-ray-induced DNA DSBs. On the one hand, x-ray doses can rise quickly due to the complexity of the procedures and on the other hand, children are more radiosensitive than adults with respect to radiation-induced malignancies. When the x-ray-induced gamma-H2AX foci were plotted versus the calculated blood dose for each paediatric patient, a low-dose hypersensitivity was found. This low-dose hypersensitive gamma-H2AX foci response might have a big impact on low-dose risk estimations. Therefore, the LAR of cancer mortality was calculated using the LNT hypothesis and the obtained gamma-H2AX foci data. A four time increased risk was found when using the gamma-H2AX data. The paper resulting from this study is presented in chapter 6. Because the biphasic dose response behaviour found in the paediatric population was completely unexpected, this behaviour needed further investigation by in vitro experiments. Dose response and repair kinetics of x- or 60Co gamma-irradiated whole blood or isolated T-lymphocytes were determined. A clear lowdose hypersensitivity was only observed when whole blood was irradiated with x-rays, simulating the in vivo irradiation conditions. Furthermore, a delayed repair was observed for x-ray irradiated whole blood with 40\% of gamma-H2AX foci still present at 24 hours post-irradiation. In contrast, irradiation of whole blood or isolated T-lymphocytes with gamma-rays resulted in a linear dose response. The results of these in vitro experiments indicate that the irradiation type and cell environment have a great impact on the gamma-H2AX dose effect behaviour and these results were published in a second paper, presented in chapter 7. An interesting population to validate the obtained in vivo x-ray-induced dose response is an adult population undergoing a contrast CT examination. Especially for CT, there is an increasing concern about possible low-dose cancer risks. Although the risks to an individual CT exposure are quite low, the population undergoing a CT examination has increased over the years and therefore, a bigger number of individuals are at risk for cancer development due to x-ray exposure for a CT examination. The low-dose hypersensitive gamma-H2AX foci response observed in the paediatric study was also found in this adult CT study. In addition, a significantly lower number of CT x-ray-induced gamma-H2AX foci was observed when a CT scanner using lower dose settings was used to perform the examination. The paper resulting from this second in vivo study is presented in chapter 8.
The third part of the PhD dissertation is a thorough discussion of the observed low-dose hypersensitivity and its importance in terms of radiation protection. As this PhD research is based on the application of the gamma-H2AX foci scoring technique, its use as low-dose biomarker is first discussed in chapter 9. Both advantages and drawbacks of the technique are treated. Furthermore, the observed in vitro dose response and repair kinetics are discussed. Both the observed in vitro and in vivo dose response behaviour can be explained by the bystander effect. Targeted cells might pass damage signals to their non-targeted neighbouring bystander cells. The mechanism of this bystander effect is not fully understood, but levels of reactive oxygen species and nitrogen oxide seem to be involved and could be transferred by the medium or by gap-junction intercellular communication. The bystander effect is discussed in chapter 10. The observed low-dose hypersensitivity points to the importance of dose-reducing technologies, discussed in chapter 11. For cardiac catheterization procedures, the use of cone-beam CT could reduce the patient dose, but its applications for paediatric procedures should be further investigated. For CT examinations, the introduction of dose-reducing iterative reconstruction could decrease the patient dose.
In conclusion (chapter 12), awareness of the physicians regarding the biological effect of low-dose x-rays might help the most to minimize long term health consequences of medical diagnostics. Some future perspectives are addressed in chapter 13. A better understanding of the observed lowdose hypersensitivity with respect to the bystander effect is necessary. To this end, bystander inhibitors and gene expression should be studied in a whole blood environment irradiated with x-ray doses used in clinical diagnostics. Furthermore, single cell irradiation with microbeam x-rays could provide more information about the mechanisms of the bystander effect.},
  author       = {Beels, Laurence},
  keyword      = {low-dose,gamma-H2AX foci,DNA double-strand breaks,x-rays},
  language     = {eng},
  pages        = {XLIII, 157},
  publisher    = {Ghent University. Faculty of Medicine and Health Sciences},
  school       = {Ghent University},
  title        = {DNA double-strand breaks induced by low-dose exposure to x-rays used in medical diagnostics},
  year         = {2011},
}

Chicago
Beels, Laurence. 2011. “DNA Double-strand Breaks Induced by Low-dose Exposure to X-rays Used in Medical Diagnostics”. Ghent, Belgium: Ghent University. Faculty of Medicine and Health Sciences.
APA
Beels, L. (2011). DNA double-strand breaks induced by low-dose exposure to x-rays used in medical diagnostics. Ghent University. Faculty of Medicine and Health Sciences, Ghent, Belgium.
Vancouver
1.
Beels L. DNA double-strand breaks induced by low-dose exposure to x-rays used in medical diagnostics. [Ghent, Belgium]: Ghent University. Faculty of Medicine and Health Sciences; 2011.
MLA
Beels, Laurence. “DNA Double-strand Breaks Induced by Low-dose Exposure to X-rays Used in Medical Diagnostics.” 2011 : n. pag. Print.