Radiation Induced DNA Double-Strand Breaks in Radiology

Abstract

Shortly after the discovery of X-rays, their damaging effect on biological tissues was observed. The determination of radiation exposure in diagnostic and interventional radiology is usually based on physical measurements or mathematical algorithms with standardized dose simulations. γ-H2AX immunofluorescence microscopy is a reliable and sensitive method for the quantification of radiation induced DNA double-strand breaks (DSB) in blood lymphocytes. The detectable amount of these DNA damages correlates well with the dose received. However, the biological radiation damage depends not only on dose but also on other individual factors like radiation sensitivity and DNA repair capacity. Iodinated contrast agents can enhance the x-ray induced DNA damage level. After their induction DSB are quickly repaired. A protective effect of antioxidants has been postulated in experimental studies. This review explains the prinicple of the γ-H2AX technique and provides an overview on studies evaluating DSB in radiologic examinations.

Key Points:

• Radiologic examinations including CT and angiography induce DNA double-strand breaks. Even after mammography a slight but significant increase is detectable in peripheral blood lymphocytes.

• The number of radiation induced double-strand breaks correlates well with the radiation dose.

• Individual factors including radiation sensitivity, DNA repair capacity and the application of iodinated contrast media has an influence on the DNA damage level.

Citation Format:

• Kuefner MA, Brand M, Engert C et al. Radiation Induced DNA Double-Strand Breaks in Radiology. Fortschr Röntgenstr 2015; 187: 872 – 878

Zusammenfassung

Der schädigende Effekt von Röntgenstrahlung auf biologische Gewebe ist bereits seit langem bekannt. Die Bestimmung der Dosisbelastung in der diagnostischen und interventionellen Radiologie erfolgt in erster Linie mithilfe physikalischer Verfahren anhand standardisierter Phantome oder mit mathematischen Dosissimulationen. Mit der γ-H2AX-Immunfluoreszenzmikroskopie steht seit einigen Jahren ein sehr sensitives Verfahren zur Quantifizierung strahleninduzierter DNA-Doppelstrangbrüche (DSB) in Blutlymphozyten zur Verfügung. Der messbare Strahlenschaden an der DNA korreliert hier sehr gut mit der deponierten Dosis. Andererseits werden jedoch auch individuelle Faktoren, wie z. B. die Strahlensensibilität oder die DNA-Reparatur berücksichtigt. Jodhaltige Kontrastmittel können den strahleninduzierten DNA-Schaden verstärken. Nach der Induktion werden die DSB rasch repariert. Mit neuen Ansätzen ist es sogar möglich, den DNA-Schaden in einzelnen Organen abzuschätzen. Erste experimentelle Studien postulieren einen protektiven Effekt von Antioxidantien. Diese Übersichtsarbeit beschreibt das Prinzip der γ-H2AX-Methode und gibt einen Überblick über die die wichtigsten Ergebnisse der bisher publizierten Studien, in denen während radiologischer Untersuchungen induzierte DSB untersucht wurden.

Key words

biological effects - radiation effects - radiobiology - radiosensitivity

• References

• 1 Hricak H, Brenner DJ, Adelstein SJ et al. Managing radiation use in medical imaging: a multifaceted challenge. Radiology 2011; 258: 889-905
• 2 Brenner DJ. What we know and what we don't know about cancer risks associated with radiation doses from radiological imaging. Br J Radiol 2014; DOI: 10.1259/bjr.20130629.
• 3 Lobrich M, Shibata A, Beucher A et al. gammaH2AX foci analysis for monitoring DNA double-strand break repair: strengths, limitations and optimization. Cell Cycle 2010; 9: 662-669
• 4 van Gent DC, Hoeijmakers JH, Kanaar R. Chromosomal stability and the DNA double-stranded break connection. Nat Rev Genet 2001; 2: 196-206
• 5 Jeggo PA, Lobrich M. DNA double-strand breaks: their cellular and clinical impact?. Oncogene 2007; 26: 7717-7719
• 6 Lobrich M, Jeggo PA. The impact of a negligent G2/M checkpoint on genomic instability and cancer induction. Nat Rev Cancer 2007; 7: 861-869
• 7 Lobrich M, Rief N, Kuhne M et al. In vivo formation and repair of DNA double-strand breaks after computed tomography examinations. Proc Natl Acad Sci USA 2005; 102: 8984-8989
• 8 Rogakou EP, Pilch DR, Orr AH et al. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 1998; 273: 5858-5868
• 9 Rothkamm K, Lobrich M. Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses. Proc Natl Acad Sci USA 2003; 100: 5057-5062
• 10 Rogakou EP, Boon C, Redon C et al. Megabase chromatin domains involved in DNA double-strand breaks in vivo. J Cell Biol 1999; 146: 905-916
• 11 Kuefner MA, Hinkmann FM, Alibek S et al. Reduction of X-ray induced DNA double-strand breaks in blood lymphocytes during coronary CT angiography using high-pitch spiral data acquisition with prospective ECG-triggering. Invest Radiol 2010; 45: 182-187
• 12 Rothkamm K, Balroop S, Shekhdar J et al. Leukocyte DNA damage after multi-detector row CT: a quantitative biomarker of low-level radiation exposure. Radiology 2007; 242: 244-251
• 13 May MS, Brand M, Wuest W et al. Induction and repair of DNA double-strand breaks in blood lymphocytes of patients undergoing ¹⁸F-FDG PET/CT examinations. Eur J Nucl Med Mol Imaging 2012; 39: 1712-1719
• 14 Beels L, Bacher K, Smeets P et al. Dose-length product of scanners correlates with DNA damage in patients undergoing contrast CT. Eur J Radiol 2012; 81: 1495-1499
• 15 Vandevoorde C, Franck C, Bacher K et al. γ-H2AX foci as in vivo effect biomarker in children emphasize the importance to minimize x-ray doses in paediatric CT imaging. Eur Radiol 2015; 25: 800-811
• 16 May MS, Wuest W, Lell MM et al. Current strategies for dosage reduction in computed tomography. Radiologe 2012; 52: 905-913
• 17 Halliburton SS, Abbara S, Chen MY. Society of Cardiovascular Computed Tomography et al. SCCT guidelines on radiation dose and dose-optimization strategies in cardiovascular CT. J Cardiovasc Comput Tomogr 2011; 5: 198-224
• 18 Kuefner MA, Grudzenski S, Hamann J et al. Effect of CT scan protocols on x-ray-induced DNA double-strand breaks in blood lymphocytes of patients undergoing coronary CT angiography. Eur Radiol 2010; 20: 2917-2924
• 19 Brand M, Sommer M, Achenbach S et al. X-ray induced DNA double-strand breaks in coronary CT angiography: Comparison of sequential, low-pitch helical and high-pitch helical data acquisition. Eur J Radiol 2012; 81: 357-362
• 20 Geisel D, Zimmermann E, Rief M et al. DNA double-strand breaks as potential indicators for the biological effects of ionising radiation exposure from cardiac CT and conventional coronary angiography: a randomised, controlled study. Eur Radiol 2012; 22: 1641-1650
• 21 Grudzenski S, Kuefner MA, Heckmann MB et al. Contrast medium-enhanced radiation damage caused by CT examinations. Radiology 2009; 253: 706-714
• 22 Piechowiak EI, Peter JF, Kleb B et al. Intravenous Iodinated Contrast Agents Amplify DNA Radiation Damage at CT. Radiology 2015; 132478 [Epub ahead of print]
• 23 Geisel D, Heverhagen JT, Kalinowski M et al. DNA double-strand breaks after percutaneous transluminal angioplasty. Radiology 2008; 248: 852-859
• 24 Beels L, Bacher K, De Wolf D et al. gamma-H2AX foci as a biomarker for patient X-ray exposure in pediatric cardiac catheterization: are we underestimating radiation risks?. Circulation 2009; 120: 1903-1909
• 25 Kuefner MA, Grudzenski S, Schwab SA et al. DNA double-strand breaks and their repair in blood lymphocytes of patients undergoing angiographic procedures. Invest Radiol 2009; 44: 440-446
• 26 Kuefner MA, Grudzenski S, Schwab SA et al. X-ray-induced DNA double-strand breaks after angiographic examinations of different anatomic regions. Fortschr Röntgenstr 2009; 181: 374-380
• 27 Schwab SA, Brand M, Schlude IK et al. X-ray induced formation of γ-H2AX foci after full-field digital mammography and digital breast-tomosynthesis. PLoS One 2013; 8 (7): e70660. DOI: 10.1371/journal.pone.0070660.
• 28 Weiss JF, Landauer MR. Protection against ionizing radiation by antioxidant nutrients and phytochemicals. Toxicology 2003; 189: 1-20
• 29 Reliene R, Pollard JM, Sobol Z et al. N-acetyl cysteine protects against ionizing radiation-induced DNA damage but not against cell killing in yeast and mammals. Mutat Res 2009; 665: 37-43
• 30 Mansour HH, Hafez HF, Fahmy NM et al. Protective effect of N-acetylcysteine against radiation induced DNA damage and hepatic toxicity in rats. Biochem Pharmacol 2008; 75: 773-780
• 31 Tiwari P, Kumar A, Balakrishnan S et al. Radiation-induced micronucleus formation and DNA damage in human lymphocytes and their prevention by antioxidant thiols. Mutat Res 2009; 676: 62-68
• 32 Wan XS, Ware JH, Zhou Z et al. Protection against radiation-induced oxidative stress in cultured human epithelial cells by treatment with antioxidant agents. Int J Radiat Oncol Biol Phys 2006; 64: 1475-1481
• 33 Kuefner MA, Brand M, Ehrlich J et al. Effect of antioxidants on X-ray-induced γ-H2AX foci in human blood lymphocytes: preliminary observations. Radiology 2012; 264: 59-67
• 34 Brand M, Vogt S, Engert C et al. Auswirkungen von verschiedenen Antioxidantien auf strahleninduzierte DNA-Doppelstrangbrüche. Fortschr Röntgenstr 2013; 185: S215-S216
• 35 Stehli J, Fuchs TA, Ghadri JR et al. Antioxidants prevent DNA double-strand breaks from x-ray-based cardiac examinations: a randomized, double-blinded, placebo-controlled trial. J Am Coll Cardiol 2014; 64: 117-118
• 36 Kuefner MA, Brand M, Engert C et al. The effect of calyculin A on the dephosphorylation of the histone γ-H2AX after formation of X-ray-induced DNA double-strand breaks in human blood lymphocytes. Int J Radiat Biol 2013; 89: 424-432
• 37 Löbrich M, Shibata A, Beucher A et al. gammaH2AX foci analysis for monitoring DNA double-strand break repair: strengths, limitations and optimization. Cell Cycle 2010; 9: 662-669
• 38 Muslimovic A, Johansson P, Hammarsten O. Measurement of H2AX Phosphrylation as a Marker of Ionizing Radiation Induced Cell Damage. In: Nenoi M, (Ed.): Current Topics in Ionizing Radiation Research. Rijeka: InTech; 2012: 3-20