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SYMPOSIUM
Year : 2010  |  Volume : 2  |  Issue : 3  |  Page : 189-196 Table of Contents     

Radiation-induced biomarkers for the detection and assessment of absorbed radiation doses


1 Division of CBRN Defence, Institute of Nuclear Medicine and Allied Sciences, Brig. S. K. Mazumdar Marg, Delhi - 110 054, India
2 Department of Medical Elementology and Toxicology, Jamia Hamdard, Hamdard Nagar, New Delhi - 110 062, India

Date of Submission01-Jul-2010
Date of Decision01-Jul-2010
Date of Acceptance06-Jul-2010
Date of Web Publication16-Aug-2010

Correspondence Address:
Rakesh Kumar Sharma
Division of CBRN Defence, Institute of Nuclear Medicine and Allied Sciences, Brig. S. K. Mazumdar Marg, Delhi - 110 054
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-7406.68500

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   Abstract 

Radiation incident involving living organisms is an uncommon but a very serious situation. The first step in medical management including triage is high-throughput assessment of the radiation dose received. Radiation exposure levels can be assessed from viability of cells, cellular organelles such as chromosome and different intermediate metabolites. Oxidative damages by ionizing radiation result in carcinogenesis, lowering of the immune response and, ultimately, damage to the hematopoietic system, gastrointestinal system and central nervous system. Biodosimetry is based on the measurement of the radiation-induced changes, which can correlate them with the absorbed dose. Radiation biomarkers such as chromosome aberration are most widely used. Serum enzymes such as serum amylase and diamine oxidase are the most promising biodosimeters. The level of gene expression and protein are also good biomarkers of radiation.

Keywords: Biodosimetry, biomarkers, gene expression, oxidative damages, radiation accident, serum amylase


How to cite this article:
Rana S, Kumar R, Sultana S, Sharma RK. Radiation-induced biomarkers for the detection and assessment of absorbed radiation doses. J Pharm Bioall Sci 2010;2:189-96

How to cite this URL:
Rana S, Kumar R, Sultana S, Sharma RK. Radiation-induced biomarkers for the detection and assessment of absorbed radiation doses. J Pharm Bioall Sci [serial online] 2010 [cited 2019 May 25];2:189-96. Available from: http://www.jpbsonline.org/text.asp?2010/2/3/189/68500

The increasing probability of occurrence of nuclear and radiological emergencies (NRE) is directly related with the increase usage of radioisotopes in medicine, agriculture, industry and power generation. At present, there is a great risk of terrorist nuclear attacks. The enhanced threat of terrorism involving innocent civilians compounded the overall radiation risk for the community. The occupational workers always wear personal dosimeters for assessment of absorbed dose. At the time of the radiation accident in public domain, the exposed persons do not have any dosimeter. That is why it becomes essential to measure the received doses retrospectively as early as possible. NREs included detonation of nuclear weapons, accidents/sabotage of nuclear facilities, exposure/dispersal of radioactive materials and accidents during handling of radioactive materials. The worst nuclear accident to date was the Chernobyl disaster that occurred in Ukraine on 24 April 1986, wherein 56 people were killed directly. It caused an estimated 4,000 additional cases of fatal cancer. [1],[2],[3] Radioactive fallout from the Chernobyl accident concentrated over or near Belarus, Ukraine and Russia, and at least 3, 50, 000 people were forcibly evacuated and resettled away from these areas. Other serious nuclear and radiation accidents include the Mayak disaster, [4],[5] Soviet submarine K-431 accident, Soviet submarine K-19 accident, [6],[7],[8],[9] Three Mile Island accident in Brazil, [10] Costa Rica radiotherapy accident, [11] Windscale fire, [12] Chalk River accidents, [13],[14] Zaragoza radiotherapy accident, [15] exposure to 137 Cs in Goiania accident, [16] Church Rock Uranium Mill Spill in New Mexico, USA, in 1979, when the United Nuclear Corporation's Church Rock uranium mill tailings disposal pond breached its demand and the SL-1 accident. [17],[18]

In April 2010, the locality of Mayapuri, Delhi was affected by a serious radiological accident. A gamma irradiator (Gamma cell produced in 1968 by AEC in Canada) no longer in use since 1985 in a chemistry laboratory at Delhi University was auctioned on a scrap market of Mayapuri in February 2010. The orphan source was sent to one of the many scrap yards existing at Mayapuri and dismantled by workers not aware of the hazard related to the highly radioactive content of the machine. During the demolishing operations to recover metal scraps, the lead shielding protecting the radioactive source was removed and the source itself was damaged. As a consequence, eight persons were directly exposed to the gamma-rays of the 60 Co source contained in the Gamma cell. One exposed person died while two others were severely affected. A national radiation emergency response team in charge of the remediation of the place where the tragedy occurred recovered most of the cobalt-60 needles contained in the source.

Techniques for early biodosimetric assessment and diagnosis of exposed occupational workers are well established. Developments of inherent biomarkers of radiation are a priority area of radiation research. Mostly, studies are emphasized on environmental or industrial accidents and clinical response to radiation therapy treatment. If a radiation accident takes place, a large population can be exposed to radiation. Ionizing radiation (IR) has a sufficient amount of energy, which can damage body parts and obstruct normal body physiology. Those cells that are dividing at a faster rate are much more sensitive toward IR, e.g., hematopoietic system, gonadal cells and developing embryo. Radiation damages the cells either through ionization or excitation of the molecules. Nuclear accidents may cause whole body, localized or partial body exposure, internal contamination, external contamination and contaminated burns and wounds. [19],[20]

Absorbed radiation in the body can be assessed through the dosimetry. Assessment of radiation doses can help in identification of the exposed individuals within the population and to predict health effects. Cytogenetic analysis of the peripheral blood lymphocytes is a long-established gold standard technique. It is a biomarker of IR exposure, but it requires large time and trained workers for analysis. To overcome this problem, many other non-invasive or minimally invasive methods have been developed, such as different metabolites in body tissue and fluids, different cytokines, dicentric assay and radiation-induced apoptosis. [21],[22]

IR is a form of energy that is basically of two types. One kind is particulate radiation that involves charged or uncharged fast-moving particles that have both energy and mass. Particulate radiation is primarily produced by disintegration of unstable atoms. The second basic type of radiation consists of electromagnetic radiation, with only energy and no mass (e.g., radio waves, microwaves, infrared waves, ultraviolet rays, gamma rays, X-rays). [23] The amount of IR absorbed per unit mass by body is called dose. It is the most important physical quantity facilitating evaluation of biological response after the radiation exposure. After interaction of living matter with radiation, energy directly delivers to the atoms and molecules of the body. [24],[25],[26] Linear energy transfer (LET) is the energy deposited per unit of the path length of radiation. Equal amount of high LET radiation particulates like a-particles, electrons, protons, neutrons and low LET like X-rays and g-rays absorbed by the body do not produces the same level of biological response. High LET causes direct action of radiation because, after interaction, it ionizes the target molecules and initiate a chain of events to produce biological response. Low LET particularly interacts with other molecules like water and produces free radicals that can diffuse to other target molecules and damage them. [27]

Early radiation lethality attributes to a specific and high-density exposure to radiation. Soon after irradiation, prodromal radiation syndrome appears, which lasts for a limited period of time. It includes nausea, vomiting, anorexia and central nervous system impairment. The appearance of acute radiation syndrome, such as vomiting, is directly dependent on the radiation dose to an overexposed person. Exposure of more than 2 Gy causes reddening of the skin, or initial erythema, which appears within a few hours to a few days and lasts only for 1 or 2 days. This information concerns either partial- or whole-body exposure. [28] Some additional changes such as desquamation, bullae formation or even skin sloughing may occur after exposure. The circulating lymphocytes are one of the most radiosensitive cells, and these are early response biomarkers for radiation dose assessment. The use of blood cell changes after whole-body radiation exposures are easily available bio-indicators of injury. Peripheral blood lymphocyte counts declines approximately 50% over 12 h from the normal value (1.4 Χ 10 9 /L), indicating severe radiation exposure [29] [Table 1].
Table 1 :Radiation biodosimetry technique comparison for ionizing radiation

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   Biomarkers of IR Top


At the time of any accidental radiation exposure or nuclear warfare, when physical dosimetry is absent, dose estimates and determination must be based on biological markers (biodosimetry). These are called biomarkers of exposure. Radiation damage can occur at both local and systemic levels. Biological response to a given radiation dose varies according to variation in age, health and gender. Location of the radioactive contamination and its information inside the body and estimation of the dose is based on the personnel dosimeters. During the last decade, there was great interest in identification of the biomarkers in response to radiation. Studies on biomarkers can also help in understanding the long-term risk of both acute and chronic exposure. [30],[31],[32] The practical applicability and usefulness of biomarkers depends on a number of characteristics, such as number of affected persons, time period of radiation exposure, collection of sample & analysis and reporting of result. After any radiation accident, dosimetry is required as soon as possible for medical triage and assigning victims to their proper treatment. Some biomarker assays require a very short time for their assessment, from hours to days after exposure, while few biomarkers can persist for years. An ideal biomarker should be specific for IR exposure, but, unfortunately, this depends on various factors. [33]

Exposure to IR shows a combination of many consequences, such as early physical symptomatology at the prodromal stage of the acute radiation syndrome (ARS), lymphocyte counts, cytogenetic biomarkers, metabolic and serum components, urinary components and somatic mutation [34] [Figure 1].
Figure 1 :Radiation responsive biomarkers

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Early physical symptomatology of the ARS

After total body irradiation (TBI), prodromal stage symptoms provide a rough estimation of the amount of the radiation dose received. It occurs within minutes to 24 h after irradiation and is lost within a limited period, which includes nausea (1.4 Gy), vomiting (1.8 Gy), diarrhoea (2.3 Gy) and anorexia (0.97 Gy). The time of onset of these symptoms and severity can be related to the dose and quality of the radiation dose received. A latent period occurs between the end of the prodromal symptoms and the onset of the later physiological complications (hematopoietic and gastrointestinal). Duration and severity are directly related to the dose received, while the onset and latency are inversely related to the dose. If the radiation dose is greater than 5.5 Gy, then it can cause high lethality, producing earlier physiological responses toward radiation. [35],[36]

Two other important radiation indicators are erythema and epilation. The threshold value for erythema is 3-4 Gy, which depends on irradiated skin area, while its median dose estimates is 6 Gy. [17],[19] Early-phase erythema appears within several to 24 h after irradiation while late erythema reappears after 2-3 weeks and lasts for several weeks. It depends on the quality of radiation and skin condition. Epilation occurs approximately 2 weeks after radiation doses larger than 2-3 Gy. Median lethal dose LD 50/60 (the dose that kills 50% of the exposed population) without any medical care is 60 days after the radiation exposure. In case of appropriate medical care, survival can be increased significantly. For earlier and probable treatment of radiation victims, medical personnel should rely heavily on clinical signs and biological dose assessment. [37]

Chromosomal aberration biomarkers of IR

Prodromal symptomatology of the radiation injury is the important biological dosimeter, but the multiple chromosomal aberrations arising in peripheral blood lymphocyte assay is the most precise method. Alterations in hematological responses are an early response biomarker for dose assessment and severity of acute radiation syndrome. Changes in blood cell counts after whole-body exposure are most suitable biomarkers for radiation injury. Depletion of peripheral blood lymphocyte cell counts around 50% over 12 h is an indicator of a potential severe radiation exposure. The total number of aberrations is directly related to the radiation dose absorbed. Dose-response curve for chromosomal aberration has been confirmed with in vitro and in vivo experiments. Such types of curves can be used for various types of radiation exposure. [38],[39],[40],[41]

Dicentric biomarker: Dicentrics and ring chromosomes (chromosome with two centromeres) are important biomarkers of the IR exposure, which are formed by asymmetrical interchromosomal exchanges. Formation of the dicentrics is directly related to the amount of the dose, and it is mostly used for biodosimetry. It is an exchange between the centromere pieces of two broken chromosomes, which, in its complete form, is accompanied by a fragment composed of the acentric pieces of these chromosomes. Particularly after high doses, multicentric configurations can be formed. Tricentrics are accompanied by two fragments, quadricentrics by three fragments, etc. The basic principle involves stimulation of isolated lymphocytes by phytohemagglutine (PHA) into mitosis and arrest of metaphase chromosomes using colchicines. Later scoring of dicentric chromosome aberration is performed in metaphase spreads. Dicentric chromosome formation is linearly related to the radiation dose, but it may be vary with the type of radiation. [23],[24] However, difference can also be seen in case of high dose-rate of X-ray and gamma ray, although the RBE for gamma and X-ray radiation is usually similar. Exposure to high-LET a-particles or median-LET neutrons is more damaging than low-LET exposure, e.g., X-rays and gamma rays. It is the most important point of concern before the measurement of the dose received and type of the radiation must be known. [25] Other important factors include age, prior exposure of individuals to carcinogens and the time interval at which sample collected. Dose detection limits by this method for in vivo exposure are closer to 0.5 Gy. Detection limit of radiation doses is 0.5 Gy. [42],[43],[44],[45],[46],[47],[48],[49]

Micronuclei biomarkers: Very low doses of IR, such as X-rays and gamma rays, might not produces double-strand DNA breaks, result in the formation of unstable chromosomal aberrations. High doses of radiation can cause double-strand breakage of DNA. Micronuclei are chromosomal fragments lacking centromeres, which are not included in the nuclei of the daughter cells at the anaphase of mitosis. These chromosomal fragments become unstable and form smaller satellite structures. It is a radiation-responsive biomarker for DNA damage the human population. Like other cytogenetic biomarkers, frequency of micronuclei is also used for retrospective dose assessment. Micronuclei show a linear dose-response curve relationship. It is sorted by cytokinesis-block micronucleous assay of peripheral blood lymphocytes. [50],[51],[52],[53],[54] In this method, cytochalsin B blocks the cytokinesis in cultured lymphocytes without inhibiting nuclear division. These cells produce binucleate cells rather than the two daughter cells to separate. Then, it becomes possible to distinguish between proliferating (following the first mitosis) and non-proliferating cells, and micronuclei (MN) should be scored only in binucleate cells. In an emergency situation, large-scale monitoring of the population in groups for unstable chromosome aberration becomes decisive. These biomarkers can be predominantly used as indicators of the mutagenic action of the IR. This retrospective dosimetry can provide information with respect to the development of diseases of different types and, primarily, on oncological health risk assessment. By using centromeric fluorescence in situ hybridization (FISH probes, acentric micronuclei can be score rapidly. The lower dose detection limit using this method is 0.1-0.3 Gy. [55],[56],[57],[58],[59]

Translocation: IR can cause various types of DNA damage that may lead to the stable chromosomal aberration. The cytogenetic biodosimetry method is sufficient and sensitive for the assessment of the condition of the cell's hereditary structures. Analysis of unstable chromosomal aberrations by the classical cytogenetic method of large groups of people exposed to IR after any nuclear accident becomes difficult because they degrade simultaneously. Translocation chromosomal aberration is stable and can also be used as biological dosimetry for dose assessment. Such type of chromosomal aberration is studied by FISH. The FISH method is the most promising cytogenetic method for biological dose assessment. An increased frequency of aberration is considered to be an indication for cancer health risk. The lower detection limit of the dose using this method is 0.1-0.25 Gy. [60],[61],[62],[63],[64]

Premature chromosome condensation: IR-induced damage can also be detected in the interphase cells by the premature chromosome condensation assay. In this method, test cells fused with the mitotic cells that transmit a signal for dissolution of the nuclear membrane cause condensation of the interphase chromosome. [65],[66] Condensation can be stimulated by polyethylene glycol (PEG). After that, cells are scored for mitosis process; if breakage occurs, then more than 46 chromosomes will appear in the interphase chromosomes. Chemical induction of PCC and FISH probes for chromosomal painting can increase the speed and accuracy of the assay. If the amount of the dose increases, then the number of the extra chromosome fragments also increases. [67],[68],[69]


   Somatic Cell Mutation Top


Markers of early biological effects (EBE) and altered structure function indicate that these are intermediates between exposure and disease. Cytogenetic damage and somatic cell mutations can be detected by the EBEs. markers indicate premalignant alterations in cell-cycle control. Somatic mutations in the marker loci of hematopoietic stem cells in response to radiation can be monitored as biological indicators of radiation dose. Various types of somatic mutations have been identified for the detection of radiation exposure, such as hemoglobin (Hb) and glycophorin A (gpa) variants in erythrocytes and mutations in HLA or hypoxanthine-guanine phosphoribosyl transferse (hprt) loci in T-lymphocytes. [70],[71]

gpa variant analysis: The gpa assay is carried out in erythrocytes mainly for retrospective dose assessment. Although human mature red blood cells do not have nuclei, mutations occur in hematopoietic progenitor cells of bone marrow. The mutant hematopoietic progenitor cells can persist for years in the bone marrow. Mutant phenotypic variations of RBCs are monitored among circulating cells. The GPA alleles encode the cell surface proteins that determine the M and N blood group antigens. In an M/N heterozygote, variant red blood cells expressing only one allele can be quantified rapidly by the flow cytometric method. But, this method of dose reconstruction can be applied only for heterozygotes, which constitute about 50% of the population. A high-dose response relationship has been found in atomic bomb survivors and victims of the Chernobyl accident. No dose-response relationship was found in Sellfield nuclear, which may be because of lower doses. The lower detection limit using the gpa variant analysis method is about 1-2 Gy. [72],[73],[74]

HPRT mutant variant analysis: The HPRT gene encodes enzymes that allow the phosphoribosylation of hypoxanthine and guanine as a precursor for DNA synthesis. It can also utilize purine analogs, e.g., 6-thioguanine, that can incorporate into the DNA and kill the cells. Mutant cells that lack this enzyme can grow in a higher concentration of 6-thioguanine, which are toxic to wild types of cells. Thus, functional inactivation of the HPRT gene is most extensively used in T-cell biodosimetry. The T-cell assay monitors mutations directly in circulating peripheral blood cells and allows mutant selection. This method allows the detection of the loss of a single allele. It shows a strong relationship between dose and induced mutations in atomic bomb survivors and radiation therapy patients. After lower dose exposure, there is an increase in the frequency of the HPRT mutant gene (e.g., various point and deletion mutations), but it can depend on time of sampling. There is an increase in size and frequency of deletions correlating with the dose. [31] The drawback of this assay is the length of time period that is required. This problem has also been overcome by either autoradiography or immunofluorescence assay that quantify in vivo HPRT mutations. HPRT mutant variant analysis can detect low-dose exposure situations (1-2 Gy). [75],[76],[77],[78]


   Protein Biomarkers Top


IR causes tissue-specific lesions, and they are hardly predictable. These alterations may arise either after months or years of exposure. Protein biomarkers of radiation exposure are the fundamental relevance for the therapeutic strategies. Radiation-induced skin injury severity depends on dose received, exposed surface of skin and radiosensitivity of each individual. After exposure, the level of a number of proteins is up- and down- regulated at different time intervals. The oxidative stress response pathway responds to different physiological stresses and expresses many components, such as cytokines, growth factors, cell-cycle and gene regulatory proteins, apoptosis, cell-signalling proteins and DNA repair enzyme proteins. Increase or decrease in acute phase proteins after exposure to IR indicates the intensity of inflammation, e.g. complement components C3 and C9, apolipoprotein, a1-anti-trypsin and apolipoprotein A-1. [79]

Various serum proteins that are involved in the coagulation system also change after irradiation insult in mice, e.g. a1-anti-trypsin, antithrombin III and thrombospondin and Pzp proteins. MHC class I expression also increases, which indicates activation of the immune system after exposure. Decrease in zinc-a-2 glycoprotein indicates loss of body mass (cachexia). Protein biomarkers of skin injury for IR may be peroxidise, zinc-a-2 glycoprotein and compliment C9. Those serum proteins whose level of expression changes in the first week of exposure serve as diagnostic biomarkers. [80],[81]


   Gene Expression Biomarkers Top


After exposure of cells to DNA-damaging agents, a highly complex molecular response is raised, which is mediated through changes in the gene expression. Transcriptional response to genotoxic stress was first identified in yeast and later on in mammalian cells. The new advancements in functional genomics approaches simultaneously quantify the expression of thousands of genes at a single time of experiment. High-throughput gene expression methods are serial analysis of gene expression (SAGE), oligonucleotide arrays and cDNA arrays. Changes in mRNA occur at doses of <1 Gy, and it shows a linear dose-response relationship. cDNA microarray can identify a number of genes with linear dose-dependent elevations in peripheral blood lymphocytes after 3 days of radiation exposure between 0.2 and 2.0 Gy g-rays. Elevated gene expression is maintained for about 24 h in different organs after TBI in mice and human peripheral blood lymphocytes (PBL) with a dose range of 0.2-2.0 Gy. [82],[83],[84]


   Tooth Enamel and Fingernail Biomarker Top


Exposure of human beings to IR results in the creation of free radicals that cause damage to biomolecules such as protein, lipid and DNA, or may also induce oxidative stress. The life span of these unpaired electrons is very short (nanoseconds) in the aqueous environment of most biological tissues. These radiation-induced signals can be fixed for a long time in calcified tissues, e.g. teeth, bones and fingernails. The potential for using EPR to measure absorbed radiation doses was first recognized and reported by Brady and co-workers (1968). EPR-based radiation dosimetry techniques are non-invasive or minimally invasive techniques that do not require the evolution or processing needed for biologically based methods. Tooth enamel is the hardest inorganic component of the body. It contains 97% hydroxyapatite, 2% water and 1% organic compound. After radiation exposure, radiation-induced free radicals are entrapped in the lattice crystalline structure of the hydroxyapatite. It can be trapped here for months to years. The Electron Paramagnetic Resonance Dosimetry Technique can measure the concentration of the free radicals that are generated in response to radiation. Linear dose response relation has been established by this method. Fingernail and hair contains a-keratin into which free radicals are incorporated and can be measured by EPR dosimetry. [85],[86]


   Nucleic Acid Biomarker Top


IR causes damage of DNA, both double-stranded or single breaks, and DNA cross linkages corresponding to dose received. Radiation creates lesions in the DNA that lead to the mutation. In response to DNA damage, a number of genes express for their repair, and the rate of repair is dependent on many factors such as the cell type, the age of the cell and the extracellular environment. A cell that has accumulated a large amount of DNA damage or one that no longer effectively repairs damage incurred to its DNA can enter one of three possible states: an irreversible state of dormancy (e.g., senescence), cell suicide (such as apoptosis or programmed cell death) and unregulated cell division, which can lead to the formation of a tumor that is cancerous.

There are five main types of damage to DNA due to endogenous cellular processes:

  1. Oxidation of bases [e.g., 8-oxo-7,8-dihydroguanine (8-oxoG)] and generation of DNA strand interruptions from reactive oxygen species.
  2. Alkylation of bases (usually methylation), such as formation of 7-methylguanine, 1-methyladenine, 6-O-methylguanine.
  3. Hydrolysis of bases, such as deamination, depurination and depyrimidination.
  4. "Bulky adduct formation" (i.e., benzo(a)pyrene diol epoxide-dG adduct).
  5. Mismatch of bases due to errors in DNA replication, in which the wrong DNA base is stitched into place in a newly forming DNA strand or a DNA base is skipped over or is mistakenly inserted.


Damage caused by exogenous agents can be in many forms, as depicted in the following paragraphs:

UV-B light causes crosslinking between adjacent cytosine and thymine bases, creating pyrimidine dimers (direct DNA damage). UV-A light creates mostly free radicals that damage DNA (indirect DNA damage). IR such as that created by radioactive decay or in cosmic rays causes breaks in DNA strands (induced damage). Thermal disruption at elevated temperature increases the rate of depurination (loss of purine bases from the DNA backbone) and single-strand breaks. For example, hydrolytic depurination is seen in the thermophilic bacteria that grow in hot springs at 40-80΀C. The rate of depurination (300 purine residues per genome per generation) is too high in these species to be repaired by the normal repair machinery. Hence, the possibility of an adaptive response cannot be ruled out. Industrial chemicals such as vinyl chloride and hydrogen peroxide and environmental chemicals such as polycyclic hydrocarbons found in smoke, soot and tar create a huge diversity of DNA adducts - ethenobases, oxidized bases, alkylated phosphotriesters and crosslinking of DNA.

Decrease in the level of 53BP1 DNA repair protein in response to increase of g-radiation dose is an efficient biomarker for the detection of double-stranded DNA breaks. ATM (ataxia telengiectasia mutated) gene phosphorylation is also an indicator of DNA damage. 8-OHdG (7, 8-dihydro-8-oxo-deoxyguanosine) is commonly regarded as a good marker of oxidative DNA damage [87],[88],[89] [Figure 2].
Figure 2 :Cellular responses to ionizing radiation

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   Radiation Metabolomic Biomarkers Top


Metabolomics involves development of rapid high-throughput and minimally invasive radiation biodosimetry. It involves characterization of the metabolic components such as cells, tissues, small molecule components and organs. Thymidine (dT) concentrations after 24 h of radiation exposure increase significantly. Three other purine biomarkers of radiation exposure involving 2'-deoxyxanthosine, xanthine and xanthosine concentration are elevated in the urine of g-irradiated mice. [90]

Normal urine metabolites excreted are the low-molecular weight (<600 Da) intermediates and end products of metabolism that are mainly acids, phenols, phenolic acids and amino acids. Purely basic compounds generally are not excreted in urine without metabolism to acidic or Zwitterionic metabolites. Therefore, urine contains a host of anionic substances, with humans excreting approximately 60 mmol organic acids per day, with a mean urinary pH of approximately 6.0. It involves measuring of small-molecule metabolite profiles and fluxes in biological matrices after genetic modification or exogenous challenges, and it has become an important component of systems biology, complementing genomics, transcriptomics and proteomics. Increases and decreases in intermediary metabolites can be considered due to advances in analytical chemical platforms for metabolite detection and quantification and in chemometric software for performing multivariate data analysis on very large data sets. As such, metabolomics can provide an unbiased evaluation of upward and downward metabolite fluxes. Negative ion mass spectrometry is well suited to record the fluxes of urinary organic anions. [91]


   Amino Acid Biomarkers Top


The concentrations of different amino acids increase after irradiation within different time intervals, such as creatine, histamine, taurine and prostaglandins. Creatine/creatinine ratio after 3 days of exposure to X-rays depends on the dose (0.25-6.5 Gy) in rats. Radiation can cause creatinurea in humans, but it is not a specific biomarker of radiation because exercise, muscular atrophy, trauma and starvation can elevate its urine level. Blood level of histamines increases in those patients who receive radiation therapy. The level of glycine and hydroxyproline amino acids is elevated up to ten-times in human urine during the first week after receiving 25-180 rem and plasma prostaglandins also increase in response to radiation. Taurine, a non-essential amino acid, is excreted in excess in exposed individuals. [92],[93]


   Conclusion Top


In the field of radiation dosimetry, it is a general consensus that there is yet no perfect biomarker of radiation. At the time of emergency, use of complimentary methods of dosimetry is the best appropriate method. In case of acute whole body exposure, measurement of chromosomal aberration is best suited for triage and further treatment of victims. At present, protein and gene expression profiling biomarkers are most widely used for absorbed dose assessment. Radiation metabolomics is a highly promising field that involves non-invasive measurement of radiation-induced changes in the metabolites.

 
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