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Year : 2015  |  Volume : 11  |  Issue : 3  |  Page : 549-557

Candidate gene biodosimeters of mice and human exposure to ionizing radiation by quantitative reverse transcription polymerase chain reaction

1 Department of Medical Physics and Biomedical Engineering, Tehran University of Medical Sciences, Tehran, Iran
2 Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Date of Web Publication9-Oct-2015

Correspondence Address:
Alireza Shirazi
Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran University of Medical Sciences, Tehran
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Source of Support: Part of this study was supported by grant numbers 25111 and 28688 from vice chancellor of research at Tehran University of Medical Sciences, Conflict of Interest: None

DOI: 10.4103/0973-1482.160912

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 > Abstract 

Understanding of cellular responses to ionizing radiation (IR) is essential for the development of predictive markers useful for assessing human exposure. Biological markers of exposure to IR in human populations are of great interest for assessing normal tissue injury in radiation oncology and for biodosimetry in nuclear incidents and accidental radiation exposures. Traditional radiation exposure biomarkers based on cytogenetic assays (biodosimetry), are time-consuming and do not provide results fast enough and requires highly trained personnel for scoring. Hence, the development of rapid biodosimetry methods is one of the highest priorities. Exposure of cells to IR activates multiple signal transduction pathways, which result in complex alterations in gene-expression. Real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR) has become the benchmark for the detection and quantification of RNA targets and is being utilized increasingly in monitoring the specific genes with more accurately and sensitively. This review evaluates the RT-qPCR as a biodosimetry method and we investigated the papers from 2000 up to now, which identified the genes-expression related the DNA repair, cell cycle checkpoint, and apoptosis induced by ionization radiation in peripheral blood and determined as biodosimeters. In conclusion, it could be say that RT-qPCR technique for determining the specific genes as biodosimeters could be a fully quantitative reliable and sensitive method. Furthermore, the results of the current review will help the researchers to recognize the most expressed genes induced by ionization radiation.

Keywords: Biodosimetry, gene-expression, ionizing radiation, quantitative reverse transcription-polymerase chain reaction

How to cite this article:
Rezaeejam H, Shirazi A, Valizadeh M, Izadi P. Candidate gene biodosimeters of mice and human exposure to ionizing radiation by quantitative reverse transcription polymerase chain reaction. J Can Res Ther 2015;11:549-57

How to cite this URL:
Rezaeejam H, Shirazi A, Valizadeh M, Izadi P. Candidate gene biodosimeters of mice and human exposure to ionizing radiation by quantitative reverse transcription polymerase chain reaction. J Can Res Ther [serial online] 2015 [cited 2022 Aug 16];11:549-57. Available from: https://www.cancerjournal.net/text.asp?2015/11/3/549/160912

 > Introduction Top

Ionizing radiation (IR) is a ubiquitous and important environmental hazard, that, at lowest dose exposures, causes little acute health effects and at higher dose exposures, can cause acute radiation syndrome and death. [1],[2],[3] accidental or incidental exposure to IR can be unforeseen and devastating [4] and the response to any radiation accident or incident requires accurate and rapid assessment of the doses received by individuals, [5] rapid and accurate evaluation of exposure dose plays an important role in early triage, diagnosis and medical treatment of the victims during emergency response efforts in nuclear accidents. [6] In cases of accidental exposure, physical dosimetry is rarely available, it is sometimes absent or fails to deliver complete information about the exposure dose, [7] and biological dosimetry, based on the scoring of chromosomal damage (specially dicentric damage) in blood samples, plays a key role and is gold-standard for radiation biodosimetry. In spite of the dicentric assay is accurate and sensitive, it is a labor-intensive assay and time consuming and do not provide results fast enough to identify people who would benefit the most from medical intervention immediately after irradiation. [5],[8],[9],[10] Many attempts have been made to improve dosimetry using different end-points that could provide individual dose estimates more rapidly with greater sample throughput would be of great value in incident management. Study on changes in gene-expression following IR exposure [11],[12] is one of the these attempts which is based on the knowledge that exposure to IR induces complex changes at the level of RNA transcripts. [5] Some studies have suggested the development of gene-expression profiles in peripheral blood lymphocytes (PBLs) as an alternate approach to radiation biodosimetry. [13],[14],[15],[16] For radiation biodosimetry purposes, a whole blood sample easily can provide prospective molecular biomarkers. [14],[17]

Gene-expression is sensitive to environmental factors, the analysis of gene-expression profiling of peripheral blood cells, particularly lymphocytes, has been used to assess the presence of certain diseases because of that, many radiobiologists have focused on gene-expression profiling analysis to find biomarkers that are suitable for assessment of individual exposure doses under different exposure conditions, [7],[10],[18],[19],[20],[21],[22],[23] Recent reports have shown that gene-expression signatures induced by IR are specific, durable, and accurate in prediction of exposure doses in both mice and humans [Table 1]. [24],[25],[26]
Table 1: Various studies presenting the gene expression markers to assess human and rat radiation exposure

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 > DNA Damage: Response and Repair Functions Top

DNA is a principal cellular target for radiation-induced cell killing, and the ability of the cell to repair DNA damage determines its fate after exposure. DNA repair process is controlled by a specific set of genes encoding the enzymes that catalyze cellular responses to DNA damage. [27] genes involved in cellular DNA damage response and repair functions, including DNA repair, cell cycle functions and apoptosis were identified as priority candidates for radiation biodosimetry to detect radiation exposure in human populations (nuclear incidents and accidental radiation exposures) [Figure 1], monitoring the progress of radiation oncology for assessing normal tissue injury, and even for predicting outcome early in a treatment regimen. [8],[13],[14],[26],[28],[29] Various forms of DNA damage are induced by IR, including single strand breaks (SSBs) and double strand breaks (DSBs), DNA-protein cross-links, oxidized bases and bulky lesion. [30],[31] DNA repair plays a critical role in protecting normal individuals from the effects of radiation. There are several DNA repair mechanisms to respond to different types of DNA damage.
Figure 1: Cellular DNA damage response

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 > Dna repair pathways Top

DNA DSBs are the most lethal lesion induced by IR and their repair is more difficult than that of other types of DNA damage. [32],[33],[34],[35],[36],[37],[38] It is well known that, the H2AX histone protein is phosphorylated after DNA DSBs, and the protein gamma-H2AX (γ-H2AX) is taken as a marker of DNA DSBs. [39] there are two distrinct and complementary pathways for DSB repair: Homolologous recombination (HR) pathway, [40],[41],[42] which is only available S and G2 phases when a sister chromatid can be used as a template for the repair reaction and nonhomologous end joining pathway, which links together the two ends of broken DNA by direct ligation and involves the majority of DSB repair. [43],[44],[45] These are quite different in the genes involved, the position in the cell cycle where they primarily act and in the speed and accuracy of repair. [37],[46],[47],[48],[49],[50],[51],[52],[53],[54] Most oxidative DNA damage induced by gamma radiation is repaired by the base excision repair (BER) pathway. [55] BER is the predominant repair pathway, which is responsible for the removal of damaged bases and SSBs through gap-filling by DNA polymerase and ligation of DNA ends. [27],[55],[56] Defects in BER have been shown to result in hypersensitivity to IR. [56] Nucleotide excision repair (NER) is the only mechanism for removing bulky adducts from DNA, but it repairs essentially all DNA lesions, and thus, in addition to its main function, it plays a back-up role for other repair systems. [57] However, NER appears not to be important for ionization radiation since cells with mutation or deletion in genes on this pathway are not more sensitive to IR. [14],[46],[58],[59],[60],[61]

 > Cell cycle checkpoints Top

Treatment of cells with IR causes delays in the movement of cells through the G1, S, and G2 phases of the cell cycle. [62] This occurs through the activation of DNA damage checkpoints, which are specific points in the cell cycle at which progression of the cell into the next phase can be blocked or slowed. [46] Initially, these checkpoints were described as delays that would allow cells more time to repair DNA damage. In G1 phase checkpoint, cells that are irradiated will exhibit a delay prior to entry into S phase that is dependent on both p53 and p21. Cells that are in S phase at the time of irradiation demonstrate a dose-dependent reduction in the rate of DNA synthesis and as a result, the overall length of time that cells need to replicate their DNA substantially increases. G2 checkpoint is divided into two steps, G2 early checkpoint, and late checkpoint. G2 early checkpoint is activated by relatively low doses of radiation (1 Gy is enough) and results in a block of cell cycle progression at the end of G2 and movement into mitosis. Unlike the early G2 checkpoint, this delay is strongly dose-dependent, and can last many hours after high doses of radiation and is applicable to cells that have been previously irradiated while in the G1 or S phases. [46]

 > Programmed Cell Death (Apoptosis) Top

p53 is one of the most common tumor suppressor genes whose function is to regulate genes that control both cell cycle checkpoints and programmed cell death (apoptosis). [46] Following DNA damage, ATM phosphorylates both p53 and MDM2. Direct phosphorylation of p53 by ATM leads to its activation as a transcription factor and thus the upregulation of its many target genes. These target genes include the pro-apoptotic genes BAX and PUMA (BBC3), which in certain cells can be sufficient to induce cell death. [46]

 > Reverse transcription polymerase chain reaction Top

Reverse transcription polymerase chain reaction (RT-PCR) is a variant of PCR. This laboratory technique is commonly used in molecular biology to detect and quantify the mRNA expression. [63] In RT-PCR, however, RNA strand is first reverse transcribed into its DNA complement (complementary DNA) using the enzyme reverse transcriptase, and the resulting cDNA is amplified using traditional PCR. [64]

Real-time reverse transcription polymerase chain reaction, also called quantitative reverse transcription PCR (RT-qPCR) is used to measure the quantity of a RT-PCR product. RT-qPCR is widely and increasingly used because of its high sensitivity, good reproducibility, and wide dynamic quantification range and fully reliable quantitative method. [65],[66],[67],[68] It is the most sensitive method for the detection and quantification of gene-expression changes (GECs) as biomarkers offers a potential efficient biological dosimetry tool in radiation therapy and early-response accident biodosimetry. This method is becoming widespread methodology in diagnostic purposes and relatively noninvasive procedures, small-sampling requirements, automation potential, and broad dose-range assessment capability. [17],[67],[69],[70],[71],[72],[73],[74],[75],[76],[77],[78],[79],[80],[81],[82]

 > Expression of Genes Related To DNA Repair, Cell Cycle Checkpoint and Apoptosis Top

X-ray repair cross complementing gene 1 (XRCC1) and hOGG1 are an essential DNA repair genes in BER pathway. XRCC1 gene involved in rejoining DNA strand breaks, therefore, the alteration in XRCC1 mRNA expression would affect repair function for DNA strand breaks and the alteration in hOGG1 mRNA expression will affect the repair function for oxidized bases including 8-oxodG and formamidopyrimidine (fapy) residues. [27] In 2006, Sudprasert et al. [27] investigated the effects of low-dose gamma radiation (5, 10, 20, 50 cGy) on expression of DNA repair genes in human blood cells (ex vivo), the study revealed a dose-dependent effect of gamma radiation on DNA damage. However interestingly, the results showed, increasing the gamma radiation decreased the mRNA expression of two repair genes, hOGG1 and XRCC1 determined by RT-PCR, with a significant decrease of expression being observed after exposure to 20 cGy. The observed decreases in both hOGG1 and XRCC1 repair gene-expression indicate that gamma radiation not only causes DNA damage but also affects the expression levels of relevant repair genes simultaneously.

The XPC gene is one of the transcriptionally regulated DNA repair genes (NER pathway) induced by both UV and IR [13],[14] as part of the p53-transmitted stress response. [83],[84] In 2007, Wiebalk et al. [85] investigated induction of XPC mRNA expression in PBLs of 99 prostate cancer patients 4 h after in vitro gamma irradiation with 5 Gy using reverse transcription of mRNA and quantitative real-time PCR. Inter-individual variation of XPC mRNA induction after ionization radiation was up to 20-fold and it was surprising because XPC is not primarily responsible for the repair of IR-induced DNA damage. However, ultimately, XPC is a good candidate gene as a biomarker.

Growth arrest and DNA damage gene 45 (GADD45) is specific genes that could induced by IR. GADD45 is recognized as a link between DNA repair and the p53-mediated cell cycle checkpoint to S-phase. [86] In 2002, Grace et al. [69] studied the GADD45 gene-expression after 24 and 48 h from ex vivo irradiation of whole blood at 1 Gy, 2 Gy, and 3 Gy exposures. Their results were shown the up-regulation of GADD45A (dose-dependent) and these data demonstrated that GADD45 could be used as a candidate gene-expression target for both radiation therapy and accident biodosimetry applications. In another study by the same researchers in 2003, [80] exposure to IR (1-3 Gy) after 48 h of repair from ex vivo experiment caused increased relative gene-expression for three genes: GADD45, DDB2 (XPE); links p53 response and DNA NER, [87] and BAX; proapoptotic gene and down-regulation of relative gene-expression for Mn-superoxide dismutase (Mn-SOD). Cyclin G and cyclin protein gene are cell cycle regulatory genes and TRAIL receptor 2 (TRAIL-R2) is an apoptosis-inducing gene and also, FHL2 (four and a half LIM domains 2) is a small GTPase family [88] and is involved in protein-protein interaction and transcriptional regulation, which is involved in apoptosis. In 2003, Kang et al. [16] identified TRAIL-R2, FHL2, cyclin G, cyclin protein genes that were well correlated with individual exposures and exposure doses. They studied on human PBLs ex vivo (5 donors) and in vitro (more than 32 donors). They examined the effect of time and dose on the response of each gene. These genes showed a dose-response for doses between 0.5 Gy and 4 Gy after 12 h (linear dose-response relationship); however, their dose responsiveness disappeared after 24 and 48 h. Nevertheless, they suggested these four genes are good candidates for potentially useful biomarkers of radiation exposure.

Cyclin dependent kinase inhibitor 1A (CDKN1A) is known to be an important effector of the p53-mediated G1 arrest in response to many stresses. [89] CDKN1A belongs to the family of cyclin-dependent kinase regulators, plays an important role in the regulation of the cell cycle and proliferation. [7] In 2004, Amundson et al. [13] studied GEC in peripheral white blood cells of radiotherapy patients. Bloods were drawn within 2 h before the initial radiation treatment, then 6 h after the first 1.5 Gy fraction, at 24 h, and at the same intervals after subsequent fractions (6 fractions). They showed the up-regulation of CDKN1A and DDB2 (XPE) and interestingly down-regulation of GADD45A. Finally, they suggested due to the CDKN1A and DDB2 are regulated by p53 in response to IR, this is a prominent role for the p53 pathway in the emerging gene-expression biomarker signature. In 2008, Paul et al. [10] developed gene-expression profiles for radiation biodosimetry. In this study, Human peripheral blood from ten healthy donors was irradiated ex vivo (0.5, 2. 5 and 8 Gy), and global gene-expression was measured 6 and 24 h after exposure. CDKN1A, SESN1 (induced by the p53 tumor suppressor and play a role in the cellular response to DNA damage and oxidative stress), PHPT1, BBC3 (PUMA) and FDXR were genes that related to cell cycle checkpoints and apoptosis genes. There was no significant difference between radiation responses of PBL from male or female donors for any of the genes tested. All genes showing increasing expression with increasing dose, but decreased the slope of the dose-response curve above 2 Gy.

Turtoi et al. in 2008 [7] identified the early radiation response genes (ERGs) in human lymphocytes after gamma radiation. Whole blood from a healthy human donor was exposed by 137 Cs gamma-radiations (absorbed dose: 1-4 Gy). Up-regulation of expression was observed in 15 genes: CD69 (CD69 molecule), CDKN1A, early growth response 1 (EGR1), early growth response 4 (EGR4), FLJ35725 (chromosome 4 ORF 23), hCG2041177 (hCG - human Celera1 Genome), hCG1643466.2, interferon-γ (IFN-g), ISG20 L (interferon stimulated exonuclease gene 20 kDa - like 1), c-JUN (jun oncogene), MDM2 (mouse double minute 2), MUC5B (mucine), PLK2 (polo-like kinase 2), RND1 (rho-family GTPase 1) and TNFSF9 (tumor necrosis factor superfamily member 9). At the end, a significant correlation between absorbed radiation dose and change in relative gene-expression was particularly evident for EGR1, EGR4 (both are early response genes required for the transition of cells from G1-to S-phase), IFN-γ (is responsible for anti-proliferative and immuno-regulating processes in human cells), c-JUN (interacts directly with specific DNA sequences to regulate their gene-expressions; it is also important in cell activation and proliferation) and TNFSF9 (its function is primarily focused on antigen presentation, co-stimulation of T-lymphocytes and induction of p53-mediated apoptosis). Results warrant the further investigation of these ERGs as potential biodosimetric markers.

In 2009, Mitsuhashi et al. [90] designed to discover blood biomarkers of cancer susceptibility using invasive multiple primary, single primary breast cancer and control subjects. Heparinized whole blood was incubated at 37°C for 2 h after 0-10 Gy (0.1, 1 and 10 Gy) of radiation, then cell cycle arrest marker CDKN1A and apoptosis marker BBC3 (PUMA) mRNA that most sensitive and universal marker mRNA for DNA damage in human whole blood were quantified. The results showed that radiation-induced both CDKN1A and BBC3 mRNA in a dose-dependent manner, and the degree of induction of CDKN1A was correlated with that of BBC3. Furthermore, the data of 0.1 Gy of radiation were correlated with those of 10 Gy for both CDKN1A and BBC3 respectively.

In 2011, Filiano et al. [91] analyzed gene-expression in radiotherapy patients and C57BL/6 Mice as a Measure of Exposure to IR. In this study, whole blood samples obtained from cancer patients undergoing TBI were used to identify potential biodosimetry genes. Time and dose-dependent changes in the expression of these biodosimetry genes were subsequently examined in vivo in mouse models. All patients received 2 Gy twice a day for three consecutive days (total dose of 12 Gy). Whole blood was collected prior to irradiation and at approximately 5, 23, and 48 h after the first fraction of radiation. Whole blood collected from nine healthy volunteers served as control samples. Eight genes (ACTA2, BBC3, CCNG1 (Cyclin G1), CDKN1A, GADD45A, MDK (Midkine), SERPINE1, TNFRSF10B (TRAIL-R2)) demonstrated increased expression in irradiated patient samples compared to baseline patient samples. Due to the fractionated nature of the TBI, it could not be determined whether the observed changes in gene-expression resulted from the accumulating dose of radiation or from increasing time after exposure. To elucidate the effects of radiation dose and time after exposure, these eight genes were evaluated further in an irradiated murine model. One gene (MDK) demonstrated no detectable expression. Two genes (ACTA2 and GADD45A) showed no significant increase in expression between nonirradiated and irradiated mice at any time. Five genes (BBC3, CCNG1, CDKN1A, SERPINE1 and TNFRSF10B) demonstrated significantly increased expression (P < 0.05) in irradiated mice compared with nonirradiated controls. In conclusion, of the eight radiation-responsive genes identified in patients, expression of five genes (BBC3, CCNG1, CDKN1A, SERPINE1, and TNFRSF10B) increased significantly in irradiated mice. Most of these genes are involved in apoptosis (BBC3 and TNFRSF10B) or cell cycle regulation (CCNG1 and CDKN1A) and have very well-characterized radiation responses.

In 2011, Kabacik et al. [5] studied on gene-expression following ionization radiation. In this study, they compared the gene-expression response to ionization radiation in human dividing lymphocytes in culture and peripheral blood leukocytes exposed ex vivo from three healthy normal donors. The goals of this study were to establish a panel of highly radiation responsive genes suitable for radiation dosimetry and to explore inter-individual variation in response to IR exposure. Blood and cultured lymphocytes were irradiated using three doses (0, 2 and 4 Gy of X-rays) and 2 times points (2 and 24 h postirradiation). The data provide evidence that there are a number of genes, which seem suitable for biological dosimetry using peripheral blood, including sestrin 1 (SESN1), growth arrest and DNA-damage inducible 45 alpha (GADD45A), cyclindependent kinase inhibitor 1A (CDKN1A), cyclin G1 (CCNG1), ferredoxin reductase (FDXR), p53 up-regulated mediator of apoptosis (BBC3) and MDM2 p53 binding protein homolog (MDM2). In conclusion, they discussed that these biomarkers could potentially be used for triage after large-scale radiological incidents and for monitoring radiation exposure during radiotherapy.

In 2011, Paul et al. [18] applied whole-genome microarray analysis to blood samples from a heterogeneous population of TBI patients (18 adult patient) and identified genes that respond to radiation exposure in vivo. Peripheral blood was collected before irradiation, at 4 h after the first 1.25-Gy fraction, and at 20-24 h after the first fraction. The 1-day samples included exposure to three 1.25-Gy fractions with approximately 4 h between fractions for a total dose of 3.75 Gy. They used RT-qPCR to validate the microarray results for seven genes (CDKN1A, FDXR, BBC3, PHPT1, SESN1, DDB2, and PCNA) that responded by microarray both in TBI patients and in their previous ex vivo irradiation studies [10] which showing good agreement between two measurement techniques.

In 2011, Li et al. [6] studied on radiation dose effect of DNA repair related gene-expression in mouse white blood cells. The goal of this study was to screen molecular biomarkers for biodosimetry from DNA repair-related gene-expression profiles. The mice were exposed to 2, 4, 6 or 8 Gy doses of Co-60 gamma-rays at 0.80 Gy/min dose rate and room temperature (23 ± 2°C). RNA was extracted from the peripheral blood of irradiated mice at 4, 8, 12, 24, and 48 h postirradiation. Finally, the mRNA transcriptional changes of 11 genes related to DNA damage and repair were detected using real-time RT-qPCR. CDKN1A, which has a regulatory role in S phase DNA replication and is known to be activated by the tumor protein p53 (TP 53), had the strongest upregulation in expression level out of the 11 genes investigated in this study. ATM is a predominantly nuclear protein that is involved in the DNA damage repair signal transduction process. ATM gene-expression decreased linearly with the all exposure dose ranges at 4-48 h postirradiation.

In 2012, Budworth et al. [8] employed the human blood ex vivo radiation model to investigate the expression responses of DNA repair genes in repeated blood samples from healthy, nonsmoking men and women exposed to 2 Gy of X-rays. The radiation response of 40 genes associated with various aspects of DNA damage response was surveyed. 12 genes were significantly modulated in transcript response 24 h after ex vivo exposure to 2 Gy exposure, relative to sham-irradiated samples. These included the cell cycle regulators (CDKN1A, GADD45A, PCNA, and CCNG1), apoptosis regulators (BAX, BBC3, and FDXR) and genes involved in specific DNA repair functions (XPC, DDB2, LIGI, POLH, and RAD51). Most of these genes (11 of 12) showed increased expression after exposure, ranging from 2.3-fold for LIG1-17-fold for FDXR. However, interestingly, RAD51, a key component of HR repair, was the only gene in this set that showed significant down regulation after exposure.

In a study from our laboratory, [92] we investigated the modulating effect of Melatonin as a radio-protector agent on gamma radiation-induced apoptosis and the differences in expression of BAX and Bcl-2 in rat PBLs. The rats were exposed to a whole body gamma radiation dose of 8 Gy by standard protocol with Co-60 Tele Therapy unit and blood samples were taken in 4 times points (4, 24, 48, and 72 h postirradiation) for measurement of BAX and Bcl-2 expression levels using RT-qPCR. The expression of BAX sharply increased (approximately 13-fold) at the initial 4 h relative to control group, and remained at the almost similar levels at 24, 48, and 72 h time points after radiation. On the other hand, the expression of Bcl-2 was decreased at initial 4 h compared to control group and sustained at the same level at 24, 48, and 72 h postirradiation. Based on this study, changes in BAX and Bcl-2 expression, as well as BAX/Bcl-2 ratio, could be representative of the molecular marker of radiation exposure.

In 2013, Omaruddin, et al. [4] examined the expression of CC3, MADH7 (Mothers against decapentaplegic homolog 7; also known as Smad7), and SEC PRO in blood samples of radiation therapy patients before and after radiotherapy (2 Gy) to assess their suitability as radiation exposure biomarkers. They showed that the expression of the SEC PRO gene was repressed in most of the patients and the MADH7 gene was found to be upregulated in most of the subjects and could serve as a molecular marker of radiation exposure.

In 2014, Srivastava et al. [93] considered an in vitro study in human blood leukocytes. They explored the effect of pretreatment with G-002M as a radioprotector on DNA damage response in irradiated human blood leukocytes. They selected four genes (DNA-PKcs, Ku80, ATM and 53BP1), which are involved in DNA repair signaling. Blood samples were exposed to a single dose of radiation (5 Gy) after an hour of G-002M pretreatment (1 mg/ml of blood). The 5 Gy radiation dose was selected based on the known lethal dose of whole body radiation for humans. The time intervals between radiation exposure and further processing of the samples were 30 min and 90 min. DNA-PKcs expression at 30-min and 90-min postirradiation was decreased by more than two-fold compared to the untreated samples. Ku80 expression at 30-min and 90-min postirradiation was increased and decreased compared to untreated samples, respectively. ATM gene-expression in response to radiation was two-fold higher at 30-min postirradiation and 3.8-fold higher after 90-min postirradiation compared to untreated samples. Expression of the 53BP1 gene was significantly higher in the radiation (5 Gy) group (2.5-fold at 30 min, 5-fold at 90 min postirradiation) compared with untreated samples. Although this study was done to determine a novel radio-protector but they potentially showed that the three genes (Ku80, ATM and 53BP1) which are related to DNA repair pathways could be a candidate as a biodosimetric markers.

 > Conclusion Top

In this review, we tried to determine the DNA repair genes as biological dosimeters which identified by real-time quantitative RT-PCR Technique. Gene-expression profiling is a potentially powerful and informative approach in biological dosimetry. Gene-expression signatures induced by IR, are specific, durable, and accurate in prediction of exposure doses in both mice and humans. Changes in gene-expression following IR exposure is based on the knowledge that exposure to IR induces complex changes in the RNA transcripts level.

As mentioned earlier, RT-qPCR is the most powerful method for quantifying cellular mRNA levels and widely used in expression profiling, to determine GECs as biomarkers. [94]

Biomarkers of IR exposure are useful in a variety of scenarios, such as medical diagnostic imaging, occupational exposures, and spaceflights. In contrast with physical dosimeters, radiation biomarkers have the potential to provide information on both radiation dose and radiation-induced changes of biological functions. {95}

In the present study, selected genes were divided into three main categories: DNA repair, cell cycle checkpoints, and apoptosis genes. Results indicate that among the genes related to DNA repair; XPC (one of the transcriptionally regulated DNA repair genes (NER pathway)), among the genes related to cell cycle checkpoints; CDKN1A (family of cyclin-dependent kinase regulators) and GADD45A (link between DNA repair and the p53-mediated cell cycle checkpoint to S-phase), and among the genes related to apoptosis; BAX and BBC3 could be present as an important candidate biodosimeteric markers [Table 2].
Table 2: Candidate gene biodosimeters

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As the GECs induced by ionization radiation are the fundamental of biodosimetry, therefore it could be suggested that these results of current study could be useful for investigating the effects of any agents (e.g., radio-protectors, radio-sensitizers, etc.) on the genes-expression.

 > Acknowledgments Top

The authors gratefully acknowledge Department of Medical Genetics, Tehran University of Medical Sciences for their great advice during this study.

 > References Top

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