Evaluation of the cytotoxicity and the genotoxicity induced by α radiation in an A549 cell line (original) (raw)
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Effects of alpha particle radiation on gene expression in human pulmonary epithelial cells
International Journal of Hygiene and Environmental Health, 2012
The general public receives approximately half of its exposure to natural radiation through alpha (␣)particles from radon ( 222 Rn) gas and its decay progeny. Epidemiological studies have found a positive correlation between exposure to 222 Rn and lung carcinogenesis. An understanding of the transcriptional responses involved in these effects remains limited. In this study, genomic technology was employed to mine for subtle changes in gene expression that may be representative of an altered physiological state. Human lung epithelial cells were exposed to 0, 0.03, 0.3 and 0.9 Gy of ␣-particle radiation. Microarray analysis was employed to determine transcript expression levels 4 h and 24 h after exposure. A total of 590 genes were shown to be differentially expressed in the ␣-particle radiated samples (false discovery rate (FDR) ≤ 0.05). Sub-set of these transcripts were time-responsive, dose-responsive and both time-and dose-responsive. Pathway analysis showed functions related to cell cycle arrest, and DNA replication, recombination and repair (FDR ≤ 0.05). The canonical pathways associated with these genes were in relation to pyrimidine metabolism, G2/M damage checkpoint regulation and p53 signaling (FDR ≤ 0.05). Overall, this gene expression profile suggests that ␣-particle radiation inhibits DNA synthesis and subsequent mitosis, and causes cell cycle arrest.
Induction of genomic instability in normal human bronchial epithelial cells by 238 Pu α-particles
Carcinogenesis, 1996
Pulmonary deposition of a-particle-emitting radon daughters is estimated to account for 10% of all lung cancer deaths in the USA. However, the nature and timing of early (preneoplastic) genetic alterations in radon-associated lung cancer are still relatively uncertain. The purpose of this investigation was to determine whether genomic instability occurs after exposure of cultured normal human bronchial epithelial cells to six equal, fractionated doses of a-particles (total doses 2-4 Gy). Two weeks after the final exposure, foci of phenotypically altered cells (PACs) were detected in 0, 63 and 77% of control, low and high dose cultures respectively. Of these, 18% exhibited extended life spans relative to unexposed controls. Elevated frequencies of binucleated cells (BNCs), a marker of genomic instability, were observed in 60 and 38% of the PAC cultures from the low and high dose groups respectively. The micronucleus assay also showed evidence of genomic instability in 40 and 38% of PAC cultures from the low dose and high dose groups respectively. No changes in microsateUite length, another marker of genomic instability, were detected in any of the PAC samples with the 28 markers used for this assay. However, one PAC (L2) showed a hemizygous deletion at 9pl3.3. Another PAC (H9), which exhibited the highest frequency of cells containing micronuclei (MN), exhibited a hemizygous deletion at 7q313. Each loss may represent a stable mutation that resulted either directly from irradiation or later in progeny of exposed cells because of a-particle-induced genomic instability. The fact that elevated levels of BNCs and MN were present in the progeny many generations after irradiation indicates that the genetic alterations detected with these two markers were not a direct consequence of radiation exposure, but of resulting genomic instability, which may be an early change after exposure to a-particles.
1997
Vahakangas et al. (10) and Bartsch et al. (12), did not find any cases with a codon 249 G → T mutation. 3 To whom correspondence should be addressed α-Particles, a type of high linear energy transfer (LET*) Radon-222, a decay product of uranium-238 and a source radiation, are emitted by the short-lived radon-222 progeny of high linear energy transfer (LET) α-particles, has been polonium-218 and polonium-214. Epidemiological studies implicated in the increased risk of lung cancer in uranium have implicated a high level of radon-222, a decay product of miners as well as non-miners. p53 mutation spectrum uranium-238, in the high incidence of lung cancer among studies of radon-associated lung cancer have failed to show uranium miners (14,15). A large proportion of available any specific mutational hot spot with the exception of a literature on the biological lesions produced by α-particles single study in which 31% of squamous cell and large cell suggests that double-strand breaks, large deletions and sister lung cancers from uranium miners showed a p53 codon chromatid exchange are the major abnormalities (16-18). 249 AGG arg → ATG met mutation. Although the results of In order to gain insight into the mutability of codons 249 laboratory studies indicate that double-strand breaks and and 250 of the p53 gene to α-particles, we have used a highly deletions are the principal genetic alterations caused by αsensitive genotypic mutation assay (19,20) to analyze αparticles, uncertainty still prevails in the description of particle-exposed normal human bronchial epithelial (NHBE) DNA damage in radon-associated human lung cancer. In cells. the present study, we have evaluated the mutability of p53 codons 249 and 250 to α-particles in normal human Materials and methods bronchial epithelial (NHBE) cells using a highly sensitive genotypic mutation assay. Exposure of NHBE cells to a Cell culture total dose of 4 Gy (equivalent to~1460 working level NHBE cells from a 15 year old male never smoker (strain 2129) and bronchial epithelial cell growth medium were purchased from Clonetics (San Diego, months in uranium mining) of high LET α-radiation CA). These cells were determined to be negative for adenovirus, hepatitis induced codon 249 AGG → AAG transitions and codon type B virus, human immunodeficiency virus, human papilloma virus and 250 CCC → ACC transversions with absolute mutation mycoplasma (21). The cryopreserved cells (passage 1) were cultured and frequencies of 3.6 ϫ 10 Ϫ7 and 3.8 ϫ 10 Ϫ7 respectively. This expanded in plastic flasks (Corning, NY) pre-coated with FNC Coating Mix mutation spectrum is consistent with our previous report (BRFF, Ijamsville, MD) (22). of radon-associated human lung cancer. Irradiation and post-irradiation cell culture Confluent NHBE cells (passage 2), cultured on 1.5 µm thick Mylar film (surface area 8 cm 2), were exposed over a 17 day period to a total dose of either 0 (unexposed control) or 4 Gy [equivalent to 1460 working level months
European Journal of Radiology, 2010
The aim of this study is to assess chromosomal damage in Tunisian hospital workers occupationally exposed to low levels of ionizing radiation (IR). Materials and Methods: The cytokinesis-block micronucleus (CBMN) assay in the peripheral lymphocytes of 67 exposed workers compared to 43 controls matched for gender, age and smoking habits was used. The clastogenic/aneugenic effect of IR was evaluated using the CBMN assay in combination with fluorescence in situ hybridization with human pan-centromeric DNA in all the exposed subjects and controls. Results: The study showed a significant increase of the micronucleus (MN) frequency in the lymphocytes of the exposed workers compared to the control group (13.63±4.9‰ vs. 6.52±4.21‰, p < 0.05). The centromere analysis performed in our study showed that MNs in hospital staff were predominantly centromere negative (72%) and the mean negative labeled micronucleus (C-MN) frequency was significantly higher in the exposed subjects than in the controls (9.04±4.57‰ vs. 1.17±0.77‰). The multivariate regression analysis, taking into account all confounding factors, showed that only the time of exposure to IR had a significant effect on the level of MNs and C-MN. Conclusion: The present study shows that chromosomal damage leading to the formation of micronucleated lymphocytes is more frequent in the hospital workers exposed to IR than in the controls, despite the low levels of exposure. The results of the study confirm the well-known clastogenic properties of ionizing radiation. In regards to health monitoring, detection of early genotoxic effects may allow for the adoption of preventive biological control measures, such as hygienic improvements in the workplace or reduction of hours of occupational exposure.
Mutation research. Fundamental and molecular mechanisms of mutagenesis, 2014
Murine embryonic C3H/10T½ fibroblasts were exposed to X-rays at doses of 0.2, 0.5, 1, 2 or 5Gy. To follow the development of radiation-induced genomic instability (RIGI), the frequency of micronuclei was measured with flow cytometry at 2 days after exposure and in the progeny of the irradiated cells at 8 and 15 days after exposure. Gene expression was measured at the same points in time by PCR arrays profiling the expression of 84 cancer-relevant genes. The micronucleus results showed a gradual decrease in the slope of the dose-response curve between days 2 and 15. The data were consistent with a model assuming two components in RIGI. The first component is characterized by dose-dependent increase in micronuclei. It may persist more than ten cell generations depending on dose, but eventually disappears. The second component is more persistent and independent of dose above a threshold higher than 0.2Gy. Gene expression analysis 2 days after irradiation at 5Gy showed consistent change...
Carcinogenicity of Ionizing Radiation: A Literature Review
Onkologiâ i radiologiâ Kazahstana, 2023
Relevance: According to WHO, malignant neoplasms rank second in population mortality structure due to a constantly increasing influence of technogenic factors that have a direct carcinogenic effect on the body and suppress defense mechanisms. Ionizing radiation plays a special role in the development of cancer. It is used in industry, agriculture, medicine, and scientific research as a diagnostic tool in modern healthcare and radiation therapy for cancer treatment. The consequences of radiation influence are not only the result of a direct effect on the body but also a delayed one through generations of parents and grandparents. According to the radiobiological hypothesis, any level of radiation, no matter how small, poses a risk of long-term consequences, including cancer, in exposed people and their descendants of the first two generations. That is, cancerous tumors are likely consequences of the influence of radiation. Despite various theories of the biological effect of low doses of ionizing radiation, most authors attach primary importance to DNA damage in the manifestation of genetic effects (the concept of non-threshold mutational action). The study aimed to highlight the role of ionizing radiation in tumorigenesis. Methods: Data from MEDLINE, Embase, Scopus, PubMed, and Cochrane Central Register of Controlled Trials was analyzed to select and analyze relevant information over the past 10 years using such keywords as "gamma irradiation," "spontaneous oncogenesis," and "prevention of oncogenesis." Results: Radiation exposure may increase the risk of cancer development due to epigenetic changes leading to increased genomic instability (GI) and/or specific suppression of tumor suppressor genes. Changes in the TP53 gene network expression occur; the most significant genes as predictors of carcinogenesis are ST13, IER3, BRCAI, LRDD, and MRAS. Epigenetic changes also influence individual susceptibility to radiation-induced cancer. In addition to the mutagenic effects of ROS and AFN, there is also evidence that oxidative stress plays a fundamental role in epigenetic modifications. Conclusion: As a result of radiation exposure, damage occurs that causes genetic and epigenetic changes, leading to changes in the level of protein expression due to changes in the methylation of cytosine residues in DNA, modification of histones, and regulation of microRNA expression.
Radiation signature on exposed cells: Relevance in dose estimation
World journal of radiology, 2015
The radiation is considered as a double edged sword, as its beneficial and detrimental effects have been demonstrated. The potential benefits are being exploited to its maximum by adopting safe handling of radionuclide stipulated by the regulatory agencies. While the occupational workers are monitored by personnel monitoring devices, for general publics, it is not a regular practice. However, it can be achieved by using biomarkers with a potential for the radiation triage and medical management. An ideal biomarker to adopt in those situations should be rapid, specific, sensitive, reproducible, and able to categorize the nature of exposure and could provide a reliable dose estimation irrespective of the time of the exposures. Since cytogenetic markers shown to have many advantages relatively than other markers, the origins of various chromosomal abnormalities induced by ionizing radiations along with dose-response curves generated in the laboratory are presented. Current status of th...
Role of Low-Level Ionizing Radiation in Multi-Step Carcinogenic Process
Health Physics, 1996
In view of our current understanding of experimental in vitro and in vivo studies, as well as of the epidemiological data, carcinogenesis is the result of many endogenous and exogenous factors. No single factor "causes" cancer. A number of extant theories of carcinogenesis and of ionizing radiation's role in the process have been reviewed. An integration of the stem cell theory, the theory of "oncogeny as partially blocked ontogeny," the initiatiodpromotiodprogression model of carcinogenesis, the oncogeneltumor suppressor gene theory, and mutatiodepigenetic theories of carcinogenesis was attempted by linking all of them with the process of intercellular communication. This integration was done by examining how extra-, intra-and inter-cellular communication might be affected by the current known facts of the types of radiationinduced biological effects, such as gene and chromosomal mutations, cell killing, including apoptosis and epigenetic alterations of gene expression. Finally, an examination of the possible role of low-level radiation in the multi-step carcinogenetic process, which might have given rise to the excess cancers attributable to radiation exposure in the survivors of the atomic bombs, was attempted.