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      Cardiovascular Changes in Atherosclerotic ApoE-Deficient Mice Exposed to Co60 (γ) Radiation

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          Abstract

          Background

          There is evidence for a role of ionizing radiation in cardiovascular diseases. The goal of this work was to identify changes in oxidative and nitrative stress pathways and the status of the endothelinergic system during progression of atherosclerosis in ApoE-deficient mice after single and repeated exposure to ionizing radiation.

          Methods and Results

          B6.129P2-ApoE tmlUnc mice on a low-fat diet were acutely exposed (whole body) to Co60 (γ) (single dose 0, 0.5, and 2 Gy) at a dose rate of 36.32 cGy/min, or repeatedly (cumulative dose 0 and 2 Gy) at a dose-rate of 0.1 cGy/min for 5 d/wk, over a period of 4 weeks. Biological endpoints were investigated after 3–6 months of recovery post-radiation. The nitrative stress marker 3-nitrotyrosine and the vasoregulator peptides endothelin-1 and endothelin-3 in plasma were increased (p<0.05) in a dose-dependent manner 3–6 months after acute or chronic exposure to radiation. The oxidative stress marker 8-isoprostane was not affected by radiation, while plasma 8-hydroxydeoxyguanosine and L-3,4-dihydroxyphenylalanine decreased (p<0.05) after treatment. At 2Gy radiation dose, serum cholesterol was increased (p = 0.008) relative to controls. Percent lesion area increased (p = 0.005) with age of animal, but not with radiation treatment.

          Conclusions

          Our observations are consistent with persistent nitrative stress and activation of the endothelinergic system in ApoE−/− mice after low-level ionizing radiation exposures. These mechanisms are known factors in the progression of atherosclerosis and other cardiovascular diseases.

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          Most cited references47

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          Radiation exposure and circulatory disease risk: Hiroshima and Nagasaki atomic bomb survivor data, 1950-2003

          Objective To investigate the degree to which ionising radiation confers risk of mortality from heart disease and stroke. Design Prospective cohort study with more than 50 years of follow-up. Setting Atomic bomb survivors in Hiroshima and Nagasaki, Japan. Participants 86 611 Life Span Study cohort members with individually estimated radiation doses from 0 to >3 Gy (86% received <0.2 Gy). Main outcome measures Mortality from stroke or heart disease as the underlying cause of death and dose-response relations with atomic bomb radiation. Results About 9600 participants died of stroke and 8400 died of heart disease between 1950 and 2003. For stroke, the estimated excess relative risk per gray was 9% (95% confidence interval 1% to 17%, P=0.02) on the basis of a linear dose-response model, but an indication of possible upward curvature suggested relatively little risk at low doses. For heart disease, the estimated excess relative risk per gray was 14% (6% to 23%, P<0.001); a linear model provided the best fit, suggesting excess risk even at lower doses. However, the dose-response effect over the restricted dose range of 0 to 0.5 Gy was not significant. Prospective data on smoking, alcohol intake, education, occupation, obesity, and diabetes had almost no impact on the radiation risk estimates for either stroke or heart disease, and misdiagnosis of cancers as circulatory diseases could not account for the associations seen. Conclusion Doses above 0.5 Gy are associated with an elevated risk of both stroke and heart disease, but the degree of risk at lower doses is unclear. Stroke and heart disease together account for about one third as many radiation associated excess deaths as do cancers among atomic bomb survivors.
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            Radiation-induced bystander effects--implications for cancer.

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              Noncancer disease incidence in atomic bomb survivors, 1958-1998.

              We examined the relationships between the incidence of noncancer diseases and atomic bomb radiation dose using the longitudinal data for about 10,000 Adult Health Study (AHS) participants during 1958-1998. The current report updates the analysis we presented in 1993 with 12 additional years of follow-up. In addition to the statistically significant positive linear dose-response relationships detected previously for the incidence of thyroid disease (P < 0.0001), chronic liver disease and cirrhosis (P = 0.001), and uterine myoma (P < 0.00001), we also found a significant positive dose response for cataract (P = 0.026), a negative linear dose-response relationship for glaucoma (P = 0.025), and significant quadratic dose-response relationships for hypertension (P = 0.028) and for myocardial infarction among survivors exposed at less than 40 years of age (P = 0.049). Significant radiation effects for calculus of the kidney and ureter were evident for men but not for women (test of heterogeneity by sex: P = 0.007). Accounting for smoking and drinking did not alter the results. Radiation effects for cataract, glaucoma, hypertension, and calculus of the kidney and ureter in men are new findings. These results attest to the need for continued follow-up of the aging A-bomb survivors to fully elucidate the effects of radiation exposure on the occurrence of noncancer diseases.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                20 June 2013
                : 8
                : 6
                : e65486
                Affiliations
                [1 ]Analytical Biochemistry and Proteomics Laboratory, Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada
                [2 ]Inhalation Toxicology Laboratory, Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada
                [3 ]Radiological Protection Research and Instrumentation Branch, Atomic Energy Canada Limited, Chalk River Laboratories, Chalk River, Ontario, Canada
                [4 ]Radiation Protection Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada
                [5 ]Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada
                Kagoshima University Graduate School of Medical and Dental Sciences, Japan
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: PK RV HW RM MH AT SW. Performed the experiments: PK RV EB AS PG HW RM SW. Analyzed the data: PK RV EB AS SW. Wrote the paper: PK RV.

                Article
                PONE-D-12-35331
                10.1371/journal.pone.0065486
                3688723
                23840332
                5ab7c4e4-4b94-4e37-b6ce-2f3d83c74c04
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 4 November 2012
                : 26 April 2013
                Page count
                Pages: 10
                Funding
                The work was supported by operational funds at Health Canada and AECL (Atomic Energy of Canada Limited). Outside of the investigators directly involved in the study, the institutional funders had no direct role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Biophysics
                Radiation Biophysics
                Radiation Effects
                Radiation Exposure
                Model Organisms
                Animal Models
                Mouse
                Chemistry
                Nuclear Chemistry
                Radiation Chemistry
                Medicine
                Cardiovascular
                Atherosclerosis
                Diagnostic Medicine
                Pathology
                General Pathology
                Biomarkers
                Oncology
                Basic Cancer Research
                Oxidative Damage
                Physics
                Biophysics
                Radiation Biophysics
                Radiation Effects
                Radiation Exposure
                Nuclear Physics
                Radiation
                Gamma Radiation

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                Uncategorized

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