| 1. |
- Babini, Gabriele, et al.
(författare)
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A systems radiation biology approach to unravel the role of chronic low-dose-rate gamma-irradiation in inducing premature senescence in endothelial cells
- 2022
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 17:3
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Tidskriftsartikel (refereegranskat)abstract
- PurposeThe aim of this study was to explore the effects of chronic low-dose-rate gamma-radiation at a multi-scale level. The specific objective was to obtain an overall view of the endothelial cell response, by integrating previously published data on different cellular endpoints and highlighting possible different mechanisms underpinning radiation-induced senescence.Materials and methodsDifferent datasets were collected regarding experiments on human umbilical vein endothelial cells (HUVECs) which were chronically exposed to low dose rates (0, 1.4, 2.1 and 4.1 mGy/h) of gamma-rays until cell replication was arrested. Such exposed cells were analyzed for different complementary endpoints at distinct time points (up to several weeks), investigating cellular functions such as proliferation, senescence and angiogenic properties, as well as using transcriptomics and proteomics profiling. A mathematical model was proposed to describe proliferation and senescence.ResultsSimultaneous ceasing of cell proliferation and senescence onset as a function of time were well reproduced by the logistic growth curve, conveying shared equilibria between the two endpoints. The combination of all the different endpoints investigated highlighted a dose-dependence for prematurely induced senescence. However, the underpinning molecular mechanisms appeared to be dissimilar for the different dose rates, thus suggesting a more complex scenario.ConclusionsThis study was conducted integrating different datasets, focusing on their temporal dynamics, and using a systems biology approach. Results of our analysis highlight that different dose rates have different effects in inducing premature senescence, and that the total cumulative absorbed dose also plays an important role in accelerating endothelial cell senescence.
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| 2. |
- D'Auria Vieira de Godoy, Paulo Roberto, et al.
(författare)
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Effect of dose and dose rate of gamma irradiation on the formation of micronuclei in bone marrow cells isolated from whole-body-irradiated mice
- 2021
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Ingår i: Environmental and Molecular Mutagenesis. - : Wiley. - 0893-6692 .- 1098-2280. ; 62:7, s. 422-427
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Tidskriftsartikel (refereegranskat)abstract
- It is well-known that the cytotoxicity and mutagenic effects of high dose rate (HDR) ionizing radiation (IR) are increased by increasing the dose but less is known about the effects of chronic low dose rate (LDR). In vitro, we have shown that in addition to the immediate interaction of IR with DNA (the direct and indirect effects), low doses and chronic LDR exposure induce endogenous oxidative stress. During elevated oxidative stress, reactive oxygen species (ROS) react with DNA modifying its structure. Here, BL6 mice were exposed to IR at LDR and HDR and were then sacrificed 3 hours and 3 weeks after exposure to examine early and late effects of IR. The levels of micronuclei, MN, were determined in bone marrow cells. Our data indicate that the effects of 200 mGy on MN-induction are transient, but 500 and 1000 mGy (both HDR and LDR) lead to increased levels of MN up to 3 weeks after the exposure.
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| 3. |
- Drobin, Kimi, et al.
(författare)
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Molecular Profiling for Predictors of Radiosensitivity in Patients with Breast or Head-and-Neck Cancer
- 2020
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 12:3
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Tidskriftsartikel (refereegranskat)abstract
- Nearly half of all cancers are treated with radiotherapy alone or in combination with other treatments, where damage to normal tissues is a limiting factor for the treatment. Radiotherapy-induced adverse health effects, mostly of importance for cancer patients with long-term survival, may appear during or long time after finishing radiotherapy and depending on the patient's radiosensitivity. Currently, there is no assay available that can reliably predict the individual's response to radiotherapy. We profiled two study sets from breast (n = 29) and head-and-neck cancer patients (n = 74) that included radiosensitive patients and matched radioresistant controls. We studied 55 single nucleotide polymorphisms (SNPs) in 33 genes by DNA genotyping and 130 circulating proteins by affinity-based plasma proteomics. In both study sets, we discovered several plasma proteins with the predictive power to find radiosensitive patients (adjusted p < 0.05) and validated the two most predictive proteins (THPO and STIM1) by sandwich immunoassays. By integrating genotypic and proteomic data into an analysis model, it was found that the proteins CHIT1, PDGFB, PNKD, RP2, SERPINC1, SLC4A, STIM1, and THPO, as well as the VEGFA gene variant rs69947, predicted radiosensitivity of our breast cancer (AUC = 0.76) and head-and-neck cancer (AUC = 0.89) patients. In conclusion, circulating proteins and a SNP variant of VEGFA suggest that processes such as vascular growth capacity, immune response, DNA repair and oxidative stress/hypoxia may be involved in an individual's risk of experiencing radiation-induced toxicity.
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| 6. |
- Sangsuwan, Traimate, 1981-, et al.
(författare)
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Oxidative Stress Levels and DNA Repair Kinetics in Senescent Primary Human Fibroblasts Exposed to Chronic Low Dose Rate of Ionizing Radiation
- 2023
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Ingår i: Frontiers in Bioscience Landmark. - 2768-6701. ; 28:11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Exposure to low dose rate (LDR) radiation may accelerate aging processes. Previously, we identified numerous LDR-induced pathways involved in oxidative stress (OS) and antioxidant systems, suggesting that these pathways protect against premature senescence (PS). This study aimed to investigate if there are differences between young replicative senescent (RS) and PS cells considering DNA repair kinetics, OS, and DNA damage localized in the telomeres. Methods: We established PS cells by culturing and passaging young primary fibroblasts exposed to LDR. Then, RS cells were established by culturing and passaging young fibroblasts until they stopped proliferating. Senescence was characterized by analyzing telomere length and senescence-associated β-galactosidase (SA-β-gal) staining. DNA damage and repair were evaluated with γH2AX foci formation; telomere identification was carried out using the fluorescence in situ hybridization (FISH) probe; and oxidative stress was assessed by measuring 8-oxo-dG in the medium. Results: The data indicate the following: young cells have a better ability to cope with LDR-induced oxidative stress; RS and PS have higher steady-state levels of DNA damage; RS have slower DNA repair kinetics; and PS/RS have elevated levels of telomeric DNA damage. Conclusion: Our main conclusion is that PS and RS differ regarding DNA repair kinetics and SA-β-gal levels.
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| 7. |
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| 8. |
- Sangsuwan, Traimate, 1981-
(författare)
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Short and long-term effects of exposure to low dose and low dose rate of gamma radiation : using in vitro and in vivo models
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Assessment of human health risks from exposure to ionizing radiation (IR) is mainly based on the extrapolation of results from epidemiological studies on populations exposed to relatively high doses and often at high dose rates (HDR). Risk estimates after exposure to low doses and in particular at low dose rates (LDR) remain controversial due to a lack of epidemiological evidence. Therefore, high priority is given to strengthening the evidence on which risk assessments can be based for low doses and LDR. It is known that the cytotoxicity of radiation decreases by decreasing dose rate. Less is known about the effects of LDR on mutation rates and premature senescence compared to HDR. We established 2 cell lines with low expression of two proteins, MTH1 or MYH, both involved in the protection of cells from mutation induction by reactive oxygen species (ROS). The cells were exposed to different doses at different dose rates, and the levels of mutation were studied. The results showed a possible dose-rate threshold for mutations for the MTH1/MYH double knockdown cells.Next, we studied the effect of dose rate on adaptive response (AR). AR is defined as the ability of a low dose of ionizing radiation to induce enhanced resistance in cells subsequently exposed to a high dose. We established dose response relations for survival and mutations for MCF-10A cells exposed/non-exposed to an adaptive dose of 50 mGy at different dose rates, followed by exposure to different high doses. We found no protective effect of 50 mGy on survival. However, we observed that 50 mGy the adaptive dose reduced the mutation frequency induced by 1 Gy challenging dose. The protection level was higher when 50 mGy was delivered at LDR.A significant amount of data suggests that oxidative stress, induced for example by LDR, can contribute to senescence. We cultured VH10 cells, beginning with passage 13, during chronic LDR exposure. The cells were passaged every week for 6 weeks until they stopped proliferating due to premature senescence at passage 19. Passage 8 VH10 cells were cultured correspondingly but without irradiation until they stopped proliferating at passage 23 in response to replicative senescence. The DNA repair kinetics and the levels of DNA damage that were localized in the telomeres of young, middle-aged, premature senescent and replicative senescent cells were investigated. The young cells repaired DSB significantly faster than the senescent cells; premature and replicative senescent cells accumulated more DNA damage in the telomeres; and as compared to middle-aged cells, young cells cope with oxidative stress of chronic irradiation more effectively.The transgenerational effects of IR were studied in Drosophila embryos. The exposed embryos were followed up for abnormality during embryogenesis until adult stage and up to 12 generations. We found that radiation induced an A5pig- phenotype (depigmented area in the A5 segment of the male body) that was transmitted up to 12 generations. This phenomenon did not follow the Mendelian inheritance model, which indicates the influence of mechanisms other than mutagenesis e.g. epigenetic mechanism.We showed that; LDR is less cytotoxic than HDR but both induce equal levels of mutation per unit dose; LDR induces premature senescence; LDR may be more effective than HDR in inducing adaptive response; and LDR and HDR exposure of Drosophila embryos can induce an abnormal phenotype that can be transmitted through generations.
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| 9. |
- Sangsuwan, Traimate, 1981-, et al.
(författare)
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Transgenerational effects of gamma radiation dose and dose rate on Drosophila flies irradiated at an early embryonal stage
- 2022
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Ingår i: Mutation research. Genetic toxicology and environmental mutagenesis. - : Elsevier BV. - 1383-5718 .- 1879-3592. ; 881
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Tidskriftsartikel (refereegranskat)abstract
- Ionizing radiation (IR) kills cells mainly through induction of DNA damages and the surviving cells may suffer from mutations. Transgenerational effects of IR are well documented, but the exact mechanisms underlying them are less well understood; they include induction of mutations in germ cells and epigenetic inheritance. Previously, effects in the offspring of mice and zebrafish exposed to IR have been reported. A few studies also showed indications of transgenerational effects of radiation in humans, particularly in nuclear power workers. In the present project, short- and long-term effects of low-dose-rate (LDR; 50 and 97 mGy/h) and high-dose-rate (HDR; 23.4, 47.1 and 495 Gy/h) IR in Drosophila embryos were investigated. The embryos were irradiated at different doses and dose rates and radiosensitivity at different developmental stages was investigated. Also, the survival of larvae, pupae and adults developed from embryos irradiated at an early stage (30 min after egg laying) were studied. The larval crawling and pupation height assays were applied to investigate radiation effects on larval locomotion and pupation behavior, respectively. In parallel, the offspring from 3 Gy irradiated early-stage embryos were followed up to 12 generations and abnormal phenotypes were studied. Acute exposure of embryos at different stages of development showed that the early stage embryo is the most sensitive. The effects on larval locomotion showed no significant differences between the dose rates but a significant decrease of locomotion activity above 7 Gy was observed. The results indicate that embryos exposed to the low dose rates have shorter eclosion times. At the same cumulative dose (1 up to 7 Gy), HDR is more embryotoxic than LDR. We also found a radiation-induced depigmentation on males (A5 segment of the dorsal abdomen, A5pig-) that can be transmitted up to 12 generations. The phenomenon does not follow the classical Mendelian laws of segregation.
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| 10. |
- Shakeri Manesh, Sara, et al.
(författare)
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MTH1, an 8-oxo-2'-deoxyguanosine triphosphatase, and MYH, a DNA glycosylase, cooperate to inhibit mutations induced by chronic exposure to oxidative stress of ionising radiation
- 2017
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Ingår i: Mutagenesis. - : Oxford University Press (OUP). - 0267-8357 .- 1464-3804. ; 32:3, s. 389-396
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Tidskriftsartikel (refereegranskat)abstract
- Our previous results showed that in addition to the immediate interaction of ionising radiation with DNA (direct and indirect effect), low-dose and chronic low-dose rate of irradiation induce endogenous oxidative stress. During oxidative stress, free radicals react with DNA, nucleoside triphosphates (dNTPs), proteins and lipids, and modify their structures. The MYH and MTH1 genes play important roles in preventing mutations induced by 8-hydroxy-guanine, which is an oxidised product of guanine. In this study, we used short-hairpin RNA to permanently knockdown MYH and MTH1 proteins in human lymphoblastoid TK6 cells. Knockdown and wild-type cells were chronically exposed to low dose rates of gamma-radiation (between 1.4 and 30 mGy/h). The cells were also subjected to acute doses delivered at a high-dose rate. Growth rate, extracellular 8-hydroxy-2'-deoxyguanosine, clonogenic cell survival and mutant frequencies were analysed in all cell types. A reduced level of cell growth and survival as well as increased mutant frequencies were observed in cells lacking both MYH and MTH1 proteins as compared to cells lacking only MYH and wild-type cells. To sum up, our results suggest that low-dose rates elevate oxidative stress. MTH1 together with MYH plays an important role in protection against mutations induced by modified dNTPs during chronic oxidative stress. In addition, we found no dose-rate effect at the level of mutations in the wild-type TK6 and MYH-KD cells. Our data interestingly indicate a dose-rate threshold for mutation induction in MTH1/MYH double knockdown cells.
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