Chronic Irradiation Research Articles

Biological effects in normal human fibroblasts following chronic and acute irradiation with both low- and high-LET radiation.

Radiobiological studies at low dose rates allow us to improve our knowledge of the mechanisms by which radiation exerts its effects on biological systems following chronic exposures. Moreover, these studies can complement available epidemiological data on the biological effects of low doses and dose rates of ionizing radiation. Very few studies have simultaneously compared the biological effects of low- and high-LET radiations at the same dose rate for chronic irradiation. We compared, for the first time in the same experiment, the effects of chronic (dose rates as low as ~18 and 5 mGy/h) and acute irradiations on clonogenicity and micronucleus formation in AG1522 normal human skin fibroblasts in the confluent state exposed to doses of low- and high-LET radiation (gamma rays and alpha particles) to investigate any differences due to the different radiation quality and different dose rate (in the dose range 0.006-0.9 Gy for alpha particles and 0.4-2.3 Gy for gamma rays). As expected, alpha particles were more effective than gamma rays at inducing cytogenetic damage and reduced clonogenic cell survival. For gamma rays, the cytogenetic damage and the reduction of clonogenic cell survival were greater when the dose was delivered acutely instead of chronically. Instead, for the alpha particles, at the same dose, we found equal cytogenetic damage and reduction of clonogenic cell survival for both chronic and acute exposure (except for the highest doses of 0.4 and 0.9 Gy, where cytogenetic damage is greater at a low dose rate). The results of this study may have an impact on space and terrestrial radioprotection of humans at low doses and low dose rates, on biodosimetry, and on the use of ionizing radiation in medicine. These results also provide insights into understanding damage induction and cell reaction mechanisms following chronic exposure (at dose rates as low as 18 and 5 mGy/h) to low- and high-LET radiation.

Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy

T cell inhibitory mechanisms prevent autoimmune reactions, while cancer immunotherapy aims to remove these inhibitory signals. Chronic ultraviolet (UV) exposure attenuates autoimmunity through promotion of poorly understood immune-suppressive mechanisms. Here we show that mice with subcutaneous melanoma are not responsive to anti-PD1 immunotherapy following chronic UV irradiation, given prior to tumor injection, due to the suppression of T cell killing ability in skin-draining lymph nodes. Using mass cytometry and single-cell RNA-sequencing analyzes, we discover that skin-specific, UV-induced suppression of T-cells killing activity is mediated by upregulation of a Ly6ahigh T-cell subpopulation. Independently of the UV effect, Ly6ahigh T cells are induced by chronic type-1 interferon in the tumor microenvironment. Treatment with an anti-Ly6a antibody enhances the anti-tumoral cytotoxic activity of T cells and reprograms their mitochondrial metabolism via the Erk/cMyc axis. Treatment with an anti-Ly6a antibody inhibits tumor growth in mice resistant to anti-PD1 therapy. Applying our findings in humans could lead to an immunotherapy treatment for patients with resistance to existing treatments.

Effects of Continuous Prenatal Low Dose Rate Irradiation on Neurobehavior, Hippocampal Cellularity, Messenger RNA and MicroRNA Expression on B6C3F1 Mice.

Epidemiological, experimental, and ecological data have indicated the controversial effect of in utero chronic low dose rate (<6 mGy/h) with accumulative low (≤100 mGy) or high (>100 mGy) dose radiation exposure. Our main goal of this study was to examine if different low dose rates of chronic pre- and/or post-natal radiation exposure with accumulative high doses could induce hippocampal cellular, mRNA, and miRNA changes leading to neuropsychiatric disorders. The comprehensive mouse phenotypic traits, organ weight, pathological, and blood mRNA and miRNA changes were also studied. Using different approaches including SmithKline, Harwell, Imperial College, Royal Hospital, Phenotype Assessment (SHIRPA), neurobehavioral tests, pathological examination, immunohistochemistry, mRNA and miRNA sequencing, and real-time quantitative polymerase chain reaction (qRT-PCR) validation, we found that in prenatally irradiated (100 mGy/d for 18 days with an accumulative dose of 1.8 Gy) 1-year-old mice, no cellular changes, including immature neurons in the subgranular zone, mature neurons and glial cells in the hilus of the dentate gyrus and development of cognitive impairment, neuropsychiatric disorders, occurred. However, a significant reduction in body weight and mass index (BMI) was indicated by the SHIRPA test. A reduced exploratory behavior was shown by an open field test. Organ weights showed significant reductions in the testes, kidneys, heart, liver and epididymides with no abnormal pathology. mRNA and miRNA sequencing and qRT-PCR validation revealed the upregulation of Rubcnl and Abhd14b, and downregulation of Hspa1b, P4ha1, and Banp genes in both the hippocampus and blood of mice prenatally irradiated with 100 mGy/d. Meanwhile, downregulation of miR-448-3p and miR1298-5p in the hippocampus, miR-320-3p, miR-423-5p, miR-486b-5p, miR-486b-3p, miR-423-3p, miR-652-3p, miR-324-3p, miR-181b-5p, miR-let-7b, and miR-6904-5p in the blood was induced. The target scan revealed that Rubcnl is one of the miR-181b-5p targets in the blood. We, therefore, concluded that prenatal chronic irradiation with a low dose rate of 100 mGy/d and accumulative dose of 1.8 Gy or below might not induce significant adverse health effects on the offspring. Further study of different low dose rate radiation exposures with accumulative high doses may provide threshold doses for authorities or regulators to set new radiation safety guidelines to replace those extrapolated from acute high dose/dose rate irradiation to reduce unnecessary emergency evacuation or spending once a nuclear accident or leakage occurs.

Analysis of Molecular Mechanisms of Chronic Irradiation Effects on Electrical Signals in Wheat Plants

The effect of ionizing radiation (IR) on plants is mainly realized by altering the status of signaling systems and modifying stress signals. Variation potential (VP) is one of the types of electrical signals in plants. IR contributes to an increase in the amplitude of the VP, but the mechanisms of such influence are practically unknown. A possible way to implement changes arising from the action of IR is the regulation of gene expression. In the present work, the changes in the gene expression of participants in the generation and propagation of VP in irradiated plants are investigated. The experiments were performed on 14–15-day-old soft wheat plants (Triticum aestivum L.) grown under chronic irradiation (source 90Sr-90Y) with a dose rate of 31.3 μGy/h. The maximum accumulated dose was about 11.3 mGy. The irradiated plants showed no changes in the expression of calcium (TPC1), anionic (ALMT1 and CLC1), potassium (AKT1) channels, H+-ATPase (HA1), and NADPH oxidase (RBOHs) genes. A decrease in the expression of the SKOR potassium channel gene was revealed. The potassium channel blocker, tetraethylammonium chloride, caused an increase in response amplitude in control plants comparable to the increase in amplitude in the irradiated group. The obtained results indicate that one of the ways IR influences the electrical signals of plants is to inhibit the expression of the potassium channel.

Chronic ultraviolet irradiation induces memory deficits via dysregulation of the dopamine pathway

The effects of ultraviolet (UV) radiation on brain function have previously been investigated; however, the specific neurotransmitter-mediated mechanisms responsible for UV radiation-induced neurobehavioral changes remain elusive. In this study, we aimed to explore the mechanisms underlying UV radiation-induced neurobehavioral changes. In a mouse model, we observed that UV irradiation of the skin induces deficits in hippocampal memory, synaptic plasticity, and adult neurogenesis, as well as increased dopamine levels in the skin, adrenal glands, and brain. Chronic UV exposure altered the expression of genes involved in dopaminergic neuron differentiation. Furthermore, chronic peripheral dopamine treatments resulted in memory deficits. Systemic administration of a dopamine D1/D5 receptor antagonist reversed changes in memory, synaptic plasticity, adult neurogenesis, and gene expression in UV-irradiated mice. Our findings provide converging evidence that chronic UV exposure alters dopamine levels in the central nervous system and peripheral organs, including the skin, which may underlie the observed neurobehavioral shifts, such as hippocampal memory deficits and impaired neurogenesis. This study underscores the importance of protection from UV exposure and introduces the potential of pharmacological approaches targeting dopamine receptors to counteract the adverse neurological impacts of UV exposure.

UV Irradiation Increases Appetite and Prevents Body Weight Gain through the Upregulation of Norepinephrine in Mice

UV irradiation of the human skin downregulates lipid synthesis and adipokine production in subcutaneous fat. Recent evidence has suggested that UV exposure limits body weight gain in mouse models of obesity. However, the relationship between norepinephrine and UV irradiation has not been previously reported. Chronic UV exposure stimulated food intake but prevented body weight gain. Leptin, an appetite-suppressing hormone, was significantly reduced in the serum of the UV-irradiated mice. In contrast, UV irradiation induced browning of subcutaneous white adipose tissues without increasing physical activity. Notably, UV irradiation significantly increased norepinephrine levels, and the inhibition of norepinephrine production reversed the effects of chronic UV irradiation on food intake and body weight gain. In conclusion, chronic UV irradiation induces norepinephrine release, resulting in the stimulation of food intake due to the downregulation of leptin levels, but it prevents weight gain by inducing the browning process and elevating energy expenditure.

Changes in the structural and functional state of the thyroid gland of small mammals when exposed to low-intensity chronic radiation.

The study gives a morphofunctional assessment of the state of the thyroid gland of tundra voles (Microtus oeconomus Pall.) in conditions of an increased radiation background (the Ukhta district of the Komi Republic (Russia) and the 30-km zone of the Chernobyl NPP), as well as in an experiment with chronic external gamma irradiation in the low dose range. The work summarizes the experience of more than 35 years of field and laboratory research. The authors have noted the high sensitivity of the thyroid gland to chronic radiation against the general irradiation of the organism both in natural conditions and in the experiment. The repeatability of the observed effects in voles from natural populations and the comparability of some effects with the morphological changes occurring in animals after exposure to ionizing radiation in the experiment indicates the radiation nature of these effects. The tundra voles living in conditions of increased radiation background have been identified for a greater variety of morphological rearrangements in the thyroid parenchyma than the experimental animals. The complex and ambiguous nature of the thyroid gland responses to radiation exposure indicates the possibility of a significant increase in the risk of negative effects of ionizing radiation in contrast with the expected results of biological effects' extrapolation from high to low doses.

Abstract 273: Extrinsic photoaging vs intrinsic aging in dermal fibroblasts: Its impact on the microenvironment and melanoma progression

Abstract Melanoma is the deadliest form of skin cancer, with chronological aging as a major negative prognostic factor due to the influence of intrinsic aging on the tumor microenvironment (TME) to promote tumor initiation and progression. Ultraviolet radiation (UVR) exposure, which is a major risk factor for melanoma, also can cause a physical premature aging phenotype, known as extrinsic photoaging, from chronic UVA irradiation of the underlying dermis. Photoaging of the skin often occurs in tandem with chronological aging, and contributes to similar physical alterations in normal skin structure. However, the molecular mechanisms of how photoaging compares to chronological aging in changing the TME and on tumor progression is still lacking. Here we found that extrinsically photoaged fibroblasts have a higher level of secretion of lysosomal proteases, Cathepsins, which have been shown to be secreted via lysosomal exocytosis and play a functional role in extracellular matrix (ECM) remodeling at neutral PH levels. We found that Cathepsins B and D are secreted at higher levels in both extrinsically photoaged young fibroblasts and in intrinsically aged fibroblasts and upregulated at the endogenous protein level. Cathepsin B has been shown to be highly expressed in metastatic but not primary melanoma patient samples, and cleaves ECM proteins such as fibronectin and tenascin. Immunofluorescent staining of in-vitro fibroblast derived matrices (CDMs) confirmed that photoaging disrupts subsequent deposited extracellular matrix proteins similarly to that of intrinsically aged healthy fibroblasts and these matrix changes influences the growth pattern of melanoma lines plated on these CDMs. Mass spectrometry analysis of secreted proteomics confirmed that aged fibroblasts secrete more cathepsins than intrinsically young fibroblasts, and Cathepsins B and D were also detected in extracellular vesicle (EV) cargo proteomics. Single-Particle Interferometric Reflectance Imaging (SP-IRIS) of EVs showed that UVA irradiation induced a significant increase in the total number of secreted of exosomes and in expression of tetraspanin protein CD63, which plays a role in cargo sorting and has been detected in high levels in the plasma of melanoma patients. We hypothesize that extrinsic photoaging of fibroblasts induces the secretion of exosomes packaged with Cathepsins that play an integral role in ECM remodeling and matrix degradation in a beneficial manner for melanoma invasion. Further studies will assess the influence on secreted cathepsins on melanomagenesis and melanoma invasion through both mechanical and biochemical changes in the TME with in-vitro and in-vivo studies. Citation Format: Vania Wang, Yash Chhabra, Laura Hueser, Ashani Weeraratna. Extrinsic photoaging vs intrinsic aging in dermal fibroblasts: Its impact on the microenvironment and melanoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 273.

Senescence-Associated Heterochromatin Foci Suppress γ-H2AX Focus Formation Induced by Radiation Exposure.

DNA damage is induced by both endogenous and exogenous factors. Repair of DNA double-strand break (DSB), a serious damage that threatens genome stability, decreases with senescence. However, the molecular mechanisms underlying the decline in DNA repair capacity during senescence remain unclear. We performed immunofluorescence staining for phosphorylated histone H2AX (γ-H2AX) in normal human fetal lung fibroblasts and human skin fibroblasts of different ages after chronic irradiation (total dose, 1 Gy; dose rate, 1 Gy/day) to investigate the effect of cellular senescence and organismal aging on DSB repair. Accumulation of DSBs was observed with cellular senescence and organismal aging, probably caused by delayed DSB repair. Importantly, the formation of γ-H2AX foci, an early event in DSB repair, is delayed with cellular senescence and organismal aging. These results suggest that the delay in γ-H2AX focus formation might delay the overall DSB repair. Interestingly, immediate γ-H2AX foci formation was suppressed in cells with senescence-associated heterochromatin foci (SAHF). To investigate the relationship between the γ-H2AX focus formation and SAHF, we used LiCl to relax the SAHFs, followed by irradiation. We demonstrated that LiCl rescued the delayed γ-H2AX foci formation associated with cellular senescence. This indicates that SAHF interferes with γ-H2AX focus formation and inhibits DSB repair in radiation-induced DSB. Our results suggest that therapeutic targeting of SAHFs have potential to resolve DSB repair dysfunction associated with cellular senescence.

Myconoside and Calceolarioside E Restrain UV-Induced Skin Photoaging by Activating NRF2-Mediated Defense Mechanisms.

Chronic and excessive ultraviolet (UVA/UVB) irradiation exposure is known as a major contributor to premature skin aging, which leads to excessive reactive oxygen species generation, disturbed extracellular matrix homeostasis, DNA damage, and chronic inflammation. Sunscreen products are the major preventive option against UVR-induced photodamage, mostly counteracting the acute skin effects and only mildly counteracting accelerated aging. Therefore, novel anti-photoaging and photopreventive compounds are a subject of increased scientific interest. Our previous investigations revealed that the endemic plant Haberlea rhodopensis Friv. (HRE) activates the antioxidant defense through an NRF2-mediated mechanism in neutrophiles. In the present study, we aimed to investigate the photoprotective potential of HRE and two of its specialized compounds-the phenylethanoid glycosides myconoside (MYC) and calceolarioside E (CAL)-in UVA/UVB-stimulated human keratinocytes in an in vitro model of photoaging. The obtained data demonstrated that the application of HRE, MYC, and CAL significantly reduced intracellular ROS formation in UVR-exposed HaCaT cells. The NRF2/PGC-1α and TGF-1β/Smad/Wnt signaling pathways were pointed out as having a critical role in the observed CAL- and MYC-induced photoprotective effect. Collectively, CAL is worth further evaluation as a potent natural NRF2 activator and a promising photoprotective agent that leads to the prevention of UVA/UVB-induced premature skin aging.

Genetic consequences of chronic gamma irradiation on agro morphological traits in chili under hydrogel enhance media

Induced mutation for the creation of desirable traits through chronic gamma irradiation provides an opportunity for the selection and development of new chili varieties. This study was conducted to assess the effects of different doses of chronic gamma irradiation on morpho-physiological traits in chili. Ten plants from each variety were exposed to different doses of chronic gamma irradiation for 277.02 h at three weeks after germination under gamma greenhouse facilities, with accumulative dose; 185.61Gy, 83.11Gy, 47.096Gy, 30.474Gy, 19.4Gy, 13.9Gy, 11.1Gy, 8.31Gy, 5.54Gy) and 2.77Gy respectively. Highly significant differences were observed among doses (Rings) of chronic gamma irradiation expressed in mean values for all investigated traits. Relatively moderate doses of chronic gamma irradiation represented by doses 47.096 Gy (Ring 4) and 19.40 Gy (Ring 6) resulted in significant stimulation for most of the studied characters. The highest heritability was recorded in days to flowering at 99.88 while the lowest was observed in fruit dry weight at 34.66 %. High genetic advance were recorded for most of the quantitative traits studied. In addition, a highly significant positive correlation was observed between total fruit per plant, total number of fruit per plant, plant height, fruit fresh weight, number of secondary branches, chlorophyll a, fruit dry weight, total chlorophyll content, stem diameter, fruit length and fruit girth. With increasing chronic gamma dose, mutagenic efficiency and efficacy generally increased. Induced variety of desirable features will considerably increase the chilli's amelioration through mutation breeding, leading to the development of improved varieties. The results of this research offer valuable information for the use of chronic gamma radiation in the mutations breeding of Capsicum annuum L., which will be advantageous for future breeding programs.

Leaf-variegated mutations induced using gamma irradiation of Anubias minima

The effects of chronic gamma irradiation on leaf mutations of Anubias minima were investigated. Tissue cultures of A. minima were exposed to chronic gamma radiation in a gamma room using Cobalt-60 sources at the Nuclear Technology Research Center, Faculty of Science, Kasetsart University, Bangkok, Thailand. Samples received a total dose of 0, 26.58, 41.12, 65.31, 79.81, 103.81, and 127.91 Gy at a dose rate of 0.6 Gy/h. At 60 days after irradiation, the number of surviving plantlets and the number of new shoots were counted and compared with the controls (0 Gy) to calculate the 50% lethal dose (LD50) and 50% growth reduction (GR50). The results showed that the radiation dose did not affect plant survival, but the GR50 was about 125 Gy in the M1V1 generation. After that, subcultures of new plantlets were transferred to a new medium, and the next generations were observed to note any new mutated characteristics after gamma irradiation. In the M1V9 generation, variegated leaf mutants could be selected. There were four different types of mutant leaves: Dark green leaves with light green specks, dark green leaves with white specks, light green leaves with dark green veins and specks, and white leaves with dark green veins and specks. After 3 months, the selected mutants of A. minima tissue transplanted into water tanks were healthy and had 100% survival.

NAT10 regulates the repair of UVB-induced DNA damage and tumorigenicity

Chemical modifications in messenger RNA (mRNA) regulate gene expression and play critical roles in stress responses and diseases. Recently we have shown that N6-methyladenosine (m6A), the most abundant mRNA modification, promotes the repair of UVB-induced DNA damage by regulating global genome nucleotide excision repair (GG-NER). However, the roles of other mRNA modifications in the UVB-induced damage response remain understudied. N4-acetylcytidine (ac4C) is deposited in mRNA by the RNA-binding acetyltransferase NAT10. This NAT10-mediated ac4C in mRNA has been reported to increase both mRNA stability and translation. However, the role of ac4C and NAT10 in the UVB-induced DNA damage response remains poorly understood. Here we show that NAT10 plays a critical role in the repair of UVB-induced DNA damage lesions through regulating the expression of the key GG-NER gene DDB2. We found that knockdown of NAT10 enhanced the repair of UVB-induced DNA damage lesions by promoting the mRNA stability of DDB2. Our findings are in contrast to the previously reported role of NAT10-mediated ac4C deposition in promoting mRNA stability and may represent a novel mechanism for ac4C in the UVB damage response. Furthermore, NAT10 knockdown in skin cancer cells decreased skin cancer cell proliferation in vitro and tumorigenicity in vivo. Chronic UVB irradiation increases NAT10 protein levels in mouse skin. Taken together, our findings demonstrate a novel role for NAT10 in the repair of UVB-induced DNA damage products by decreasing the mRNA stability of DDB2 and suggest that NAT10 is a potential novel target for preventing and treating skin cancer.

Влияние средних и малых доз ионизирующего излучения на высшую нервную деятельность человека и животных

According to the available data, the effect of high doses of ionizing radiation on the human central nervous system (CNS) takes form of cognitive dysfunction and increased risk of development of malignant neoplasms. At the same time, there is a growing concern about the possible effects of low, moderate doses of ionizing radiation and chronic irradiation, on cognitive functions, as well as their potential long-term consequences manifesting as neurodegenerative diseases. There is both epidemiological and experimental evidence confirming that low and moderate doses of ionizing radiation affect cognitive abilities. The underlying mechanisms include disruption of normal neurogenesis in the hippocampus, development of long-term sustained neuroinflammation, disorders of synaptic plasticity, energy metabolism, and oxidative status. On the part of CNS, the body is most sensitive to radiation during the period of active formation of the brain. Irradiated at that time, people may suffer consequences thereof for several months and years, or have them manifesting only much later, in old age. Improvement of radiation safety and development of means and ways of prevention and treatment of radiation-induced CNS disorders require further research efforts aimed at establishing causal relationships between chronic exposure to radiation and low-dose irradiation and their adverse effects on the part of CNS in the long term post-exposure.

Altered ovarian transcriptome is linked to early mortality and abnormalities in zebrafish embryos after maternal exposure to gamma irradiation

Recent laboratory studies focusing on multigenerational approach demonstrated drastic phenotypic effects after chronic fish irradiation exposure. No irradiation effect at phenotypic scale was observed for F0 (reproductive performances) while early mortality and malformations were observed in F1 offspring whether they were irradiated or not. The objective was to study molecular mechanisms likely to be involved in these phenotypic effects induced by parental irradiation. Thus, F0 adult zebrafish were irradiated for ten days until reproduction and maternal involvement in offspring development was assessed. Levels of maternal provided cortisol and vitellogenin, needed for embryo development, were not impacted by irradiation. However, maternal transcriptome highlighted irradiation effect on processes involved in oocyte development, as well as on essential maternal factors needed for offspring development. Therefore, this study highlighted the importance of parental exposure on offspring fate and of the importance of multigenerational exposure in risk assessment.

Macrophage migration inhibitory factor (MIF) and its homolog D-dopachrome tautomerase (D-DT) are significant promotors of UVB- but not chemically induced non-melanoma skin cancer

Non-melanoma skin cancer (NMSC) is the most common cancer in Caucasians worldwide. We investigated the pathophysiological role of MIF and its homolog D-DT in UVB- and chemically induced NMSC using Mif−/−, D-dt−/− and Mif−/−/D-dt−/− mice on a hairless SKH1 background. Knockout of both cytokines showed similar attenuating effects on inflammation after acute UVB irradiation and tumor formation during chronic UVB irradiation, without additive protective effects noted in double knockout mice, indicating that both cytokines activate a similar signaling threshold. In contrast, genetic deletion of Mif and D-dt had no major effects on chemically induced skin tumors. To get insight into the contributing mechanisms, we used an in vitro 3D skin model with incorporated macrophages. Application of recombinant MIF and D-DT led to an accumulation of macrophages within the epidermal part that could be reversed by selective inhibitors of MIF and D-DT pathways. In summary, our data indicate that MIF and D-DT contribute to the development and progression of UVB- but not chemically induced NMSC, a role at least partially accounted by effects of both cytokines on epidermal macrophage accumulation. These data highlight that MIF and D-DT are both potential therapeutic targets for the prevention of photocarcinogenesis but not chemical carcinogenesis.

State of the Scots Pine Seed Progeny from the Polessky State Radiation-Ecological Reserve, Belarus

We studied the state of seed progeny in Scots pine populations from the Polessky State Radiation-Ecological Reserve (PGRZ), Belarus. The seed progeny of the studied populations is characterized by an increased frequency of cytogenetic disorders and abortive seeds, as well as reduced germination. At the same time, Scots pine seeds from populations that have developed for a long time under chronic irradiation are characterized by increased resistance to additional γ-irradiation. Thus, the current levels of radiation exposure at the territory of the PGRZ can inhibit the reproductive capacity of Scots pine and serve as a selection factor for increased resistance to radiation.

Late Effects of Chronic Low Dose Rate Total Body Irradiation on the Heart Proteome of ApoE-/- Mice Resemble Premature Cardiac Ageing.

Recent epidemiologic studies support an association between chronic low-dose radiation exposure and the development of cardiovascular disease (CVD). The molecular mechanisms underlying the adverse effect of chronic low dose exposure are not fully understood. To address this issue, we have investigated changes in the heart proteome of ApoE deficient (ApoE-/-) C57Bl/6 female mice chronically irradiated for 300 days at a very low dose rate (1 mGy/day) or at a low dose rate (20 mGy/day), resulting in cumulative whole-body doses of 0.3 Gy or 6.0 Gy, respectively. The heart proteomes were compared to those of age-matched sham-irradiated ApoE-/- mice using label-free quantitative proteomics. Radiation-induced proteome changes were further validated using immunoblotting, enzyme activity assays, immunohistochemistry or targeted transcriptomics. The analyses showed persistent alterations in the cardiac proteome at both dose rates; however, the effect was more pronounced following higher dose rates. The altered proteins were involved in cardiac energy metabolism, ECM remodelling, oxidative stress, and ageing signalling pathways. The changes in PPARα, SIRT, AMPK, and mTOR signalling pathways were found at both dose rates and in a dose-dependent manner, whereas more changes in glycolysis and ECM remodelling were detected at the lower dose rate. These data provide strong evidence for the possible risk of cardiac injury following chronic low dose irradiation and show that several affected pathways following chronic irradiation overlap with those of ageing-associated heart pathology.

Evaluation of micronuclei and antioxidant status in hospital radiation workers occupationally exposed to low-dose ionizing radiation

PurposeThere is scientific evidence that ionizing radiation (IR) can be responsible for various health hazards that are one of the concerns in occupational exposure. This study was performed to evaluate DNA damage and antioxidant status in hospital workers who are occupationally exposed to low doses of IR.Materials and methodsIn this study, twenty occupationally exposed to low doses of IR (CT and angiography) comprising with control groups which matched them. In order to investigate the effects of chronic irradiation of radiation workers, Micronuclei (MN) frequency and the antioxidant activity of Superoxide Dismutase (SOD), Catalase (CAT) and Total Antioxidant Capacity (TAC) were measured. Then, to check adaptation against high challenge dose, the samples (in all groups) were irradiated in vitro and MN frequency was compared. Finally, to investigated the effect of the high dose after the acute and chronic low dose of ionizing radiation, MN frequency was compared in two groups (the control group that was to in-vitro irradiated (acute low dose + high dose) and radiation workers (chronic low dose + high dose)).ResultsMN frequency in the occupationally exposed group (n = 30) increased significantly when compared to the control group (p-value < 0.0001). However, chronic irradiation of radiation workers could not lead to an adaptive Sresponse, while acute low-doses could produce this effect (p-value ˂ 0.05). In addition, the activity levels of antioxidant enzymes SOD, CAT, and TAC were not statistically different between the radiation workers and the control group (p-value > 0.05).ConclusionsWe observed that exposure to low doses of IR leads to increased cytogenetic damage, could not cause an adaptive-response, and improve antioxidant capacity in radiation workers. Controlling healthcare workers' exposure is the first step to improving the health of hospital workers and the quality of patient care, thus decreasing human and economic costs.

Comparative analysis of epigenetic variability in two pine species exposed to chronic radiation in the Chernobyl and Fukushima affected zones

Comparative analysis of epigenetic variability in two pine species affected as a result of the Chernobyl and Fukushima accidents is presented. The absorbed dose rate within the affected Chernobyl sites varies over a wider range (1.5–24.6 μGy/h) than within the Fukushima sites (3.5–6.5 μGy/h). It was shown that chronic irradiation can change the level of whole genome methylation in pine populations, but in different ways. The genomes of Japanese red pines are hypomethylated, and the degree of methylation and hydroxymethylation decreases with an increase in the level of radiation exposure. In contrast, the percentages of genome methylation and hydroxymethylation in Scots pine populations exceed the reference levels. The observed discrepancy in the patterns of genome-wide DNA methylation can be attributed partly to the design of the study (differences in the climate, radiation dose, age and species of the pines) which could affect the results. In the frame of IRAP analysis, a larger number of different bands was observed in the Chernobyl populations compared to the Japanese populations. Both the Japanese and Chernobyl populations are characterized by significant genetic variability. However, the main part of this variability is observed within populations. The dendrograms, based on presence/absence of IRAP fragments and Nei's genetic distances, revealed subdivisions of the Chernobyl and Japanese populations according to the level of radioactive contamination. Analysis of the results presented will improve our understanding of the mechanisms underlying the responses of pine trees to chronic radiation exposure.