Immune status of people living in the Tande-Tande sub-village (Indonesia), an area with high indoor radon concentration.

On Earth, there are significant variations in terms of exposure to naturally occurring radiation among different areas. Radon, a naturally-occurring radioactive gas that is the primary cause of lung cancer in nonsmokers and the second most prevalent cause among smokers, poses a considerable risk. Indoor radon, in particular, constitutes the most substantial source of natural radiation to which individuals are exposed. This study assessed the immune status of a population chronically exposed to high indoor radon concentration in Indonesia. Fifty-seven subjects from the Tande-Tande sub-village (high indoor radon concentration area) were compared to fifty-three participants living in the Topoyo village (low concentration area). We contrasted the immunological conditions of these two populations by measuring levels of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-4 (IL-4), and IL-10 in serum. Moreover, we also measured levels of the nuclear factor kappa B (NF-κB), superoxide dismutase (SOD), glutathione peroxidase (GPX), and protein kinase B in its phosphorylated (pAkt) and non-phosphorylated form (Akt) in peripheral blood mononuclear cells (PBMCs) of a subset of participants (31 from each population). TNF-α, IFN-γ, and IL-4 levels in Tande-Tande sub-village inhabitants were significantly lower than those in the control group living in the Topoyo village (p = 0.001, p = 0.017, and p = 0.002). The concentration of IL-10 also tended to be lower in people living in the high indoor radon concentration area, but it did not differ significantly between Tande-Tande sub-village inhabitants and Topoyo inhabitants (p = 0.106). Protein levels of NF-κB, pAkt, and Akt in Tande-Tande sub-village inhabitants also did not differ significantly between Tande-Tande sub-village inhabitants and Topoyo inhabitants (p = 0.234, p = 0.210, and p = 0.657). Similarly, activities of SOD and GPX did not differ significantly between the two populations (p = 0.569 and p = 0.949). Overall, despite their chronic exposure to high indoor radon concentrations, our study revealed no increase in the levels of TNF-α, IFN-γ, IL-10, IL-4, SOD, and GPX in the inhabitants of Tande-Tande sub-village compared with people living in the Topoyo village. Furthermore, our study demonstrated no activation in the Akt pathway, as indicated by the pAkt/Akt ratio observed in PBMC lysates of individuals residing in the Tande-Tande sub-village.

Transcriptomic analysis reveals sex-specific differences in the expression of Dcl1 and Fis1 genes in the radio-adaptive response of thymocytes to TRP53-mediated apoptosis.

BACKGROUND: Radio-Adaptive Response (RAR) is a biological defense mechanism whereby exposure to low dose ionizing radiation (IR) mitigates the detrimental effects of high dose irradiation. RAR has been widely observed in vivo using as endpoint less induction of apoptosis. However, sex differences associated with RAR and variations between males and females on global gene expression influenced by RAR have not been still investigated. In addition, the response to radiation-induced apoptosis is associated with phosphorylation of TRP53 at both the serine 15 (ser-18 in the mouse) and serine 392 (ser-389 in mice) residues, but the role of these two phosphorylated forms in male and female RAR remains to be elucidated. RESULTS: We analyzed the effect of administering priming low dose radiation (0.075 Gy of X-rays) prior to high dose radiation (1.75 Gy of γ-rays) on the level of caspase-3-mediated apoptosis and on global transcriptional expression in thymocytes of male and female mice. Here, we provide the first evidence of a differential sex effect of RAR on the reduction of thymocyte apoptosis with males showing lesser levels of caspase-3-mediated apoptosis than females. Analysis of transcriptomic profiles of 1944 genes involved in apoptosis signaling in radio-adapted thymocytes identified 17 transcripts exhibiting differential expression between both sexes. Among them, Dlc1 and Fis1 are closely related to the apoptosis mediated by the TRP53 protein. Our data demonstrate that overexpression of Dlc1 and Fis1 occur concomitantly with a highest accumulation of phosphoserine-18-TRP53 and caspase-3 in radio-adapted thymocytes of female mice. In an opposite way, both down-modulation of Fis1 and phosphoserine-389-TRP53 accumulation appear to be associated with protection from thymocyte apoptosis mediated by caspase-3 in males. CONCLUSIONS: Transcriptomic analysis performed in this work reveals for the first time sex-specific differences in gene expression influenced by RAR. Our results also suggest a sex-dependent dual role for phosphoserine-18-TRP53 and phosphoserine-389-TRP53 in the regulation of the radio-adaptive response in mouse thymocytes.

Dose and Radioadaptive Response Analysis of Micronucleus Induction in Mouse Bone Marrow.

Enhanced cellular DNA repair efficiency and suppression of genomic instability have been proposed as mechanisms underlying radio-adaptive responses following low-dose radiation exposures. We previously showed that low-dose γ irradiation does not generate radio-adaptation by lowering radiation-induced cytogenetic damage in mouse spleen. Since radiation may exert tissue-specific effects, we extended these results here by examining the effects of γ radiation on cytogenetic damage and proliferative index in bone marrow erythrocytes of C57BL/6 and BALB/c mice. In C57BL/6 mice, the induction of micronuclei in polychromatic erythrocytes (MN-PCE) was observed at radiation doses of 100 mGy and greater, and suppression of erythroblast maturation occurred at doses of >500 mGy. A linear dose-response relationship for MN-PCE frequencies in C57BL/6 mice was established for radiation doses between 100 mGy and 1 Gy, with departure from linearity at doses of >1 Gy. BALB/c mice exhibited increased MN-PCE frequencies above baseline following a 20 mGy radiation exposure but did not exhibit radio-sensitivity relative to C57BL/6 mice following 2 Gy exposure. Radio-adaptation of bone marrow erythrocytes was not observed in either strain of mice exposed to low-dose priming γ irradiation (single doses of 20 mGy or 100 mGy or multiple 20 mGy doses) administered at various times prior to acute 2 Gy irradiation, confirming the lack of radio-adaptive response for induction of cytogenetic damage or suppression or erythrocyte proliferation/maturation in bone marrow of these mouse strains.

p53-mediated metabolic response to low doses of ionizing radiation.

PURPOSE: Unlike treatment with high doses of radiation that causes considerable DNA damage resulting in injury and p53 activation, exposure of cells or whole animals to low doses of radiation (LDR, ∼10cGy) can induce a protective radio adaptive response. Despite ample information about the contribution of the p53 pathway to high doses of radiation-induced effects, our understanding of the role of p53 in LDR-induced response remains incomplete. This review provides a brief summary of the p53 response to LDR exposure focusing on metabolic regulation. CONCLUSION: Consistent with growing evidence indicating a critical role of metabolic pathways in the modulation of stress responses, the radio adaptive response was mediated by the LDR-induced metabolic switch from oxidative phosphorylation to glycolysis. Remarkably, this metabolic reprogramming depends on p53 downregulation, suggesting a previously unrecognized p53-mediated metabolic response. Of note is that the LDR-induced p53 response is temporary but may become persistent if LDR exposure is recurrent and protracted. While further investigation is necessary, the model where LDR induces p53 downregulation concurrent with anabolic reprogramming may offer novel mechanistic insight into the radio adaptive response. It suggests a model in which LDR exposure is protective when transient or intermittent but may become detrimental when chronic because prolonged p53 downregulation would lead to inactivation of this critical tumor suppressor, causing a loss of p53-dependent DNA damage checkpoint, genomic instability, dysregulated metabolism, and thus increased cancer risk.

Radio-adaptive response and correlation of non-homologous end joining repair gene polymorphisms [XRRC5 (3R/2R/1R/0R), XRCC6(C/G) and XRCC7 (G/T)] in human peripheral blood mononuclear cells exposed to gamma radiation.

BACKGROUND: Radio-adaptive response (RAR) is transient phenomena, where cells conditioned with a small dose (priming) of ionizing radiation shows significantly reduced DNA damage with a subsequent high challenging dose. The role of DNA double strand break repair gene polymorphism in RAR is not known. In the present study attempt was made to find out the influence of NHEJ repair gene polymorphisms [a VNTR; XRCC5 (3R/2R/1R/0R); two single nucleotide polymorphisms (SNPs); XRCC6 (C/G) and XRCC7 (G/T)] with DNA damage, repair and mRNA expression in human PBMCs in dose and adaptive response studies. Genomic DNA extracted from venous blood samples of 20 random healthy donors (16 adaptive and 4 non-adaptive) and genotyping of NHEJ repair genes was carried out using PCR amplified length polymorphism. RESULTS: The dose response study revealed significant positive correlation of genotypes at XRRC5 (3R/2R/1R/0R), XRCC6(C/G) and XRCC7 (G/T) with DNA damage. Donors having genotypes with 2R allele at XRCC5 showed significant positive correlation with mRNA expression level (0R/2R: r = 0.846, P = 0.034; 1R/2R: r = 0.698, P = 0.0001 and 2R/2R: r = 0.831, P = 0.0001) for dose response. Genotypes C/C and C/G of XRCC6 showed a significant positive correlation (P = 0.0001), whereas, genotype T/T of XRCC7 showed significant negative correlation (r = - 0.376, P = 0.041) with mRNA expression. CONCLUSION: Interestingly, adaptive donors having C/G genotype of XRCC6 showed significantly higher (P < 0.05) mRNA expression level in primed cells suggesting their role in RAR. In addition, NHEJ repair gene polymorphisms play crucial role with radio-sensitivity and RAR in human PBMCs.

Biologic Impact of Different Ultra-Low-Fluence Irradiations in Human Fibroblasts.

In this study, we aimed to evaluate the cellular response of healthy human fibroblasts induced by different types of ultra-low-fluence radiations, including gamma rays, neutrons and high linear energy transfer (LET) heavy ions. NB1RGB cells were pretreated with ultra-low-fluence radiations (~0.1 cGy/7-8 h) of 137Cs gamma rays, 241Am-Be neutrons, helium, carbon and iron ions before being exposed to an X-ray-challenging dose (1.5 Gy). Helium (LET = 2.3 keV/µm), carbon (LET = 13.3 keV/µm) and iron (LET = 200 keV/µm) ions were generated with the Heavy Ion Medical Accelerator in Chiba (HIMAC), Japan. No differences in cell death-measured by colony-forming assay-were observed regardless of the radiation type applied. In contrast, mutation frequency, which was detected through cell transformation into 6-thioguanine resistant clones, was 1.9 and 4.0 times higher in cells pretreated with helium and carbon ions, respectively, compared to cells exposed to X-ray-challenging dose alone. Moreover, cells pretreated with iron ions or gamma-rays showed a mutation frequency similar to cells exposed to X-ray-challenging dose alone, while cells pretreated with neutrons had 0.15 times less mutations. These results show that cellular responses triggered by ultra-low-fluence irradiations are radiation-quality dependent. Altogether, this study shows that ultra-low-fluence irradiations with the same level as those reported in the International Space Station are capable of inducing different cellular responses, including radio-adaptive responses triggered by neutrons and genomic instability mediated by high-LET heavy ions, while electromagnetic radiations (gamma rays) seem to have no biologic impact.

Differential radio-adaptive responses in BALB/c and C57BL/6 mice: pivotal role of calcium and nitric oxide signalling.

Purpose: Our earlier studies demonstrated that transient radio-adaptive responses (RAR) in BALB/c mice were due to MAPK hyperactivation. The objective of this study was to determine the time duration of this low dose induced MAPK activation in BALB/c mice and to find out if similar adaptive responses are observed in C57BL/6 mice. Materials and methods: Mice were irradiated with 0.1 Gy priming dose (PD), 2 Gy challenge dose (CD) with an interval of 4 h (P + CD) and radiation induced immunosuppression in splenic lymphocytes was monitored as the endpoint for RAR. Results: Time kinetics following 0.1 Gy demonstrated persistence of MAPK hyperactivation till 48 h. Similar experiments in C57BL/6 mice indicated absence of RAR at 24 h following CD, in spite of MAPK activation which was also confirmed by time kinetics. Therefore, upstream activators of MAPK, viz., reactive oxygen and nitrogen species (ROS, RNS) and calcium levels were estimated. There was increased intracellular calcium (Ca2+) and nitric oxide (NO) in BALB/c and an increase in intracellular ROS in C57BL/6 mice 24 h after PD. Inhibition of NO and calcium chelation abrogated RAR in BALB/c mice. In vitro treatment of spleen cells with combination of NO donor and Ca2+ ionophore mimicked the effect of PD and induced adaptive response after 2 Gy not only in BALB/c but also in C57BL/6 mice confirming their crucial role in RAR. Conclusions: These results suggest that low dose induced differential induction of Ca2+ and NO signaling along with MAPK was responsible for contrasting RAR with respect to immune system of BALB/c and C57BL/6 mice. Abbreviations [3H]-TdR: 3H-methyl-thymidine; BAPTA: 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; CD: Challenge Dose; CFSE: Carboxy Fluorescein Succinamidyl Ester; on A: Concanavalin A; DAF-FM: 4-amino-5-methylamino-2',7'-difluorescein; DCF-DA: 2',7'-dichlorofluorescein diacetate; DSB: Double Strand Break; ELISA: Enzyme Linked ImmunoSorbent Assay; ERK: Extracellular signal-Regulated protein Kinase; FBS: Fetal Bovine Serum; HIF-1A: Hypoxia-Inducible Factor 1-alpha; LDR: Low Dose Radiation; MAPK: Mitogen Activated Protein Kinase; MAPKK/MKK: MAPK Kinase; MAPKKK: MAPK Kinase Kinase; NO: Nitric Oxide; NOS: Nitric Oxide Synthase; P + CD: Priming + Challenge dose; PBS: Phosphate Buffered Saline; PBST: Phosphate Buffered Saline-Tween 20; PD: Priming Dose; PI3K: Phosphatidyl Inositol 3-Kinase; PKC: Protein Kinase C; RAR: Radio Adaptive Response; RNS: Reactive Nitrogen Species; ROS: Reactive Oxygen Species; RPMI-1640: Roswell Park Memorial Institute-1640 medium; SAPK/JNK: Stress-Activated Protein Kinase/ c-Jun NH2-terminal Kinase; SEM: Standard Error of Mean; SNAP: S-nitro amino penicillamine; TP53: Tumor Protein 53; γ-H2AX: Gamma- H2A histone family member X; Th1: Type 1 helper T cell responses; Th2: Type 2 helper T cell responses.

The assessment of radio-adaptive response in graves' hyperthyroidism patients following radioactive iodine uptake.

Low doses of radiation affect the response of cells to higher doses; this phenomenon is called radio-adaptive response, which leads to increased resistance to subsequent higher doses. We have investigated the adaptive response using 0.37 MBq priming dose of I-131 followed by 296-444 MBq challenging dose in peripheral human lymphocyte cells. The study was performed on 42 patients with Graves' disease and 29 healthy adult persons as a control group. The patients were divided into two groups. In the first group, patients were referred for radioactive iodine therapy with a specific dose, and iodine was given to them on the day of referral. In the second group, patients were referred for radioactive iodine uptake and radioactive iodine therapy, and iodine uptake was initially performed, then 24 h later, iodine therapy was done. In both groups, 1 month after treatment, blood samples were taken to cytokinesis-block micronucleus (MN) assay. The number of MN in binuclear lymphocyte cells was counted as an end point test. The mean frequency of MN in first, second, and control groups was 75.86 ± 12.68, 71.45 ± 12.56, and 20.06 ± 7.30, respectively. Our results showed that the frequency of total chromosome aberration in both radiation groups was higher than controls. However, in the first group was higher than another group, but their difference was not statistically significant. According to the results, we cannot approve the hypothesis that 0.37 MBq I-131 administration before iodine therapy could induce a radio-adaptive response in lymphocytes of Graves' patients.

Radio-adaptive Response in Myocardial Perfusion Imaging Induced by Technetium-99m.

PURPOSE OF THE STUDY: Low dose radiation will induce adaptation and following exposure to an adaptive dose, the cells are more resistance to following challenging doses. This phenomenon is known as radio-adaptive response. The aim of this study was to investigate the percentage of apoptotic cells in the peripheral blood samples of the patients which undergo myocardial perfusion imaging (MPI) with technetium-99m (Tc-99m) before thallium scan to assess the induction of radio-adaptive response. MATERIALS AND METHODS: In this study, 97 samples from 74 patients, referred to nuclear medicine center of Mazandaran Heart Hospital for MPI, which had no history of diagnostic, therapeutic, occupational, and radioactive exposures during past 2 years, were provided. The participants were classified into four groups including control, patients which were scanned solely with technetium, the patients which examined by thallium and the last group were the patients that examined by technetium followed by thallium. Then 2 ml Peripheral blood samples were obtained, and after 24 h incubating, the samples were studied by neutral comet assay. Statistical analysis was carried out using Student's t-test along with one-way analysis of variance. RESULTS: The mean percentage of apoptotic cells in the exposed groups were higher than the control. Furthermore, among exposed groups, the apoptotic cells in thallium group were more than others and this index was significantly lower in the group which was undergone technetium administration before thallium scan. CONCLUSIONS: These findings suggest that exposure to Tc-99m could induce a radio-adaptive response against the exposure of thallium-201.

Effect of modeled microgravity on radiation-induced adaptive response of root growth in Arabidopsis thaliana.

Space particles have an inevitable impact on organisms during space missions; radio-adaptive response (RAR) is a critical radiation effect due to both low-dose background and sudden high-dose radiation exposure during solar storms. Although it is relevant to consider RAR within the context of microgravity, another major space environmental factor, there is no existing evidence as to its effects on RAR. In the present study, we established an experimental method for detecting the effects of gamma-irradiation on the primary root growth of Arabidopsis thaliana, in which RAR of root growth was significantly induced by several dose combinations. Microgravity was simulated using a two-dimensional rotation clinostat. It was shown that RAR of root growth was significantly inhibited under the modeled microgravity condition, and was absent in pgm-1 plants that had impaired gravity sensing in root tips. These results suggest that RAR could be modulated in microgravity. Time course analysis showed that microgravity affected either the development of radio-resistance induced by priming irradiation, or the responses of plants to challenging irradiation. After treatment with the modeled microgravity, attenuation in priming irradiation-induced expressions of DNA repair genes (AtKu70 and AtRAD54), and reduced DNA repair efficiency in response to challenging irradiation were observed. In plant roots, the polar transportation of the phytohormone auxin is regulated by gravity, and treatment with an exogenous auxin (indole-3-acetic acid) prevented the induction of RAR of root growth, suggesting that auxin might play a regulatory role in the interaction between microgravity and RAR of root growth.

Radio-adaptive response to environmental exposures at Chernobyl.

The genetic consequences resulting from environmental exposure to ionizing radiation have a significant impact on both radiation regulatory policies and the comprehension of the human health risks associated with radiation exposure. The primary objectives of the study were to assess 1) genotoxicity of exposure to radiation as a function of absorbed dose and dose rate, and 2) induction of a radio-adaptive response following a priming dose at varying dose rates. Results demonstrated that sub-acute environmental exposures of 10cGy gamma radiation resulted in indistinguishable levels of chromosomal damage as compared to controls. A radio-adaptive response was observed in all experimental groups, exposed to a subsequent acute challenge dose of 1.5 Gy, demonstrating that low dose rates of low energy transfer (LET) radiation are effective in reducing genetic damage from a subsequent acute low-LET radiation exposure. Furthermore, the data presented herein demonstrate a potential beneficial effect of sub-chronic exposure to low levels of low-LET radiation in an environmental setting and do not support the Linear No Threshold (LNT) hypothesis.