Radon inhalation decreases DNA damage induced by oxidative stress in mouse organs via the activation of antioxidative functions.

Radon inhalation decreases the level of lipid peroxide (LPO); this is attributed to the activation of antioxidative functions. This activation contributes to the beneficial effects of radon therapy, but there are no studies on the risks of radon therapy, such as DNA damage. We evaluated the effect of radon inhalation on DNA damage caused by oxidative stress and explored the underlying mechanisms. Mice were exposed to radon inhalation at concentrations of 2 or 20 kBq/m3 (for one, three, or 10 days). The 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels decreased in the brains of mice that inhaled 20 kBq/m3 radon for three days and in the kidneys of mice that inhaled 2 or 20 kBq/m3 radon for one, three or 10 days. The 8-OHdG levels in the small intestine decreased by approximately 20-40% (2 kBq/m3 for three days or 20 kBq/m3 for one, three or 10 days), but there were no significant differences in the 8-OHdG levels between mice that inhaled a sham treatment and those that inhaled radon. There was no significant change in the levels of 8-oxoguanine DNA glycosylase, which plays an important role in DNA repair. However, the level of Mn-superoxide dismutase (SOD) increased by 15-60% and 15-45% in the small intestine and kidney, respectively, following radon inhalation. These results suggest that Mn-SOD probably plays an important role in the inhibition of oxidative DNA damage.

Residential exposure to radon and levels of histone γH2AX and DNA damage in peripheral blood lymphocytes of residents of Kowary city regions (Poland).

INTRODUCTION: Radon-induced biological effects have been studied mainly through epidemiological investigations, and well-controlled in vitro and in vivo experiments. To provide data explaining radon exposure-induced harmful effects in natural environment, exposure assessment under these conditions is needed. The objective of the study was to examine the level of genetic damage assessed with biomarkers of DNA single- and double-strand breaks (SSBs and DSBs) in peripheral blood mononuclear cells obtained from individuals continuously exposed to Rn in homes. Naturally elevated Rn concentrations in homes can be found in the South of Poland, in Kowary city. METHODS: Measurements of expression of phosphorylated histone γH2AX was used as a marker of DNA double strand breaks. To detect DNA single and double-strand breaks and alkali labile sites, the alkaline comet assay was used. Oxidative damage of DNA was evaluated by formamidopyrimidyne (FPG)-modified comet assay. The blood was collected from 94 volunteers living in Kowary. Subjects were grouped according to their status of living in radon concentration ≥100 Bq/m3 (n = 67), and <100 Bq/m3 (n = 27). RESULTS: The statistically significant differences in levels of DNA damage in peripheral lymphocytes assessed with comet assay were found to be associated with levels of radon exposure in indoor air (p = 0.034). DNA damage in the comet assay was significantly correlated with DNA damage assessed with γH2AX staining. CONCLUSIONS: Results of the present study indicate the suitability of alkaline comet assay for the detection of DNA damage in peripheral blood lymphocytes of people environmentally exposed to radon.

Genetic and physiological effects of the natural radioactive gas radon on the epiphytic plant Tillandsia brachycaulos.

Radon (222Rn) is the most abundant natural radioactive gas in nature and triggers carcinogenesis. Few reports exist on whether radon can damage plants as it does animals. Therefore, we chose Tillandsia brachycaulos, a common indicator plant, as the material to detect the physiological and genetic changes caused by radon. With an increase in radon concentration, DNA indices (tail length, tail DNA, tail moment and Olive tail moment) from the comet assay and malondialdehyde (MDA) content increased significantly, suggesting that T. brachycaulos inevitably suffered from radiation damage. However, neither the leaf relative conductivity nor the soluble protein content changed significantly with radon fumigation, and no dose-dependent effect existed between the chlorophyll content and radon concentration, indicating that T. brachycaulos had resistance to radon stress. Foliar trichomes most likely excluded the pollutant from plants because DNA damage in T. brachycaulos with trichomes manually removed was considerably greater than that with trichomes. Moreover, the antioxidant enzyme system further reduced the damage of radon to plants because the activity of superoxide dismutase (SOD) increased significantly with the radon concentration.

Protective effects of hot spring water drinking and radon inhalation on ethanol-induced gastric mucosal injury in mice.

Radon therapy using radon (222Rn) gas is classified into two types of treatment: inhalation of radon gas and drinking water containing radon. Although short- or long-term intake of spa water is effective in increasing gastric mucosal blood flow, and spa water therapy is useful for treating chronic gastritis and gastric ulcer, the underlying mechanisms for and precise effects of radon protection against mucosal injury are unclear. In the present study, we examined the protective effects of hot spring water drinking and radon inhalation on ethanol-induced gastric mucosal injury in mice. Mice inhaled radon at a concentration of 2000 Bq/m3 for 24 h or were provided with hot spring water for 2 weeks. The activity density of 222Rn ranged from 663 Bq/l (start point of supplying) to 100 Bq/l (end point of supplying). Mice were then orally administered ethanol at three concentrations. The ulcer index (UI), an indicator of mucosal injury, increased in response to the administration of ethanol; however, treatment with either radon inhalation or hot spring water inhibited the elevation in the UI due to ethanol. Although no significant differences in antioxidative enzymes were observed between the radon-treated groups and the non-treated control groups, lipid peroxide levels were significantly lower in the stomachs of mice pre-treated with radon or hot spring water. These results suggest that hot spring water drinking and radon inhalation inhibit ethanol-induced gastric mucosal injury.

γ-H2AX/53BP1/pKAP-1 foci and their linear tracks induced by in vitro exposure to radon and its progeny in human peripheral blood lymphocytes.

The biodosimetric information is critical for evaluating the human health hazards caused by radon and its progeny. Here, we demonstrated that the formation of phosphorylated histone variant H2AX (γ-H2AX), p53-binding protein 1 (53BP1) and phosphorylated KRAB-associated protein 1 (pKAP-1) foci and their linear tracks in human peripheral blood lymphocytes (HPBLs) in vitro exposed to radon and its progeny were dependent on the cumulative absorbed dose of radon exposure but was unrelated to the concentration of radon. Among them, γ-H2AX foci and its linear tracks were the most sensitive indicators with the lowest estimable cumulative absorbed dose of 1.74 mGy from their linear dose-response curves and sustained for 12 h after termination of radon exposure. In addition, three types of foci showed an overdispersed non-Poisson distribution in HPBLs. The ratios of pKAP-1/γ-H2AX foci co-localization, 53BP1/γ-H2AX foci co-localization and 53BP1/pKAP-1 foci co-localization were significantly increased in HPBLs exposed to radon while they were unrelated to the cumulative dose of radon exposure, suggesting that γ-H2AX, pKAP-1 and 53BP1 play an important role in the repair of heterochromatic double-strand breaks. Altogether, our findings provide an experimental basis for estimating the biological dose of internal α-particle irradiation from radon and its progeny exposure in humans.

Difference in the action mechanism of radon inhalation and radon hot spring water drinking in suppression of hyperuricemia in mice.

Although radon therapy is indicated for hyperuricemia, the underlying mechanisms of action have not yet been elucidated in detail. Therefore, we herein examined the inhibitory effects of radon inhalation and hot spring water drinking on potassium oxonate (PO)-induced hyperuricemia in mice. Mice inhaled radon at a concentration of 2000 Bq/m(3) for 24 h or were given hot spring water for 2 weeks. Mice were then administrated PO at a dose of 500 mg/kg. The results obtained showed that serum uric acid levels were significantly increased by the administration of PO. Radon inhalation or hot spring water drinking significantly inhibited elevations in serum uric acid levels through the suppression of xanthine oxidase activity in the liver. Radon inhalation activated anti-oxidative functions in the liver and kidney. These results suggest that radon inhalation inhibits PO-induced hyperuricemia by activating anti-oxidative functions, while hot spring water drinking may suppress PO-induced elevations in serum uric acid levels through the pharmacological effects of the chemical compositions dissolved in it.

Relative biological effectiveness of radon: An in vitro study using chromosome aberrations as a biomarker.

PURPOSE: The need to determine a reliable relative biological effectiveness (RBE) value for alpha exposures has become important as reports remain controversial. Although a radiation-weighting factor of 20 has been designated for alpha particles, uncertainty exists on realistic value of the RBE of alpha radiation. The aim of this study was to estimate RBE values for radon using chromosome aberrations as the endpoint in respect to various dose rates of gamma radiation. MATERIALS AND METHODS: Human blood samples were exposed ex vivo to different doses of radon ranging from 0.0011-0.008 Gy. Blood samples were also exposed to gamma radiation with dose rates of 1, 0.1, 0.01 and 0.001 Gy/min. Chromosome aberrations in giemsa-stained first division metaphase preparations were scored. RESULTS: Dose response curves for dicentric chromosomal aberration yields were generated for both radon and gamma rays. Radon dose rates were compared with gamma dose rates to deduce RBE values. The values obtained were 16, 25, 29 and 38 for reference gamma dose-rates of 1, 0.1, 0.01 and 0.001 Gy/min, respectively. CONCLUSIONS: The study indicates that an RBE value of radon can range between 16 and 38, if one were to consider chromosome aberrations as an effective biomarker of risk due to ionizing radiation.

Dosimetry of 223Ra-chloride: dose to normal organs and tissues.

PURPOSE: (223)Ra-Chloride (also called Alpharadin®) targets bone metastases with short range alpha particles. In recent years several clinical trials have been carried out showing, in particular, the safety and efficacy of palliation of painful bone metastases in patients with castration-resistant prostate cancer using (223)Ra-chloride. The purpose of this work was to provide a comprehensive dosimetric calculation of organ doses after intravenous administration of (223)Ra-chloride according to the present International Commission on Radiological Protection (ICRP) model for radium. METHODS: Absorbed doses were calculated for 25 organs or tissues. RESULTS: Bone endosteum and red bone marrow show the highest dose coefficients followed by liver, colon and intestines. After a treatment schedule of six intravenous injections with 0.05 MBq/kg of (223)Ra-chloride each, corresponding to 21 MBq for a 70 kg patient, the absorbed alpha dose to the bone endosteal cells is about 16 Gy and the corresponding absorbed dose to the red bone marrow is approximately 1.5 Gy. CONCLUSION: The comprehensive list of dose coefficients presented in this work will assist in comparing and evaluating organ doses from various therapy modalities used in nuclear medicine and will provide a base for further development of patient-specific dosimetry.

Antinociceptive effects of radon inhalation on formalin-induced inflammatory pain in mice.

Radon therapy is clinically useful for the treatment of inflammatory diseases. The mechanisms of pain relief remain to be fully elucidated. In this study, we investigated the antinociceptive effects of radon inhalation in a mouse model of formalin-induced inflammatory pain. Immediately, after radon inhalation at a concentration of background level (ca. 19 Bq/m(3)), 1,000 or 2,000 Bq/m(3) for 24 h, 1.35 % formalin (0.5 % formaldehyde in saline, 20 µl) was subcutaneously injected into the hind paw of mice, and we measured licking response time. Radon inhalation inhibited the second phase of response in formalin test. Formalin administration induced nociception and increased tumor necrosis factor alpha (TNF-α) and nitric oxide (NO) levels in serum and leukocyte migration in paws. Concurrently, formalin injection decreased antioxidative functions. Radon inhalation produced antinociceptive effects, i.e., lowered serum TNF-α and NO levels, and restored antioxidative functions. The results showed that radon inhalation inhibited formalin-induced inflammatory pain.

Radon.

Radon is a radioactive gas that emanates from uranium-bearing soil and porous rock. Although radon is most highly concentrated in areas of high uranium concentration, the presence of trace amounts of uranium in most ground sources means that all humans are exposed to radon to some degree. Radon migrates out of soil and rock into the surrounding air, resulting in accumulation in poorly ventilated or closed areas. Such areas represent the primary environments in which humans are exposed to radioactivity from radon to experience detrimental health effects. There is no convincing evidence that any cancers other than lung cancer are associated with exposure to radon. There is, on the other hand, consistent evidence of a substantially elevated risk of lung cancer among Canadians exposed to radon in certain occupational settings, particularly uranium mining. While the combined evidence for a positive association between residential radon exposure and lung cancer is less compelling, the inherent methodological difficulties in mounting such studies may render it impossible for any single study to detect the relationship more conclusively. The best available evidence to date from pooled analyses indicates a positive, but weak association between residential radon and lung cancer risk. Residential radon is of critical importance because it is ubiquitous; a small excess risk that may exist in relation to radon exposures encountered in a residential setting translates into the potential for a far greater number of excess cancers in the general population than does exposure of a relatively small number of miners, even though the latter may be exposed to much higher levels of ionizing radiation. Fortunately, a number of techniques are available to homeowners to reduce radon concentrations in their homes.

Radon-induced proteomic profile of lung tissue in rats.

The aim of this study was to investigate the differential expression of proteins in lung of rats following long-term exposure to radon. The total proteins of lung tissue from Wistar rats exposed to radon for cumulative doses up to 100, 200, or 400 WLM (working level months) were isolated by two-dimensional electrophoresis (2-DE) and analyzed with ImageMaster 2D Platinum software. Comparison of the 2-DE images between the control and radon-exposed groups resulted in 14 upregulated and 9 downregulated protein spots, of which 15 were identified by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) or matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry (MALDI-TOF/TOF-MS). The simultaneous up-expressions of RAGE and S100A6 indicated that both proteins might be applied as biomarkers for lung injury induced by long-term radon exposure.

Content of fibronectin and glycosaminoglycans in blood serum of rats with SiO2-induced inflammation after radon-containing water bath.

In animals with SiO(2)-induced inflammation, exposure in radon-containing water promoted normalization of fibronectin content on days 3 and 10 and reduced the content of glycosaminoglycans on days 3 and 20 compared to the corresponding values in intact animals and rats with SiO(2)-induced inflammation not exposed to radon.

Study on biologic effects of radon and thermal therapy on osteoarthritis.

UNLABELLED: Radon therapy uses radon (222Rn) gas, which mainly emits alpha-rays and induces a small amount of active oxygen in the body. We first examined the temporal changes in antioxidants, immune, vasoactive, and pain-associated substances in human blood by therapy to elucidate the mechanism of osteoarthritis in which radon therapy is used as a treatment. Results showed that radon inhalation enhanced the antioxidation and immune function, and the findings suggest that radon therapy contributes to the prevention of osteoarthritis related to peroxidation reactions and immune depression. Moreover, the changes in vasoactive and pain-associated substances indicated increases in tissue perfusion brought about by radon therapy, suggesting that radon inhalation plays a role in alleviating pain. PERSPECTIVE: The findings suggest that an appropriate amount of active oxygen is produced in the body after radon inhalation, and this contributes to the alleviation of the symptoms of active oxygen diseases such as osteoarthritis.

A consistent two-mutation model of lung cancer for different data sets of radon-exposed rats.

A two-mutation carcinogenesis model, formulated in terms of biologically motivated equations for mutation and expansion steps, has been applied in a mechanistic modelling of the lung cancer incidence in two large data sets of rats exposed to radon, both separately and jointly. Results indicate that (1) the equations employed are able to provide an accurate description of the separate data sets, (2) the parameters in the equations take on similar values for both data sets, and (3) it is possible to construct a consistent and well-fitting solution for the joint data set. It proved not to be necessary to take into account the effect of uranium ore dust, administered to part of the data or the different rat strains of the data sets. The joint solution provides a firm basis to investigate the effects of exposure, exposure rate and age at exposure on cumulative incidence, excess relative risk and excess absolute risk. For the same total exposure, cumulative incidence reaches a maximum for exposure rates between 1 and 10 WLM per day. The so-called inverse-exposure-rate effect acts for higher exposure rates. The influence of age at exposure, however, seems to be even more pronounced. Exposure at a young age leads to considerably higher incidences than exposure at a later age. Parameters derived in this study compare fairly well with those derived for uranium miners, suggesting that a consistent model description for the induction of lung cancer by radon in rats and humans may be possible.

Low radon doses sensitize MCF-7 human breast cancer cells to taxol.

We studied whether human breast cancer cells show increased sensitivity to the chemotherapeutic agent taxol when they have been treated with low radiation doses (1.7-3.2 x 10(-3) Gy) from the gas radon. To this end, MCF-7 cells were cultivated in a medium either with or without dissolved radon for 3 days and then exposed to taxol (50 nM). Cells exposed to low doses of radon and then to a concentration of 50 nM of taxol exhibit a lower proliferation rate and a lower viability than cells treated with the same concentration of taxol but not irradiated. These findings indicate an important interaction of radon and taxol in the inhibition of MCF-7 cell growth.

[Free radical processes in combined chronic inhalation effect of xenobiotics on the rat]. / Vil'noradykal'ni protsesy za sumisnoï khronichnoï ingaliatsiinoï diï ksenobiotykiv na organizm shchuriv.

The chronic combined inhalation influence of nitric oxides (II, IV), amorphic hydrophobic silicon dioxide, lead and radon on the free radical processes intensively was investigated. The dienic conjugates, lipid hydroperoxides and MDA concentration in the liver and kidney of the white mongrel male-rats was defined. It has been shown that lipid peroxidation process displaies sensitivity toward complex exposure of the most wide-spreader xenobiotics. It was expressed in the content decreasing of there products at the first step of our experience as a result of the action of the adaptive and compensative mechanisms directed to the suppression of the peroxidation processes. As a result of the antioxidant system powers exhaustion it was found the content rising of the lipid peroxidation products at the last step of our experience. It has been proposed to use the total content index of the lipid peroxidation products as a criteria of the organism resistant ion toward action of the exogenic factors of various origin.

[Combined action of xenobiotics on the status of the antioxidant system of the body]. / Sumisna diia ksenobiotykiv na stan antyokydantnoï systemy organizmu.

The chronic combined inhalational effect of lead, radon, nitric oxides (NO, NO2) and amorphous hydrophobic silicon dioxide on the activity of enzymes such as superoxide dismutase, catalase, glutathione peroxidase, glutathione-s-transferase, g-glutamyl transpeptidase, peroxidases and also on the protein reducing glutathione concentration of the mongrel male-rat was investigated. It has been shown that organism antioxidant system displaces activity toward of the most widespread xenobiotics, expressing the rising of itself activity during whole experience. The dynamic of changes of the antioxidant system activity also was analyzed. Moreover, at the first step of our experience there was the sharp activity rise as a result of action of the mechanisms of adaptation and compensation. At the following intermediate step we were observing exhaustion of the antioxidant system and including of additional powers at the last step.

Modeling radioprotective mechanisms in the dose effect relation at low doses and low dose rates of ionizing radiation.

A new model (Random Coincidence Model--Radiation Adapted (RCM-RA)) is proposed which explains a possible pseudo threshold for stochastic radiation effects. It describes the formation of cancer in the case of multistep fixation of lesions in the critical regions of tumor associated genes such as proto-oncogenes or tumor-suppressor genes. The RCM-RA contains two different possibilities of DNA damage to complementary nucleotides. The damage may be caused either by radiation or by natural processes such as cellular radicals or thermal damage or by chemical cytotoxins. The model is based on the premise that radiation initially is bionegative, damaging organisms at their different levels of organization. The radiation, however, also induces various cellular radioprotective mechanisms which decrease the damage by natural processes. Considering both effects together, the theory explains apparent thresholds in the dose-response relation for radiation carcinogenesis without contradiction to the classical assumption that radiation is predominantly bionegative at doses typically found in occupational exposures.

Influence of low doses of radiation due to 222Rn on proliferation of fibroblasts and MCF-7 human breast cancer cells in vitro.

The aim of the present study is to analyze the effects of low doses of radiation due to radon (within the range present in the environment) in the proliferation of normal (fibroblasts) and tumoral (MCF-7 human breast cancer cells) mammalian cells. Both fibroblast and MCF-7 cells were incubated in culture media with different levels of radon (doses of 10-15 000 microGy), or non-radon (control). After incubation the number of cells per plate was measured with a hemocytometer. The dissolution of radon in the culture media decreased the proliferation of MCF-7 cells (not the fibroblasts). Within the range of doses used in this experiment, the lowest as well as the highest doses of radiation had the lowest antiproliferative effects. Intermediate doses strongly decreased the number of final cells with respect to those in the control population.