Assessment of the effects of repeated doses of potassium iodide intake during pregnancy on male and female rat offspring using metabolomics and lipidomics.

Preparedness for nuclear accident responsiveness includes interventions to protect pregnancies against prolonged exposure to radioactive iodine. The aim of this study was to investigate a new design consisting of repeated administration of potassium iodide (KI, 1 mg/kg) for 8 days in late pregnancy gestational day 9-16 (GD9-GD16) in rats. The later-life effects of this early-life iodine thyroid blocking (ITB) strategy were assessed in offspring two months afterbirth. Functional behavioral tests including forced swimming test (FST) and rotarod test (RRT) in rats of both genders showed lower FST performance in KI-treated females and lower RRT performance in KI-treated male pups. This performance decline was associated with metabolic disruptions in cortex involving amino acid metabolism, tyrosine metabolism, as well as docosahexaenoic acid (DHA) lipids and signaling lipids in males and females. Beyond these behavior-associated metabolic changes, a portion of the captured metabolome (17-25%) and lipidome (3.7-7.35%) remained sensitive to in utero KI prophylactic treatment in both cortex and plasma of post-weaning rats, with some gender-related variance. Only part of these disruptions was attributed to lower levels of TSH and T4 (males only). The KI-induced metabolic shifts involved a broad spectrum of functions encompassing metabolic and cell homeostasis and cell signaling functions. Irrespective Regardless of gender and tissues, the predominant effects of KI affected neurotransmitters, amino acid metabolism, and omega-3 DHA metabolism. Taken together, data demonstrated that repeated daily KI administration at 1 mg/kg/day for 8 days during late pregnancy failed to protect the mother-fetus against nuclear accident radiation. Abbreviations: CV-ANOVA: Cross-validation analysis of variance; DHA: Docosahexaenoic acid; FST: Forced swimming test; FT3: plasma free triiodothyronine; FT4: plasma free thyroxine; GD: Gestational day; ITB: Iodine thyroid blocking; KI: potassium iodide; LC/MS: Liquid chromatography coupled with mass spectrometry; MTBE: Methyl tert-butyl ether; m/z: mass-to-charge ratio; PLS-DA: Partial least squares-discriminant analysis; PRIODAC: Repeated stable iodide prophylaxis in accidental radioactive releases; RRT: Rotarod test; TSH: Thyroid-stimulating hormone; VIP: Variable importance in projection.

Imaging neuronal pathways with 52Mn PET: Toxicity evaluation in rats.

Manganese in its divalent state (Mn2+) has features that make it a unique tool for tracing neuronal pathways. It is taken up and transported by neurons in an activity-dependent manner and it can cross synapses. It also acts as a contrast agent for magnetic resonance imaging (MRI) enabling visualization of neuronal tracts. However, due to the limited sensitivity of MRI systems relatively high Mn2+ doses are required. This is undesirable, especially in long-term studies, because of the known toxicity of the metal. In order to overcome this limitation, we propose 52Mn as a positron emission tomography (PET) neuronal tract tracer. We used 52Mn for imaging dopaminergic pathways after a unilateral injection into the ventral tegmental area (VTA), as well as the striatonigral pathway after an injection into the dorsal striatum (STR) in rats. Furthermore, we tested potentially noxious effects of the radioactivity dose with a behavioral test and histological staining. 24 h after 52Mn administration, the neuronal tracts were clearly visible in PET images and statistical analysis confirmed the observed distribution of the tracer. We noticed a behavioral impairment in some animals treated with 170 kBq of 52Mn, most likely caused by dysfunction of dopaminergic cells. Moreover, there was a substantial DNA damage in the brain tissue after applying 150 kBq of the tracer. However, all those effects were completely eliminated by reducing the 52Mn dose to 20-30 kBq. Crucially, the reduced dose was still sufficient for PET imaging.

[Simulation of Radionuclide Behaviour in Terrestrial Ecosystems in Studies of Ecological Consequences of Accident at Chernobyl NPP].

The article analyzes the results of using the imitation modeling method for the study, prediction and recon- struction processes of radionuclide. behaviour in terrestrial ecosystems after the Chernobyl accident. Also discussed are some additional issues associated with the application of this method and perspectives of radio- ecological modeling.

[Composition and Density of Soil Fauna in the Region with Enhanced Radioactivity Level (Komi Republic, Vodnyi)].

Studies on the influence of high levels of radiation on soil fauna were carried out in 2012 in the territory formed as a result of the activity of the enterprise for extraction and production of radium from reservoir water and waste of uranium ore from 1931 to 1956. At present the local radioactive pollution in this area is caused by the presence of heavy natural radionuclides 226Ra, 238U and products of their disintegration in soils. The oppression of soil invertebrate.fauna in pine forests and meadows with high levels of radionuclides and heavy metals is revealed. Also shown is the decrease in the number and density of different taxonomic groups of invertebrates, reduction of the diversity and spectrum of trophic groups and vital forms in the area with a high content of radionuclides in soil. Our results are in agreement with the results obtained by the similar studies showing negative influence of high-level ionizing radiation on soil fauna.

[Radiation doses and allozyme variability in the population of the northern red-backed vole (Clethrionomys rutilus) from the east urals radioactive trace zone].

The paper estimates the external (due to radionuclides accumulated in the soil) and internal (due to incorporated radionuclides) exposure of rodents that live in the head of the East Urals Radioactive Trace (EURT). It is shown that in the last decades the dose rates were lower than the values that lead to doubling the number of mutations in the allozyme loci in mammals. The variability ofthe eight allozyme loci in populations of northern red-backed voles from the EURT zone and their neighboring plots, as well as the territories of the Urals and Trans-Urals with background levels of radioactive contamination, are analyzed. No differences in the pattern and frequency of allozymes that would distinguish the EURT samples from a number of other populations of the Urals, were found. In the control sample "Sysert", "unique" for the Ural populations of northern red-backed voles, alleles of the loci Got and Sod were marked, conspecific to a closely related species--the bank vole. This fact can be regarded as evidence of recent cross-species hybridization.

Systematic review: Progression of beryllium sensitization to chronic beryllium disease.

BACKGROUND: The relevance of beryllium sensitization testing for occupational health practice and prevention is unclear. AIMS: To analyse the natural course of beryllium sensitization and clarify the prognosis following cessation of exposure among sensitized workers. METHODS: An electronic literature search was conducted in PubMed, Embase, Toxline and Cochrane databases supplemented by a manual search. Data abstraction and study quality assessment with adapted guideline checklists were performed independently by three reviewers. Seven studies met the eligibility criteria and were included in the systematic review; however, six of the seven studies were of low methodological quality. RESULTS: A substantial (although not specifically quantifiable) proportion of beryllium-sensitized employees will develop chronic beryllium disease (CBD). To date, it is unknown if cessation of exposure in sensitized workers reduces the progression rate to CBD. CONCLUSIONS: To determine the utility of regular assessments for beryllium sensitization among exposed workers, there is a need for prospective studies. This should include detailed and continuous exposure monitoring, regular tests for beryllium sensitization and a thorough diagnostic evaluation of sensitized workers to confirm or exclude CBD.

[Substantiation of radio-ecological monitoring of forest ecosystems at various stages after the accident radioactive fallout].

This study analyzes the long-term dynamics of distribution ofradionuclides in forest ecosystems. Three stages in the formation of radio-ecological situation in the forests are distinguished. Proposals for optimization of sampling for radio-ecological monitoring of forest ecosystems at various periods after a radiation accident are formulated.

[The role of radiation and non-radiation factors in the development and progression of acute leukemia in children].

At 278 ALL and AML patients the kind of hereditary pathology in the family; clinikal-laboratory features and a course of acute leukemia and terms of longevity of children were studied. Degree of integrated pollution of territory (air, water, soil) by heavy metals and radionuclides and also the irradiation doses have been considered. Results which have been received testify about the certain contribution of genetic components and adverse factors of environment in of development of acute leukemia and their course at children. The definition of different leukemogenic factors action on the condition of hemopoietic system gives the chance to generate the abnormally high risk groups of oncological hematological pathologies among the children's population and to improve the diagnostic and treatment-and-prophylactic actions.

Dose-Limiting Bone Marrow Toxicities After Peptide Receptor Radionuclide Therapy Are More Prevalent in Women Than in Men.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) can cause dose-limiting toxicities (DLTs) of the bone marrow, liver, and kidneys. It is yet unknown whether women and men are equally at risk of these DLTs. METHODS: Neuroendocrine tumor patients treated with 177Lu-DOTATATE between 2000 and 2015 in our phase II trial with available laboratory data were included. For all DLTs, the highest Common Terminology Criteria for Adverse Events (version 4.03) grades that occurred from the start of PRRT until 3 months after the last cycle were scored. RESULTS: At baseline, women (n = 439) had a significantly lower body mass index, Karnofsky Performance Score, hemoglobin level, and creatinine clearance and a significantly higher platelet level than men (n = 534). Both groups received a median activity of 29.6 GBq (800 mCi). After the start of PRRT, women more frequently developed grade ≥2 thrombocytopenia compared with men (25% vs 18%, P = 0.004) due to a significant increase in grade ≥3 thrombocytopenia (11% vs 6%, P = 0.008). Furthermore, the incidence of grade ≥3 anemia was higher in women (7% vs 3%, P = 0.002). In the multivariable regression model, female sex (odds ratio, 2.50; 95% confidence interval, 1.67-3.74) was confirmed to be an independent risk factor for grade ≥2 thrombocytopenia, among baseline platelet count, bone metastases, uptake on 111In-DTPA-octreotide scan, Karnofsky Performance Score, alkaline phosphatase, lymphocytes, albumin, and renal function. CONCLUSIONS: Female neuroendocrine tumor patients more often experienced PRRT-induced toxicities of platelets and hemoglobin than males, but this did not lead to a lower cumulative activity.

Human health risk assessment of environmental and dietary exposure to natural radionuclides in the Catalan stretch of the Ebro River, Spain.

This study was aimed at assessing the levels of 210Pb and 210Po concentrations as well as gross alpha and beta activities in environmental monitors from the Catalan stretch of the Ebro River (Spain), potentially influenced by the presence of sediments with high concentrations of 238U and its decay chain daughters in the Flix reservoir. The chronic daily intake of 210Pb and 210Po through ingestion and inhalation of soils was evaluated, and the derived non-carcinogenic and carcinogenic risks were characterized. The low concentration of radioisotopes in soils resulted in a negligible annual effective dose. The levels of 210Pb and 210Po were determined in various groups of highly consumed food (fish and seafood, vegetables, fruits, and rice), and their dietary intake was calculated. The annual effective dose for the adult people from food intake was estimated in 3.3×10(-2) mSv, mostly due to 210Po. Overall, the current radioactivity levels in the Catalan stretch of the Ebro River should not mean any additional health risk for the population living nearby. However, an integral assessment of the risks derived from exposure to other pollutants (e.g., metals and organochlorine compounds) jointly with radionuclides could be of great interest.

Denitrifying bacteria isolated from terrestrial subsurface sediments exposed to mixed-waste contamination.

In terrestrial subsurface environments where nitrate is a critical groundwater contaminant, few cultivated representatives are available to verify the metabolism of organisms that catalyze denitrification. In this study, five species of denitrifying bacteria from three phyla were isolated from subsurface sediments exposed to metal radionuclide and nitrate contamination as part of the U.S. Department of Energy's Oak Ridge Integrated Field Research Challenge (OR-IFRC). Isolates belonged to the genera Afipia and Hyphomicrobium (Alphaproteobacteria), Rhodanobacter (Gammaproteobacteria), Intrasporangium (Actinobacteria), and Bacillus (Firmicutes). Isolates from the phylum Proteobacteria were complete denitrifiers, whereas the Gram-positive isolates reduced nitrate to nitrous oxide. rRNA gene analyses coupled with physiological and genomic analyses suggest that bacteria from the genus Rhodanobacter are a diverse population of denitrifiers that are circumneutral to moderately acidophilic, with a high relative abundance in areas of the acidic source zone at the OR-IFRC site. Based on genome analysis, Rhodanobacter species contain two nitrite reductase genes and have not been detected in functional-gene surveys of denitrifying bacteria at the OR-IFRC site. Nitrite and nitrous oxide reductase gene sequences were recovered from the isolates and from the terrestrial subsurface by designing primer sets mined from genomic and metagenomic data and from draft genomes of two of the isolates. We demonstrate that a combination of cultivation and genomic and metagenomic data is essential to the in situ characterization of denitrifiers and that current PCR-based approaches are not suitable for deep coverage of denitrifiers. Our results indicate that the diversity of denitrifiers is significantly underestimated in the terrestrial subsurface.

[Cytological and cytogenetic damages of spermatogonial cells in mice in the acute and late periods after irradiation by protons, helium ions, and gamma-rays].

Experiments with small test animals have been carried out to study the survival rate of spermatogenic cells in the acute period after exposure to protons with the energy 9 GeV, helium ions with the energy 4 GeV/nucleon, and 60Co gamma radiation in doses of 0.5-7.5 Gy and the reciprocal translocation frequency in spermatocytes under meiosis at the diakinesis-metaphase-1 stage six months after the exposure of the animals to protons with the energy 50 MeV and 9 GeV, helium ions with the energy 4 GeV/nucleon, and 60Co gamma-radiation in doses of 0.5-4.0 Gy. It is shown that the dependence of the effect on the dose is linear or near to linear for all kinds of radiation used. Relative biological effectiveness coefficients of the accelerated nuclei obtained by correlating equally effective doses of the standard and investigated radiations turned out to be higher in survival rate of type B spermatogonium and amounted to 2.0 and 1.3 for 9 GeV protons and helium ions respectively. At the same time, the use of the nonparametric method to determine the RBE coefficients in the course of finding out the reciprocal translocation frequency in spermatocytes points to an increase in the RBE coefficients of charged particles from 1.0 to 2.0.

[Comparative characteristic of fatty acid content of lipids from expired air condensate in children with recurrent bronchitis residing in radiative contaminated territories and "clear" regions concerning radionuclide contamination].

The differences in the fat acid spectrum of expired air condensate in children with recurrent bronchitis who are residents of the radiation contaminated territories and children with analogous diagnosis living in the "clear" region regarding the radionuclide contamination consisted in the increased saturation of lipid complex indices against the decrease in content of polyunsaturated fat acids, antioxidant properties of pulmonary surfactant and activity of adaptation-compensatory processes in lipid bilayer of its membrane structures.

Quantitative encapsulation and retention of 227Th and decay daughters in core-shell lanthanum phosphate nanoparticles.

Targeted alpha therapy (TAT) offers great promise for treating recalcitrant tumors and micrometastatic cancers. One drawback of TAT is the potential damage to normal tissues and organs due to the relocation of decay daughters from the treatment site. The present study evaluates La(227Th)PO4 core (C) and core +2 shells (C2S) nanoparticles (NPs) as a delivery platform of 227Th to minimize systemic distribution of decay daughters, 223Ra and 211Pb. In vitro retention of decay daughters within La(227Th)PO4 C NPs was influenced by the concentration of reagents used during synthesis, in which the leakage of 223Ra was between 0.4 ± 0.2% and 20.3 ± 1.1% in deionized water. Deposition of two nonradioactive LaPO4 shells onto La(227Th)PO4 C NPs increased the retention of decay daughters to >99.75%. The toxicity of the nonradioactive LaPO4 C and C2S NP delivery platforms was examined in a mammalian breast cancer cell line, BT-474. No significant decrease in cell viability was observed for a monolayer of BT-474 cells for NP concentrations below 233.9 µg mL-1, however cell viability decreased below 60% when BT-474 spheroids were incubated with either LaPO4 C or C2S NPs at concentrations exceeding 29.2 µg mL-1. La(227Th)PO4 C2S NPs exhibit a high encapsulation and in vitro retention of radionuclides with limited contribution to cellular cytotoxicity for TAT applications.

Nickel-63 microirradiators.

Here we report the fabrication of two types of microirradiators, consisting of a recessed disk and protruding wire with low-beta-energy radionuclide Ni-63 electrodeposited onto a 25 microm diameter Pt wire. Ni-63 is constricted to a small surface area of the microelectrode; hence, this tool provides a means of delivery of localized, large dose density of beta radiation to the object but a minimal dose exposure to the user. The activity levels of Ni-63 emitted from the recessed disk and protruding wire are 0.25 and 1 Bq, respectively. The corresponding beta particles flux levels emitted from the recessed disk and protruding wire are 51 and 11 kBq/cm(2), respectively. These values, measured experimentally using liquid scintillation counting, fit very well the expected values of activity for each microirradiator, calculated considering the self-absorption effect, typical for low-energy beta particles. In order to determine the optimal configuration the dose rates for varying distances from the object were calculated.

Phase II study of transarterial holmium-166-chitosan complex treatment in patients with a single, large hepatocellular carcinoma.

PURPOSE: Holmium-166 ((166)Ho) is a neutron-activated radioactive isotope whose effectiveness in hepatocellular carcinoma (HCC) was first reported in a preclinical study in 1991. Chitosan is a polymer of 2-deoxy-2-amino-D-glucose that readily forms a chelate with heavy metals and converts from a solution under acidic conditions into a gel under neutral or basic conditions. We performed a prospective trial of a transarterial administration of a radiopharmaceutical (166)Ho-chitosan complex in patients with single, large HCC. PATIENTS AND METHODS: The study involved 54 patients who had single HCC (>or=3 cm) without a vascular shunt and were either inoperable or refused surgery. The (166)Ho-chitosan complex was administered at a dose of 20 mCi per cm of tumor diameter (capping at 200 mCi) via the artery that directly fed the tumor. RESULTS: The median tumor size was 5.3 cm (range: 3-13 cm). The response rate was 78% (42/54), and 31 patients had a complete response for a median duration of 27 months. The incidence of grade 3 or 4 leukopenia was 18.6%, anemia 7.4%, thrombocytopenia 27.8%, AST/ALT elevation 26%/24%, and total bilirubin elevation 5.6%. There were two treatment-related deaths (3.7%). Subset analysis revealed a substantial difference between the two groups categorized by tumor size (3-5 vs. >5 cm) with respect to response rate (p = 0.004) and overall survival (p = 0.02). CONCLUSION: We found that transarterial administration of the (166)Ho-chitosan complex was highly effective in the treatment of HCC with acceptable toxicities, especially for patients with tumors of 3-5 cm.

Radionuclides in cigarettes may lead to carcinogenesis via p16(INK4a) inactivation.

It is widely accepted that tobacco smoke is responsible for the vast majority of lung cancers worldwide. There are many known and suspected carcinogens present in cigarette smoke, including alpha-emitting radioisotopes. Epidemiologic studies have shown that increased lung cancer risk is associated with exposure to ionizing radiation, and it is estimated that the majority of smoking-induced lung cancers may be at least partly attributable to the inhaled and deposited radiation dose from radioisotopes in the cigarette smoke itself. Recent research shows that silencing of the tumor suppressor gene p16(INK4a) (p16) by promoter methylation plays a role in smoking-related lung cancer. Inactivation of p16 has also been associated with lung cancer incidence in radiation-exposed workers, suggesting that radionuclides in cigarette smoke may be acting with other compounds to cause smoking-induced lung cancer. We evaluated the mechanism of ionizing radiation as an accepted cause of lung cancer in terms of its dose from tobacco smoke and silencing of p16. Because both radiation and cigarette smoking are associated with inactivation of p16, and p16 inactivation has been shown to play a major role in carcinogenesis, ionizing radiation from cigarette smoke likely plays a role in lung cancer risk. How large a role it plays, relative to chemical carcinogens and other modes of action, remains to be elucidated.

Alpha emitting radionuclides in drainage from Quinta do Bispo and Cunha Baixa uranium mines (Portugal) and associated radiotoxicological risk.

Two large uranium mines, Quinta do Bispo and Cunha Baixa, district of Viseu, North of Portugal, were exploited until 1991. Sulfuric acid was used for in situ uranium leaching in Cunha Baixa mine and for heap leaching of low grade ores at both mines. Large amounts of mining and milling residues were accumulated nearby. Since closure of mines, the treatment of acid mine waters has been maintained and treated water is released into surface water lines. Analysis of radionuclides in the soluble phase and in the suspended matter of water samples from the uranium mines, from the creeks receiving the discharges of mine effluents, from the rivers and from wells in this area, show an enhancement of radioactivity levels. For example, downstream the discharge of mine effluents into Castelo Stream, the concentrations of dissolved uranium isotopes and uranium daughters were up to 14 times the concentrations measured upstream; (238)U concentration in suspended particulate matter of Castelo Stream reached 72 kBq kg(-1), which is about 170 times higher than background concentrations in Mondego River. Nevertheless, radionuclide concentrations decreased rapidly to near background values within a distance of about 7 kilometers from the discharge point. Enhancement of radioactivity in underground waters was positively correlated with a decrease in water pH and with an increase of sulfate ion concentration, pointing out to Cunha Baixa mine as the source of groundwater contamination. The radiotoxic exposure risk arising from using these well waters as drinking water and as irrigation water is discussed and implementation of environmental remediation measures is advised.

EFFECT OF ADDITIONAL ACUTE IRRADIATION ON CYTOMORPHOLOGICAL ABNORMALITIES OF ERYTHROCYTES OF THE PRUSSIAN CARP (CARASSIUS GIBELIO BLOCH) FROM WATER BODY CONTAMINATED WITH RADIONUCLIDES. / VPLYV DODATKOVOGO GOSTROGO OPROMINENNIa NA TsYTOMORFOLOGIChNI PORUShENNIa ERYTROTsYTIV KARASIa SRIBLIaSTOGO (CARASSIUS GIBELIO BLOCH) IZ ZABRUDNENOÏ RADIONUKLIDAMY VODOY̆MY.

OBJECTIVE: Assessment of the effect of additional acute irradiation (AAI) in sub-lethal range on the peculiarities of formation of qualitative composition of red blood and adaptive possibilities of the hematopoietic system of fish in reservoirs within the Chernobyl Exclusion Zone (CEZ), contaminated with radionuclides. MATERIALS AND METHODS: We studied the Prussian carp Carassius gibelio Bloch (2-3 years old) from Vershyna Lake (impacted reservoir in the CEZ) and Dibrova Lake (reference reservoir), where the average absorbed dose rate (ADR) was, respectively, 110.80 and 0.07 µGy/h. The fish were exposed by a single X-ray dose at the unit RUM-17 (ADR - 0.89 Gy/min) at dose of 2.5, 5.0 and 10.0 Gy. Morphological and cytogenetic studies of red blood cells were per- formed dynamically for the 1st, 7th and 30th day after irradiation. The blood was taken from the tail vein and stained by Pappenheim's method. Cytomorphological abnormalities of erythrocytes were analyzed for 3000 cells (‰). RESULTS: In blood of fish from the impacted reservoir (Vershyna Lake) on the 1st day after AAI, the average number of all types of deformations of erythrocytes cells increased in 2.1 times, and in fish of the reference reservoir (Dibrova Lake) - in 5.2 times. General spectrum of erythrocyte disturbances in fish of Vershyna Lake has increased from 4 to 6 types (in 1.5 times), and Dibrova Lake - from 2 to 5 types (in 2.5 times). However, further observations of the dynamics of morphological disorders of fish's blood cells from Vershyna Lake on the 7th and the 30th day after AAI showed a significant increase in pathological processes in comparison with the reference reservoir, namely - an increase in the number of gross damage of DNA molecules - amitosis (on average in 14.8 times), erythrocytes with septum in the nucleus (in 1.9 times), as well as structural disorders in the cells - protuberances (in 10.5 times), cells with vacuolate cytoplasm (in 8.6 times). CONCLUSIONS: The red blood cells of the fish of the impacted reservoir show a greater vulnerability to AAI, which manifests itself in an increase in the number of erythrocytes with pathology of mitosis and may indicate a violation of the genetic structures of cells due to long-term radiation exposure.