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Sample records for chronic low-dose exposure

  1. [The advance of model of action in low-dose chronic benzene exposure induced hematotoxicity].

    PubMed

    Gao, Chen; Zhang, Zhengbao; Chen, Liping; Chen, Wen

    2015-09-01

    Benzene is classified as Group 1 carcinogen by IARC. It has been found that benzene induces hematotoxicity even in low dose exposure. The identification of key events during benzene induced hematotoxicty leads to adjustment of occupational exposure limits of benzene. In this review, we focus on the exposure, metabolism, target organs, key epigenetic changes, toxicty effects and end points of low-dose chronic benzene exposure induced hematotoxicity and finally discuss the perspectives on the future study of this area.

  2. Micro RNA responses to chronic or acute exposures to low dose ionizing radiation

    PubMed Central

    Chaudhry, M. Ahmad; Omaruddin, Romaica A.; Kreger, Bridget; de Toledo, Sonia M.; Azzam, Edouard I.

    2014-01-01

    Human health risks of exposure to low dose ionizing radiation remain ambiguous and are the subject of intense debate. A wide variety of biological effects are induced after cellular exposure to ionizing radiation, but the underlying molecular mechanism(s) remain to be completely understood. We hypothesized that low dose c-radiation-induced effects are controlled by the modulation of micro RNA (miRNA) that participate in the control of gene expression at the posttranscriptional level and are involved in many cellular processes. We monitored the expression of several miRNA in human cells exposed to acute or chronic low doses of 10 cGy or a moderate dose of 400 cGy of 137Cs γ-rays. Dose, dose rate and time dependent differences in the relative expression of several miRNA were investigated. The expression patterns of many miRNA differed after exposure to either chronic or acute 10 cGy. The expression of miRNA let-7e, a negative regulator of RAS oncogene, and the c-MYC miRNA cluster were upregulated after 10 cGy chronic dose but were downregulated after 3 h of acute 10 cGy. The miR-21 was upregulated in chronic or acute low dose and moderate dose treated cells and its target genes hPDCD4, hPTEN, hSPRY2, and hTPM1 were found to be downregulated. These findings provide evidence that low dose and dose rate c-irradiation dictate the modulation of miRNA, which can result in a differential cellular response than occurs at high doses. This information will contribute to understanding the risks to human health after exposure to low dose radiation. PMID:22367372

  3. Neurotoxicity of chronic low-dose exposure to organic solvents: a skeptical review.

    PubMed

    Lees-Haley, P R; Williams, C W

    1997-11-01

    The health effects of long-term, low-level exposure to organic solvents have been studied for many years. While the volume of literature is great, definitive conclusions regarding chronic neurobehavioral effects of environmental exposure are premature. Methodological shortcomings in research preclude confidence in studies allegedly supporting a causal link between chronic low-dose solvent exposure and lasting neurobehavioral deficits. In this article, the shortcomings reviewed include selection bias in recruitment of research subjects, overreliance on subjective recall in determining levels and duration of exposure, between-study variability in kinds of solvents examined, variability in tests selected to assess neurobehavioral functioning, and diversity in reported findings. The implications of these for characterizing the state of organic solvent research are discussed.

  4. Chronic exposure of low dose salinomycin inhibits MSC migration capability in vitro.

    PubMed

    Scherzad, Agmal; Hackenberg, Stephan; Froelich, Katrin; Rak, Kristen; Hagen, Rudolf; Taeger, Johannes; Bregenzer, Maximillian; Kleinsasser, Norbert

    2016-03-01

    Salinomycin is a polyether antiprotozoal antibiotic that is used as a food additive, particularly in poultry farming. By consuming animal products, there may be a chronic human exposure to salinomycin. Salinomycin inhibits the differentiation of preadipocytes into adipocytes. As human mesenchymal stem cells (MSC) may differentiate into different mesenchymal cells, it thus appeared worthwhile to investigate whether chronic salinomycin exposure impairs the functional properties of MSC and induces genotoxic effects. Bone marrow MSC were treated with low-dose salinomycin (100 nM) (MSC-Sal) for 4 weeks, while the medium containing salinomycin was changed every other day. Functional changes were evaluated and compared to MSC without salinomycin treatment (MSC-control). MSC-Sal and MSC-control were positive for cluster of differentiation 90 (CD90), CD73 and CD44, and negative for CD34. There were no differences observed in cell morphology or cytoskeletal structures following salinomycin exposure. The differentiation into adipocytes and osteocytes was not counteracted by salinomycin, and proliferation capability was not inhibited following salinomycin exposure. The migration of MSC-Sal was attenuated significantly as compared to the MSC-control. There were no genotoxic effects after 4 weeks of salinomycin exposure. The present study shows an altered migration capacity as a sign of functional impairment of MSC induced by chronic salinomycin exposure. Further in vitro toxicological investigations, particularly with primary human cells, are required to understand the impact of chronic salinomycin consumption on human cell systems.

  5. Chronic exposure of low dose salinomycin inhibits MSC migration capability in vitro

    PubMed Central

    SCHERZAD, AGMAL; HACKENBERG, STEPHAN; FROELICH, KATRIN; RAK, KRISTEN; HAGEN, RUDOLF; TAEGER, JOHANNES; BREGENZER, MAXIMILLIAN; KLEINSASSER, NORBERT

    2016-01-01

    Salinomycin is a polyether antiprotozoal antibiotic that is used as a food additive, particularly in poultry farming. By consuming animal products, there may be a chronic human exposure to salinomycin. Salinomycin inhibits the differentiation of preadipocytes into adipocytes. As human mesenchymal stem cells (MSC) may differentiate into different mesenchymal cells, it thus appeared worthwhile to investigate whether chronic salinomycin exposure impairs the functional properties of MSC and induces genotoxic effects. Bone marrow MSC were treated with low-dose salinomycin (100 nM) (MSC-Sal) for 4 weeks, while the medium containing salinomycin was changed every other day. Functional changes were evaluated and compared to MSC without salinomycin treatment (MSC-control). MSC-Sal and MSC-control were positive for cluster of differentiation 90 (CD90), CD73 and CD44, and negative for CD34. There were no differences observed in cell morphology or cytoskeletal structures following salinomycin exposure. The differentiation into adipocytes and osteocytes was not counteracted by salinomycin, and proliferation capability was not inhibited following salinomycin exposure. The migration of MSC-Sal was attenuated significantly as compared to the MSC-control. There were no genotoxic effects after 4 weeks of salinomycin exposure. The present study shows an altered migration capacity as a sign of functional impairment of MSC induced by chronic salinomycin exposure. Further in vitro toxicological investigations, particularly with primary human cells, are required to understand the impact of chronic salinomycin consumption on human cell systems. PMID:26998269

  6. Low-dose, Chronic Exposure to Silver Nanoparticles Causes Mild Mitochondrial Alterations in the Liver of Sprague-Dawley Rat

    DTIC Science & Technology

    2014-05-10

    AFRL-AFOSR-UK-TR-2014-0032 Low-dose, chronic exposure to silver nanoparticles causes mild mitochondrial alterations in the liver ...TITLE AND SUBTITLE Low-dose, chronic exposure to silver nanoparticles causes mild mitochondrial alterations in the liver of Sprague-Dawley rat 5a...alterations were found in heart and kidney levels, and despite the fact that the alterations found in liver mitochondria did not appear to compromise ATP

  7. Chronic exposure to low dose bacterial lipopolysaccharide inhibits leptin signaling in vagal afferent neurons.

    PubMed

    de La Serre, Claire B; de Lartigue, Guillaume; Raybould, Helen E

    2015-02-01

    Bacterially derived factors are implicated in the causation and persistence of obesity. Ingestion of a high fat diet in rodents and obesity in human subjects is associated with chronic elevation of low plasma levels of lipopolysaccharide (LPS), a breakdown product of Gram-negative bacteria. The terminals of vagal afferent neurons are positioned within the gut mucosa to convey information from the gut to the brain to regulate food intake and are responsive to LPS. We hypothesized that chronic elevation of LPS could alter vagal afferent signaling. We surgically implanted osmotic mini-pumps that delivered a constant, low-dose of LPS into the intraperitoneal cavity of rats (12.5 μg/kg/hr for 6 weeks). LPS-treated rats developed hyperphagia and showed marked changes in vagal afferent neuron function. Chronic LPS treatment reduced vagal afferent leptin signaling, characterized by a decrease in leptin-induced STAT3 phosphorylation. In addition, LPS treatment decreased cholecystokinin-induced satiety. There was no alteration in leptin signaling in the hypothalamus. These findings offer a mechanism by which a change in gut microflora can promote hyperphagia, possibly leading to obesity.

  8. Chronic exposure of adult rats to low doses of methylmercury induced a state of metabolic deficit in the somatosensory cortex.

    PubMed

    Kong, Hang-Kin; Wong, Ming-Hung; Chan, Hing-Man; Lo, Samuel Chun-Lap

    2013-11-01

    Because of the ever-increasing bioaccumulation of methylmercury (MeHg) in the marine food chain, human consumers are exposed to low doses of MeHg continually through seafood consumption. Epidemiological studies strongly suggest that chronic prenatal exposure to nanomolar of MeHg has immense negative impacts on neurological development in neonates. However, effects of chronic exposure to low doses (CELDs) of MeHg in adult brains on a molecular level are unknown. The current study aims to investigate the molecular effects of CELD of MeHg on adult somatosensory cortex in a rat model using proteomic techniques. Young adult rats were fed with a low dose of MeHg (40 μg/kg body weight/day) for a maximum of 12 weeks. Whole proteome expression of the somatosensory cortex (S1 area) of normal rats and those with CELD to MeHg were compared. Levels of MeHg, total calcium, adenosine triphosphate (ATP), and pyruvate were also measured. Comparative proteomic studies of the somatosensory cortexes revealed that 94 proteins involved in the various metabolic processes (including carbohydrate metabolism, generation of precursors for essential metabolites, energy, proteins, cellular components for morphogenesis, and neurotransmission) were down-regulated. Consequently, levels of important end products of active metabolism including ATP, pyruvate, and total calcium were also found to be significantly reduced concomitantly. Our results showed that CELD of MeHg induced a state of metabolic deficit in the somatosensory cortex of adult rats.

  9. Cancer and non-cancer brain and eye effects of chronic low-dose ionizing radiation exposure

    PubMed Central

    2012-01-01

    Background According to a fundamental law of radiobiology (“Law of Bergonié and Tribondeau”, 1906), the brain is a paradigm of a highly differentiated organ with low mitotic activity, and is thus radio-resistant. This assumption has been challenged by recent evidence discussed in the present review. Results Ionizing radiation is an established environmental cause of brain cancer. Although direct evidence is lacking in contemporary fluoroscopy due to obvious sample size limitation, limited follow-up time and lack of focused research, anecdotal reports of clusters have appeared in the literature, raising the suspicion that brain cancer may be a professional disease of interventional cardiologists. In addition, although terminally differentiated neurons have reduced or mild proliferative capacity, and are therefore not regarded as critical radiation targets, adult neurogenesis occurs in the dentate gyrus of the hippocampus and the olfactory bulb, and is important for mood, learning/memory and normal olfactory function, whose impairment is a recognized early biomarker of neurodegenerative diseases. The head doses involved in radiotherapy are high, usually above 2 Sv, whereas the low-dose range of professional exposure typically involves lifetime cumulative whole-body exposure in the low-dose range of < 200 mSv, but with head exposure which may (in absence of protection) arrive at a head equivalent dose of 1 to 3 Sv after a professional lifetime (corresponding to a brain equivalent dose around 500 mSv). Conclusions At this point, a systematic assessment of brain (cancer and non-cancer) effects of chronic low-dose radiation exposure in interventional cardiologists and staff is needed. PMID:22540409

  10. Effects of chronic exposure to low doses of trichloroethylene on steroid hormone and insulin levels in normal men.

    PubMed Central

    Goh, V H; Chia, S E; Ong, C N

    1998-01-01

    The aim of this study was to examine the serum levels of insulin and some adrenal steroid hormones in men chronically exposed to low doses of trichloroethylene (TCE). A total of 85 workers participated in this study. Each worker had urine collected and analyzed for trichloroacetic acids (UTCA) on the same day that a blood sample was taken for analyses of serum testosterone, sex hormone-binding globulin (SHBG), androstenedione, cortisol, aldosterone, and insulin. The mean concentration of environmental TCE was 29.6 ppm and the mean UTCA was 22.4 mg/g creatinine (range 0.8-136.4). TCE exposure did not cause any significant changes to the adrenal steroid hormone productions. The results showed that UTCA was significantly correlated to serum insulin levels. Insulin and SHBG responded in tandem, with the highest levels found in workers exposed to TCE for less than 2 years; levels of both parameters were significantly lowered in those exposed for more than 2 years. A triphasic response in insulin levels to TCE, which depended on the duration of exposure, was noted. Initial exposure caused an acute rise in insulin levels. This was followed by a fall to normal levels in those exposed 2-4 years and then a slight rise in those exposed for more than 6 years. The mechanism for this pattern of response to TCE exposure is yet unknown. PMID:9417767

  11. Chronic exposure to low doses of pharmaceuticals disturbs the hepatic expression of circadian genes in lean and obese mice.

    PubMed

    Anthérieu, Sébastien; Le Guillou, Dounia; Coulouarn, Cédric; Begriche, Karima; Trak-Smayra, Viviane; Martinais, Sophie; Porceddu, Mathieu; Robin, Marie-Anne; Fromenty, Bernard

    2014-04-01

    Drinking water can be contaminated with pharmaceuticals. However, it is uncertain whether this contamination can be harmful for the liver, especially during obesity. Hence, the goal of our study was to determine whether chronic exposure to low doses of pharmaceuticals could have deleterious effects on livers of lean and obese mice. To this end, lean and ob/ob male mice were treated for 4 months with a mixture of 11 drugs provided in drinking water at concentrations ranging from 10 to 10⁶ ng/l. At the end of the treatment, some liver and plasma abnormalities were observed in ob/ob mice treated with the cocktail containing 10⁶ ng/l of each drug. For this dosage, a gene expression analysis by microarray showed altered expression of circadian genes (e.g. Bmal1, Dbp, Cry1) in lean and obese mice. RT-qPCR analyses carried out in all groups of animals confirmed that expression of 8 different circadian genes was modified in a dose-dependent manner. For some genes, a significant modification was observed for dosages as low as 10²-10³ ng/l. Drug mixture and obesity presented an additive effect on circadian gene expression. These data were validated in an independent study performed in female mice. Thus, our study showed that chronic exposure to trace pharmaceuticals disturbed hepatic expression of circadian genes, particularly in obese mice. Because some of the 11 drugs can be found in drinking water at such concentrations (e.g. acetaminophen, carbamazepine, ibuprofen) our data could be relevant in environmental toxicology, especially for obese individuals exposed to these contaminants.

  12. Chronic exposure to low doses of pharmaceuticals disturbs the hepatic expression of circadian genes in lean and obese mice

    SciTech Connect

    Anthérieu, Sébastien; Le Guillou, Dounia; Coulouarn, Cédric; Begriche, Karima; Trak-Smayra, Viviane; Martinais, Sophie; Porceddu, Mathieu; Robin, Marie-Anne; Fromenty, Bernard

    2014-04-01

    Drinking water can be contaminated with pharmaceuticals. However, it is uncertain whether this contamination can be harmful for the liver, especially during obesity. Hence, the goal of our study was to determine whether chronic exposure to low doses of pharmaceuticals could have deleterious effects on livers of lean and obese mice. To this end, lean and ob/ob male mice were treated for 4 months with a mixture of 11 drugs provided in drinking water at concentrations ranging from 10 to 10{sup 6} ng/l. At the end of the treatment, some liver and plasma abnormalities were observed in ob/ob mice treated with the cocktail containing 10{sup 6} ng/l of each drug. For this dosage, a gene expression analysis by microarray showed altered expression of circadian genes (e.g. Bmal1, Dbp, Cry1) in lean and obese mice. RT-qPCR analyses carried out in all groups of animals confirmed that expression of 8 different circadian genes was modified in a dose-dependent manner. For some genes, a significant modification was observed for dosages as low as 10{sup 2}–10{sup 3} ng/l. Drug mixture and obesity presented an additive effect on circadian gene expression. These data were validated in an independent study performed in female mice. Thus, our study showed that chronic exposure to trace pharmaceuticals disturbed hepatic expression of circadian genes, particularly in obese mice. Because some of the 11 drugs can be found in drinking water at such concentrations (e.g. acetaminophen, carbamazepine, ibuprofen) our data could be relevant in environmental toxicology, especially for obese individuals exposed to these contaminants. - Highlights: • The contamination of drinking water with drugs may have harmful effects on health. • Some drugs can be more hepatotoxic in the context of obesity and fatty liver. • Effects of chronic exposure of trace drugs were studied in lean and obese mouse liver. Drugs and obesity present additive effects on circadian gene expression and toxicity. • Trace

  13. Synaptotoxicity of chronic low-dose pre- and post-natal ethanol exposure: A new animal model

    SciTech Connect

    Walewski, J.L.

    1992-01-01

    Chronic Low-dose Pre- and Post-natal Ethanol exposure (CLPPEE) is the most frequent cause of teratogenically induced mental deficiency in the Western world. Although the Fetal Alcohol Syndrome (FAAS) is associated with high levels of alcohol consumption, the relative teratogenic risk of moderate ethanol consumption is not well defined. CLPPEE may affect some processes involved in synapse formation, affecting the proper development and maturation of the nervous system. Ethanol was admixed (3 v/v%) with high-protein liquid diet (Bio-Serve) as the only nutrient source. The controls received an isocaloric sucrose liquid diet mixture. Ethanol treatment began on day 8 of pregnancy. 3 v/v% ethanol did not significantly reduce the body weights or diet consumption of dams, nor the gross growth of ethanol-exposed pups. Standard neuromuscular twitch preparations in vivo, utilizing the sciatic nerve-gastrocnemius muscle, were done on 1, 2, 3 and 7 week old pups. The physiologic functional tests of nursing pups (1-3 weeks), indicated that the ethanol-treated pups had abnormal responses to indirect stimulation. The deficit was determined to be pre-synaptic. The ethanol-exposed at these ages demonstrated abnormal responses to presynaptic challenge. Histochemical staining revealed motor nerve terminal morphology. In 2 and 3 week ethanol-treated pups, the number of nerve terminal branches, and endplate lengths were significantly reduced. Reversibility was examined by allowing the pups to mature while receiving only standard rat chow and water. Tests were repeated at 7 weeks of age. The responses of the ethanol-exposed to pharmacologic challenge, and motor nerve terminal morphology were still significantly different in the young adult animals. CLPPEE, at doses sub-threshold for FAS, affects the normal development of the skeletal neuromuscular system, with long-lasting effects on motor nerve terminal function and morphology.

  14. Chronic Dietary Exposure to a Low-Dose Mixture of Genistein and Vinclozolin Modifies the Reproductive Axis, Testis Transcriptome, and Fertility

    PubMed Central

    Eustache, Florence; Mondon, Françoise; Canivenc-Lavier, Marie Chantal; Lesaffre, Corinne; Fulla, Yvonne; Berges, Raymond; Cravedi, Jean Pierre; Vaiman, Daniel; Auger, Jacques

    2009-01-01

    Background The reproductive consequences and mechanisms of action of chronic exposure to low-dose endocrine disruptors are poorly understood. Objective We assessed the effects of a continuous, low-dose exposure to a phytoestrogen (genistein) and/or an antiandrogenic food contaminant (vinclozolin) on the male reproductive tract and fertility. Methods Male rats were exposed by gavage to genistein and vinclozolin from conception to adulthood, alone or in combination, at low doses (1 mg/kg/day) or higher doses (10 and 30 mg/kg/day). We studied a number of standard reproductive toxicology end points and also assessed testicular mRNA expression profiles using long-oligonucleotide microarrays. Results The low-dose mixture and high-dose vinclozolin produced the most significant alterations in adults: decreased sperm counts, reduced sperm motion parameters, decreased litter sizes, and increased post implantation loss. Testicular mRNA expression profiles for these exposure conditions were strongly correlated. Functional clustering indicated that many of the genes induced belong to the “neuroactive ligand-receptor interactions” family encompassing several hormonally related actors (e.g., follicle-stimulating hormone and its receptor). All exposure conditions decreased the levels of mRNAs involved in ribosome function, indicating probable decreased protein production. Conclusions Our study shows that chronic exposure to a mixture of a dose of a phytoestrogen equivalent to that in the human diet and a low dose—albeit not environmental—of a common anti-androgenic food contaminant may seriously affect the male reproductive tract and fertility. PMID:19672408

  15. Chronic Low Dose Rate Ionizing Radiation Exposure Induces Premature Senescence in Human Fibroblasts that Correlates with Up Regulation of Proteins Involved in Protection against Oxidative Stress

    PubMed Central

    Loseva, Olga; Shubbar, Emman; Haghdoost, Siamak; Evers, Bastiaan; Helleday, Thomas; Harms-Ringdahl, Mats

    2014-01-01

    The risks of non-cancerous diseases associated with exposure to low doses of radiation are at present not validated by epidemiological data, and pose a great challenge to the scientific community of radiation protection research. Here, we show that premature senescence is induced in human fibroblasts when exposed to chronic low dose rate (LDR) exposure (5 or 15 mGy/h) of gamma rays from a 137Cs source. Using a proteomic approach we determined differentially expressed proteins in cells after chronic LDR radiation compared to control cells. We identified numerous proteins involved in protection against oxidative stress, suggesting that these pathways protect against premature senescence. In order to further study the role of oxidative stress for radiation induced premature senescence, we also used human fibroblasts, isolated from a patient with a congenital deficiency in glutathione synthetase (GS). We found that these GS deficient cells entered premature senescence after a significantly shorter time of chronic LDR exposure as compared to the GS proficient cells. In conclusion, we show that chronic LDR exposure induces premature senescence in human fibroblasts, and propose that a stress induced increase in reactive oxygen species (ROS) is mechanistically involved. PMID:28250385

  16. Measuring DNA Damage and Repair in Mouse Splenocytes After Chronic In Vivo Exposure to Very Low Doses of Beta- and Gamma-Radiation.

    PubMed

    Flegal, Matthew; Blimkie, Melinda S; Wyatt, Heather; Bugden, Michelle; Surette, Joel; Klokov, Dmitry

    2015-07-03

    Low dose radiation exposure may produce a variety of biological effects that are different in quantity and quality from the effects produced by high radiation doses. Addressing questions related to environmental, occupational and public health safety in a proper and scientifically justified manner heavily relies on the ability to accurately measure the biological effects of low dose pollutants, such as ionizing radiation and chemical substances. DNA damage and repair are the most important early indicators of health risks due to their potential long term consequences, such as cancer. Here we describe a protocol to study the effect of chronic in vivo exposure to low doses of γ- and β-radiation on DNA damage and repair in mouse spleen cells. Using a commonly accepted marker of DNA double-strand breaks, phosphorylated histone H2AX called γH2AX, we demonstrate how it can be used to evaluate not only the levels of DNA damage, but also changes in the DNA repair capacity potentially produced by low dose in vivo exposures. Flow cytometry allows fast, accurate and reliable measurement of immunofluorescently labeled γH2AX in a large number of samples. DNA double-strand break repair can be evaluated by exposing extracted splenocytes to a challenging dose of 2 Gy to produce a sufficient number of DNA breaks to trigger repair and by measuring the induced (1 hr post-irradiation) and residual DNA damage (24 hrs post-irradiation). Residual DNA damage would be indicative of incomplete repair and the risk of long-term genomic instability and cancer. Combined with other assays and end-points that can easily be measured in such in vivo studies (e.g., chromosomal aberrations, micronuclei frequencies in bone marrow reticulocytes, gene expression, etc.), this approach allows an accurate and contextual evaluation of the biological effects of low level stressors.

  17. Chronic exposure of adult, postnatal and in utero rat models to low-dose 137Cesium: impact on circulating biomarkers

    PubMed Central

    Manens, Line; Grison, Stéphane; Bertho, Jean-Marc; Lestaevel, Philippe; Guéguen, Yann; Benderitter, Marc; Aigueperse, Jocelyne; Souidi, Maâmar

    2016-01-01

    The presence of 137Cesium (137Cs) in the environment after nuclear accidents at Chernobyl and more recently Fukushima Daiichi raises many health issues for the surrounding populations chronically exposed through the food chain. To mimic different exposure situations, we set up a male rat model of exposure by chronic ingestion of a 137Cs concentration likely to be ingested daily by residents of contaminated areas (6500 Bq.l−1) and tested contaminations lasting 9 months for adult, neonatal and fetal rats. We tested plasma and serum biochemistry to identify disturbances in general indicators (lipids, proteins, carbohydrates and electrolytes) and in biomarkers of thyroid, heart, brain, bone, kidney, liver and testis functions. Analysis of the general indicators showed increased levels of cholesterol (+26%), HDL cholesterol (+31%), phospholipids B (+15%) and phosphorus (+100%) in the postnatal group only. Thyroid, heart, brain, bone and kidney functions showed no blood changes in any model. The liver function evaluation showed changes in total bilirubin (+67%) and alkaline phosphatase (–11%) levels, but only for the rats exposed to 137Cs intake in adulthood. Large changes in 17β-estradiol (–69%) and corticosterone (+36%) levels affected steroidogenesis, but only in the adult model. This study showed that response profiles differed according to age at exposure: lipid metabolism was most radiosensitive in the postnatal model, and steroid hormone metabolism was most radiosensitive in rats exposed in adulthood. There was no evidence of deleterious effects suggesting a potential impact on fertility or procreation. PMID:27466399

  18. Low-dose radiation exposure and carcinogenesis.

    PubMed

    Suzuki, Keiji; Yamashita, Shunichi

    2012-07-01

    Absorption of energy from ionizing radiation by the genetic material in the cell leads to damage to DNA, which in turn leads to cell death, chromosome aberrations and gene mutations. While early or deterministic effects result from organ and tissue damage caused by cell killing, latter two are considered to be involved in the initial events that lead to the development of cancer. Epidemiological studies have demonstrated the dose-response relationships for cancer induction and quantitative evaluations of cancer risk following exposure to moderate to high doses of low-linear energy transfer radiation. A linear, no-threshold model has been applied to assessment of the risks resulting from exposure to moderate and high doses of ionizing radiation; however, a statistically significant increase has hardly been described for radiation doses below 100 mSv. This review summarizes our current knowledge of the physical and biological features of low-dose radiation and discusses the possibilities of induction of cancer by low-dose radiation.

  19. Chronic Internal Exposure to Low Dose 137Cs Induces Positive Impact on the Stability of Atherosclerotic Plaques by Reducing Inflammation in ApoE-/- Mice

    PubMed Central

    Le Gallic, Clélia; Phalente, Yohann; Manens, Line; Dublineau, Isabelle; Benderitter, Marc; Gueguen, Yann; Lehoux, Stephanie; Ebrahimian, Teni G.

    2015-01-01

    After Chernobyl and Fukushima Daï Chi, two major nuclear accidents, large amounts of radionuclides were released in the environment, mostly caesium 137 (137Cs). Populations living in contaminated territories are chronically exposed to radionuclides by ingestion of contaminated food. However, questions still remain regarding the effects of low dose ionizing radiation exposure on the development and progression of cardiovascular diseases. We therefore investigated the effects of a chronic internal exposure to 137Cs on atherosclerosis in predisposed ApoE-/- mice. Mice were exposed daily to 0, 4, 20 or 100 kBq/l 137Cs in drinking water, corresponding to range of concentrations found in contaminated territories, for 6 or 9 months. We evaluated plaque size and phenotype, inflammatory profile, and oxidative stress status in different experimental groups. Results did not show any differences in atherosclerosis progression between mice exposed to 137Cs and unexposed controls. However, 137Cs exposed mice developed more stable plaques with decreased macrophage content, associated with reduced aortic expression of pro-inflammatory factors (CRP, TNFα, MCP-1, IFNγ) and adhesion molecules (ICAM-1, VCAM-1 and E-selectin). Lesions of mice exposed to 137Cs were also characterized by enhanced collagen and smooth muscle cell content, concurrent with reduced matrix metalloproteinase MMP8 and MMP13 expression. These results suggest that low dose chronic exposure of 137Cs in ApoE-/- mice enhances atherosclerotic lesion stability by inhibiting pro-inflammatory cytokine and MMP production, resulting in collagen-rich plaques with greater smooth muscle cell and less macrophage content. PMID:26046630

  20. Chronic Internal Exposure to Low Dose 137Cs Induces Positive Impact on the Stability of Atherosclerotic Plaques by Reducing Inflammation in ApoE-/- Mice.

    PubMed

    Le Gallic, Clélia; Phalente, Yohann; Manens, Line; Dublineau, Isabelle; Benderitter, Marc; Gueguen, Yann; Lehoux, Stephanie; Ebrahimian, Teni G

    2015-01-01

    After Chernobyl and Fukushima Daï Chi, two major nuclear accidents, large amounts of radionuclides were released in the environment, mostly caesium 137 (137Cs). Populations living in contaminated territories are chronically exposed to radionuclides by ingestion of contaminated food. However, questions still remain regarding the effects of low dose ionizing radiation exposure on the development and progression of cardiovascular diseases. We therefore investigated the effects of a chronic internal exposure to 137Cs on atherosclerosis in predisposed ApoE-/- mice. Mice were exposed daily to 0, 4, 20 or 100 kBq/l 137Cs in drinking water, corresponding to range of concentrations found in contaminated territories, for 6 or 9 months. We evaluated plaque size and phenotype, inflammatory profile, and oxidative stress status in different experimental groups. Results did not show any differences in atherosclerosis progression between mice exposed to 137Cs and unexposed controls. However, 137Cs exposed mice developed more stable plaques with decreased macrophage content, associated with reduced aortic expression of pro-inflammatory factors (CRP, TNFα, MCP-1, IFNγ) and adhesion molecules (ICAM-1, VCAM-1 and E-selectin). Lesions of mice exposed to 137Cs were also characterized by enhanced collagen and smooth muscle cell content, concurrent with reduced matrix metalloproteinase MMP8 and MMP13 expression. These results suggest that low dose chronic exposure of 137Cs in ApoE-/- mice enhances atherosclerotic lesion stability by inhibiting pro-inflammatory cytokine and MMP production, resulting in collagen-rich plaques with greater smooth muscle cell and less macrophage content.

  1. Chronic exposure to a low dose of ingested petroleum disrupts corticosterone receptor signalling in a tissue-specific manner in the house sparrow (Passer domesticus)

    PubMed Central

    Lattin, Christine R.; Romero, L. Michael

    2014-01-01

    Stress-induced concentrations of glucocorticoid hormones (including corticosterone, CORT) can be suppressed by chronic exposure to a low dose of ingested petroleum. However, endocrine-disrupting chemicals could interfere with CORT signalling beyond the disruption of hormone titres, including effects on receptors in different target tissues. In this study, we examined the effects of 6 weeks of exposure to a petroleum-laced diet (1% oil weight:food weight) on tissue mass and intracellular CORT receptors in liver, fat, muscle and kidney (metabolic tissues), spleen (an immune tissue) and testes (a reproductive tissue). In the laboratory, male house sparrows were fed either a 1% weathered crude oil (n = 12) or a control diet (n = 12); glucocorticoid receptors and mineralocorticoid receptors were quantified using radioligand binding assays. In oil-exposed birds, glucocorticoid receptors were lower in one metabolic tissue (liver), higher in another metabolic tissue (fat) and unchanged in four other tissues (kidney, muscle, spleen and testes) compared with control birds. We saw no differences in mineralocorticoid receptors between groups. We also saw a trend towards reduced mass of the testes in oil-exposed birds compared with controls, but no differences in fat, kidney, liver, muscle or spleen mass between the two groups. This is the first study to examine the effects of petroleum on CORT receptor density in more than one or two target tissues. Given that a chronic low dose of ingested petroleum can affect stress-induced CORT titres as well as receptor density, this demonstrates that oil can act at multiple levels to disrupt an animal’s response to environmental stressors. This also highlights the potential usefulness of the stress response as a bioindicator of chronic crude oil exposure. PMID:27293679

  2. Fukushima simulation experiment: assessing the effects of chronic low-dose-rate internal 137Cs radiation exposure on litter size, sex ratio, and biokinetics in mice

    PubMed Central

    Nakajima, Hiroo; Yamaguchi, Yoshiaki; Yoshimura, Takashi; Fukumoto, Manabu; Todo, Takeshi

    2015-01-01

    To investigate the transgenerational effects of chronic low-dose-rate internal radiation exposure after the Fukushima Daiichi Nuclear Power Plant accident in Japan, 18 generations of mice were maintained in a radioisotope facility, with free access to drinking water containing 137CsCl (0 and 100 Bq/ml). The 137Cs distribution in the organs of the mice was measured after long-term ad libitum intake of the 137CsCl water. The litter size and the sex ratio of the group ingesting the 137Cs water were compared with those of the control group, for all 18 generations of mice. No significant difference was noted in the litter size or the sex ratio between the mice in the control group and those in the group ingesting the 137Cs water. The fixed internal exposure doses were ∼160 Bq/g and 80 Bq/g in the muscles and other organs, respectively. PMID:26825299

  3. [Influence of chronic exposure to low doses of space ionizing radiation on the character of formation of microbial assemblage in the habitat of orbital station].

    PubMed

    Tsetlin, V V; Deshevaia, E A

    2003-01-01

    Statistically valid relations between radiation conditions in compartments of MIR station and the micromicete population (CFU number) on the surface of the equipment and the interior have been established. It was found that in conditions of a chronic exposure to space radiation the number of CFU increased in one thousand and more times with increasing of absorbed dose rate from 200 up to 1000 microGy/day. The results of land-based model experiments confirmed morphological changes in the "flight" strains of funguses under exposure to low doses of gamma (100-800 microGy/day) and neutron (0.2-2 neutron/cm2.s) radiation. It was found that the morphological changes in the control (museum) cultures of funguses of the same species, which were expressed in the weak increase of vegetative mycelium, were detected only after repeated gamma- and gamma + neutron irradiation.

  4. Fukushima simulation experiment: assessing the effects of chronic low-dose-rate internal 137Cs radiation exposure on litter size, sex ratio, and biokinetics in mice.

    PubMed

    Nakajima, Hiroo; Yamaguchi, Yoshiaki; Yoshimura, Takashi; Fukumoto, Manabu; Todo, Takeshi

    2015-12-01

    To investigate the transgenerational effects of chronic low-dose-rate internal radiation exposure after the Fukushima Daiichi Nuclear Power Plant accident in Japan, 18 generations of mice were maintained in a radioisotope facility, with free access to drinking water containing (137)CsCl (0 and 100 Bq/ml). The (137)Cs distribution in the organs of the mice was measured after long-term ad libitum intake of the (137)CsCl water. The litter size and the sex ratio of the group ingesting the (137)Cs water were compared with those of the control group, for all 18 generations of mice. No significant difference was noted in the litter size or the sex ratio between the mice in the control group and those in the group ingesting the (137)Cs water. The fixed internal exposure doses were ∼160 Bq/g and 80 Bq/g in the muscles and other organs, respectively.

  5. Human circulating plasma DNA significantly decreases while lymphocyte DNA damage increases under chronic occupational exposure to low-dose gamma-neutron and tritium β-radiation.

    PubMed

    Korzeneva, Inna B; Kostuyk, Svetlana V; Ershova, Liza S; Osipov, Andrian N; Zhuravleva, Veronika F; Pankratova, Galina V; Porokhovnik, Lev N; Veiko, Natalia N

    2015-09-01

    The blood plasma of healthy people contains cell-fee (circulating) DNA (cfDNA). Apoptotic cells are the main source of the cfDNA. The cfDNA concentration increases in case of the organism's cell death rate increase, for example in case of exposure to high-dose ionizing radiation (IR). The objects of the present research are the blood plasma and blood lymphocytes of people, who contacted occupationally with the sources of external gamma/neutron radiation or internal β-radiation of tritium N = 176). As the controls (references), blood samples of people, who had never been occupationally subjected to the IR sources, were used (N = 109). With respect to the plasma samples of each donor there were defined: the cfDNA concentration (the cfDNA index), DNase1 activity (the DNase1 index) and titre of antibodies to DNA (the Ab DNA index). The general DNA damage in the cells was defined (using the Comet assay, the tail moment (TM) index). A chronic effect of the low-dose ionizing radiation on a human being is accompanied by the enhancement of the DNA damage in lymphocytes along with a considerable cfDNA content reduction, while the DNase1 content and concentration of antibodies to DNA (Ab DNA) increase. All the aforementioned changes were also observed in people, who had not worked with the IR sources for more than a year. The ratio cfDNA/(DNase1×Ab DNA × TM) is proposed to be used as a marker of the chronic exposure of a person to the external low-dose IR. It was formulated the assumption that the joint analysis of the cfDNA, DNase1, Ab DNA and TM values may provide the information about the human organism's cell resistivity to chronic exposure to the low-dose IR and about the development of the adaptive response in the organism that is aimed, firstly, at the effective cfDNA elimination from the blood circulation, and, secondly - at survival of the cells, including the cells with the damaged DNA.

  6. Environmentally Relevant Chronic Low-Dose Tritium and Gamma Exposures do not Increase Somatic Intrachromosomal Recombination in pKZ1 Mouse Spleen.

    PubMed

    Bannister, Laura; Serran, Mandy; Bertrand, Lindsey; Klokov, Dmitry; Wyatt, Heather; Blimkie, Melinda; Gueguen, Yann; Priest, Nicholas; Jourdain, Jean-René; Sykes, Pamela

    2016-12-01

    The toxicity of tritium is a public health concern given its presence and mobility in the environment. For risk predictions using radiological protection models, it is essential to allocate an appropriate radiation weighting factor (WR). This in turn should be consistent with the observed relative biological effectiveness (RBE) of tritium beta radiation. Although the International Commission on Radiological Protection (ICRP) currently recommends a WR of 1 for the calculation of committed effective dose for X rays, gamma rays and electrons of all energies, including tritium energies, there are concerns that tritium health risks are underestimated and that current regulatory tritium drinking water standards need revision. In this study, we investigated potential cytotoxic and genotoxic effects in mouse spleen after one month and eight months of chronic exposure to low-dose tritiated water (HTO). The dose regimes studied were designed to mimic human chronic consumption of HTO at levels of 10 kBq/l, 1 MBq/l and 20 MBq/l. The total doses from these radiation exposures ranged from 0.01 to 180 mGy. We also compared the biological effects of exposure to HTO with equivalent exposure to external whole-body (60)Co gamma rays. Changes in spleen weight and somatic intrachromosomal recombination (DNA inversions) in spleen tissue of pKZ1(Tg/+) mice were monitored. Our results showed no overall changes in either spleen organ weights and no increase mouse splenic intrachromosomal recombination frequencies, indicating that current drinking water standards for tritium exposure in the form of HTO are likely to be adequately protective against cytotoxic and genotoxic damage in spleen. These results demonstrate no evidence for cytotoxicity or genotoxicity in mouse spleen following chronic exposures to HTO activities (or equivalent gamma doses) up to 20 MBq/L.

  7. Neurobehavioral deficits and brain oxidative stress induced by chronic low dose exposure of persistent organic pollutants mixture in adult female rat.

    PubMed

    Lahouel, Asma; Kebieche, Mohamed; Lakroun, Zohra; Rouabhi, Rachid; Fetoui, Hamadi; Chtourou, Yassine; Djamila, Zama; Soulimani, Rachid

    2016-10-01

    Persistent organic pollutants (POPs) are long-lived organic compounds that are considered one of the major risks to ecosystem and human health. Recently, great concerns are raised about POPs mixtures and its potential toxicity even in low doses of daily human exposure. The brain is mostly targeted by these lipophilic compounds because of its important contain in lipids. So, it would be quite interesting to study the effects of exposure to these mixtures and evaluate their combined toxicity on brain cells. The present study was designed to characterize the cognitive and locomotors deficits and brain areas redox status in rat model. An orally chronic exposure to a representative mixture of POPs composed of endosulfan (2.6 μg/kg), chlorpyrifos (5.2 μg/kg), naphthalene (0.023 μg/kg) and benzopyrane (0.002 μg/kg); the same mixture with concentration multiplied by 10 and 100 was also tested. Exposed rats have shown a disturbance of memory and a decrease in learning ability concluded by Morris water maze and the open field tests results and anxiolytic behaviour in the test of light/dark box compared to control. Concerning brain redox homeostasis, exposed rats have shown an increased malondialdehyde (MDA) amount and an alteration in glutathione (GSH) levels in both the brain mitochondria and cytosolic fractions of the cerebellum, striatum and hippocampus. These effects were accompanied by a decrease in levels of cytosolic glutathione S-transferase (GST) and a highly significant increase in superoxide dismutase (SOD) and catalase (CAT) activities in both cytosolic and mitochondrial fractions. The current study suggests that environmental exposure to daily even low doses of POPs mixtures through diet induces oxidative stress status in the brain and especially in the mitochondria with important cognitive and locomotor behaviour variations in the rats.

  8. Chronic Exposure to Low Doses of Dioxin Promotes Liver Fibrosis Development in the C57BL/6J Diet-Induced Obesity Mouse Model

    PubMed Central

    Duval, Caroline; Teixeira-Clerc, Fatima; Leblanc, Alix F.; Touch, Sothea; Emond, Claude; Guerre-Millo, Michèle; Lotersztajn, Sophie; Barouki, Robert; Aggerbeck, Martine; Coumoul, Xavier

    2016-01-01

    Background: Exposure to persistent organic pollutants (POPs) has been associated with the progression of chronic liver diseases, yet the contribution of POPs to the development of fibrosis in non-alcoholic fatty liver disease (NAFLD), a condition closely linked to obesity, remains poorly documented. Objectives: We investigated the effects of subchronic exposure to low doses of the POP 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor ligand, on NAFLD progression in diet-induced obese C57BL/6J mice. Methods: Male C57BL/6J mice were fed either a 10% low-fat (LFD) or a 45% high-fat (HFD) purified diet for 14 weeks and TCDD-exposed groups were injected once a week with 5 μg/kg TCDD or the vehicle for the last 6 weeks of the diet. Results: Liver histology and triglyceride levels showed that exposure of HFD fed mice to TCDD worsened hepatic steatosis, as compared to either HFD alone or LFD plus TCDD and the mRNA levels of key genes of hepatic lipid metabolism were strongly altered in co-treated mice. Further, increased liver collagen staining and serum transaminase levels showed that TCDD induced liver fibrosis in the HFD fed mice. TCDD in LFD fed mice increased the expression of several inflammation and fibrosis marker genes with no additional effect from a HFD. Conclusions: Exposure to TCDD amplifies the impairment of liver functions observed in mice fed an enriched fat diet as compared to a low fat diet. The results provide new evidence that environmental pollutants promote the development of liver fibrosis in obesity-related NAFLD in C57BL/6J mice. Citation: Duval C, Teixeira-Clerc F, Leblanc AF, Touch S, Emond C, Guerre-Millo M, Lotersztajn S, Barouki R, Aggerbeck M, Coumoul X. 2017. Chronic exposure to low doses of dioxin promotes liver fibrosis development in the C57BL/6J diet-induced obesity mouse model. Environ Health Perspect 125:428–436; http://dx.doi.org/10.1289/EHP316 PMID:27713108

  9. In vivo exposure of swiss albino mice to chronic low dose of dimethylnitrosamine (DMN) lowers poly-ADP-ribosylation (PAR) of bone marrow cell and blood lymphocyte proteins.

    PubMed

    Kma, L; Sharan, R N

    2006-08-01

    Efforts to identify an easy and convenient biomarker of carcinogenesis with potentials of application in mass screening program continue. In a series of investigations on mice exposed to different carcinogens, poly-ADP-ribosylation (PAR) of cellular proteins of different tissues has been shown to be a potential biomarker of carcinogenesis. Because blood based biomarker of carcinogenesis offers significant advantage in its use in a cancer screening program, this investigation was undertaken to find correlations between initiation of carcinogenesis and PAR of bone marrow cell (BMC) and blood lymphocyte (BL) proteins in mice chronically exposed to low dose of dimethylnitrosamine (DMN) for up to four weeks in vivo. The exposure was either alone or in combination with 3-aminobenzamide (3-AB), an inhibitor of PAR. Total PAR of cellular proteins and of histone H1 protein were monitored by slot and Western blot immunoprobe assays, respectively. The PAR of total cellular proteins as well as of histone H1 was down-regulated in duration of exposure dependent manners. The results suggest that BMC and BL mirrored status of PAR in other tissues. This finding opens up the possibility of using PAR as a biomarker of carcinogenesis in a blood based test utilizing immunoprobe assay of cellular PAR.

  10. Multiomics reveal non-alcoholic fatty liver disease in rats following chronic exposure to an ultra-low dose of Roundup herbicide

    PubMed Central

    Mesnage, Robin; Renney, George; Séralini, Gilles-Eric; Ward, Malcolm; Antoniou, Michael N.

    2017-01-01

    The impairment of liver function by low environmentally relevant doses of glyphosate-based herbicides (GBH) is still a debatable and unresolved matter. Previously we have shown that rats administered for 2 years with 0.1 ppb (50 ng/L glyphosate equivalent dilution; 4 ng/kg body weight/day daily intake) of a Roundup GBH formulation showed signs of enhanced liver injury as indicated by anatomorphological, blood/urine biochemical changes and transcriptome profiling. Here we present a multiomic study combining metabolome and proteome liver analyses to obtain further insight into the Roundup-induced pathology. Proteins significantly disturbed (214 out of 1906 detected, q < 0.05) were involved in organonitrogen metabolism and fatty acid β-oxidation. Proteome disturbances reflected peroxisomal proliferation, steatosis and necrosis. The metabolome analysis (55 metabolites altered out of 673 detected, p < 0.05) confirmed lipotoxic conditions and oxidative stress by showing an activation of glutathione and ascorbate free radical scavenger systems. Additionally, we found metabolite alterations associated with hallmarks of hepatotoxicity such as γ-glutamyl dipeptides, acylcarnitines, and proline derivatives. Overall, metabolome and proteome disturbances showed a substantial overlap with biomarkers of non-alcoholic fatty liver disease and its progression to steatohepatosis and thus confirm liver functional dysfunction resulting from chronic ultra-low dose GBH exposure. PMID:28067231

  11. Multiomics reveal non-alcoholic fatty liver disease in rats following chronic exposure to an ultra-low dose of Roundup herbicide.

    PubMed

    Mesnage, Robin; Renney, George; Séralini, Gilles-Eric; Ward, Malcolm; Antoniou, Michael N

    2017-01-09

    The impairment of liver function by low environmentally relevant doses of glyphosate-based herbicides (GBH) is still a debatable and unresolved matter. Previously we have shown that rats administered for 2 years with 0.1 ppb (50 ng/L glyphosate equivalent dilution; 4 ng/kg body weight/day daily intake) of a Roundup GBH formulation showed signs of enhanced liver injury as indicated by anatomorphological, blood/urine biochemical changes and transcriptome profiling. Here we present a multiomic study combining metabolome and proteome liver analyses to obtain further insight into the Roundup-induced pathology. Proteins significantly disturbed (214 out of 1906 detected, q < 0.05) were involved in organonitrogen metabolism and fatty acid β-oxidation. Proteome disturbances reflected peroxisomal proliferation, steatosis and necrosis. The metabolome analysis (55 metabolites altered out of 673 detected, p < 0.05) confirmed lipotoxic conditions and oxidative stress by showing an activation of glutathione and ascorbate free radical scavenger systems. Additionally, we found metabolite alterations associated with hallmarks of hepatotoxicity such as γ-glutamyl dipeptides, acylcarnitines, and proline derivatives. Overall, metabolome and proteome disturbances showed a substantial overlap with biomarkers of non-alcoholic fatty liver disease and its progression to steatohepatosis and thus confirm liver functional dysfunction resulting from chronic ultra-low dose GBH exposure.

  12. Interaction of four low dose toxic metals with essential metals in brain, liver and kidneys of mice on sub-chronic exposure.

    PubMed

    Cobbina, Samuel Jerry; Chen, Yao; Zhou, Zhaoxiang; Wu, Xueshan; Feng, Weiwei; Wang, Wei; Li, Qian; Zhao, Ting; Mao, Guanghua; Wu, Xiangyang; Yang, Liuqing

    2015-01-01

    This study reports on interactions between low dose toxic and essential metals. Low dose Pb (0.01mg/L), Hg (0.001mg/L), Cd (0.005mg/L) and As (0.01mg/L) were administered singly to four groups of 3-week old mice for 120 days. Pb exposure increased brain Mg and Cu by 55.5% and 266%, respectively. Increased brain Mg resulted from metabolic activity of brain to combat insults, whiles Cu overload was due to alteration and dysfunction of CTR1 and ATP7A molecules. Reduction of liver Ca by 56.0% and 31.6% (on exposure to As and Cd, respectively) resulted from inhibition of Ca-dependent ATPase in nuclei and endoplasmic reticulum through binding with thiol groups. Decreased kidney Mg, Ca and Fe was due to uptake of complexes of As and Cd with thiol groups from proximal tubular lumen. At considerably low doses, the study establishes that, toxic metals disturb the homeostasis of essential metals.

  13. Advanced Computational Approaches for Characterizing Stochastic Cellular Responses to Low Dose, Low Dose Rate Exposures

    SciTech Connect

    Scott, Bobby, R., Ph.D.

    2003-06-27

    OAK - B135 This project final report summarizes modeling research conducted in the U.S. Department of Energy (DOE), Low Dose Radiation Research Program at the Lovelace Respiratory Research Institute from October 1998 through June 2003. The modeling research described involves critically evaluating the validity of the linear nonthreshold (LNT) risk model as it relates to stochastic effects induced in cells by low doses of ionizing radiation and genotoxic chemicals. The LNT model plays a central role in low-dose risk assessment for humans. With the LNT model, any radiation (or genotoxic chemical) exposure is assumed to increase one¡¯s risk of cancer. Based on the LNT model, others have predicted tens of thousands of cancer deaths related to environmental exposure to radioactive material from nuclear accidents (e.g., Chernobyl) and fallout from nuclear weapons testing. Our research has focused on developing biologically based models that explain the shape of dose-response curves for low-dose radiation and genotoxic chemical-induced stochastic effects in cells. Understanding the shape of the dose-response curve for radiation and genotoxic chemical-induced stochastic effects in cells helps to better understand the shape of the dose-response curve for cancer induction in humans. We have used a modeling approach that facilitated model revisions over time, allowing for timely incorporation of new knowledge gained related to the biological basis for low-dose-induced stochastic effects in cells. Both deleterious (e.g., genomic instability, mutations, and neoplastic transformation) and protective (e.g., DNA repair and apoptosis) effects have been included in our modeling. Our most advanced model, NEOTRANS2, involves differing levels of genomic instability. Persistent genomic instability is presumed to be associated with nonspecific, nonlethal mutations and to increase both the risk for neoplastic transformation and for cancer occurrence. Our research results, based on

  14. Are radiosensitivity data derived from natural field conditions consistent with data from controlled exposures? A case study of Chernobyl wildlife chronically exposed to low dose rates.

    PubMed

    Garnier-Laplace, J; Geras'kin, S; Della-Vedova, C; Beaugelin-Seiller, K; Hinton, T G; Real, A; Oudalova, A

    2013-07-01

    The discrepancy between laboratory or controlled conditions ecotoxicity tests and field data on wildlife chronically exposed to ionising radiation is presented for the first time. We reviewed the available chronic radiotoxicity data acquired in contaminated fields and used a statistical methodology to support the comparison with knowledge on inter-species variation of sensitivity to controlled external γ irradiation. We focus on the Chernobyl Exclusion Zone and effects data on terrestrial wildlife reported in the literature corresponding to chronic dose rate exposure situations (from background ~100 nGy/h up to ~10 mGy/h). When needed, we reconstructed the dose rate to organisms and obtained consistent unbiased data sets necessary to establish the dose rate-effect relationship for a number of different species and endpoints. Then, we compared the range of variation of radiosensitivity of species from the Chernobyl-Exclusion Zone with the statistical distribution established for terrestrial species chronically exposed to purely gamma external irradiation (or chronic Species radioSensitivity Distribution - SSD). We found that the best estimate of the median value (HDR50) of the distribution established for field conditions at Chernobyl (about 100 μGy/h) was eight times lower than the one from controlled experiments (about 850 μGy/h), suggesting that organisms in their natural environmental were more sensitive to radiation. This first comparison highlights the lack of mechanistic understanding and the potential confusion coming from sampling strategies in the field. To confirm the apparent higher sensitive of wildlife in the Chernobyl Exclusion Zone, we call for more a robust strategy in field, with adequate design to deal with confounding factors.

  15. [Characteristics of micromycets Fusarium oxysporum recovered from an artificial soil for space greenhouse after chronic exposure to low doses of ionizing radiation].

    PubMed

    Smolianina, S O; Tsetlin, V V; Berkovich, Iu A; Korsak, I V

    2007-01-01

    Growth and development of Fusarium oxysporum intact strain and strains subjected to irradiation by low gamma-neutron doses were studied during cultivation on intact substrate and substrate irradiated by a gamma-source at 29 microGy. There was a striking difference in growth and sporification between the strains cultivated on irradiated and intact substrates. Irradiated Fusarium oxysporum strains exhibited manifest antagonism to one another and the non-irradiated strain. Electroconductivity of substrate after gamma-irradiation at low doses was noted to slow down markedly. The authors come to the conclusion that nutrient molecules may become more available to micromycets because of alteration of proton activity in consequence of preliminary irradiation.

  16. Influence of Exposure to Chronic Persistent Low-Dose Ionizing Radiation on the Tumor Biology of Clear-Cell Renal-Cell Carcinoma. An Immunohistochemical and Morphometric Study of Angiogenesis and Vascular Related Factors.

    PubMed

    Ruiz-Saurí, Amparo; Valencia-Villa, Gerardo; Romanenko, Alina; Pérez, Jesús; García, Raúl; García, Heydi; Benavent, José; Sancho-Tello, María; Carda, Carmen; Llombart-Bosch, Antonio

    2016-10-01

    Increased angiogenesis is related to boosted growth and malignancy in carcinomas. "Chronic Persistent Low-Dose Ionizing Radiation" (CPLDIR) exposure increases incidence and aggressive behavior of clear-cell renal-cell carcinoma (CCRCC). The aim was to study the biology of angiogenesis, including microvessel density (MVD), in human clear-cell renal-cell carcinomas (CCRCC) originating from a radio-contaminated geographical area (Ukraine) and to compare with similar tumors diagnosed in non-contaminated regions of Europe (Spain, Valencia) and Latin America (Colombia, Barranquilla). MVD was comparatively examined in 124 patients diagnosed with CCRCC from three geographical areas by means of digital micro-imaging and computerized analysis. Additionally, 50 adult normal kidneys were used for controls (autopsy kidneys from Valencia and Barranquilla). Furthermore, an immunohistochemical study of several vascular related growth factors was undertaken using a similar methodology. MVD as well as VEFG are the most discriminating factors associated with an aggressive behavior of CCRCC. Their expression increased in proportion to the level of exposure to chronic low-dose ionizing radiation in Ukrainian patients in the 25 years since the Chernobyl accident substantiated by comparison with the two control groups of renal carcinomas present in non-irradiated areas (Spain and Colombia). No major biological differences relating to angiogenesis appear to exist between the CCRCC diagnosed in two distant geographical areas of the world. HIF-1α expression was similar in all groups, with no statistical significance. Present findings demonstrate the existence of a significant relationship between MVD and VEGF in CCRCC: an increased expression of VEGF is associated with a high level of angiogenesis.

  17. Chronic exposure to low doses of lipopolysaccharide and high-fat feeding increases body mass without affecting glucose tolerance in female rats

    PubMed Central

    Dudele, Anete; Fischer, Christina W; Elfving, Betina; Wegener, Gregers; Wang, Tobias; Lund, Sten

    2015-01-01

    Obesity-related inflammation may have a causal role in the development of diabetes and insulin resistance, and studies using animal models of chronic experimental endotoxemia have shown the link. However, many studies use only males, and much less is known about the role of obesity-related inflammation in females. Therefore, we addressed how experimentally induced chronic inflammation affects body mass, energy intake, and glucose metabolism in female rats. Adult female Sprague Dawley rats were instrumented with slow release pellets that delivered a constant daily dose of 53 or 207 μg of lipopolysaccharide (LPS) per rat for 60 days. Control rats were instrumented with vehicle pellets. Due to inflammatory nature of high-fat diet (HFD) half of the rats received HFD (60% of calories from lard), while the other half remained on control diet to detect possible interactions between two modes of induced inflammation. Our results showed that chronic LPS administration increased female rat body mass and calorie intake in a dose-dependent manner, and that HFD further exacerbated these effects. Despite these effects, no effects of LPS and HFD were evident on female rat glucose metabolism. Only LPS elevated expression of inflammatory markers in the hypothalamus. To conclude, female rats respond to experimentally induced chronic inflammation by increasing body mass, but do not develop glucose intolerance in the given period of time. PMID:26537342

  18. Radiation Risk from Chronic Low Dose-Rate Radiation Exposures: The Role of Life-Time Animal Studies - Workshop October 2005

    SciTech Connect

    Gayle Woloschak

    2009-12-16

    As a part of Radiation research conference, a workshop was held on life-long exposure studies conducted in the course of irradiation experiements done at Argonne National Laboratory between 1952-1992. A recent review article documents many of the issues discussed at that workshop.

  19. Low dose TBT exposure decreases amphipod immunocompetence and reproductive fitness.

    PubMed

    Jacobson, Therese; Sundelin, Brita; Yang, Gongda; Ford, Alex T

    2011-01-17

    The antifouling agent tributyltin (TBT) is a highly toxic pollutant present in many aquatic ecosystems. Despite of regulations on the usage of TBT, it remains in high concentrations in sediments both in harbors and in off-shore sites. The toxicity of TBT in mollusks is well documented. However, adverse effects in other aquatic organisms, such as crustaceans, are less well known. This study is an effort to assess the effects of environmentally realistic concentrations of TBT on an ecologically important species in Swedish fresh and brackish water ecosystems, the benthic amphipod Monoporeia affinis. Field collected animals were exposed during gonad maturation to TBT (70 and 170 ng/g sediment d wt) for five weeks in static microcosms with natural sediment. Exposure concentrations were chosen to reflect effects at concentrations found in Swedish coastal sediment, but below expected effects on survival. TBT exposure resulted in a statistically significant adverse effect on oocyte viability and a doubling of the prevalence of microsporidian parasites in females, from 17% in the control to 34% in the 170 ng TBT/g sediment d wt exposure. No effects on survival were observed. Borderline significant effects were observed on male sexual maturation in the 70 ng TBT/g d wt exposure and on ecdysteroid levels in the 170 ng/g sediment d wt exposure. Both reproduction and parasite infection effects are of ecological importance since they have the potential to affect population viability in the field. This study gives further evidence to the connection between low dose contaminant exposure and increases in microsporidian parasite infection.

  20. Costs, benefits and redundant mechanisms of adaption to chronic low-dose stress in yeast

    PubMed Central

    Markiewicz-Potoczny, Marta; Lydall, David

    2016-01-01

    ABSTRACT All organisms live in changeable, stressful environments. It has been reported that exposure to low-dose stresses or poisons can improve fitness. However, examining the effects of chronic low-dose chemical exposure is challenging. To address this issue we used temperature sensitive mutations affecting the yeast cell division cycle to induce low-dose stress for 40 generation times, or more. We examined cdc13-1 mutants, defective in telomere function, and cdc15-2 mutants, defective in mitotic kinase activity. We found that each stress induced similar adaptive responses. Stress-exposed cells became resistant to higher levels of stress but less fit, in comparison with unstressed cells, in conditions of low stress. The costs and benefits of adaptation to chronic stress were reversible. In the cdc13-1 context we tested the effects of Rad9, a central player in the response to telomere defects, Exo1, a nuclease that degrades defective telomeres, and Msn2 and Msn4, 2 transcription factors that contribute to the environmental stress response. We also observed, as expected, that Rad9 and Exo1 modulated the response of cells to stress. In addition we observed that adaptation to stress could still occur in these contexts, with associated costs and benefits. We conclude that functionally redundant cellular networks control the adaptive responses to low dose chronic stress. Our data suggests that if organisms adapt to low dose stress it is helpful if stress continues or increases but harmful should stress levels reduce. PMID:27628486

  1. Analysis of the Effect of Chronic and Low-Dose Radiation Exposure on Spermatogenic Cells of Male Large Japanese Field Mice ( Apodemus speciosus ) after the Fukushima Daiichi Nuclear Power Plant Accident.

    PubMed

    Takino, Sachio; Yamashiro, Hideaki; Sugano, Yukou; Fujishima, Yohei; Nakata, Akifumi; Kasai, Kosuke; Hayashi, Gohei; Urushihara, Yusuke; Suzuki, Masatoshi; Shinoda, Hisashi; Miura, Tomisato; Fukumoto, Manabu

    2017-02-01

    In this study we analyzed the effect of chronic and low-dose-rate (LDR) radiation on spermatogenic cells of large Japanese field mice ( Apodemus speciosus ) after the Fukushima Daiichi Nuclear Power Plant (FNPP) accident. In March 2014, large Japanese field mice were collected from two sites located in, and one site adjacent to, the FNPP ex-evacuation zone: Tanashio, Murohara and Akogi, respectively. Testes from these animals were analyzed histologically. External dose rate from radiocesium (combined (134)Cs and (137)Cs) in these animals at the sampling sites exhibited 21 μGy/day in Tanashio, 304-365 μGy/day in Murohara and 407-447 μGy/day in Akogi. In the Akogi group, the numbers of spermatogenic cells and proliferating cell nuclear antigen (PCNA)-positive cells per seminiferous tubule were significantly higher compared to the Tanashio and Murohara groups, respectively. TUNEL-positive apoptotic cells tended to be detected at a lower level in the Murohara and Akogi groups compared to the Tanashio group. These results suggest that enhanced spermatogenesis occurred in large Japanese field mice living in and around the FNPP ex-evacuation zone. It remains to be elucidated whether this phenomenon, attributed to chronic exposure to LDR radiation, will benefit or adversely affect large Japanese field mice.

  2. Analysis of the Mortality Experience amongst U.S. Nuclear Power Industry Workers after Chronic Low-Dose Exposure to Ionizing Radiation

    SciTech Connect

    Howe, Geoffrey R.; Zablotska, Lydia B.; Fix, Jack J.; Egel, John N.; Buchanan, Jeffrey A.

    2004-11-01

    Workers employed in 15 utilities that generate nuclear power in the United States have been followed for up to 18 years between 1979 and 1997. Their cumulative dose from whole-body ionizing radiation has been determined from the dose records maintained by the facilities themselves and the REIRS and REMS systems maintained by the Nuclear Regulatory Commission and the Department of Energy, respectively. Mortality in the cohort from a number of causes has been analyzed with respect to individual radiation doses. The cohort displays a very substantial healthy worker effect, i.e. considerably lower cancer and noncancer mortality than the general population. Based on 26 and 368 deaths, respectively, positive though statistically nonsignificant associations were seen for mortality from leukemia (excluding chronic lymphocytic leukemia) and all solid cancers combined, with excess relative risks per sievert of 5.67 (95% confidence interval (CI) -2.56, 30.4) and 0.596 (95% CI -2.01, 4.64), respectively. These estimates are very similar to those from the atomic bomb survivors study, though the wide confidence intervals are also consistent with lower or higher risk estimates. A strong positive and statistically significant association between radiation dose and deaths from arteriosclerotic heart disease including coronary heart disease was also observed in the cohort, with an ERR of 8.78 (95% CI 2.10, 20.0). While associations with heart disease have been reported in some other occupational studies, the magnitude of the present association is not consistent with them and therefore needs cautious interpretation and merits further attention. At present, the relatively small number of deaths and the young age of the cohort (mean age at end of follow-up is 45 years) limit the power of the study, but further follow-up and the inclusion of the present data in an ongoing IARC combined analysis of nuclear workers from 15 countries will have greater power for testing the main hypotheses

  3. A meta-analysis of leukaemia risk from protracted exposure to low-dose gamma radiation

    PubMed Central

    Schubauer-Berigan, M K

    2010-01-01

    Context More than 400 000 workers annually receive a measurable radiation dose and may be at increased risk of radiation-induced leukaemia. It is unclear whether leukaemia risk is elevated with protracted, low-dose exposure. Objective We conducted a meta-analysis examining the relationship between protracted low-dose ionising radiation exposure and leukaemia. Data sources Reviews by the National Academies and United Nations provided a summary of informative studies published before 2005. PubMed and Embase databases were searched for additional occupational and environmental studies published between 2005 and 2009. Study selection We selected 23 studies that: (1) examined the association between protracted exposures to ionising radiation and leukaemia excluding chronic lymphocytic subtype; (2) were a cohort or nested case–control design without major bias; (3) reported quantitative estimates of exposure; and (4) conducted exposure–response analyses using relative or excess RR per unit exposure. Methods Studies were further screened to reduce information overlap. Random effects models were developed to summarise between-study variance and obtain an aggregate estimate of the excess RR at 100 mGy. Publication bias was assessed by trim and fill and Rosenthal's file drawer methods. Results We found an ERR at 100 mGy of 0.19 (95% CI 0.07 to 0.32) by modelling results from 10 studies and adjusting for publication bias. Between-study variance was not evident (p=0.99). Conclusions Protracted exposure to low-dose gamma radiation is significantly associated with leukaemia. Our estimate agreed well with the leukaemia risk observed among exposed adults in the Life Span Study (LSS) of atomic bomb survivors, providing increased confidence in the current understanding of leukaemia risk from ionising radiation. However, unlike the estimates obtained from the LSS, our model provides a precise, quantitative summary of the direct estimates of excess risk from studies of

  4. The effects of repeated low-dose sarin exposure

    SciTech Connect

    Shih, T.-M. . E-mail: tsungming.a.shih@us.army.mil; Hulet, S.W.; McDonough, J.H.

    2006-09-01

    This project assessed the effects of repeated low-dose exposure of guinea pigs to the organophosphorus nerve agent sarin. Animals were injected once a day, 5 days per week (Monday-Friday), for 2 weeks with fractions (0.3x, 0.4x, 0.5x, or 0.6x) of the established LD{sub 5} dose of sarin (42 {mu}g/kg, s.c.). The animals were assessed for changes in body weight, red blood cell (RBC) acetylcholinesterase (AChE) levels, neurobehavioral reactions to a functional observational battery (FOB), cortical electroencephalographic (EEG) power spectrum, and intrinsic acetylcholine (ACh) neurotransmitter (NT) regulation over the 2 weeks of sarin exposure and for up to 12 days postinjection. No guinea pig receiving 0.3, 0.4 or 0.5 x LD{sub 5} of sarin showed signs of cortical EEG seizures despite decreases in RBC AChE levels to as low as 10% of baseline, while seizures were evident in animals receiving 0.6 x LD{sub 5} of sarin as early as the second day; subsequent injections led to incapacitation and death. Animals receiving 0.5 x LD{sub 5} sarin showed obvious signs of cholinergic toxicity; overall, 2 of 13 animals receiving 0.5 x LD{sub 5} sarin died before all 10 injections were given, and there was a significant increase in the angle of gait in the animals that lived. By the 10th day of injection, the animals receiving saline were significantly easier to remove from their cages and handle and significantly less responsive to an approaching pencil and touch on the rump in comparison with the first day of testing. In contrast, the animals receiving 0.4 x LD{sub 5} sarin failed to show any significant reductions in their responses to an approaching pencil and a touch on the rump as compared with the first day. The 0.5 x LD{sub 5} sarin animals also failed to show any significant changes to the approach and touch responses and did not adjust to handling or removal from the cage from the first day of injections to the last day of handling. Thus, the guinea pigs receiving the 0

  5. Low-dose mercury exposure in early life: relevance of thimerosal to fetuses, newborns and infants.

    PubMed

    Dórea, José G

    2013-01-01

    This review explores the different aspects of constitutional factors in early life that modulate toxicokinetics and toxicodynamics of low-dose mercury resulting from acute ethylmercury (etHg) exposure in Thimerosal-containing vaccines (TCV). Major databases were searched for human and experimental studies that addressed issues related to early life exposure to TCV. It can be concluded that: a) mercury load in fetuses, neonates, and infants resulting from TCVs remains in blood of neonates and infants at sufficient concentration and for enough time to penetrate the brain and to exert a neurologic impact and a probable influence on neurodevelopment of susceptible infants; b) etHg metabolism related to neurodevelopmental delays has been demonstrated experimentally and observed in population studies; c) unlike chronic Hg exposure during pregnancy, neurodevelopmental effects caused by acute (repeated/cumulative) early life exposure to TCV-etHg remain unrecognized; and d) the uncertainty surrounding low-dose toxicity of etHg is challenging but recent evidence indicates that avoiding cumulative insults by alkyl-mercury forms (which include Thimerosal) is warranted. It is important to a) maintain trust in vaccines while reinforcing current public health policies to abate mercury exposure in infancy; b) generally support WHO policies that recommend vaccination to prevent and control existing and impending infectious diseases; and c) not confuse the 'need' to use a specific 'product' (TCV) by accepting as 'innocuous' (or without consequences) the presence of a proven 'toxic alkyl-mercury' (etHg) at levels that have not been proven to be toxicologically safe.

  6. Comparison of high dose inhaled steroids, low dose inhaled steroids plus low dose theophylline, and low dose inhaled steroids alone in chronic asthma in general practice

    PubMed Central

    Lim, S.; Jatakanon, A.; Gordon, D.; Macdonald, C.; Chung, K. F.; Barnes, P.

    2000-01-01

    BACKGROUND—Theophylline is widely used in the treatment of asthma, and there is evidence that theophylline has anti-inflammatory or immunomodulatory effects. A study was undertaken to determine whether theophylline added to low dose inhaled steroids would be as efficacious as high dose inhaled steroids in asthma.
METHODS—In a study in general practice of 155 recruited asthmatic patients with continuing symptomatic asthma while on 400 µg beclomethasone dipropionate (BDP) daily and inhaled β2 agonist as required, the effect of (1) continuing low dose inhaled steroids alone (LDS, 200 µg BDP twice daily), (2) low dose inhaled steroids plus low dose theophylline (LDT, 400 mg daily), or (3) high dose inhaled steroids (HDS, 500 µg BDP) over a six month period was examined.
RESULTS—One hundred and thirty patients completed the study. Between group comparison using analysis of variance showed no overall differences in peak flow measurements, diurnal variation, and symptom scores. Changes in evening peak flows approached significance at the 5% level (p=0.077). The mean improvement in evening peak flow in the LDT compared with the LDS group was 20.6 l/min (95% confidence interval (CI) -2.5 to 38.8). In the LDT group there was an increase in evening peak flows at the end of the study compared with entry values (22.5 l/min), while in the LDS and HDS groups evening peak flows increased by 1.9 and 8.3 l/min, respectively. There was no significant difference in exacerbations or in side effects.
CONCLUSION—There were no overall significant differences between the low dose steroid, low dose steroid with theophylline, and the high dose steroid groups. The greatest within-group improvement in evening peak flows was found after theophylline. A larger study may be necessary to show significant effects.

 PMID:10992535

  7. [Cytogenetic indices for somatic mutagenesis in mammals exposed to chronic low-dose irradiation].

    PubMed

    Kostenko, S A; Ermakova, O V; Sushko, S N; Fyedorova, E V; Dzhus, P P; Baschlykova, L A; Kurylenko, Yu F; Raskosha, O V; Savin, A O; Shaforost, A S

    2015-01-01

    We used cytogenetic analysis in the studies of the biological effects of a radiation factor of natural and artificial origin (under conditions ofthe 30-km exclusion zone ofthe Chernobyl experimental landfills in Ukraine, Belarus and Russia). The studies have been performed on various types of mammals: domestic animals--cows, pigs, horses and rodents--root voles, the Af mouse line, and yellow necked field mouse, bank voles. We found significant changes in the level of MN and chromosomal aberrations in the animals that were exposed to the conditions of chronic low-dose radiation for a long time (bothin the habitat and upon exposure in the Chernobyl zone) regardless of the type of animal and nature of contamination.

  8. Low-Dose Oxygen Enhances Macrophage-Derived Bacterial Clearance following Cigarette Smoke Exposure.

    PubMed

    Bain, William G; Tripathi, Ashutosh; Mandke, Pooja; Gans, Jonathan H; D'Alessio, Franco R; Sidhaye, Venkataramana K; Aggarwal, Neil R

    2016-01-01

    Background. Chronic obstructive pulmonary disease (COPD) is a common, smoking-related lung disease. Patients with COPD frequently suffer disease exacerbations induced by bacterial respiratory infections, suggestive of impaired innate immunity. Low-dose oxygen is a mainstay of therapy during COPD exacerbations; yet we understand little about whether oxygen can modulate the effects of cigarette smoke on lung immunity. Methods. Wild-type mice were exposed to cigarette smoke for 5 weeks, followed by intratracheal instillation of Pseudomonas aeruginosa (PAO1) and 21% or 35-40% oxygen. After two days, lungs were harvested for PAO1 CFUs, and bronchoalveolar fluid was sampled for inflammatory markers. In culture, macrophages were exposed to cigarette smoke and oxygen (40%) for 24 hours and then incubated with PAO1, followed by quantification of bacterial phagocytosis and inflammatory markers. Results. Mice exposed to 35-40% oxygen after cigarette smoke and PAO1 had improved survival and reduced lung CFUs and inflammation. Macrophages from these mice expressed less TNF-α and more scavenger receptors. In culture, macrophages exposed to cigarette smoke and oxygen also demonstrated decreased TNF-α secretion and enhanced phagocytosis of PAO1 bacteria. Conclusions. Our findings demonstrate a novel, protective role for low-dose oxygen following cigarette smoke and bacteria exposure that may be mediated by enhanced macrophage phagocytosis.

  9. The Effects of Repeated Low-Dose Sarin Exposure

    DTIC Science & Technology

    2005-08-01

    this report, the investigators complied with the regulations and standards of the Animal Welfare Act and adhered to the principles of the Guide for...the Care and Use of Laboratory Animals (NRC 1996). The use of trade names does not constitute an official endorsement or approval of the use of...exposure of guinea pigs to the organophosphorus nerve agent sarin. Animals were injected once a day, 5 days per week (Monday-Friday), for 2 weeks with

  10. Effects of chronic low-dose ultraviolet B radiation on DNA damage and repair in mouse skin.

    PubMed

    Mitchell, D L; Greinert, R; de Gruijl, F R; Guikers, K L; Breitbart, E W; Byrom, M; Gallmeier, M M; Lowery, M G; Volkmer, B

    1999-06-15

    Chronic exposure to sunlight causes skin cancer in humans, yet little is known about how habitual exposure to low doses of ultraviolet B radiation (UVB) affects DNA damage in the skin. We treated Skh-1 hairless mice with daily doses of suberythemal UVB for 40 days and analyzed the amount and distribution of DNA photodamage using RIAs and immunofluorescence micrography. We found that DNA damage accumulated in mouse skin as a result of chronic irradiation and that this damage persisted in the dermis and epidermis for several weeks after the chronic treatment was terminated. Although the persistent damage was evenly distributed throughout the dermis, it remained in the epidermis as a small number of heavily damaged cells at the dermal-epidermal boundary. Rates of DNA damage induction and repair were determined at different times over the course of chronic treatment in response to a higher challenge dose of UVB light. The amount of damage induced by the challenge dose increased in response to chronic exposure, and excision repair of cyclobutane pyrimidine dimers and pyrimidine(6-4)pyrimidone dimers was significantly reduced. The sensitization of mouse epidermal DNA to photoproduct induction, the reduction in excision repair, and the accumulation of nonrepairable DNA damage in the dermis and epidermis suggest that chronic low-dose exposure to sunlight may significantly enhance the predisposition of mammalian skin to sunlight-induced carcinogenesis.

  11. LINK BETWEEN LOW-DOSE ENVIRONMENTALLY RELEVANT CADMIUM EXPOSURES AND ASTHENOZOOSPERMIA IN A RAT MODEL

    PubMed Central

    Benoff, Susan; Auborn, Karen; Marmar, Joel L.; Hurley, Ian R.

    2008-01-01

    Objective To define the mechanism(s) underlying an association between asthenozoospermia and elevated blood, seminal plasma and testicular cadmium levels in infertile human males using a rat model of environmentally relevant cadmium exposures. Setting University medical center andrology research laboratory. Animals Male Wistar rats (n = 60), documented to be sensitive to the testicular effects of cadmium. Interventions Rats were given ad libitum access to water supplemented with 14% sucrose and 0, 5, 50 or 100 mg/L cadmium for 1, 4 or 8 weeks being at puberty. Main outcome measure(s) Testicular cadmium levels were determined by atomic absorption, cauda epididymal sperm motility by visual inspection, and testicular gene expression by DNA microarray hybridization. Results Chronic, low dose cadmium exposures produced a time- and dose-dependent reduction in sperm motility. Transcription of genes regulated by calcium and expression of L-type voltage-dependent calcium channel mRNA splicing variants were altered by cadmium exposure. Expression of calcium binding proteins involved in modulation of sperm motility was unaffected. Conclusions A causal relationship between elevated testicular cadmium and asthenozoospermia was identified. Aberrrant sperm motility was correlated with altered expression of L-type voltage-dependent calcium channel isoforms found on the sperm tail, which regulate calcium and cadmium influx. PMID:18308070

  12. Safety and efficacy of low-dose, subacute exposure of mature ewes to sodium chlorate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective was to determine the safety and efficacy of low-dose, subacute exposure of mature ewes to NaClO3 in the drinking water. Twenty-five ewes (BW = 62.5 ± 7.3 kg) were placed indoors in individual pens with ad libitum access to water and feed. After 7 d of adaptation, ewes were assigned ran...

  13. Effects of Chronic Low-Dose Radiation on Human Neural Progenitor Cells.

    PubMed

    Katsura, Mari; Cyou-Nakamine, Hiromasa; Zen, Qin; Zen, Yang; Nansai, Hiroko; Amagasa, Shota; Kanki, Yasuharu; Inoue, Tsuyoshi; Kaneki, Kiyomi; Taguchi, Akashi; Kobayashi, Mika; Kaji, Toshiyuki; Kodama, Tatsuhiko; Miyagawa, Kiyoshi; Wada, Youichiro; Akimitsu, Nobuyoshi; Sone, Hideko

    2016-01-22

    The effects of chronic low-dose radiation on human health have not been well established. Recent studies have revealed that neural progenitor cells are present not only in the fetal brain but also in the adult brain. Since immature cells are generally more radiosensitive, here we investigated the effects of chronic low-dose radiation on cultured human neural progenitor cells (hNPCs) derived from embryonic stem cells. Radiation at low doses of 31, 124 and 496 mGy per 72 h was administered to hNPCs. The effects were estimated by gene expression profiling with microarray analysis as well as morphological analysis. Gene expression was dose-dependently changed by radiation. By thirty-one mGy of radiation, inflammatory pathways involving interferon signaling and cell junctions were altered. DNA repair and cell adhesion molecules were affected by 124 mGy of radiation while DNA synthesis, apoptosis, metabolism, and neural differentiation were all affected by 496 mGy of radiation. These in vitro results suggest that 496 mGy radiation affects the development of neuronal progenitor cells while altered gene expression was observed at a radiation dose lower than 100 mGy. This study would contribute to the elucidation of the clinical and subclinical phenotypes of impaired neuronal development induced by chronic low-dose radiation.

  14. Effects of Chronic Low-Dose Radiation on Human Neural Progenitor Cells

    PubMed Central

    Katsura, Mari; Cyou-Nakamine, Hiromasa; Zen, Qin; Zen, Yang; Nansai, Hiroko; Amagasa, Shota; Kanki, Yasuharu; Inoue, Tsuyoshi; Kaneki, Kiyomi; Taguchi, Akashi; Kobayashi, Mika; Kaji, Toshiyuki; Kodama, Tatsuhiko; Miyagawa, Kiyoshi; Wada, Youichiro; Akimitsu, Nobuyoshi; Sone, Hideko

    2016-01-01

    The effects of chronic low-dose radiation on human health have not been well established. Recent studies have revealed that neural progenitor cells are present not only in the fetal brain but also in the adult brain. Since immature cells are generally more radiosensitive, here we investigated the effects of chronic low-dose radiation on cultured human neural progenitor cells (hNPCs) derived from embryonic stem cells. Radiation at low doses of 31, 124 and 496 mGy per 72 h was administered to hNPCs. The effects were estimated by gene expression profiling with microarray analysis as well as morphological analysis. Gene expression was dose-dependently changed by radiation. By thirty-one mGy of radiation, inflammatory pathways involving interferon signaling and cell junctions were altered. DNA repair and cell adhesion molecules were affected by 124 mGy of radiation while DNA synthesis, apoptosis, metabolism, and neural differentiation were all affected by 496 mGy of radiation. These in vitro results suggest that 496 mGy radiation affects the development of neuronal progenitor cells while altered gene expression was observed at a radiation dose lower than 100 mGy. This study would contribute to the elucidation of the clinical and subclinical phenotypes of impaired neuronal development induced by chronic low-dose radiation. PMID:26795421

  15. Effects of Chronic Low-Dose Radiation on Human Neural Progenitor Cells

    NASA Astrophysics Data System (ADS)

    Katsura, Mari; Cyou-Nakamine, Hiromasa; Zen, Qin; Zen, Yang; Nansai, Hiroko; Amagasa, Shota; Kanki, Yasuharu; Inoue, Tsuyoshi; Kaneki, Kiyomi; Taguchi, Akashi; Kobayashi, Mika; Kaji, Toshiyuki; Kodama, Tatsuhiko; Miyagawa, Kiyoshi; Wada, Youichiro; Akimitsu, Nobuyoshi; Sone, Hideko

    2016-01-01

    The effects of chronic low-dose radiation on human health have not been well established. Recent studies have revealed that neural progenitor cells are present not only in the fetal brain but also in the adult brain. Since immature cells are generally more radiosensitive, here we investigated the effects of chronic low-dose radiation on cultured human neural progenitor cells (hNPCs) derived from embryonic stem cells. Radiation at low doses of 31, 124 and 496 mGy per 72 h was administered to hNPCs. The effects were estimated by gene expression profiling with microarray analysis as well as morphological analysis. Gene expression was dose-dependently changed by radiation. By thirty-one mGy of radiation, inflammatory pathways involving interferon signaling and cell junctions were altered. DNA repair and cell adhesion molecules were affected by 124 mGy of radiation while DNA synthesis, apoptosis, metabolism, and neural differentiation were all affected by 496 mGy of radiation. These in vitro results suggest that 496 mGy radiation affects the development of neuronal progenitor cells while altered gene expression was observed at a radiation dose lower than 100 mGy. This study would contribute to the elucidation of the clinical and subclinical phenotypes of impaired neuronal development induced by chronic low-dose radiation.

  16. Biofilm formation of Clostridium perfringens and its exposure to low-dose antimicrobials

    PubMed Central

    Charlebois, Audrey; Jacques, Mario; Archambault, Marie

    2014-01-01

    Clostridium perfringens is an opportunistic pathogen that can cause food poisoning in humans and various enterotoxemia in animal species. Very little is known on the biofilm of C. perfringens and its exposure to subminimal inhibitory concentrations of antimicrobials. This study was undertaken to address these issues. Most of the C. perfringens human and animal isolates tested in this study were able to form biofilm (230/277). Porcine clinical isolates formed significantly more biofilm than the porcine commensal isolates. A subgroup of clinical and commensal C. perfringens isolates was randomly selected for further characterization. Biofilm was found to protect C. perfringens bacterial cells from exposure to high concentrations of tested antimicrobials. Exposure to low doses of some of these antimicrobials tended to lead to a diminution of the biofilm formed. However, a few isolates showed an increase in biofilm formation when exposed to low doses of tylosin, bacitracin, virginiamycin, and monensin. Six isolates were randomly selected for biofilm analysis using scanning laser confocal microscopy. Of those, four produced more biofilm in presence of low doses of bacitracin whereas biofilms formed without bacitracin were thinner and less elevated. An increase in the area occupied by bacteria in the biofilm following exposure to low doses of bacitracin was also observed in the majority of isolates. Morphology examination revealed flat biofilms with the exception of one isolate that demonstrated a mushroom-like biofilm. Matrix composition analysis showed the presence of proteins, beta-1,4 linked polysaccharides and extracellular DNA, but no poly-beta-1,6-N-acetyl-D-glucosamine. This study brings new information on the biofilm produced by C. perfringens and its exposure to low doses of antimicrobials. PMID:24795711

  17. Biofilm formation of Clostridium perfringens and its exposure to low-dose antimicrobials.

    PubMed

    Charlebois, Audrey; Jacques, Mario; Archambault, Marie

    2014-01-01

    Clostridium perfringens is an opportunistic pathogen that can cause food poisoning in humans and various enterotoxemia in animal species. Very little is known on the biofilm of C. perfringens and its exposure to subminimal inhibitory concentrations of antimicrobials. This study was undertaken to address these issues. Most of the C. perfringens human and animal isolates tested in this study were able to form biofilm (230/277). Porcine clinical isolates formed significantly more biofilm than the porcine commensal isolates. A subgroup of clinical and commensal C. perfringens isolates was randomly selected for further characterization. Biofilm was found to protect C. perfringens bacterial cells from exposure to high concentrations of tested antimicrobials. Exposure to low doses of some of these antimicrobials tended to lead to a diminution of the biofilm formed. However, a few isolates showed an increase in biofilm formation when exposed to low doses of tylosin, bacitracin, virginiamycin, and monensin. Six isolates were randomly selected for biofilm analysis using scanning laser confocal microscopy. Of those, four produced more biofilm in presence of low doses of bacitracin whereas biofilms formed without bacitracin were thinner and less elevated. An increase in the area occupied by bacteria in the biofilm following exposure to low doses of bacitracin was also observed in the majority of isolates. Morphology examination revealed flat biofilms with the exception of one isolate that demonstrated a mushroom-like biofilm. Matrix composition analysis showed the presence of proteins, beta-1,4 linked polysaccharides and extracellular DNA, but no poly-beta-1,6-N-acetyl-D-glucosamine. This study brings new information on the biofilm produced by C. perfringens and its exposure to low doses of antimicrobials.

  18. Alteration of cytokine profiles in mice exposed to chronic low-dose ionizing radiation

    SciTech Connect

    Shin, Suk Chul; Lee, Kyung-Mi; Kang, Yu Mi; Kim, Kwanghee; Kim, Cha Soon; Yang, Kwang Hee; Jin, Young-Woo; Kim, Chong Soon; Kim, Hee Sun

    2010-07-09

    While a high-dose of ionizing radiation is generally harmful and causes damage to living organisms, a low-dose of radiation has been shown to be beneficial in a variety of animal models. To understand the basis for the effect of low-dose radiation in vivo, we examined the cellular and immunological changes evoked in mice exposed to low-dose radiation at very low (0.7 mGy/h) and low (3.95 mGy/h) dose rate for the total dose of 0.2 and 2 Gy, respectively. Mice exposed to low-dose radiation, either at very low- or low-dose rate, demonstrated normal range of body weight and complete blood counts. Likewise, the number and percentage of peripheral lymphocyte populations, CD4{sup +} T, CD8{sup +} T, B, or NK cells, stayed unchanged following irradiation. Nonetheless, the sera from these mice exhibited elevated levels of IL-3, IL-4, leptin, MCP-1, MCP-5, MIP-1{alpha}, thrombopoietin, and VEGF along with slight reduction of IL-12p70, IL-13, IL-17, and IFN-{gamma}. This pattern of cytokine release suggests the stimulation of innate immunity facilitating myeloid differentiation and activation while suppressing pro-inflammatory responses and promoting differentiation of naive T cells into T-helper 2, not T-helper 1, types. Collectively, our data highlight the subtle changes of cytokine milieu by chronic low-dose {gamma}-radiation, which may be associated with the functional benefits observed in various experimental models.

  19. Perinatal Exposure to Low-Dose Methoxychlor Impairs Testicular Development in C57BL/6 Mice

    PubMed Central

    Du, Xiaohong; Zhang, Hua; Liu, Yuanwu; Yu, Wanpeng; Huang, Chaobin; Li, Xiangdong

    2014-01-01

    Methoxychlor (MXC), an organochlorine pesticide, has adverse effects on male reproduction at toxicological doses. Humans and wild animals are exposed to MXC mostly through contaminated dietary intake. Higher concentrations of MXC have been found in human milk, raising the demand for the risk assessment of offspring after maternal exposure to low doses of MXC. In this study, pregnant mice (F0) were given intraperitoneal daily evening injections of 1 mg/kg/d MXC during their gestational (embryonic day 0.5, E0.5) and lactational periods (postnatal day 21.5, P21.5), and the F1 males were assessed. F1 testes were collected at P0.5, P21.5 and P45.5. Maternal exposure to MXC disturbed the testicular development. Serum testosterone levels decreased, whereas estradiol levels increased. To understand the molecular mechanisms of exposure to MXC in male reproduction, the F1 testes were examined for changes in the expression of steroidogenesis- and spermatogenesis- related genes. RT-PCR analysis demonstrated that MXC significantly decreased Cyp11a1 and increased Cyp19a1; furthermore, it downregulated certain spermatogenic genes (Dazl, Boll, Rarg, Stra8 and Cyclin-a1). In summary, perinatal exposure to low-dose MXC disturbs the testicular development in mice. This animal study of exposure to low-dose MXC in F1 males suggests similar dysfunctional effects on male reproduction in humans. PMID:25048109

  20. Low Dose Gamma Irradiation Potentiates Secondary Exposure to Gamma Rays or Protons in Thyroid Tissue Analogs

    SciTech Connect

    Green, Lora M

    2006-05-25

    We have utilized our unique bioreactor model to produce three-dimensional thyroid tissue analogs that we believe better represent the effects of radiation in vivo than two-dimensional cultures. Our thyroid model has been characterized at multiple levels, including: cell-cell exchanges (bystander), signal transduction, functional changes and modulation of gene expression. We have significant preliminary data on structural, functional, signal transduction and gene expression responses from acute exposures at high doses (50-1000 rads) of gamma, protons and iron (Green et al., 2001a; 2001b; 2002a; 2002b; 2005). More recently, we used our DOE funding (ending Feb 06) to characterize the pattern of radiation modulated gene expression in rat thyroid tissue analogs using low-dose/low-dose rate radiation, plus/minus acute challenge exposures. Findings from these studies show that the low-dose/low-dose rate “priming” exposures to radiation invoked changes in gene expression profiles that varied with dose and time. The thyrocytes transitioned to a “primed” state, so that when the tissue analogs were challenged with an acute exposure to radiation they had a muted response (or an increased resistance) to cytopathological changes relative to “un-primed” cells. We measured dramatic differences in the primed tissue analogs, showing that our original hypothesis was correct: that low dose gamma irradiation will potentiate the repair/adaptation response to a secondary exposure. Implications from these findings are that risk assessments based on classical in vitro tissue culture assays will overestimate risk, and that low dose rate priming results in a reduced response in gene expression to a secondary challenge exposure, which implies that a priming dose provides enhanced protection to thyroid cells grown as tissue analogs. If we can determine that the effects of radiation on our tissue analogs more closely resemble the effects of radiation in vivo, then we can better

  1. Data integration reveals key homeostatic mechanisms following low dose radiation exposure

    SciTech Connect

    Tilton, Susan C.; Matzke, Melissa M.; Sowa, Marianne B.; Stenoien, David L.; Weber, Thomas J.; Morgan, William F.; Waters, Katrina M.

    2015-05-15

    , ROS/RNS and DNA repair pathways detected • Low dose exposure alters metabolites involved in nitric oxide biosynthesis and wound healing. • Computationally predicted regulators of primary mechanisms were experimentally validated.

  2. Mesothelioma: cases associated with non-occupational and low dose exposures

    PubMed Central

    Hillerdal, G.

    1999-01-01

    OBJECTIVES: To estimate the importance of low dose exposure to asbestos on the risk of mesothelioma. METHODS: A review of the literature. RESULTS AND CONCLUSIONS: There is no evidence of a threshold level below which there is no risk of mesothelioma. Low level exposure more often than not contains peak concentrations which can be very high for short periods. There might exist a background level of mesothelioma occurring in the absence of exposure ot asbestos, but there is no proof of this and this "natural level" is probably much lower than the 1- 2/million/year which has been often cited.   PMID:10492646

  3. Adverse reproductive effects of maternal low-dose melamine exposure during pregnancy in rats.

    PubMed

    Chu, Ching Yan; Tang, Ling Ying; Li, Lu; Shum, Alisa Sau Wun; Fung, Kwok Pui; Wang, Chi Chiu

    2017-01-01

    Melamine is a heterocyclic, aromatic amine and nitrogen-enriched environmental toxicant, found in not only adulterated foodstuffs but also industrial household tableware and paints. Previous studies demonstrated adverse effects of high-dose melamine on human infants and pregnant animals, but effects of low-dose melamine on pregnancy have not been reported. In this study, reproductive effects of low-dose melamine were investigated in pregnant rats. Melamine in the range of 12.5-50 mg/kg was administered to pregnant rats at different gestational stages. Maternal weight gain was not significantly affected, and other maternal morbidity was not observed. Low-dose melamine exposure during pregnancy increased fetal size but reduced somite number in gastrulation (GD8.5-GD10.5) and organogenesis (GD10.5-GD16.5) periods, and increased incidence of stillbirth in whole gestational period (GD0.5 to delivery). Embryotoxicity of melamine was further confirmed by whole embryo culture in vitro that melamine retarded embryonic growth, impaired development of brain and heart, and induced open neural tube and atrioventricular defects with increased apoptosis. In conclusion, adverse reproductive effects of low-dose melamine during pregnancy were identified in the developing rat embryos and the perinatal effects of melamine were gestational and developmental stage dependent. Detailed hazard and risk assessment of melamine in reproduction system are warrant. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 131-138, 2017.

  4. Short Communication: Viremic Control Is Independent of Repeated Low-Dose SHIVSF162p3 Exposures

    PubMed Central

    Henning, Tara R.; Hanson, Debra; Vishwanathan, Sundaram A.; Butler, Katherine; Dobard, Charles; Garcia-Lerma, Gerardo; Radzio, Jessica; Smith, James; McNicholl, Janet M.

    2014-01-01

    Abstract The repeat low-dose virus challenge model is commonly used in nonhuman primate studies of HIV transmission and biomedical preventions. For some viruses or challenge routes, it is uncertain whether the repeated exposure design might induce virus-directed innate or adaptive immunity that could affect infection or viremic outcomes. Retrospective cohorts of male Indian rhesus (n=40) and female pigtail (n=46) macaques enrolled in repeat low-dose rectal or vaginal SHIVSF162p3 challenge studies, respectively, were studied to compare the relationship between the number of previous exposures and peak plasma SHIV RNA levels or viral load area under the curve (AUC), surrogate markers of viral control. Repeated mucosal exposures of 10 or 50 TCID50 of virus for rectal and vaginal exposures, respectively, were performed. Virus levels were measured by quantitative reverse-transcriptase real-time PCR. The cumulative number of SHIVSF162p3 exposures did not correlate with observed peak virus levels or with AUC in rectally challenged rhesus macaques [peak: rho (ρ)=0.04, p=0.8; AUC: ρ=0.33, p=0.06] or vaginally challenged pigtail macaques (peak: ρ=−0.09, p=0.7; AUC: ρ=0.11, p=0.6). Infections in these models occur independently of exposure history and provide assurance that neither inoculation route nor number of exposures required for infection correlates with postinfection viremia. These data also indicate that both the vaginal and rectal repeated low-dose virus exposure models using SHIVSF162p3 provide a reliable system for nonhuman primate studies. PMID:25313448

  5. Low-dose sarin exposure produces long term changes in brain neurochemistry of mice.

    PubMed

    Oswal, Dhawal P; Garrett, Teresa L; Morris, Mariana; Lucot, James B

    2013-01-01

    Sarin is a toxic organophosphorus (OP) nerve agent that has been reported to cause long-term alterations in behavioral and neuropsychological processes. The present study was designed to investigate the effect of low dose sarin exposure on the monoamine neurotransmitter systems in various brain regions of mice. The rationale was to expand our knowledge about the noncholinergic neurochemical alterations associated with low dose exposure to this cholinesterase inhibitor. We analyzed the levels of monoamines and their metabolites in different brain areas after exposure of male C57BL/6 mice to a subclinical dose of sarin (0.4 LD50). Mice did not show any signs of cholinergic toxicity or pathological changes in brain tissue. At 1, 4 and 8 weeks post-sarin exposure brains were collected for neurochemical analysis. A significant decrease in the dopamine (DA) turnover, as measured by the metabolite to parent ratio, was observed in the frontal cerebral cortex (FC) at all time points tested. DA turnover was significantly increased in the amygdala at 4 weeks but not at 1 or 8 weeks after exposure. The caudate nucleus displayed a decrease in DA turnover at 1 week but no significant change was observed at 4 and 8 weeks suggesting a reversible effect. In addition to this, serotonin (5-HT) levels were transiently altered at various time points in all the brain regions studied (increase in FC, caudate nucleus and decrease in amygdala). Since there were no signs of cholinergic toxicity or cell death after sarin exposure, different non-cholinergic mechanisms may be involved in regulating these effects. Our results demonstrate that non-symptomatic dose of OP nerve agent sarin has potent long-term, region-specific effects on the monoaminergic neurotransmitter systems. Data also suggests differential effects of sarin on the various DA projections. These neurochemical alterations could be associated with long term behavioral and neuropsychological changes associated with low dose OP

  6. Low-dose gamma irradiation of food protein increases its allergenicity in a chronic oral challenge.

    PubMed

    Vaz, A F M; Souza, M P; Medeiros, P L; Melo, A M M A; Silva-Lucca, R A; Santana, L A; Oliva, M L V; Perez, K R; Cuccovia, I M; Correia, M T S

    2013-01-01

    Few chronic food protein models have described the relationship between allergenicity and the molecular structure of food protein after physical processing. The effect of γ-radiation on the structure of food protein was measured by fluorescence, circular dichroism and microcalorimetry. BALB/c mice were intraperitoneally sensitized and then given non-irradiated and irradiated Con-A by daily gavage for 28days. The tendency to form insoluble amorphous aggregates and partially unfolded species was observed after irradiation. The administration of non-irradiated and irradiated samples at low-dose significantly increased weight loss as well as plasma levels of eotaxin in animals repeatedly exposed to Con-A. Significant lymphocytic infiltrate filling completely the stroma of microvilli and tubular glands was observed in the small intestinal of the group given Con-A irradiated at a low dose. This phenotype was not observed in animals treated with Con-A irradiated at a high dose.

  7. Cardiovascular diseases related to ionizing radiation: The risk of low-dose exposure (Review)

    PubMed Central

    Baselet, Bjorn; Rombouts, Charlotte; Benotmane, Abderrafi Mohammed; Baatout, Sarah; Aerts, An

    2016-01-01

    Traditionally, non-cancer diseases are not considered as health risks following exposure to low doses of ionizing radiation. Indeed, non-cancer diseases are classified as deterministic tissue reactions, which are characterized by a threshold dose. It is judged that below an absorbed dose of 100 mGy, no clinically relevant tissue damage occurs, forming the basis for the current radiation protection system concerning non-cancer effects. Recent epidemiological findings point, however, to an excess risk of non-cancer diseases following exposure to lower doses of ionizing radiation than was previously thought. The evidence is the most sound for cardiovascular disease (CVD) and cataract. Due to limited statistical power, the dose-risk relationship is undetermined below 0.5 Gy; however, if this relationship proves to be without a threshold, it may have considerable impact on current low-dose health risk estimates. In this review, we describe the CVD risk related to low doses of ionizing radiation, the clinical manifestation and the pathology of radiation-induced CVD, as well as the importance of the endothelium models in CVD research as a way forward to complement the epidemiological data with the underlying biological and molecular mechanisms. PMID:27748824

  8. Severe Tardive Dystonia on Low Dose Short Duration Exposure to Atypical Antipsychotics: Factors Explored

    PubMed Central

    Chandra, Nilanjan C.; Sheth, Shabina A.; Mehta, Ritambhara Y.; Dave, Kamlesh R.

    2017-01-01

    Tardive dystonia (TD) is a serious side effect of antipsychotic medications, more with typical antipsychotics, that is potentially irreversible in affected patients. Studies show that newer atypical antipsychotics have a lower risk of TD. As a result, many clinicians may have developed a false sense of security when prescribing these medications. We report a case of 20-year-old male with hyperthymic temperament and borderline intellectual functioning, who developed severe TD after low dose short duration exposure to atypical antipsychotic risperidone and then olanzapine. The goal of this paper is to alert the reader to be judicious and cautious before using casual low dose second generation antipsychotics in patient with no core psychotic features, hyperthymic temperament, or borderline intellectual functioning suggestive of organic brain damage, who are more prone to develop adverse effects such as TD and monitor the onset of TD in patients taking atypical antipsychotics. PMID:28250568

  9. Combination of low-dose mirtazapine and ibuprofen for prophylaxis of chronic tension-type headache.

    PubMed

    Bendtsen, L; Buchgreitz, L; Ashina, S; Jensen, R

    2007-02-01

    Chronic headaches are difficult to treat and represent the biggest challenge in headache centres. Mirtazapine has a prophylactic and ibuprofen an acute effect in tension-type headache. Combination therapy may increase efficacy and lower side effects. We aimed to evaluate the prophylactic effect of a combination of low-dose mirtazapine and ibuprofen in chronic tension-type headache. Ninety-three patients were included in the double-blind, placebo-controlled, parallel trial. Following a 4-week run-in period they were randomized to four groups for treatment with a combination of mirtazapine 4.5 mg and ibuprofen 400 mg, placebo, mirtazapine 4.5 mg or ibuprofen 400 mg daily for 8 weeks. Eighty-four patients completed the study. The primary efficacy parameter, change in area under the headache curve from run-in to the last 4 weeks of treatment, did not differ between combination therapy (190) and placebo (219), P = 0.85. Explanatory analyses revealed worsening of headache already in the third week of treatment with ibuprofen alone. In conclusion, the combination of low-dose mirtazapine and ibuprofen is not effective for the treatment of chronic tension-type headache. Moreover, the study suggests that daily intake of ibuprofen worsens headache already after few weeks in chronic tension-type headache.

  10. Adaption By Low Dose Radiation Exposure: A Look at Scope and Limitations for Radioprotection.

    PubMed

    Mitchel, Ron E J

    2015-01-01

    The procedures and dose limitations used for radiation protection in the nuclear industry are founded on the assumption that risk is directly proportional to dose, without a threshold. Based on this idea that any dose, no matter how small, will increase risk, radiation protection regulations generally attempt to reduce any exposure to "as low as reasonably achievable" (ALARA). We know however, that these regulatory assumptions are inconsistent with the known biological effects of low doses. Low doses induce protective effects, and these adaptive responses are part of a general response to low stress. Adaptive responses have been tightly conserved during evolution, from single celled organisms up to humans, indicating their importance. Here we examine cellular and animal studies that show the influence of radiation induced protective effects on diverse diseases, and examine the radiation dose range that is effective for different tissues in the same animal. The concept of a dose window, with upper and lower effective doses, as well as the effect of multiple stressors and the influence of genetics will also be examined. The effect of the biological variables on low dose responses will be considered from the point of view of the limitations they may impose on any revised radiation protection regulations.

  11. Emesis as a Screening Diagnostic for Low Dose Rate (LDR) Total Body Radiation Exposure

    PubMed Central

    Camarata, A. S.; Switchenko, J. M.; Demidenko, E.; Flood, A. B.; Swartz, H. M.; Ali, A. N.

    2015-01-01

    Current radiation disaster manuals list the time-to-emesis (TE) as the key triage indicator of radiation dose. The data used to support TE recommendations were derived primarily from nearly instantaneous, high dose rate exposures as part of variable condition accident databases. To date, there has not been a systematic differentiation between triage dose estimates associated with high and low dose rate (LDR) exposures, even though it is likely that after a nuclear detonation or radiologic disaster, many surviving casualties would have received a significant portion of their total exposure from fallout (LDR exposure) rather than from the initial nuclear detonation or criticality event (high dose rate exposure). This commentary discusses the issues surrounding the use of emesis as a screening diagnostic for radiation dose after LDR exposure. As part of this discussion, previously published clinical data on emesis after LDR total body irradiation (TBI) is statistically re-analyzed as an illustration of the complexity of the issue and confounding factors. This previously published data includes 107 patients who underwent TBI up to 10.5 Gy in a single fraction delivered over several hours at 0.02 to 0.04 Gy/min. Estimates based on these data for the sensitivity of emesis as a screening diagnostic for low dose rate radiation exposure range from 57.1% to 76.6%, and the estimates for specificity range from 87.5% to 99.4%. Though the original data contain multiple confounding factors, the evidence regarding sensitivity suggests that emesis appears to be quite poor as a medical screening diagnostic for LDR exposures. PMID:26910032

  12. Specific metabolic fingerprint of a dietary exposure to a very low dose of endosulfan.

    PubMed

    Canlet, Cécile; Tremblay-Franco, Marie; Gautier, Roselyne; Molina, Jérôme; Métais, Benjamin; Blas-Y Estrada, Florence; Gamet-Payrastre, Laurence

    2013-01-01

    Like other persistent organochlorine pesticides, endosulfan residues have been detected in foods including fruit, vegetables, and fish. The aim of our study was to assess the impact of a dietary exposure to low doses of endosulfan from foetal development until adult age on metabolic homeostasis in mice and to identify biomarkers of exposure using an (1)H-NMR-based metabonomic approach in various tissues and biofluids. We report in both genders an increase in plasma glucose as well as changes in levels of factors involved in the regulation of liver oxidative stress, confirming the prooxidant activities of this compound. Some metabolic changes were distinct in males and females. For example in plasma, a decrease in lipid LDL and choline content was only observed in female. Lactate levels in males were significantly increased. In conclusion, our results show that metabolic changes in liver could be linked to the onset of pathologies like diabetes and insulin resistance. Moreover from our results it appears that the NMR-based metabonomic approach could be useful for the characterization in plasma of a dietary exposure to low dose of pesticide in human.

  13. Mitochondrial proteomic alterations caused by long-term low-dose copper exposure in mouse cortex.

    PubMed

    Lin, Xuemei; Wei, Gang; Huang, Zhijun; Qu, Zhongsen; Huang, Xinfeng; Xu, Hua; Liu, Jianjun; Zhuang, Zhixiong; Yang, Xifei

    2016-11-30

    Mitochondrial dysfunction is involved in neurotoxicity caused by exposure of various chemicals such as copper. However, the effects of long-term low-dose copper exposure on mitochondrial proteome remain unclear. In this study, we found the treatment of copper (0.13ppm copper sulfate in drinking water) for 12 months caused abnormal expression of a total of 13 mitochondrial proteins (7 up-regulated and 6 down-regulated) as revealed by two-dimensional electrophoresis coupled with mass spectrometry in mouse cortex. Protein functional analysis revealed that these differentially expressed proteins mainly included apoptosis-associated proteins, axon guidance-associated proteins, axonogenesis-associated proteins and mitochondrial respiratory chain complex. Among these differentially expressed mitochondrial proteins, GRP75 (75kDa glucose-regulated protein) and GRP78 (78kDa glucose-regulated protein) were found to be significantly down-regulated as confirmed by Western-blot analysis. The down-regulation of GRP75 was shown to promote apoptosis. The down-regulation of GRP78/BiP could up-regulate endoplasmic reticulum (ER) stress mediators and thus cause apoptosis. Our study suggested that these differentially expressed mitochondrial proteins such as GRP75 and GRP78 could be involved in neurotoxicity caused by long-term low-dose copper exposure and serve as potential molecular targets for the treatment of copper neurotoxicity.

  14. Chronic low-dose-rate ionising radiation affects the hippocampal phosphoproteome in the ApoE−/− Alzheimer's mouse model

    PubMed Central

    Kempf, Stefan J.; Janik, Dirk; Barjaktarovic, Zarko; Braga-Tanaka, Ignacia; Tanaka, Satoshi; Neff, Frauke; Saran, Anna; Larsen, Martin R.; Tapio, Soile

    2016-01-01

    Accruing data indicate that radiation-induced consequences resemble pathologies of neurodegenerative diseases such as Alzheimer's. The aim of this study was to elucidate the effect on hippocampus of chronic low-dose-rate radiation exposure (1 mGy/day or 20 mGy/day) given over 300 days with cumulative doses of 0.3 Gy and 6.0 Gy, respectively. ApoE deficient mutant C57Bl/6 mouse was used as an Alzheimer's model. Using mass spectrometry, a marked alteration in the phosphoproteome was found at both dose rates. The radiation-induced changes in the phosphoproteome were associated with the control of synaptic plasticity, calcium-dependent signalling and brain metabolism. An inhibition of CREB signalling was found at both dose rates whereas Rac1-Cofilin signalling was found activated only at the lower dose rate. Similarly, the reduction in the number of activated microglia in the molecular layer of hippocampus that paralleled with reduced levels of TNFα expression and lipid peroxidation was significant only at the lower dose rate. Adult neurogenesis, investigated by Ki67, GFAP and NeuN staining, and cell death (activated caspase-3) were not influenced at any dose or dose rate. This study shows that several molecular targets induced by chronic low-dose-rate radiation overlap with those of Alzheimer's pathology. It may suggest that ionising radiation functions as a contributing risk factor to this neurodegenerative disease. PMID:27708245

  15. Environmental exposure to low-doses of ionizing radiation. Effects on early nephrotoxicity in mice.

    PubMed

    Bellés, Montserrat; Gonzalo, Sergio; Serra, Noemí; Esplugas, Roser; Arenas, Meritxell; Domingo, José Luis; Linares, Victoria

    2017-03-31

    Nuclear accidents of tremendous magnitude, such as those of Chernobyl (1986) and Fukushima (2011), mean that individuals living in the contaminated areas are potentially exposed to ionizing radiation (IR). However, the dose-response relationship for effects of low doses of radiation is not still established. The present study was aimed at investigating in mice the early effects of low-dose internal radiation exposure on the kidney. Adult male (C57BL/6J) mice were divided into three groups. Two groups received a single subcutaneous (s.c.) doses of cesium ((137)Cs) with activities of 4000 and 8000Bq/kg bw. A third group (control group) received a single s.c. injection of 0.9% saline. To evaluate acute and subacute effects, mice (one-half of each group) were euthanized at 72h and 10 days post-exposure to (137)Cs, respectively. Urine samples were collected for biochemical analysis, including the measurement of F2-isoprostane (F2-IsoP) and kidney injury molecule-1 (KIM-1) levels. Moreover, the concentrations of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a sensitive marker of oxidative DNA damage, were measured in renal tissue. Urinary excretion of total protein significantly increased at 72h in mice exposed to Cs4000. Uric acid and lactate dehydrogenase (LDH) decreased significantly at both times post-exposure in animals exposed to Cs8000. After 72h and 10d of exposure to Cs4000, a significant increase in the γ-glutamil transferase (GGT) and N-acetyl-β-D-glucosaminidase (NAG) activities was observed. In turn, F2-IsoP levels increased -mainly in the Cs4000 group- at 72h post-exposure. Following irradiation ((137)Cs), the highest level of KIM-1 was corresponded to the Cs4000 group at 72h. Likewise, the main DNA damage was detected in mice exposed to Cs4000, mainly at 10d after irradiation. The alterations observed in several biomarkers suggest an immediate renal damage following exposure to low doses of IR (given as (137)Cs). Further investigations are required to clarify

  16. Causes of genome instability: the effect of low dose chemical exposures in modern society

    PubMed Central

    Langie, Sabine A.S.; Koppen, Gudrun; Desaulniers, Daniel; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Amedei, Amedeo; Azqueta, Amaya; Bisson, William H.; Brown, Dustin; Brunborg, Gunnar; Charles, Amelia K.; Chen, Tao; Colacci, Annamaria; Darroudi, Firouz; Forte, Stefano; Gonzalez, Laetitia; Hamid, Roslida A.; Knudsen, Lisbeth E.; Leyns, Luc; Lopez de Cerain Salsamendi, Adela; Memeo, Lorenzo; Mondello, Chiara; Mothersill, Carmel; Olsen, Ann-Karin; Pavanello, Sofia; Raju, Jayadev; Rojas, Emilio; Roy, Rabindra; Ryan, Elizabeth; Ostrosky-Wegman, Patricia; Salem, Hosni K.; Scovassi, Ivana; Singh, Neetu; Vaccari, Monica; Van Schooten, Frederik J.; Valverde, Mahara; Woodrick, Jordan; Zhang, Luoping; van Larebeke, Nik; Kirsch-Volders, Micheline; Collins, Andrew R.

    2015-01-01

    Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome’s integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus, genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. This review raises the hypothesis that in addition to known human carcinogens, exposure to low dose of other chemicals present in our modern society could contribute to carcinogenesis by indirectly affecting genome stability. The selected chemicals with their mechanisms of action proposed to indirectly contribute to genome instability are: heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make scientists aware of the increasing need to unravel the underlying mechanisms via which chemicals at low doses can induce genome instability and thus promote carcinogenesis. PMID:26106144

  17. Causes of genome instability: the effect of low dose chemical exposures in modern society.

    PubMed

    Langie, Sabine A S; Koppen, Gudrun; Desaulniers, Daniel; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Amedei, Amedeo; Azqueta, Amaya; Bisson, William H; Brown, Dustin G; Brunborg, Gunnar; Charles, Amelia K; Chen, Tao; Colacci, Annamaria; Darroudi, Firouz; Forte, Stefano; Gonzalez, Laetitia; Hamid, Roslida A; Knudsen, Lisbeth E; Leyns, Luc; Lopez de Cerain Salsamendi, Adela; Memeo, Lorenzo; Mondello, Chiara; Mothersill, Carmel; Olsen, Ann-Karin; Pavanello, Sofia; Raju, Jayadev; Rojas, Emilio; Roy, Rabindra; Ryan, Elizabeth P; Ostrosky-Wegman, Patricia; Salem, Hosni K; Scovassi, A Ivana; Singh, Neetu; Vaccari, Monica; Van Schooten, Frederik J; Valverde, Mahara; Woodrick, Jordan; Zhang, Luoping; van Larebeke, Nik; Kirsch-Volders, Micheline; Collins, Andrew R

    2015-06-01

    Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome's integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus, genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. This review raises the hypothesis that in addition to known human carcinogens, exposure to low dose of other chemicals present in our modern society could contribute to carcinogenesis by indirectly affecting genome stability. The selected chemicals with their mechanisms of action proposed to indirectly contribute to genome instability are: heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make scientists aware of the increasing need to unravel the underlying mechanisms via which chemicals at low doses can induce genome instability and thus promote carcinogenesis.

  18. Schizophrenia-like GABAergic gene expression deficits in cerebellar Golgi cells from rats chronically exposed to low-dose phencyclidine.

    PubMed

    Bullock, W Michael; Bolognani, Federico; Botta, Paolo; Valenzuela, C Fernando; Perrone-Bizzozero, Nora I

    2009-12-01

    One of the most consistent findings in schizophrenia is the decreased expression of the GABA synthesizing enzymes GAD(67) and GAD(65) in specific interneuron populations. This dysfunction is observed in distributed brain regions including the prefrontal cortex, hippocampus, and cerebellum. In an effort to understand the mechanisms for this GABA deficit, we investigated the effect of the N-methyl-D-aspartate receptor (NMDAR) antagonist phencyclidine (PCP), which elicits schizophrenia-like symptoms in both humans and animal models, in a chronic, low-dose exposure paradigm. Adult rats were given PCP at a dose of 2.58 mg/kg/day i.p. for a month, after which levels of various GABAergic cell mRNAs and other neuromodulators were examined in the cerebellum by qRT-PCR. Administration of PCP decreased the expression of GAD(67), GAD(65), and the presynaptic GABA transporter GAT-1, and increased GABA(A) receptor subunits similar to those seen in patients with schizophrenia. Additionally, we found that the mRNA levels of two Golgi cell selective NMDAR subunits, NR2B and NR2D, were decreased in PCP-treated rats. Furthermore, we localized the deficits in GAD(67) expression solely to these interneurons. Slice electrophysiological studies showed that spontaneous firing of Golgi cells was reduced by acute exposure to low-dose PCP, suggesting that these neurons are particularly vulnerable to NMDA receptor antagonism. In conclusion, our results demonstrate that chronic exposure to low levels of PCP in rats mimics the GABAergic alterations reported in the cerebellum of patients with schizophrenia (Bullock et al., 2008. Am. J. Psychiatry 165, 1594-1603), further supporting the validity of this animal model.

  19. Behavioral and neurochemical abnormalities after exposure to low doses of high-energy iron particles

    NASA Astrophysics Data System (ADS)

    Hunt, Walter A.; Joseph, James A.; Rabin, Bernard M.

    Exposure of rats to high-energy iron particles (600 MeV/amu) has been found to alter behavior after doses as low as 10 rads. The performance of a task that measures upper body strength was significantly degraded after irradiation. In addition, an impairment in the regulation of dopamine release in the caudate nucleus (a motor center in the brain), lasting at least 6 months, was also found and correlated with the performance deficits. A general indication of behavioral toxicity and an index of nausea and emesis, the conditioned taste aversion, was also evident. The sensitivity to iron particles was 10-600 times greater than to gamma photons. These results suggest that behavioral and neurobiological damage may be a consequence of exposure to low doses of heavy particles and that this possibility should be extensively studied.

  20. Low-dose CT screening for lung cancer with automatic exposure control: phantom study.

    PubMed

    Gomi, Shiho; Muramatsu, Yoshihisa; Tsukagoshi, Shinsuke; Suzuki, Masahiro; Kakinuma, Ryutaro; Tsuchiya, Ryosuke; Moriyama, Noriyuki

    2008-07-01

    We conducted a study to determine optimal scan conditions for automatic exposure control (AEC) in computed tomography (CT) of low-dose chest screening in order to provide consistent image quality without increasing the collective dose. Using a chest CT phantom, we set CT-AEC scan conditions with a dose-reduction wedge (DR-Wedge) to the same radiation dose as those for low-tube current, fixed-scan conditions. Image quality was evaluated with the use of the standard deviation of the CT number, contrast-noise ratios (CNR), and receiver-operating characteristic (ROC) analysis. At the same radiation dose, in the scan conditions using CT-AEC with the DR-Wedge, the SD of the CT number of each slice position was stable. The CNR values were higher at the lung apex and lung base under CT-AEC with the DR-Wedge than under standard scan conditions (p < 0.0002). In addition, ROC analysis of blind evaluation by four radiologists and three technologists showed that the image quality was improved for the lung apex (p < 0.009), tracheal bifurcation (p < 0.038), and lung base (p < 0.022) in the scan conditions using CT-AEC with the DR-Wedge. We achieved improvement of image quality without increasing the collective dose by using CT-AEC with the DR-Wedge under low-dose scan conditions.

  1. Pre- and Postnatal Exposure to Low Dose Glufosinate Ammonium Induces Autism-Like Phenotypes in Mice

    PubMed Central

    Laugeray, Anthony; Herzine, Ameziane; Perche, Olivier; Hébert, Betty; Aguillon-Naury, Marine; Richard, Olivier; Menuet, Arnaud; Mazaud-Guittot, Séverine; Lesné, Laurianne; Briault, Sylvain; Jegou, Bernard; Pichon, Jacques; Montécot-Dubourg, Céline; Mortaud, Stéphane

    2014-01-01

    Glufosinate ammonium (GLA) is one of the most widely used herbicides in agriculture. As is the case for most pesticides, potential adverse effects of GLA have not been studied from the perspective of developmental neurotoxicity. Early pesticides exposure may weaken the basic structure of the developing brain and cause permanent changes leading to a wide range of lifelong effects on health and/or behavior. Here, we addressed the developmental impact of GLA by exposing female mice to low dose GLA during both pre- and postnatal periods and analyzed potential developmental and behavioral changes of the offspring during infancy and adulthood. A neurobehavioral test battery revealed significant effects of GLA maternal exposure on early reflex development, pup communication, affiliative behaviors, and preference for social olfactory cues, but emotional reactivity and emotional memory remained unaltered. These behavioral alterations showed a striking resemblance to changes seen in animal models of Autistic Spectrum Disorders. At the brain level, GLA maternal exposure caused some increase in relative brain weight of the offspring. In addition, reduced expression of Pten and Peg3 – two genes implicated in autism-like deficits – was observed in the brain of GLA-exposed pups at postnatal day 15. Our work thus provides new data on the link between pre- and postnatal exposure to the herbicide GLA and the onset of autism-like symptoms later in life. It also raises fundamental concerns about the ability of current safety testing to assess risks of pesticide exposure during critical developmental periods. PMID:25477793

  2. Low-Dose Inorganic Mercury Increases Severity and Frequency of Chronic Coxsackievirus-Induced Autoimmune Myocarditis in Mice

    PubMed Central

    Nyland, Jennifer F.; Fairweather, DeLisa; Shirley, Devon L.; Davis, Sarah E.; Rose, Noel R.; Silbergeld, Ellen K.

    2012-01-01

    Mercury is a widespread environmental contaminant with neurotoxic impacts that have been observed over a range of exposures. In addition, there is increasing evidence that inorganic mercury (iHg) and organic mercury (including methyl mercury) have a range of immunotoxic effects, including immune suppression and induction of autoimmunity. In this study, we investigated the effect of iHg on a model of autoimmune heart disease in mice induced by infection with coxsackievirus B3 (CVB3). We examined the role of timing of iHg exposure on disease; in some experiments, mice were pretreated with iHg (200 μg/kg, every other day for 15 days) before disease induction with virus inoculation, and in others, they were treated with iHg after the acute (viral) phase of disease but before the development of dilated cardiomyopathy (DCM). iHg alone had no effect on heart pathology. Pretreatment with iHg before CVB3 infection significantly increased the severity of chronic myocarditis and DCM compared with control animals receiving vehicle alone. In contrast, treatment with iHg after acute myocarditis did not affect the severity of chronic disease. The increased chronic myocarditis, fibrosis, and DCM induced by iHg pretreatment were not due to increased viral replication in the heart, which was unaltered by iHg treatment. iHg pretreatment induced a macrophage infiltrate and mixed cytokine response in the heart during acute myocarditis, including significantly increased interleukin (IL)-12, IL-17, interferon-γ, and tumor necrosis factor-α levels. IL-17 levels were also significantly increased in the spleen during chronic disease. Thus, we show for the first time that low-dose Hg exposure increases chronic myocarditis and DCM in a murine model. PMID:21984480

  3. [Effect of long-term exposure to low dose gamma-irradiation on the rat thyroid status].

    PubMed

    Nadol'nik, L I; Netsetskaia, Z V; Vinogradov, V V

    2004-01-01

    The effect of long-term exposure to low-dose external radiation on the rat thyroid status was studied. The experiments were carried out on Wistar female rats. The single doses absorbed were 0.1; 0.25; 0.5 Gy. The rats were irradiated 20 times (5 days x 4 weeks). The animals were decapitated after 1, 30 and 180 days following the last irradiation. Blood serum was assayed for content of thyroxin (T4) and triiodothyronine (T3) radioimmunologically. The liver was spectrophotometrically assayed for thyroid-induced NADP-malatedehydrogenase (NADP-MDH). It was shown that the long-term 0.5-Gy irradiation of the animals induced a decrease in blood T4 and T3 concentrations 1.34-1.71-fold and 1.24-1.43-fold after 1, 30 and 180 days, respectively. The T3 level was diminished most pronouncedly after 1 day, whereas that of T4--after 30 days following the exposure. With the doses of 0.1 and 0.25 Gy absorbed, the T4 and T3 concentration remained unchanged throughout all the periods studied. The activity of NADP-MDH was decreased 1.55-2.46-fold in all the experimental animals, and it was held decreased after 180 days (1.43-1.50-fold) in 0.25- and 0.5-Gy-irradiated groups, which indicates a disturbance in thyroid hormone metabolism in rats exposed chronically to low-dose radiation. After 180 days, the experimental animals experienced an elevation of thyroid gland weight on 15-20%. The thyroid status disturbance seemed to be due to both inhibited T4 and T3 biosynthesis in thyroid and disturbed hormone peripheral metabolism under radiation exposure.

  4. Gene expression profiling in the fetal cardiac tissue after folate and low dose trichloroethylene exposure

    PubMed Central

    Caldwell, Patricia T.; Manziello, Ann; Howard, Jamie; Palbykin, Brittany; Runyan, Raymond B.; Selmin, Ornella

    2014-01-01

    Background Previous studies show gene expression alterations in rat embryo hearts and cell lines that correspond to the cardio-teratogenic effects of trichloroethylene (TCE) in animal models. One potential mechanism of TCE teratogenicity may be through altered regulation of calcium homeostatic genes with a corresponding inhibition of cardiac function. It has been suggested that TCE may interfere with the folic acid/methylation pathway in liver and kidney and alter gene regulation by epigenetic mechanisms. According to this hypothesis, folate supplementation in the maternal diet should counteract TCE effects on gene expression in the embryonic heart. Approach To identify transcriptional targets altered in the embryonic heart after exposure to TCE, and possible protective effects of folate, we used DNA microarray technology to profile gene expression in embryonic mouse hearts with maternal TCE exposure and dietary changes in maternal folate. Results Exposure to low doses of TCE (10ppb) caused extensive alterations in transcripts encoding proteins involved in transport, ion channel, transcription, differentiation, cytoskeleton, cell cycle and apoptosis. Exogenous folate did not offset the effects of TCE exposure on normal gene expression and both high and low levels of folate produced additional significant changes in gene expression. Conclusions A mechanism where TCE induces a folate deficiency does not explain altered gene expression patterns in the embryonic mouse heart. The data further suggest that use of folate supplementation, in the presence of this toxin, may be detrimental and non-protective of the developing embryo. PMID:19813261

  5. Achieving Consistent Multiple Daily Low-Dose Bacillus anthracis Spore Inhalation Exposures in the Rabbit Model

    PubMed Central

    Barnewall, Roy E.; Comer, Jason E.; Miller, Brian D.; Gutting, Bradford W.; Wolfe, Daniel N.; Director-Myska, Alison E.; Nichols, Tonya L.; Taft, Sarah C.

    2012-01-01

    Repeated low-level exposures to biological agents could occur before or after the remediation of an environmental release. This is especially true for persistent agents such as B. anthracis spores, the causative agent of anthrax. Studies were conducted to examine aerosol methods needed for consistent daily low aerosol concentrations to deliver a low-dose (less than 106 colony forming units (CFU) of B. anthracis spores) and included a pilot feasibility characterization study, acute exposure study, and a multiple 15 day exposure study. This manuscript focuses on the state-of-the-science aerosol methodologies used to generate and aerosolize consistent daily low aerosol concentrations and resultant low inhalation doses to rabbits. The pilot feasibility characterization study determined that the aerosol system was consistent and capable of producing very low aerosol concentrations. In the acute, single day exposure experiment, targeted inhaled doses of 1 × 102, 1 × 103, 1 × 104, and 1 × 105 CFU were used. In the multiple daily exposure experiment, rabbits were exposed multiple days to targeted inhaled doses of 1 × 102, 1 × 103, and 1 × 104 CFU. In all studies, targeted inhaled doses remained consistent from rabbit-to-rabbit and day-to-day. The aerosol system produced aerosolized spores within the optimal mass median aerodynamic diameter particle size range to reach deep lung alveoli. Consistency of the inhaled dose was aided by monitoring and recording respiratory parameters during the exposure with real-time plethysmography. Overall, the presented results show that the animal aerosol system was stable and highly reproducible between different studies and over multiple exposure days. PMID:22919662

  6. DNA fragmentation in leukocytes following repeated low dose sarin exposure in guinea pigs.

    PubMed

    Dave, J R; Connors, R A; Genovese, R F; Whipple, R A; Chen, R W; DeFord, S M; Moran, A V; Tortella, E C

    2007-11-01

    The objective of this study was to determine levels of DNA fragmentation in blood leukocytes and parietal cortex from guinea pigs following repeated low-level exposure to the chemical warfare nerve agent (CWNA) sarin. Guinea pigs were injected (s.c.) once a day for 10 days with saline, or 0.1, 0.2, or 0.4 LD50 (50% mean lethal dose) sarin dissolved in sterile physiological saline. Blood and parietal cortex was collected after injection at 0, 3, and 17 days recovery and evaluated for DNA fragmentation using single-cell gel electrophoresis (Comet assay). Cells were imaged using comet analysis software and three parameters of DNA fragmentation measured: tail length, percent DNA in the tail, and tail moment arm. Repeated low-dose exposure to sarin produced a dose-dependent response in leukocytes at 0 and 3 days post-exposure. There was a significant increase in all measures of DNA fragmentation at 0.2 and 0.4 LD50, but not at 0.1 LD50. There was no significant increase in DNA fragmentation in any of the groups at 17 days post-exposure. Sarin did not produce a systematic dose-dependent response in parietal cortex at any of the time points. However, significant increases in DNA fragmentation at 0.1 and 0.4 LD50 were observed at 0 and 3 days post-exposure. All measures of DNA fragmentation in both leukocytes and neurons returned to control levels by 17 days post-exposure, indicating a small and non-persistent increase in DNA fragmentation following repeated low-level exposure to sarin.

  7. Effects of low-dose alcohol exposure on simulated merchant ship piloting by maritime cadets.

    PubMed

    Howland, J; Rohsenow, D J; Cote, J; Gomez, B; Mangione, T W; Laramie, A K

    2001-03-01

    The US Department of Transportation (DOT) regulates on-the-job alcohol use by operators of certain categories of commercial transport. For aircraft, trains, and commercial vessels, operators are subject to sanctions for having > or = 0.04 g% blood alcohol concentration (BAC). This study examines the effects of alcohol (between 0.04 and 0.05 g% BAC) on simulated merchant ship handling. A two-group randomized factorial design was used to compare beverage alcohol to placebo while controlling for baseline performance on a previous day. The study was conducted in the Maritime Simulation Center at Maine Maritime Academy, Castine, ME. Participants were 38 volunteer deck officer cadets in their junior or senior year, at least 21 years of age, with previous experience on a bridge simulator. Following a baseline trial on Day 1, on Day 2 participants were randomized to receive alcohol (0.6 g/kg for males and 0.5 g/kg for females) or placebo. After allowing time for absorption, participants completed a bridge simulator task. For baseline and performance trials, participants were randomized to one of four bridge simulator scenarios, each representing passage of a fully loaded container vessel through a channel with commercial traffic. The aggregate scenario score given by blinded maritime educators measured performance. A main effect for alcohol was found indicating that performance was significantly impaired by this low dose of alcohol relative to performance in the placebo condition. These findings are consistent with current federal regulations that limit low-dose alcohol exposure for the operators of commercial transport vehicles. Further research is required to determine effects at lower BACs.

  8. Comparative toxicity of low dose tributyltin chloride on serum, liver, lung and kidney following subchronic exposure.

    PubMed

    Mitra, Sumonto; Gera, Ruchi; Singh, Vikas; Khandelwal, Shashi

    2014-02-01

    Tributyltin (TBT) pollution is rampant worldwide and is a growing threat due to its bio-accumulative property. Isolated studies of TBT toxicity on different organs are available but consolidated information is greatly lacking. We planned this study to delineate the effect of subchronic (1 month) exposure to low dose TBT-chloride (TBTC) (1 and 5 mg/kg) in male Wistar rats. Total tin concentration was found to be significantly increased in liver, kidney and blood, and marginally in lungs. Organo-somatic indices were seen to be altered with little effect on serum biochemical markers (liver and kidney function, and general parameters). Reactive oxygen species but not lipid peroxidation content was observed to be significantly elevated both in the tissues and serum. TBTC was found to act as a hyperlipidemic agent and it also affected heme biosynthetic pathway. Hematological analysis showed that TBTC exposure resulted in minor alterations in RBC parameters. Histological studies demonstrated marked tissue damage in all the 3 organs. Calcium inhibitors (BAPTA-AM, EGTA) and antioxidants (NAC, C-PC) significantly restored TBTC induced loss in cell viability, under ex-vivo conditions. Antioxidants were evidently more efficient in comparison to the calcium inhibitors, implying major role of oxidative stress pathways in TBTC toxicity.

  9. Pulmonary Injury after Combined Exposures to Low-Dose Low-LET Radiation and Fungal Spores

    PubMed Central

    Marples, B.; Downing, L.; Sawarynski, K. E.; Finkelstein, J. N.; Williams, J. P.; Martinez, A. A.; Wilson, G. D.; Sims, M. D.

    2013-01-01

    Exposure to infectious microbes is a likely confounder after a nuclear terrorism event. In combination with radiation, morbidity and mortality from an infection may increase significantly. Pulmonary damage after low-dose low-LET irradiation is characterized by an initial diffuse alveolar inflammation. By contrast, inhaled fungal spores produce localized damage around pulmonary bronchioles. In the present study, we assessed lung injury in C57BL/6 mice after combined exposures to whole-body X radiation and inhaled fungal spores. Either animals were exposed to Aspergillus spores and immediately irradiated with 2 Gy, or the inoculation and irradiation were separated by 8 weeks. Pulmonary injury was assessed at 24 and 48 h and 1, 2, 4, 8, and 24 weeks later using standard H&E-stained sections and compared with sham-treated age-matched controls. Immunohistochemistry for invasive inflammatory cells (macrophages, neutrophils and B and T lymphocytes) was performed. A semi-quantitative assessment of pulmonary injury was made using three distinct parameters: local infiltration of inflammatory cells, diffuse inflammation, and thickening and distortion of alveolar architecture. Radiation-induced changes in lung architecture were most evident during the first 2 weeks postexposure. Fungal changes were seen over the first 4 weeks. Simultaneous combined exposures significantly increased the duration of acute pulmonary damage up to 24 weeks (P < 0.01). In contrast, administration of the fungus 8 weeks after irradiation did not produce enhanced levels of acute pulmonary damage. These data imply that the inhalation of fungal spores at the time of a radiation exposure alters the susceptibility of the lungs to radiation-induced injury. PMID:21275606

  10. Long-term health effects of persistent exposure to low-dose lr192 gamma-rays.

    PubMed

    Li, Hongbo; Wang, Lin; Jiang, Zujun; Li, Li; Xiao, Zhifang; Liu, Zenghui; Zhang, Shuang; Jin, Hui; Su, Lei; Xiao, Yang

    2016-10-01

    The aim of the present study was to investigate the effect of persistent low-dose iridium-192 (Ir192) exposure on immunological function, chromosome aberration and the telomerase activity of bone marrow mononuclear cells (BMNCs), in order to increase clinical knowledge of the late effects of persistent low-dose Ir192 gamma-ray exposure. Patients (n=54) accidentally exposed to persistent low-dose Ir192 were included in this 10-year follow-up study. Clinical symptoms, peripheral blood, bone marrow, cellular and humoral immune status, chromosome aberrations and the telomerase activity of BMNCs were analyzed in this study. Exposure to low-dose Ir192 resulted in different degrees of clinical symptoms and significantly lowered complement C3 and C4 levels, CD3(+), CD4(+) and CD8(+) T cell levels, the lymphocyte transformation rate and the percentage of natural killer (NK) cells. It also led to increases in peripheral blood and bone marrow abnormality rates, chromosome aberration rate and BMNC telomerase activity. Exposure to persistent low-dose Ir192 radiation resulted in different degrees of immune dysfunction, and abnormalities of blood cells and bone marrow, which recovered within 1-3 years. Chromosome aberrations were observed to take 5-10 years to recover. However, it would take >10 years for the telomerase activity of BMNCs to be reduced to normal levels. A prolonged follow-up time is required in order to monitor clonal proliferative diseases such as leukemia.

  11. Long-term health effects of persistent exposure to low-dose lr192 gamma-rays

    PubMed Central

    Li, Hongbo; Wang, Lin; Jiang, Zujun; Li, Li; Xiao, Zhifang; Liu, Zenghui; Zhang, Shuang; Jin, Hui; Su, Lei; Xiao, Yang

    2016-01-01

    The aim of the present study was to investigate the effect of persistent low-dose iridium-192 (Ir192) exposure on immunological function, chromosome aberration and the telomerase activity of bone marrow mononuclear cells (BMNCs), in order to increase clinical knowledge of the late effects of persistent low-dose Ir192 gamma-ray exposure. Patients (n=54) accidentally exposed to persistent low-dose Ir192 were included in this 10-year follow-up study. Clinical symptoms, peripheral blood, bone marrow, cellular and humoral immune status, chromosome aberrations and the telomerase activity of BMNCs were analyzed in this study. Exposure to low-dose Ir192 resulted in different degrees of clinical symptoms and significantly lowered complement C3 and C4 levels, CD3+, CD4+ and CD8+ T cell levels, the lymphocyte transformation rate and the percentage of natural killer (NK) cells. It also led to increases in peripheral blood and bone marrow abnormality rates, chromosome aberration rate and BMNC telomerase activity. Exposure to persistent low-dose Ir192 radiation resulted in different degrees of immune dysfunction, and abnormalities of blood cells and bone marrow, which recovered within 1–3 years. Chromosome aberrations were observed to take 5–10 years to recover. However, it would take >10 years for the telomerase activity of BMNCs to be reduced to normal levels. A prolonged follow-up time is required in order to monitor clonal proliferative diseases such as leukemia. PMID:27698774

  12. Low doses of glyphosate change the response of soybean to later glyphosate exposures

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The stimulatory effect of low doses of toxic substances is known as hormesis. Many herbicides that cause severe injury to plants at recommended rates, promote growth or have other stimulatory effects at very low doses. The objective of this study was to evaluate glyphosate-induced hormesis in soyb...

  13. Influence of a pre-stimulation with chronic low-dose UVB on stress response mechanisms in human skin fibroblasts.

    PubMed

    Drigeard Desgarnier, Marie-Catherine; Fournier, Frédéric; Droit, Arnaud; Rochette, Patrick J

    2017-01-01

    Exposure to solar ultraviolet type B (UVB), through the induction of cyclobutane pyrimidine dimer (CPD), is the major risk factor for cutaneous cancer. Cells respond to UV-induced CPD by triggering the DNA damage response (DDR) responsible for signaling DNA repair, programmed cell death and cell cycle arrest. Underlying mechanisms implicated in the DDR have been extensively studied using single acute UVB irradiation. However, little is known concerning the consequences of chronic low-dose of UVB (CLUV) on the DDR. Thus, we have investigated the effect of a CLUV pre-stimulation on the different stress response pathways. We found that CLUV pre-stimulation enhances CPD repair capacity and leads to a cell cycle delay but leave residual unrepaired CPD. We further analyzed the consequence of the CLUV regimen on general gene and protein expression. We found that CLUV treatment influences biological processes related to the response to stress at the transcriptomic and proteomic levels. This overview study represents the first demonstration that human cells respond to chronic UV irradiation by modulating their genotoxic stress response mechanisms.

  14. [Morphometric analysis of follicular structure of the thyroid gland after chronic low-dose gamma-irradiation].

    PubMed

    Pavlov, A V; Ermakova, O V; Korableva, T V; Raskosha, O V

    2013-01-01

    A quantitative study of follicle average cross-sectional diameter distribution was conducted in the thyroid gland (TG) of mouse like rodents (25 tundra voles, 24 CBA mice, 16 Wistar rats) after chronic exposure to low-level external y-radiation both in the environment and under the experimental condition (absorbed dose range 0.05-0.5 Gy). Spectrum analysis of TG follicle cross-sectional diameter distribution in the irradiated animals has demonstrated a universal regularity: in comparison with the unirradiated animals there was a significant (1.3-1.7-fold) increase in content of small follicles (with a cross-sectional diameter lower than 36-41 microm in the studied animal species). A similar phenomenon was reproduced in the model experiments (TG regeneration in rats after hemithyroidectomy). The observed activation of the folliculogenesis processes after chronic low-dose irradiation in small doses may be interpreted as a nonspecific adaptive reaction of TG to radiation induced damage of its parenchyma.

  15. Influence of a pre-stimulation with chronic low-dose UVB on stress response mechanisms in human skin fibroblasts

    PubMed Central

    Drigeard Desgarnier, Marie-Catherine; Fournier, Frédéric; Droit, Arnaud

    2017-01-01

    Exposure to solar ultraviolet type B (UVB), through the induction of cyclobutane pyrimidine dimer (CPD), is the major risk factor for cutaneous cancer. Cells respond to UV-induced CPD by triggering the DNA damage response (DDR) responsible for signaling DNA repair, programmed cell death and cell cycle arrest. Underlying mechanisms implicated in the DDR have been extensively studied using single acute UVB irradiation. However, little is known concerning the consequences of chronic low-dose of UVB (CLUV) on the DDR. Thus, we have investigated the effect of a CLUV pre-stimulation on the different stress response pathways. We found that CLUV pre-stimulation enhances CPD repair capacity and leads to a cell cycle delay but leave residual unrepaired CPD. We further analyzed the consequence of the CLUV regimen on general gene and protein expression. We found that CLUV treatment influences biological processes related to the response to stress at the transcriptomic and proteomic levels. This overview study represents the first demonstration that human cells respond to chronic UV irradiation by modulating their genotoxic stress response mechanisms. PMID:28301513

  16. Response of phytoplankton community to low-dose atrazine exposure combined with phosphorus fluctuations.

    PubMed

    Pannard, Alexandrine; Le Rouzic, Bertrand; Binet, Françoise

    2009-07-01

    The effects of atrazine on a controlled phytoplankton community derived from a natural freshwater wetland exposed to low doses of this photosynthesis-inhibiting herbicide were examined. The community was exposed for 7 weeks to doses of 0.1, 1, and 10 microg L(-1) atrazine, combined with changes in nutrient concentration, and the photosynthetic activity, biomass, and community structure were noted during the experiment. Responses of the phytoplankton community were examined in terms of photosynthetic activity, biomass, and community structure. Significant effects of atrazine on the phytoplankton assemblage, in terms of primary production and community structure, were highlighted, even at doses as low as 1 and 0.1 microg L(-1), when associated with phosphorus fluctuations. The most abundant Chlorophyceae decreased in concentration with increasing atrazine dose, whereas cyanobacteria were more tolerant to atrazine, particularly with increased nutrient supply. The subinhibitory doses of atrazine used in the present study confirmed the higher sensitivity of long-term exposure of multispecies assemblages under resource competition. Our study supports the emerging hypothesis that the increasing prevalence of cyanobacterial blooms in European aquatic systems may result from a combination of unbalanced nutrient enrichment and selective pressures from multiple toxicants.

  17. Survey on low-dose medical radiation exposure in occupational workers: the effect on hematological change

    NASA Astrophysics Data System (ADS)

    Ryu, J. K.; Cho, S. M.; Cho, J. H.; Dong, K. R.; Chung, W. K.; Lee, J. W.

    2013-03-01

    This study examined the changes in the hematological index caused by low-dose medical radiation exposure in workers in a medical radiation-exposed environment. The cumulative dose was obtained using thermoluminescent dosimeters over a 9-year period, and the changes in hematological index count (red blood cells (RBCs), hemoglobin, platelets, white blood cells (WBCs), monocytes, lymphocytes, neutrophils, basophils, and eosinophils) were examined in both the occupational workers and controls. In total, 370 occupational workers and 335 controls were compared. The analysis led to the following observations: (1) The average cumulative dose in males and females was 9.65±15.2 and 4.82±5.55 mSv, respectively. (2) In both males and females, there was a very low correlation between the occupation period and the cumulative dose (r<±0.25). (3) When the occupation period was longer, the WBC counts both decreased and increased in the male workers and the RBC counts were lower in the workers than in the control group (p<0.05). In females, the WBC counts both decreased and increased in the workers and the eosinophil counts were lower in the workers than in the control group (p<0.01). (4) When the cumulative dose was large, the lymphocyte counts decreased in male workers and the platelet count was lower in the workers than in the control group (p<0.05). In females, the lymphocyte count and RBC count were lower in the workers than in the control group (p<0.05). Abnormal distributions of some blood indices were observed in the occupational radiation workers compared with the controls. Attempts were made to limit radiation exposure to personnel, but the employees did not always follow the preset rules. Actually, the adverse effects of low-level radiation were attributed to probability. Overall, workers should obey the radiation protection regulations provided by the government and a national system of radiation protection is needed.

  18. Increased Mitochondrial DNA Copy Number in Occupations Associated with Low-Dose Benzene Exposure

    PubMed Central

    Pesatori, Angela Cecilia; Dioni, Laura; Hoxha, Mirjam; Bollati, Valentina; Albetti, Benedetta; Byun, Hyang-Min; Bonzini, Matteo; Fustinoni, Silvia; Cocco, Pierluigi; Satta, Giannina; Zucca, Mariagrazia; Merlo, Domenico Franco; Cipolla, Massimo; Bertazzi, Pier Alberto; Baccarelli, Andrea

    2011-01-01

    Background: Benzene is an established leukemogen at high exposure levels. Although low-level benzene exposure is widespread and may induce oxidative damage, no mechanistic biomarkers are available to detect biological dysfunction at low doses. Objectives: Our goals were to determine in a large multicenter cross-sectional study whether low-level benzene is associated with increased blood mitochondrial DNA copy number (mtDNAcn, a biological oxidative response to mitochondrial DNA damage and dysfunction) and to explore potential links between mtDNAcn and leukemia-related epigenetic markers. Methods: We measured blood relative mtDNAcn by real-time polymerase chain reaction in 341 individuals selected from various occupational groups with low-level benzene exposures (> 100 times lower than the Occupational Safety and Health Administration/European Union standards) and 178 referents from three Italian cities (Genoa, Milan, Cagliari). Results: In each city, benzene-exposed participants showed higher mtDNAcn than referents: mtDNAcn was 0.90 relative units in Genoa bus drivers and 0.75 in referents (p = 0.019); 0.90 in Milan gas station attendants, 1.10 in police officers, and 0.75 in referents (p-trend = 0.008); 1.63 in Cagliari petrochemical plant workers, 1.25 in referents close to the plant, and 0.90 in referents farther from the plant (p-trend = 0.046). Using covariate-adjusted regression models, we estimated that an interquartile range increase in personal airborne benzene was associated with percent increases in mtDNAcn equal to 10.5% in Genoa (p = 0.014), 8.2% (p = 0.008) in Milan, 7.5% in Cagliari (p = 0.22), and 10.3% in all cities combined (p < 0.001). Using methylation data available for the Milan participants, we found that mtDNAcn was associated with LINE-1 hypomethylation (–2.41%; p = 0.007) and p15 hypermethylation (+15.95%, p = 0.008). Conclusions: Blood MtDNAcn was increased in persons exposed to low benzene levels, potentially reflecting mitochondrial

  19. Corticosterone protects against memory impairments and reduced hippocampal BDNF levels induced by a chronic low dose of ethanol in C57BL/6J mice.

    PubMed

    Ebada, Mohamed Elsaed; Latif, Liaque M; Kendall, David A; Pardon, Marie Christine

    2014-01-01

    Acute low doses of ethanol can produce reversible memory deficits, but it is unknown whether they persist upon chronic use. We investigated whether the chronic intake of a low dose of ethanol induces memory impairments in the ethanol-preferring C57BL/6J mouse strain. Because stress precipitates alcohol abuse and the stress hormone corticosterone contributes to memory processes, ethanol consumption and toxic effects, we also determined the impact of co-treatment with corticosterone on these effects. BDNF contributes to memory function and toxic effects of ethanol, therefore its levels were quantified in the hippocampus and frontal cortex. Ethanol (1% in drinking water) and corticosterone (250 μg/mL) were administered using the two-bottle choice test to monitor their appetitive properties. Spatial and non-spatial memory performance was assessed using the spontaneous alternation, object recognition and object location tests. The chronic exposure to a low dose of ethanol caused spatial and non-spatial memory deficits after withdrawal associated with a reduction in hippocampal BDNF levels, which were prevented by co-treatment with corticosterone (~21 mg/kg/day). The protective effect of corticosterone on memory was no longer observed at higher doses (~41 mg/kg/day), but persisted for hippocampal BDNF levels. C57BL/6J mice did not develop an appetence for 1% ethanol, but the addition of corticosterone increased voluntary consumption of and preference for the ethanol+corticosterone solutions. Although acute low doses of corticosterone (1 mg/kg) were found to rescue established memory impairments, this is the first report of a protective effect of chronic doses of corticosterone in the range of 20-32 mg/kg, and particularly against memory deficits induced by alcohol.

  20. Obesity in the United States – Dysbiosis from Exposure to Low-Dose Antibiotics?

    PubMed Central

    Riley, Lee W.; Raphael, Eva; Faerstein, Eduardo

    2013-01-01

    The rapid increase in obesity prevalence in the United States in the last 20 years is unprecedented and not well explained. Here, we explore a hypothesis that the obesity epidemic may be driven by population-wide chronic exposures to low-residue antibiotics that have increasingly entered the American food chain over the same time period. We propose this hypothesis based on two recent bodies of published reports – (1) those that provide evidence for the spread of antibiotics into the American food chain, and (2) those that examine the relationship between the gut microbiota and body physiology. The livestock use of antimicrobial agents has sharply increased in the US over the same 20-year period of the obesity epidemic, especially with the expansion of intensified livestock production, such as the concentrated animal feeding operations. Observational and experimental studies support the idea that changes in the intestinal microbiota exert a profound effect on body physiology. We propose that chronic exposures to low-residue antimicrobial drugs in food could disrupt the equilibrium state of intestinal microbiota and cause dysbiosis that can contribute to changes in body physiology. The obesity epidemic in the United States may be partly driven by the mass exposure of Americans to food containing low-residue antimicrobial agents. While this hypothesis cannot discount the impact of diet and other factors associated with obesity, we believe studies are warranted to consider this possible driver of the epidemic. PMID:24392444

  1. Repeated low-dose organophosphate DFP exposure leads to the development of depression and cognitive impairment in a rat model of Gulf War Illness.

    PubMed

    Phillips, Kristin F; Deshpande, Laxmikant S

    2016-01-01

    Approximately 175,000-250,000 of the returning veterans from the 1991 Persian Gulf War exhibit chronic multi-symptom illnesses that includes neurologic co-morbidities such as depression, anxiety and cognitive impairments. Amongst a host of causative factors, exposure to low levels of the nerve agent Sarin has been strongly implicated for expression of Gulf War Illness (GWI). Nerve agents similar to pesticides are organophosphate (OP) compounds. There is evidence from civilian population that exposure to OPs such as in agricultural workers and nerve agents such as the survivors and first-responders of the Tokyo subway Sarin gas attack suffer from chronic neurological problems similar to GWI symptoms. Given this unique chemical profile, OPs are ideal to study the effects of nerve agents and develop models of GWI in civilian laboratories. In this study, we used repeated low-dose exposure to OP agent diisopropyl fluorophosphate (DFP) over a 5-day period to approximate the duration and level of Sarin exposure during the Persian Gulf War. We tested the rats at 3-months post DFP exposure. Using a battery of behavioral assays, we observed the presence of symptoms of chronic depression, anxiety and memory problems as characterized by increased immobility time in the Forced Swim Test, anhedonia in the Sucrose Preference Test, anxiety in the Elevated Plus Maze, and spatial memory impairments in the Object Location Test, respectively. Chronic low dose DFP exposure was also associated with hippocampal neuronal damage as characterized by the presence of Fluoro-Jade staining. Given that OP exposure is considered a leading cause of GWI related morbidities, this animal model will be ideally suited to study underlying molecular mechanisms for the expression of GWI neurological symptoms and identify drugs for the effective treatment of GWIs.

  2. Gestational and lactational exposure to low-dose bisphenol A increases Th17 cells in mice offspring.

    PubMed

    Luo, Shimeng; Li, Yun; Li, Yingpei; Zhu, Qixing; Jiang, Jianhua; Wu, Changhao; Shen, Tong

    2016-10-01

    Increasing evidence demonstrates that perinatal exposure to Bisphenol A (BPA) can cause immune disorders throughout the life span. However, the biological basis for these immune disorders is poorly understood and the effects of exposure to BPA on Th17 development are unknown. The present study sought to characterize alterations of Th17 cells in childhood and adulthood following gestational and lactational exposure to environmentally relevant low-dose of BPA and the underlying mechanisms. Pregnant dams were exposed to BPA (10, 100 or 1000nM) via drinking water from gestational day (GD) 0 to postnatal day (PND) 21. At PNDs 21 and 42, offspring mice were anesthetized, blood was obtained for cytokine assay and spleens were collected for Th17 cell frequency and RORγt mRNA expression analysis. Perinatal exposure to low-dose BPA resulted in a dose-dependent and gender-specific persistent rise in Th17 cells accompanied by an increase of RORγt mRNA expression in the offsprings. The contents of major Th17 cell-derived cytokines (IL-17 and IL-21) and those essential for Th17 cell differentiation (IL-6 and IL-23) were also increased compared to those in controls. These changes were more pronounced in female than in male offsprings. However, perinatal exposure to low-dose BPA had little effect on serum TGF-β, another key regulator for Th17 cell development. Our results suggest that gestational and lactational exposure to a low-dose of BPA can affect Th17 cell development via an action on its transcription factor and the regulatory cytokines. These findings provide novel insight into sustained immune disorders by BPA exposure during development.

  3. Changes in mammary histology and transcriptome profiles by low-dose exposure to environmental phenols at critical windows of development.

    PubMed

    Gopalakrishnan, Kalpana; Teitelbaum, Susan L; Lambertini, Luca; Wetmur, James; Manservisi, Fabiana; Falcioni, Laura; Panzacchi, Simona; Belpoggi, Fiorella; Chen, Jia

    2017-01-01

    Exposure to environmental chemicals has been linked to altered mammary development and cancer risk at high doses using animal models. Effects at low doses comparable to human exposure remain poorly understood, especially during critical developmental windows. We investigated the effects of two environmental phenols commonly used in personal care products - methyl paraben (MPB) and triclosan (TCS) - on the histology and transcriptome of normal mammary glands at low doses mimicking human exposure during critical windows of development. Sprague-Dawley rats were exposed during perinatal, prepubertal and pubertal windows, as well as from birth to lactation. Low-dose exposure to MPB and TCS induced measurable changes in both mammary histology (by Masson's Trichrome Stain) and transcriptome (by microarrays) in a window-specific fashion. Puberty represented a window of heightened sensitivity to MPB, with increased glandular tissue and changes of expression in 295 genes with significant enrichment in functions such as DNA replication and cell cycle regulation. Long-term exposure to TCS from birth to lactation was associated with increased adipose and reduced glandular and secretory tissue, with expression alterations in 993 genes enriched in pathways such as cholesterol synthesis and adipogenesis. Finally, enrichment analyses revealed that genes modified by MPB and TCS were over-represented in human breast cancer gene signatures, suggesting possible links with breast carcinogenesis. These findings highlight the issues of critical windows of susceptibility that may confer heightened sensitivity to environmental insults and implicate the potential health effects of these ubiquitous environmental chemicals in breast cancer.

  4. Dose Response for Chromosome Aberrations in Human Lymphocytes and Fibroblasts after Exposure to Very Low Doses of High LET Radiation

    NASA Technical Reports Server (NTRS)

    Hada, M.; George, Kerry; Cucinotta, Francis A.

    2011-01-01

    The relationship between biological effects and low doses of absorbed radiation is still uncertain, especially for high LET radiation exposure. Estimates of risks from low-dose and low-dose-rates are often extrapolated using data from Japanese atomic bomb survivors with either linear or linear quadratic models of fit. In this study, chromosome aberrations were measured in human peripheral blood lymphocytes and normal skin fibroblasts cells after exposure to very low dose (1-20 cGy) of 170 MeV/u Si-28- ions or 600 MeV/u Fe-56-ions. Chromosomes were analyzed using the whole chromosome fluorescence in situ hybridization (FISH) technique during the first cell division after irradiation, and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving greater than 2 breaks in 2 or more chromosomes). The curves for doses above 10 cGy were fitted with linear or linear-quadratic functions. For Si-28- ions no dose response was observed in the 2-10 cGy dose range, suggesting a non-target effect in this range.

  5. Chronic low-dose γ-irradiation of Drosophila melanogaster larvae induces gene expression changes and enhances locomotive behavior

    PubMed Central

    Kim, Cha Soon; Seong, Ki Moon; Lee, Byung Sub; Lee, In Kyung; Yang, Kwang Hee; Kim, Ji-Young; Nam, Seon Young

    2015-01-01

    Although radiation effects have been extensively studied, the biological effects of low-dose radiation (LDR) are controversial. This study investigates LDR-induced alterations in locomotive behavior and gene expression profiles of Drosophila melanogaster. We measured locomotive behavior using larval pupation height and the rapid iterative negative geotaxis (RING) assay after exposure to 0.1 Gy γ-radiation (dose rate of 16.7 mGy/h). We also observed chronic LDR effects on development (pupation and eclosion rates) and longevity (life span). To identify chronic LDR effects on gene expression, we performed whole-genome expression analysis using gene-expression microarrays, and confirmed the results using quantitative real-time PCR. The pupation height of the LDR-treated group at the first larval instar was significantly higher (∼2-fold increase in PHI value, P < 0.05). The locomotive behavior of LDR-treated male flies (∼3 − 5 weeks of age) was significantly increased by 7.7%, 29% and 138%, respectively (P < 0.01), but pupation and eclosion rates and life spans were not significantly altered. Genome-wide expression analysis identified 344 genes that were differentially expressed in irradiated larvae compared with in control larvae. We identified several genes belonging to larval behavior functional groups such as locomotion (1.1%), oxidation reduction (8.0%), and genes involved in conventional functional groups modulated by irradiation such as defense response (4.9%), and sensory and perception (2.5%). Four candidate genes were confirmed as differentially expressed genes in irradiated larvae using qRT-PCR (>2-fold change). These data suggest that LDR stimulates locomotion-related genes, and these genes can be used as potential markers for LDR. PMID:25792464

  6. Low-dose exposure to di-(2-ethylhexyl) phthalate (DEHP) increases susceptibility to testicular autoimmunity in mice.

    PubMed

    Hirai, Shuichi; Naito, Munekazu; Kuramasu, Miyuki; Ogawa, Yuki; Terayama, Hayato; Qu, Ning; Hatayama, Naoyuki; Hayashi, Shogo; Itoh, Masahiro

    2015-09-01

    Exposure to di-(2-ethylhexyl) phthalate (DEHP) induces spermatogenic disturbance (SD) through oxidative stress, and affects the immune system by acting as an adjuvant. Recently, we reported that in mice, a low dose of DEHP, which did not affect spermatogenesis, was able to alter the testicular immune microenvironment. Experimental autoimmune orchitis (EAO) can be induced by repeated immunization with testicular antigens, and its pathology is characterized by production of autoantibodies and SD. In the present study, we investigated the effect of a low-dose DEHP on the susceptibility of mice to EAO. The exposure to DEHP-containing feed (0.01%) caused a modest functional damage to the blood-testis barrier (BTB) with an increase in testicular number of interferon gamma (IFN-γ)-positive cells and resulted in the production of autoantibodies targeting haploid cells, but did not affect spermatogenesis. While only single immunization with testicular antigens caused very mild EAO, the concurrent DEHP exposure induced severe EAO with significant increases in number of interferon gamma-positive cells and macrophages, as well as lymphocytic infiltration and serum autoantibody titer accompanied by severe SD. To summarize, the exposure of mice to the low-dose DEHP does not induce significant SD, but it may cause an increase in IFN-γ positive cells and modest functional damage to the BTB in the testis. These changes lead to an autoimmune response against haploid cell autoantigens, resulting in increased susceptibility to EAO.

  7. Metabonomic analysis of urine from rats after low-dose exposure to 3-chloro-1,2-propanediol using UPLC-MS.

    PubMed

    Liu, Liyan; He, Yujie; Lu, Huimin; Wang, Maoqing; Sun, Changhao; Na, Lixin; Li, Ying

    2013-05-15

    To study the toxic effect of chronic exposure to 3-chloro-1,2-propanediol (3-MCPD) at low doses, a metabonomics approach based on ultrahigh-performance liquid chromatography and quadruple time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was performed. Two different doses of 3-MCPD (1.1 and 5.5mg/kg bw/d) were administered to Wistar rats for 120 days (1.1mg/kg bw/d: lowest observed adverse effect level [LOAEL]). The metabolite profiles and biochemical parameters were obtained at five time points after treatment. For the 3-MCPD-treated groups, a significant change in urinary N-acetyl-β-d-glucosaminidase and β-d-galactosidase was detected on day 90, while some biomarkers based on the metabonomics, such as N-acetylneuraminic acid, N-acetyl-l-tyrosine, and gulonic acid, were detected on day 30. These results suggest that these biomarkers changed more sensitively and earlier than conventional biochemical parameters and were thus considered early and sensitive biomarkers of exposure to 3-MCPD; these biomarkers provide more information on toxicity than conventional biochemical parameters. These results might be helpful to investigate the toxic mechanisms of 3-MCPD and provide a scientific basis for assessing the effect of chronic exposure to low-dose 3-MCPD on human health.

  8. Data Integration Reveals Key Homeostatic Mechanisms Following Low Dose Radiation Exposure

    SciTech Connect

    Tilton, Susan C.; Matzke, Melissa M.; Sowa, Marianne B.; Stenoien, David L.; Weber, Thomas J.; Morgan, William F.; Waters, Katrina M.

    2015-05-01

    The goal of this study was to define pathways regulated by low dose radiation to understand how biological systems respond to subtle perturbations in their environment and prioritize pathways for human health assessment. Using an in vitro 3-D human full thickness skin model, we have examined the temporal response of dermal and epidermal layers to 10 cGy X-ray using transcriptomic, proteomic, phosphoproteomic and metabolomic platforms. Bioinformatics analysis of each dataset independently revealed potential signaling mechanisms affected by low dose radiation, and integrating data shed additional insight into the mechanisms regulating low dose responses in human tissue. We examined direct interactions among datasets (top down approach) and defined several hubs as significant regulators, including transcription factors (YY1, MYC and CREB1), kinases (CDK2, PLK1) and a protease (MMP2). These data indicate a shift in response across time - with an increase in DNA repair, tissue remodeling and repression of cell proliferation acutely (24 – 72 hr). Pathway-based integration (bottom up approach) identified common molecular and pathway responses to low dose radiation, including oxidative stress, nitric oxide signaling and transcriptional regulation through the SP1 factor that would not have been identified by the individual data sets. Significant regulation of key downstream metabolites of nitrative stress were measured within these pathways. Among the features identified in our study, the regulation of MMP2 and SP1 were experimentally validated. Our results demonstrate the advantage of data integration to broadly define the pathways and networks that represent the mechanisms by which complex biological systems respond to perturbation.

  9. A model of cardiovascular disease giving a plausible mechanism for the effect of fractionated low-dose ionizing radiation exposure.

    PubMed

    Little, Mark P; Gola, Anna; Tzoulaki, Ioanna

    2009-10-01

    Atherosclerosis is the main cause of coronary heart disease and stroke, the two major causes of death in developed society. There is emerging evidence of excess risk of cardiovascular disease at low radiation doses in various occupationally exposed groups receiving small daily radiation doses. Assuming that they are causal, the mechanisms for effects of chronic fractionated radiation exposures on cardiovascular disease are unclear. We outline a spatial reaction-diffusion model for atherosclerosis and perform stability analysis, based wherever possible on human data. We show that a predicted consequence of multiple small radiation doses is to cause mean chemo-attractant (MCP-1) concentration to increase linearly with cumulative dose. The main driver for the increase in MCP-1 is monocyte death, and consequent reduction in MCP-1 degradation. The radiation-induced risks predicted by the model are quantitatively consistent with those observed in a number of occupationally-exposed groups. The changes in equilibrium MCP-1 concentrations with low density lipoprotein cholesterol concentration are also consistent with experimental and epidemiologic data. This proposed mechanism would be experimentally testable. If true, it also has substantive implications for radiological protection, which at present does not take cardiovascular disease into account. The Japanese A-bomb survivor data implies that cardiovascular disease and cancer mortality contribute similarly to radiogenic risk. The major uncertainty in assessing the low-dose risk of cardiovascular disease is the shape of the dose response relationship, which is unclear in the Japanese data. The analysis of the present paper suggests that linear extrapolation would be appropriate for this endpoint.

  10. Model of avascular tumor growth and response to low dose exposure

    NASA Astrophysics Data System (ADS)

    Rodriguez Aguirre, J. M.; Custidiano, E. R.

    2011-12-01

    A single level cellular automata model is described and used to simulate early tumor growth, and the response of the tumor cells under low dose radiation affects. In this model the cell cycle of the population of normal and cancer cells is followed. The invasion mechanism of the tumor is simulated by a local factor that takes into account the microenvironment hardness to cell development, in a picture similar to the AMTIH model. The response of normal and cancer cells to direct effects of radiation is tested for various models and a model of bystander response is implemented.

  11. Seizures associated with low-dose tramadol for chronic pain treatment

    PubMed Central

    Beyaz, Serbülent Gökhan; Sonbahar, Tuğba; Bayar, Fikret; Erdem, Ali Fuat

    2016-01-01

    The management of cancer pain still poses a major challenge for clinicians. Tramadol is a centrally acting synthetic opioid analgesic. Its well-known side effects include nausea, vomiting, and dizziness; seizures are a rare side effect. Some reports have found that tramadol triggers seizure activity at high doses, whereas a few preclinical studies have found that this seizure activity is not dose-related. We herein present a case involving a patient with laryngeal cancer who developed seizures while on low-dose oral tramadol. PMID:27212778

  12. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

    PubMed

    Goodson, William H; Lowe, Leroy; Carpenter, David O; Gilbertson, Michael; Manaf Ali, Abdul; Lopez de Cerain Salsamendi, Adela; Lasfar, Ahmed; Carnero, Amancio; Azqueta, Amaya; Amedei, Amedeo; Charles, Amelia K; Collins, Andrew R; Ward, Andrew; Salzberg, Anna C; Colacci, Annamaria; Olsen, Ann-Karin; Berg, Arthur; Barclay, Barry J; Zhou, Binhua P; Blanco-Aparicio, Carmen; Baglole, Carolyn J; Dong, Chenfang; Mondello, Chiara; Hsu, Chia-Wen; Naus, Christian C; Yedjou, Clement; Curran, Colleen S; Laird, Dale W; Koch, Daniel C; Carlin, Danielle J; Felsher, Dean W; Roy, Debasish; Brown, Dustin G; Ratovitski, Edward; Ryan, Elizabeth P; Corsini, Emanuela; Rojas, Emilio; Moon, Eun-Yi; Laconi, Ezio; Marongiu, Fabio; Al-Mulla, Fahd; Chiaradonna, Ferdinando; Darroudi, Firouz; Martin, Francis L; Van Schooten, Frederik J; Goldberg, Gary S; Wagemaker, Gerard; Nangami, Gladys N; Calaf, Gloria M; Williams, Graeme; Wolf, Gregory T; Koppen, Gudrun; Brunborg, Gunnar; Lyerly, H Kim; Krishnan, Harini; Ab Hamid, Hasiah; Yasaei, Hemad; Sone, Hideko; Kondoh, Hiroshi; Salem, Hosni K; Hsu, Hsue-Yin; Park, Hyun Ho; Koturbash, Igor; Miousse, Isabelle R; Scovassi, A Ivana; Klaunig, James E; Vondráček, Jan; Raju, Jayadev; Roman, Jesse; Wise, John Pierce; Whitfield, Jonathan R; Woodrick, Jordan; Christopher, Joseph A; Ochieng, Josiah; Martinez-Leal, Juan Fernando; Weisz, Judith; Kravchenko, Julia; Sun, Jun; Prudhomme, Kalan R; Narayanan, Kannan Badri; Cohen-Solal, Karine A; Moorwood, Kim; Gonzalez, Laetitia; Soucek, Laura; Jian, Le; D'Abronzo, Leandro S; Lin, Liang-Tzung; Li, Lin; Gulliver, Linda; McCawley, Lisa J; Memeo, Lorenzo; Vermeulen, Louis; Leyns, Luc; Zhang, Luoping; Valverde, Mahara; Khatami, Mahin; Romano, Maria Fiammetta; Chapellier, Marion; Williams, Marc A; Wade, Mark; Manjili, Masoud H; Lleonart, Matilde E; Xia, Menghang; Gonzalez, Michael J; Karamouzis, Michalis V; Kirsch-Volders, Micheline; Vaccari, Monica; Kuemmerle, Nancy B; Singh, Neetu; Cruickshanks, Nichola; Kleinstreuer, Nicole; van Larebeke, Nik; Ahmed, Nuzhat; Ogunkua, Olugbemiga; Krishnakumar, P K; Vadgama, Pankaj; Marignani, Paola A; Ghosh, Paramita M; Ostrosky-Wegman, Patricia; Thompson, Patricia A; Dent, Paul; Heneberg, Petr; Darbre, Philippa; Sing Leung, Po; Nangia-Makker, Pratima; Cheng, Qiang Shawn; Robey, R Brooks; Al-Temaimi, Rabeah; Roy, Rabindra; Andrade-Vieira, Rafaela; Sinha, Ranjeet K; Mehta, Rekha; Vento, Renza; Di Fiore, Riccardo; Ponce-Cusi, Richard; Dornetshuber-Fleiss, Rita; Nahta, Rita; Castellino, Robert C; Palorini, Roberta; Abd Hamid, Roslida; Langie, Sabine A S; Eltom, Sakina E; Brooks, Samira A; Ryeom, Sandra; Wise, Sandra S; Bay, Sarah N; Harris, Shelley A; Papagerakis, Silvana; Romano, Simona; Pavanello, Sofia; Eriksson, Staffan; Forte, Stefano; Casey, Stephanie C; Luanpitpong, Sudjit; Lee, Tae-Jin; Otsuki, Takemi; Chen, Tao; Massfelder, Thierry; Sanderson, Thomas; Guarnieri, Tiziana; Hultman, Tove; Dormoy, Valérian; Odero-Marah, Valerie; Sabbisetti, Venkata; Maguer-Satta, Veronique; Rathmell, W Kimryn; Engström, Wilhelm; Decker, William K; Bisson, William H; Rojanasakul, Yon; Luqmani, Yunus; Chen, Zhenbang; Hu, Zhiwei

    2015-06-01

    Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

  13. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

    PubMed Central

    Goodson, William H.; Lowe, Leroy; Carpenter, David O.; Gilbertson, Michael; Manaf Ali, Abdul; Lopez de Cerain Salsamendi, Adela; Lasfar, Ahmed; Carnero, Amancio; Azqueta, Amaya; Amedei, Amedeo; Charles, Amelia K.; Collins, Andrew R.; Ward, Andrew; Salzberg, Anna C.; Colacci, Anna Maria; Olsen, Ann-Karin; Berg, Arthur; Barclay, Barry J.; Zhou, Binhua P.; Blanco-Aparicio, Carmen; Baglole, Carolyn J.; Dong, Chenfang; Mondello, Chiara; Hsu, Chia-Wen; Naus, Christian C.; Yedjou, Clement; Curran, Colleen S.; Laird, Dale W.; Koch, Daniel C.; Carlin, Danielle J.; Felsher, Dean W.; Roy, Debasish; Brown, Dustin G.; Ratovitski, Edward; Ryan, Elizabeth P.; Corsini, Emanuela; Rojas, Emilio; Moon, Eun-Yi; Laconi, Ezio; Marongiu, Fabio; Al-Mulla, Fahd; Chiaradonna, Ferdinando; Darroudi, Firouz; Martin, Francis L.; Van Schooten, Frederik J.; Goldberg, Gary S.; Wagemaker, Gerard; Nangami, Gladys N.; Calaf, Gloria M.; Williams, Graeme P.; Wolf, Gregory T.; Koppen, Gudrun; Brunborg, Gunnar; Lyerly, H. Kim; Krishnan, Harini; Ab Hamid, Hasiah; Yasaei, Hemad; Sone, Hideko; Kondoh, Hiroshi; Salem, Hosni K.; Hsu, Hsue-Yin; Park, Hyun Ho; Koturbash, Igor; Miousse, Isabelle R.; Scovassi, A.Ivana; Klaunig, James E.; Vondráček, Jan; Raju, Jayadev; Roman, Jesse; Wise, John Pierce; Whitfield, Jonathan R.; Woodrick, Jordan; Christopher, Joseph A.; Ochieng, Josiah; Martinez-Leal, Juan Fernando; Weisz, Judith; Kravchenko, Julia; Sun, Jun; Prudhomme, Kalan R.; Narayanan, Kannan Badri; Cohen-Solal, Karine A.; Moorwood, Kim; Gonzalez, Laetitia; Soucek, Laura; Jian, Le; D’Abronzo, Leandro S.; Lin, Liang-Tzung; Li, Lin; Gulliver, Linda; McCawley, Lisa J.; Memeo, Lorenzo; Vermeulen, Louis; Leyns, Luc; Zhang, Luoping; Valverde, Mahara; Khatami, Mahin; Romano, Maria Fiammetta; Chapellier, Marion; Williams, Marc A.; Wade, Mark; Manjili, Masoud H.; Lleonart, Matilde E.; Xia, Menghang; Gonzalez Guzman, Michael J.; Karamouzis, Michalis V.; Kirsch-Volders, Micheline; Vaccari, Monica; Kuemmerle, Nancy B.; Singh, Neetu; Cruickshanks, Nichola; Kleinstreuer, Nicole; van Larebeke, Nik; Ahmed, Nuzhat; Ogunkua, Olugbemiga; Krishnakumar, P.K.; Vadgama, Pankaj; Marignani, Paola A.; Ghosh, Paramita M.; Ostrosky-Wegman, Patricia; Thompson, Patricia A.; Dent, Paul; Heneberg, Petr; Darbre, Philippa; Leung, Po Sing; Nangia-Makker, Pratima; Cheng, Qiang (Shawn); Robey, R.Brooks; Al-Temaimi, Rabeah; Roy, Rabindra; Andrade-Vieira, Rafaela; Sinha, Ranjeet K.; Mehta, Rekha; Vento, Renza; Di Fiore, Riccardo; Ponce-Cusi, Richard; Dornetshuber-Fleiss, Rita; Nahta, Rita; Castellino, Robert C.; Palorini, Roberta; Hamid, Roslida A.; Langie, Sabine A.S.; Eltom, Sakina E.; Brooks, Samira A.; Ryeom, Sandra; Wise, Sandra S.; Bay, Sarah N.; Harris, Shelley A.; Papagerakis, Silvana; Romano, Simona; Pavanello, Sofia; Eriksson, Staffan; Forte, Stefano; Casey, Stephanie C.; Luanpitpong, Sudjit; Lee, Tae-Jin; Otsuki, Takemi; Chen, Tao; Massfelder, Thierry; Sanderson, Thomas; Guarnieri, Tiziana; Hultman, Tove; Dormoy, Valérian; Odero-Marah, Valerie; Sabbisetti, Venkata; Maguer-Satta, Veronique; Rathmell, W.Kimryn; Engström, Wilhelm; Decker, William K.; Bisson, William H.; Rojanasakul, Yon; Luqmani, Yunus; Chen, Zhenbang; Hu, Zhiwei

    2015-01-01

    Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology. PMID:26106142

  14. Dose Response for Chromosome Aberrations in Human Lymphocytes and Fibroblasts After Exposure to Very Low Dose of High Let Radiation

    NASA Technical Reports Server (NTRS)

    Hada, M.; George, K.; Chappell, L.; Cucinotta, F. A.

    2011-01-01

    The relationship between biological effects and low doses of absorbed radiation is still uncertain, especially for high LET radiation exposure. Estimates of risks from low-dose and low-dose-rates are often extrapolated using data from Japanese atomic bomb survivor with either linear or linear quadratic models of fit. In this study, chromosome aberrations were measured in human peripheral blood lymphocytes and normal skin fibroblasts cells after exposure to very low dose (0.01 - 0.20 Gy) of 170 MeV/u Si-28 ions or 600 MeV/u Fe-56 ions, including doses where on average less than one direct ion traversal per cell nucleus occurs. Chromosomes were analyzed using the whole-chromosome fluorescence in situ hybridization (FISH) technique during the first cell division after irradiation, and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving >2 breaks in 2 or more chromosomes). The responses for doses above 0.1 Gy (more than one ion traverses a cell) showed linear dose responses. However, for doses less than 0.1 Gy, both Si-28 ions and Fe-56 ions showed a dose independent response above background chromosome aberrations frequencies. Possible explanations for our results are non-targeted effects due to aberrant cell signaling [1], or delta-ray dose fluctuations [2] where a fraction of cells receive significant delta-ray doses due to the contributions of multiple ion tracks that do not directly traverse cell nuclei where chromosome aberrations are scored.

  15. Early Developmental Low-Dose Methylmercury Exposure Alters Learning and Memory in Periadolescent but Not Young Adult Rats

    PubMed Central

    Albores-Garcia, Damaris; Hernandez, Alberto J.; Loera, Miriam J.

    2016-01-01

    Few studies have assessed the effects of developmental methylmercury (MeHg) exposure on learning and memory at different ages. The possibility of the amelioration or worsening of the effects has not been sufficiently investigated. This study aimed to assess whether low-dose MeHg exposure in utero and during suckling induces differential disturbances in learning and memory of periadolescent and young adult rats. Four experimental groups of pregnant Sprague-Dawley rats were orally exposed to MeHg or vehicle from gestational day 5 to weaning: (1) control (vehicle), (2) 250 μg/kg/day MeHg, (3) 500 μg/kg/day MeHg, and (4) vehicle, and treated on the test day with MK-801 (0.15 mg/kg i.p.), an antagonist of the N-methyl D-aspartate receptor. The effects were evaluated in male offspring through the open field test, object recognition test, Morris water maze, and conditioned taste aversion. For each test and stage assessed, different groups of animals were used. MeHg exposure, in a dose-dependent manner, disrupted exploratory behaviour, recognition memory, spatial learning, and acquisition of aversive memories in periadolescent rats, but alterations were not observed in littermates tested in young adulthood. These results suggest that developmental low-dose exposure to MeHg induces age-dependent detrimental effects. The relevance of decreasing exposure to MeHg in humans remains to be determined. PMID:26885512

  16. Early Developmental Low-Dose Methylmercury Exposure Alters Learning and Memory in Periadolescent but Not Young Adult Rats.

    PubMed

    Albores-Garcia, Damaris; Acosta-Saavedra, Leonor C; Hernandez, Alberto J; Loera, Miriam J; Calderón-Aranda, Emma S

    2016-01-01

    Few studies have assessed the effects of developmental methylmercury (MeHg) exposure on learning and memory at different ages. The possibility of the amelioration or worsening of the effects has not been sufficiently investigated. This study aimed to assess whether low-dose MeHg exposure in utero and during suckling induces differential disturbances in learning and memory of periadolescent and young adult rats. Four experimental groups of pregnant Sprague-Dawley rats were orally exposed to MeHg or vehicle from gestational day 5 to weaning: (1) control (vehicle), (2) 250 μg/kg/day MeHg, (3) 500 μg/kg/day MeHg, and (4) vehicle, and treated on the test day with MK-801 (0.15 mg/kg i.p.), an antagonist of the N-methyl D-aspartate receptor. The effects were evaluated in male offspring through the open field test, object recognition test, Morris water maze, and conditioned taste aversion. For each test and stage assessed, different groups of animals were used. MeHg exposure, in a dose-dependent manner, disrupted exploratory behaviour, recognition memory, spatial learning, and acquisition of aversive memories in periadolescent rats, but alterations were not observed in littermates tested in young adulthood. These results suggest that developmental low-dose exposure to MeHg induces age-dependent detrimental effects. The relevance of decreasing exposure to MeHg in humans remains to be determined.

  17. [Rapid dicentric assay of human blood lymphocytes after exposure to low doses of ionizing radiation].

    PubMed

    Repin, M V; Repina, L A

    2011-01-01

    The probability of losses of different chromosome aberrations during the dicentric chromosome assay of metaphase cells with incomplete sets of chromosome centromeres was estimated using a mathematical model for low doses of ionizing radiation. A dicentric assay of human blood lymphocytes without determination of the total amount of chromosome centromeres in cells without chromosome aberrations (rapid dicentric assay) has been proposed. The rapid dicentric analysis allows to register chromosome aberrations in full compliance with the conventional classification. The experimental data have shown no statistically significant difference between the frequencies of dicentric chromosomes detected by rapid and classical dicentric chromosome assays of human lymphocytes exposed to 0.5 Gy of 60Co gamma-rays. The rate of the rapid dicentric assay was almost twice as high as that of the classical dicentric assay.

  18. Low dose chronic treatment of human keratinocytes with inorganic arsenic causes hyperproliferation and altered protein phosphorylation

    SciTech Connect

    Steinberg, M.L.; Su, L.; Snow, E.T. |

    1997-10-01

    Chronic exposure to arsenate [As(V)] or arsenite [As(III)] causes hyperproliferation of normal and SV40-transformed human epidermal keratinocytes. Line 327 SV40-infected human keratinocytes were grown in the presence of either As(III) or As(V) (0.01 to 10 {mu}M) in complete medium for seven days prior to harvesting and counting. Both As(III) and As(V) were cytotoxic at micromolar concentrations, however submicromolar arsenic caused a significant increase in cell growth. Cell numbers in cultures exposed to As(V) were increased more than 186% relative to controls, and an even larger stimulation in cell growth was observed after treatment with 50 nM As(III). Normal non-SV40 T-antigen. Preliminary cell cycle analysis using unselected, log-phase cultures of arsenic-treated keratinocytes shows an increased proportion of cells in S- and G2/M-phase. Isoelectric focusing of phosphotyrosine-containing proteins from cells labeled with {sup 32}P-inorganic phosphate showed that the hyperproliferation of keratinocytes grown in low concentrations of arsenic is accompanied by altered tyrosine-specific protein phosphorylation. A number of phosphorylated proteins were observed in As-treated cells that were not observed in the controls; and minor bands at IEPs of 3.0, 4.2, 7.2, 7.5 and 8.2. These results, together with the lack of direct enzyme inhibition by arsenic shown by Su et al., this volume, suggest that arsenic-induced skin lesions and carcinogenesis may be the result of altered cell cycle control rather than DNA damage or reduced DNA repair.

  19. Over-exposure correction in knee cone-beam CT imaging with automatic exposure control using a partial low dose scan

    NASA Astrophysics Data System (ADS)

    Choi, Jang-Hwan; Muller, Kerstin; Hsieh, Scott; Maier, Andreas; Gold, Garry; Levenston, Marc; Fahrig, Rebecca

    2016-03-01

    C-arm-based cone-beam CT (CBCT) systems with flat-panel detectors are suitable for diagnostic knee imaging due to their potentially flexible selection of CT trajectories and wide volumetric beam coverage. In knee CT imaging, over-exposure artifacts can occur because of limitations in the dynamic range of the flat panel detectors present on most CBCT systems. We developed a straightforward but effective method for correction and detection of over-exposure for an Automatic Exposure Control (AEC)-enabled standard knee scan incorporating a prior low dose scan. The radiation dose associated with the low dose scan was negligible (0.0042mSv, 2.8% increase) which was enabled by partially sampling the projection images considering the geometry of the knees and lowering the dose further to be able to just see the skin-air interface. We combined the line integrals from the AEC and low dose scans after detecting over-exposed regions by comparing the line profiles of the two scans detector row-wise. The combined line integrals were reconstructed into a volumetric image using filtered back projection. We evaluated our method using in vivo human subject knee data. The proposed method effectively corrected and detected over-exposure, and thus recovered the visibility of exterior tissues (e.g., the shape and density of the patella, and the patellar tendon), incorporating a prior low dose scan with a negligible increase in radiation exposure.

  20. LOW-DOSE AIRBORNE ENDOTOXIN EXPOSURE ENHANCES BRONCHIAL RESPONSIVENESS TO INHALED ALLERGEN IN ATOPIC ASTHMATICS

    EPA Science Inventory

    Endotoxin exposure has been associated with both protection against development of TH2-immune responses during childhood and exacerbation of asthma in persons who already have allergic airway inflammation.1 Occupational and experimental inhalation exposures to endotoxin have been...

  1. Low dose exposure to Bisphenol A alters development of gonadotropin-releasing hormone 3 neurons and larval locomotor behavior in Japanese Medaka.

    PubMed

    Inagaki, T; Smith, N; Lee, E K; Ramakrishnan, S

    2016-01-01

    Accumulating evidence indicates that chronic low dose exposure to Bisphenol A (BPA), an endocrine disruptor, may disrupt normal brain development and behavior mediated by the gonadotropin-releasing hormone (GnRH) pathways. While it is known that GnRH neurons in the hypothalamus regulate reproductive physiology and behavior, functional roles of extra-hypothalamic GnRH neurons remain unclear. Furthermore, little is known whether BPA interacts with extra-hypothalamic GnRH3 neural systems in vulnerable developing brains. Here we examined the impact of low dose BPA exposure on the developing GnRH3 neural system, eye and brain growth, and locomotor activity in transgenic medaka embryos and larvae with GnRH3 neurons tagged with GFP. Fertilized eggs were collected daily and embryos/larvae were chronically exposed to 200ng/ml of BPA, starting at 1 day post fertilization (dpf). BPA significantly increased fluorescence intensity of the GnRH3-GFP neural population in the terminal nerve (TN) of the forebrain at 3dpf, but decreased the intensity at 5dpf, compared with controls. BPA advanced eye pigmentation without affecting eye and brain size development, and accelerated times to hatch. Following chronic BPA exposure, 20dpf larvae showed suppression of locomotion, both in distance covered and speed of movement (47% and 43% reduction, respectively). BPA-induced hypoactivity was accompanied by decreased cell body sizes of individual TN-GnRH3 neurons (14% smaller than those of controls), but not of non-GnRH3 neurons. These novel data demonstrate complex neurobehavioral effects of BPA on the development of extra-hypothalamic GnRH3 neurons in teleost fish.

  2. Long-term exposures to low doses of silver nanoparticles enhanced in vitro malignant cell transformation in non-tumorigenic BEAS-2B cells.

    PubMed

    Choo, Wun Hak; Park, Cho Hee; Jung, Shi Eun; Moon, Byeonghak; Ahn, Huiyeon; Ryu, Jung Seok; Kim, Keun-Soo; Lee, Yong Hwa; Yu, Il Je; Oh, Seung Min

    2016-12-01

    To predict carcinogenic potential of AgNPs on the respiratory system, BEAS-2B cells (human bronchial epithelial cells) were chronically exposed to low- and non-cytotoxic dose (0.13 and 1.33μg/ml) of AgNPs for 4months (#40 passages). To assess malignant cell transformation of chronic exposure to AgNPs, several bioassays including anchorage independent agar colony formation, cell migration/invasion assay, and epithelial-mesenchymal transition (EMT) were performed in BEAS-2B cells. Chronic exposure to AgNPs showed a significant increase of anchorage independent agar colony formation and cell migration/invasion. EMT, which is the loss of epithelial markers (E-Cadherin and Keratin) and the gain of mesenchymal marker (N-cadherin and Vimentin), was induced by chronic exposure to AgNPs. These responses indicated that chronic exposure to AgNPs could acquire characteristics of tumorigenic cells from normal BEAS-2B cells. In addition, caspase-3, p-p53, p-p38, and p-JNK were significantly decreased, while p-ERK1/2 was significantly increased. MMP-9 related to cell migration/invasion was upregulated, while a MMP-9 inhibitor, TIMP-1 was down-regulated. These results indicated that BEAS-2B cells exposed to AgNPs could induce anti-apoptotic response/anoikis resistance, and cell migration/invasion by complex regulation of MAPK kinase (p38, JNK, and ERK) and p53 signaling pathways. Therefore, we suggested that long-term exposure to low-dose of AgNPs could enhance malignant cell transformation in non-tumorigenic BEAS-2B cells. Our findings provide useful information needed to assess the carcinogenic potential of AgNPs.

  3. Estimates of relative risks for cancers in a population after prolonged low-dose-rate radiation exposure: a follow-up assessment from 1983 to 2005.

    PubMed

    Hwang, Su-Lun; Hwang, Jing-Shiang; Yang, Yi-Ta; Hsieh, Wanhua A; Chang, Tien-Chun; Guo, How-Ran; Tsai, Mong-Hsun; Tang, Jih-Luh; Lin, I-Feng; Chang, Wushou Peter

    2008-08-01

    Radiation effects on cancer risks in a cohort of Taiwanese residents who received protracted low-dose-rate gamma-radiation exposures from (60)Co-contaminated reinforcing steel used to build their apartments were studied, and risks were compared to those in other radiation-exposed cohorts. Analyses were based on a more extended follow-up of the cohort population in which 117 cancer cases diagnosed between 1983 and 2005 among 6,242 people with an average excess cumulative exposure estimate of about 48 mGy. Cases were identified from Taiwan's National Cancer Registry. Radiation effects on cancer risk were estimated using proportional hazards models and were summarized in terms of the hazard ratio associated with a 100-mGy increase in dose (HR(100mGy)). A significant radiation risk was observed for leukemia excluding chronic lymphocytic leukemia (HR(100mGy) 1.19, 90% CI 1.01-1.31). Breast cancer exhibited a marginally significant dose response (HR(100mGy) 1.12, 90% CI 0.99-1.21). The results further strengthen the association between protracted low-dose radiation and cancer risks, especially for breast cancers and leukemia, in this unique cohort population.

  4. Exposure to low doses of formaldehyde during pregnancy suppresses the development of allergic lung inflammation in offspring

    SciTech Connect

    Maiellaro, Marília; Correa-Costa, Matheus; Vitoretti, Luana Beatriz; Gimenes Júnior, João Antônio; Câmara, Niels Olsen Saraiva; Tavares-de-Lima, Wothan; Farsky, Sandra Helena Poliselli; Lino-dos-Santos-Franco, Adriana

    2014-08-01

    Formaldehyde (FA) is an environmental and occupational pollutant, and its toxic effects on the immune system have been shown. Nevertheless, no data are available regarding the programming mechanisms after FA exposure and its repercussions for the immune systems of offspring. In this study, our objective was to investigate the effects of low-dose exposure of FA on pregnant rats and its repercussion for the development of allergic lung inflammation in offspring. Pregnant Wistar rats were assigned in 3 groups: P (rats exposed to FA (0.75 ppm, 1 h/day, 5 days/week, for 21 days)), C (rats exposed to vehicle of FA (distillated water)) and B (rats non-manipulated). After 30 days of age, the offspring was sensitised with ovalbumin (OVA)-alum and challenged with aerosolized OVA (1%, 15 min, 3 days). After 24 h the OVA challenge the parameters were evaluated. Our data showed that low-dose exposure to FA during pregnancy induced low birth weight and suppressed the development of allergic lung inflammation and tracheal hyperresponsiveness in offspring by mechanisms mediated by reduced anaphylactic antibodies synthesis, IL-6 and TNF-alpha secretion. Elevated levels of IL-10 were found. Any systemic alteration was detected in the exposed pregnant rats, although oxidative stress in the uterine environment was evident at the moment of the delivery based on elevated COX-1 expression and reduced cNOS and SOD-2 in the uterus. Therefore, we show the putative programming mechanisms induced by FA on the immune system for the first time and the mechanisms involved may be related to oxidative stress in the foetal microenvironment. - Highlights: • Formaldehyde exposure does not cause lung inflammation in pregnant rats. • Formaldehyde exposure suppresses allergic lung inflammation in the offspring. • Formaldehyde exposure induces oxidative stress in uterine environment.

  5. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain.

    PubMed

    Younger, Jarred; Parkitny, Luke; McLain, David

    2014-04-01

    Low-dose naltrexone (LDN) has been demonstrated to reduce symptom severity in conditions such as fibromyalgia, Crohn's disease, multiple sclerosis, and complex regional pain syndrome. We review the evidence that LDN may operate as a novel anti-inflammatory agent in the central nervous system, via action on microglial cells. These effects may be unique to low dosages of naltrexone and appear to be entirely independent from naltrexone's better-known activity on opioid receptors. As a daily oral therapy, LDN is inexpensive and well-tolerated. Despite initial promise of efficacy, the use of LDN for chronic disorders is still highly experimental. Published trials have low sample sizes, and few replications have been performed. We cover the typical usage of LDN in clinical trials, caveats to using the medication, and recommendations for future research and clinical work. LDN may represent one of the first glial cell modulators to be used for the management of chronic pain disorders.

  6. Oral exposure to low-dose of nonylphenol impairs memory performance in Sprague-Dawley rats.

    PubMed

    Kawaguchi, Shinichiro; Kuwahara, Rika; Kohara, Yumi; Uchida, Yutaro; Oku, Yushi; Yamashita, Kimihiro

    2015-02-01

    Nonylphenol ethoxylate (NPE) is a non-ionic surfactant, that is degraded to short-chain NPE and 4-nonylphenol (NP) by bacteria in the environment. NP, one of the most common environmental endocrine disruptors, exhibits weak estrogen-like activity. In this study, we investigated whether oral administration of NP (at 0.5 and 5 mg/kg doses) affects spatial learning and memory, general activity, emotionality, and fear-motivated learning and memory in male and female Sprague-Dawley (SD) rats. SD rats of both sexes were evaluated using a battery of behavioral tests, including an appetite-motivated maze test (MAZE test) that was used to assess spatial learning and memory. In the MAZE test, the time required to reach the reward in male rats treated with 0.5 mg/kg NP group and female rats administered 5 mg/kg NP was significantly longer than that for control animals of the corresponding sex. In other behavioral tests, no significant differences were observed between the control group and either of the NP-treated groups of male rats. In female rats, inner and ambulation values for animals administered 0.5 mg/kg NP were significantly higher than those measured in control animals in open-field test, while the latency in the group treated with 5 mg/kg NP was significantly shorter compared to the control group in step-through passive avoidance test. This study indicates that oral administration of a low-dose of NP slightly impairs spatial learning and memory performance in male and female rats, and alters emotionality and fear-motivated learning and memory in female rats only.

  7. An animal model to study health effects during continuous low-dose exposure to the nerve agent VX.

    PubMed

    Rocksén, David; Elfsmark, Daniel; Heldestad, Victoria; Wallgren, Karin; Cassel, Gudrun; Göransson Nyberg, Ann

    2008-08-19

    In the present study, we have developed an animal model to study long-term health effects of continuous exposure of toxic chemical agents, in awake, freely moving rats. The aim was to evaluate the effect of low-dose exposure of the nerve agent VX, and to find specific biomarkers for intoxication. To exclude the influence of stress, we used an implanted radio-telemetric device for online registration of physiological parameters, and an osmotic pump, implanted subcutaneously, for continuous exposure of the toxic agent. Our results showed that the lowest observable effect dose of VX in Wistar rats was 5 microg/kg/24 h, after continuous exposure by the osmotic pump. Although we observed significant inhibition of acetylcholinesterase (AChE) in blood and a significant decrease in body weight gain at this dose, no change in blood pressure, heart rate or respiratory rate was registered. However, a significant decrease in the thyroid hormone, free T4, was measured in blood after 8 weeks, indicating that low doses of VX might affect the thyroid function. Rats given repeated daily injections were more sensitive to VX and needed only 1/10 of the concentration to reach a similar level of AChE inhibition, compared to animals exposed by the osmotic pump. Moreover, the results showed that exposure of VX in our experimental design, does not induce an increase in corticosterone blood levels. Thus, the model used in this investigation renders minimal stress and will not cause unnecessary pain to the animals, indicating that this model could be a useful tool to study long-term effects of various toxic substances in freely moving rats.

  8. DNA Damage Following Pulmonary Exposure by Instillation to Low Doses of Carbon Black (Printex 90) Nanoparticles in Mice

    PubMed Central

    Kyjovska, Zdenka O; Jacobsen, Nicklas R; Saber, Anne T; Bengtson, Stefan; Jackson, Petra; Wallin, Håkan; Vogel, Ulla

    2015-01-01

    We previously observed genotoxic effects of carbon black nanoparticles at low doses relative to the Danish Occupational Exposure Limit (3.5 mg/m3). Furthermore, DNA damage occurred in broncho-alveolar lavage (BAL) cells in the absence of inflammation, indicating that inflammation is not required for the genotoxic effects of carbon black. In this study, we investigated inflammatory and acute phase response in addition to genotoxic effects occurring following exposure to nanoparticulate carbon black (NPCB) at even lower doses. C57BL/6JBomTac mice were examined 1, 3, and 28 days after a single instillation of 0.67, 2, 6, and 162 µg Printex 90 NPCB and vehicle. Cellular composition and protein concentration was evaluated in BAL fluid as markers of inflammatory response and cell damage. DNA strand breaks in BAL cells, lung, and liver tissue were assessed using the alkaline comet assay. The pulmonary acute phase response was analyzed by Saa3 mRNA real-time quantitative PCR. Instillation of the low doses of NPCB induced a slight neutrophil influx one day after exposure. Pulmonary exposure to small doses of NPCB caused an increase in DNA strand breaks in BAL cells and lung tissue measured using the comet assay. We interpret the increased DNA strand breaks occurring following these low exposure doses of NPCB as DNA damage caused by primary genotoxicity in the absence of substantial inflammation, cell damage, and acute phase response. Environ. Mol. Mutagen. 56:41–49, 2015. © 2014 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society PMID:25042074

  9. Repeated low-dose exposures to sarin, soman, or VX affect acoustic startle in guinea pigs.

    PubMed

    Smith, C D; Lee, R B; Moran, A V; Sipos, M L

    2016-01-01

    Chemical warfare nerve agents (CWNAs) are known to cause behavioral abnormalities in cases of human exposures and in animal models. The behavioral consequences of single exposures to CWNAs that cause observable toxic signs are particularly well characterized in animals; however, less is known regarding repeated smaller exposures that may or may not cause observable toxic signs. In the current study, guinea pigs were exposed to fractions (0.1, 0.2, or 0.4) of a medial lethal dose (LD50) of sarin, soman, or VX for two weeks. On each exposure day, and for a post-exposure period, acoustic startle response (ASR) was measured in each animal. Although relatively few studies use guinea pigs to measure behavior, this species is ideal for CWNA-related experiments because their levels of carboxylesterases closely mimic those of humans, unlike rats or mice. Results showed that the 0.4 LD50 doses of soman and VX transiently increased peak startle amplitude by the second week of injections, with amplitude returning to baseline by the second week post-exposure. Sarin also increased peak startle amplitude independent of week. Latencies to peak startle and PPI were affected by agent exposure but not consistently among the three agents. Most of the changes in startle responses returned to baseline following the cessation of exposures. These data suggest that doses of CWNAs not known to produce observable toxic signs in guinea pigs can affect behavior in the ASR paradigm. Further, these deficits are transient and usually return to baseline shortly after the end of a two-week exposure period.

  10. Changes in the Metabolome in Response to Low-Dose Exposure to Environmental Chemicals Used in Personal Care Products during Different Windows of Susceptibility

    PubMed Central

    Chen, Jia; Belpoggi, Fiorella; Manservisi, Fabiana; Sánchez-Guijo, Alberto; Wudy, Stefan A.; Teitelbaum, Susan L.

    2016-01-01

    The consequences of ubiquitous exposure to environmental chemicals remain poorly defined. Non-targeted metabolomic profiling is an emerging method to identify biomarkers of the physiological response to such exposures. We investigated the effect of three commonly used ingredients in personal care products, diethyl phthalate (DEP), methylparaben (MPB) and triclosan (TCS), on the blood metabolome of female Sprague-Dawley rats. Animals were treated with low levels of these chemicals comparable to human exposures during prepubertal and pubertal windows as well as chronically from birth to adulthood. Non-targeted metabolomic profiling revealed that most of the variation in the metabolites was associated with developmental stage. The low-dose exposure to DEP, MPB and TCS had a relatively small, but detectable impact on the metabolome. Multiple metabolites that were affected by chemical exposure belonged to the same biochemical pathways including phenol sulfonation and metabolism of pyruvate, lyso-plasmalogens, unsaturated fatty acids and serotonin. Changes in phenol sulfonation and pyruvate metabolism were most pronounced in rats exposed to DEP during the prepubertal period. Our metabolomics analysis demonstrates that human level exposure to personal care product ingredients has detectable effects on the rat metabolome. We highlight specific pathways such as sulfonation that warrant further study. PMID:27467775

  11. [Alteration of thyroid hormone secretion after long-term exposure to low doses of endocrine disruptor DDT].

    PubMed

    Iaglova, N V; Iaglov, V V

    2014-01-01

    Endocrine disruptors are exogenous substances that exhibit hormone-like action and consequently disrupt homeostatic action of endogenous hormones. DDT is the most common disruptor. The objective was to evaluate changes in thyroid hormone secretion after long-term exposure to low doses of DDT. The experiment was performed on male Wistar rats. The rats were given DDT at doses of 1.89±0.86 мg/kg/day and 7.77±0.17 мg/kg/day for 6 and 10 weeks. Dose dependent increase of serum total thyroxine, total triiodthyronine, and thyroid peroxidase was revealed after 6 weeks exposure. After 10 weeks free thyroxine secretion was reduced. Such alterations of the thyroid status are typical for iodine deficient goiter. The data obtained indicate that the main mechanism of DDT action includes disruption of thyroxine secretion by thyrocytes, but not inhibition of deiodinase activity and decrease of blood thyroid binding proteins.

  12. TU-C-18A-01: Models of Risk From Low-Dose Radiation Exposures: What Does the Evidence Say?

    SciTech Connect

    Bushberg, J; Boreham, D; Ulsh, B

    2014-06-15

    what dose level are risk vs. benefit discussions with patients appropriate, 3) at what dose level should we tell a pregnant woman that the baby’s health risk from a prenatal radiation exposure is “significant”, 4) is informed consent needed for patients undergoing medical imaging, and 5) at what dose level is evacuation appropriate after a radiological accident. Examples of the tremendous impact that choosing different risks models can have on the answers to these types of questions will be given.A moderated panel discussion will allow audience members to pose questions to the faculty members, each of whom is an established expert in his respective discipline. Learning Objectives: Understand the fundamental principles, strengths and limitations of radiation epidemiology and radiation biology for determining the risk from exposures to low doses of ionizing radiation Become familiar with common models of risk used to describe the dose-response relationship at low dose levels Learn to identify strengths and weaknesses in studies designed to measure the effect of low doses of ionizing radiation Understand the implications of different risk models on public policy and health care decisions.

  13. Chronic Low Dose Fructose infusion Does Not Reverse Glucagon-Mediated Decrease in Hepatic Glucose Utilization

    PubMed Central

    Johnson, Paulette M.; Chen, Sheng-Song; Santomango, Tammy S.; Williams, Phillip E; Lacy, D. Brooks; McGuinness, Owen P.

    2013-01-01

    Objective An adaptation to chronic total parenteral nutrition (TPN; 75% of non protein calories as glucose) is the liver becomes a major consumer of glucose with lactate release as a by-product. The liver is able to further increase liver glucose uptake when a small dose of fructose is acutely infused via the portal system. Glucagon, commonly elevated during inflammatory stress, is a potent inhibitor of glucose uptake by the liver during TPN. The aim was to determine if chronic fructose infusion could overcome the glucagon-mediated decrease in hepatic glucose uptake. Material/methods Studies were performed in conscious insulin-treated chronically catheterized pancreatectomized dogs that adapted to TPN for 33 h. They were then assigned to one of 4 groups: TPN (C), TPN + fructose (4.4 μmol·kg−1·min−1, F), TPN+ glucagon (0.2 pmol·kg−1·min−1, GGN), or a TPN + fructose and glucagon (F+GGN) for an additional 63h (33–96h). Insulin, fructose and glucagon were infused into the portal vein. During that period all animals received a fixed insulin infusion 0.4mU· kg−1·min−1 (33–96h) and the glucose infusion rates were adjusted to maintain euglycemia (6.6 mM). Results Chronic fructose infusion was unable to further enhance net hepatic glucose uptake (NHGU; μmol·kg−1·min−1) (31.1±2.8 vs. 36.1±5.0; C vs. F) nor was it able to overcome glucagon-mediated decrease in NHGU (10.0±4.4 vs. 12.2±3.9; GGN vs. F+GGN). Conclusion In summary, chronic fructose infusion cannot augment liver glucose uptake during TPN nor can it overcome the inhibitory effects of glucagon. PMID:20940071

  14. Exposure to low doses of formaldehyde during pregnancy suppresses the development of allergic lung inflammation in offspring.

    PubMed

    Maiellaro, Marília; Correa-Costa, Matheus; Vitoretti, Luana Beatriz; Gimenes Júnior, João Antônio; Câmara, Niels Olsen Saraiva; Tavares-de-Lima, Wothan; Farsky, Sandra Helena Poliselli; Lino-dos-Santos-Franco, Adriana

    2014-08-01

    Formaldehyde (FA) is an environmental and occupational pollutant, and its toxic effects on the immune system have been shown. Nevertheless, no data are available regarding the programming mechanisms after FA exposure and its repercussions for the immune systems of offspring. In this study, our objective was to investigate the effects of low-dose exposure of FA on pregnant rats and its repercussion for the development of allergic lung inflammation in offspring. Pregnant Wistar rats were assigned in 3 groups: P (rats exposed to FA (0.75 ppm, 1 h/day, 5 days/week, for 21 days)), C (rats exposed to vehicle of FA (distillated water)) and B (rats non-manipulated). After 30 days of age, the offspring was sensitised with ovalbumin (OVA)-alum and challenged with aerosolized OVA (1%, 15 min, 3 days). After 24 h the OVA challenge the parameters were evaluated. Our data showed that low-dose exposure to FA during pregnancy induced low birth weight and suppressed the development of allergic lung inflammation and tracheal hyperresponsiveness in offspring by mechanisms mediated by reduced anaphylactic antibodies synthesis, IL-6 and TNF-alpha secretion. Elevated levels of IL-10 were found. Any systemic alteration was detected in the exposed pregnant rats, although oxidative stress in the uterine environment was evident at the moment of the delivery based on elevated COX-1 expression and reduced cNOS and SOD-2 in the uterus. Therefore, we show the putative programming mechanisms induced by FA on the immune system for the first time and the mechanisms involved may be related to oxidative stress in the foetal microenvironment.

  15. Some Behavioral Effects of Exposure to Low Doses of Fe-56 Particles

    NASA Technical Reports Server (NTRS)

    Rabin, Bernard M.; Joseph, James A.; Shukitt-Hale, Barbara

    1999-01-01

    Future missions in space (such as a mission to Mars) will involve long-term travel beyond the magnetic field of the Earth. As a result, astronauts will be exposed to radiation qualities and doses that differ from those experienced in low earth orbit, including exposure to heavy particles, such as Fe-56, which are a component of cosmic rays. Although the hazards of exposure to heavy particles are often minimized, they can affect neural functioning, and as a consequence, behavior. Unless the effects of exposure to cosmic rays can somehow be reduced, their effects on the brain throughout long duration flights could be disastrous. In the extreme case, it is possible that the effects of cosmic rays on space travelers could result in symptomatology resembling that of Alzheimer's or Parkinson's diseases or of advancing age, including significant cognitive and/or motor impairments. Because successful operations in space depend in part on the performance capabilities of astronauts, such impairments could jeopardize their ability to satisfy mission requirements, as well as have long-term consequences on the health of astronauts. As such, understanding the nature and extent of this risk may be vital to the effective performance and possibly the survival of astronauts during future missions in space.

  16. Chronic low-dose melatonin treatment maintains nigrostriatal integrity in an intrastriatal rotenone model of Parkinson's disease.

    PubMed

    Carriere, Candace H; Kang, Na Hyea; Niles, Lennard P

    2016-02-15

    Parkinson's disease is a major neurodegenerative disorder which primarily involves the loss of dopaminergic neurons in the substantia nigra and related projections in the striatum. The pesticide/neurotoxin, rotenone, has been shown to cause systemic inhibition of mitochondrial complex I activity in nigral dopaminergic neurons, with consequent degeneration of the nigrostriatal pathway, as observed in Parkinson's disease. A novel intrastriatal rotenone model of Parkinson's disease was used to examine the neuroprotective effects of chronic low-dose treatment with the antioxidant indoleamine, melatonin, which can upregulate neurotrophic factors and other protective proteins in the brain. Sham or lesioned rats were treated with either vehicle (0.04% ethanol in drinking water) or melatonin at a dose of 4 µg/mL in drinking water. The right striatum was lesioned by stereotactic injection of rotenone at three sites (4 μg/site) along its rostrocaudal axis. Apomorphine administration to lesioned animals resulted in a significant (p<0.001) increase in ipsilateral rotations, which was suppressed by melatonin. Nine weeks post-surgery, animals were sacrificed by transcardial perfusion. Subsequent immunohistochemical examination revealed a decrease in tyrosine hydroxylase immunoreactivity within the striatum and substantia nigra of rotenone-lesioned animals. Melatonin treatment attenuated the decrease in tyrosine hydroxylase in the striatum and abolished it in the substantia nigra. Stereological cell counts indicated a significant (p<0.05) decrease in dopamine neurons in the substantia nigra of rotenone-lesioned animals, which was confirmed by Nissl staining. Importantly, chronic melatonin treatment blocked the loss of dopamine neurons in rotenone-lesioned animals. These findings strongly support the therapeutic potential of long-term and low-dose melatonin treatment in Parkinson's disease.

  17. Early Brain Response to Low-Dose Radiation Exposure Involves Molecular Networks and Pathways Associated with Cognitive Functions, Advanced Aging and Alzheimer's Disease

    SciTech Connect

    Lowe, Xiu R; Bhattacharya, Sanchita; Marchetti, Francesco; Wyrobek, Andrew J.

    2008-06-06

    Understanding the cognitive and behavioral consequences of brain exposures to low-dose ionizing radiation has broad relevance for health risks from medical radiation diagnostic procedures, radiotherapy, environmental nuclear contamination, as well as earth orbit and space missions. Analyses of transcriptome profiles of murine brain tissue after whole-body radiation showed that low-dose exposures (10 cGy) induced genes not affected by high dose (2 Gy), and low-dose genes were associated with unique pathways and functions. The low-dose response had two major components: pathways that are consistently seen across tissues, and pathways that were brain tissue specific. Low-dose genes clustered into a saturated network (p < 10{sup -53}) containing mostly down-regulated genes involving ion channels, long-term potentiation and depression, vascular damage, etc. We identified 9 neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose radiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Mice exposed to high-dose radiation did not show these effects and associations. Our findings indicate that the molecular response of the mouse brain within a few hours after low-dose irradiation involves the down-regulation of neural pathways associated with cognitive dysfunctions that are also down regulated in normal human aging and Alzheimer's disease.

  18. Cross-generational effects of parental low dose BPA exposure on the Gonadotropin-Releasing Hormone3 system and larval behavior in medaka (Oryzias latipes).

    PubMed

    Inagaki, T; Smith, N L; Sherva, K M; Ramakrishnan, S

    2016-12-01

    Growing evidence indicates that chronic exposure to Bisphenol A (BPA) may disrupt normal brain function and behavior mediated by gonadotropin-releasing hormone (GnRH) pathways. Previous studies have shown that low dose BPA (200ng/ml) exposure during embryogenesis altered development of extra-hypothalamic GnRH3 systems and non-reproductive locomotor behavior in medaka. Effects of parental low-dose BPA exposure on the development of GnRH3 systems and locomotor behavior of offspring are not well known. This study examines whether the neurophysiological and behavioral effects of BPA in parents (F0 generation) are carried over to their offspring (F1 generation) using stable transgenic medaka embryos/larvae with GnRH3 neurons tagged with green fluorescent protein (GFP). Parental fish were exposed to BPA (200ng/ml) for either life-long or different developmental time windows. Fertilized F1 eggs were collected and raised in egg/fish water with no environmental exposure to BPA. All experiments were performed on F1 embryos/larvae, which were grouped based on the following parental (F0) BPA exposure conditions - (i) Group 1 (G1): through life; (ii) G2: during embryogenesis and early larval development [1-14days post fertilization (dpf)]; (iii) G3: during neurogenesis (1-5dpf); and (iv) G4: during sex differentiation (5-14dpf). Embryos from unexposed vehicle treated parents served as controls (G0). G1 embryos showed significantly reduced survival rates and delayed hatching time compared to other groups, while G4 embryos hatched significantly earlier than all other groups. At 3 dpf, the GnRH3-GFP intensity was increased by 47% in G3 embryos and decreased in G4 embryos by 59% compared to controls. At 4dpf, G1 fish showed 42% increased intensity, while GFP intensity was reduced by 44% in G3 subjects. In addition, the mean brain size of G1, G3 and G4 embryos were smaller than that of control at 4dpf. At 20dpf, all larvae from BPA-treated parents showed significantly decreased

  19. Negative effects of low dose atrazine exposure on the development of effective immunity to FV3 in Xenopus laevis.

    PubMed

    Sifkarovski, Jason; Grayfer, Leon; De Jesús Andino, Francisco; Lawrence, B Paige; Robert, Jacques

    2014-11-01

    The recent dramatic increase of the prevalence and range of amphibian host species and populations infected by ranaviruses such as Frog Virus 3 (FV3) raises concerns about the efficacies of amphibian antiviral immunity. In this context, the potential negative effects of water contaminants such as the herbicide atrazine, at environmentally relevant levels, on host antiviral immunity remains unclear. Here we describe the use of the amphibian Xenopus laevis as an ecotoxicology platform to elucidate the consequences of exposure to ecologically relevant doses of atrazine on amphibian antiviral immunity. X. laevis were exposed at tadpole and adult stages as well as during metamorphosis to atrazine (range from 0.1 to 10.0 ppb) prior to infection with FV3. Quantitative analysis of gene expression revealed significant changes in the pro-inflammatory cytokine, TNF-α and the antiviral type I IFN gene in response to FV3 infection. This was most marked in tadpoles that were exposed to atrazine at doses as low 0.1 ppb. Furthermore, atrazine exposure significantly compromised tadpole survival following FV3 infections. In contrast, acute atrazine exposure of mature adult frogs did not induce detectable effects on anti-FV3 immunity, but adults that were exposed to atrazine during metamorphosis exhibited pronounced defects in FV3-induced TNF-α gene expression responses and slight diminution in type I IFN gene induction. Thus, even at low doses, atrazine exposure culminates in impaired development of amphibian antiviral defenses.

  20. Subacute effects of low dose lead nitrate and mercury chloride exposure on kidney of rats.

    PubMed

    Apaydın, Fatma Gökçe; Baş, Hatice; Kalender, Suna; Kalender, Yusuf

    2016-01-01

    Lead nitrate and mercury chloride are the most common heavy metal pollutants. In the present study, the effects of lead and mercury induced nephrotoxicity were studied in Wistar rats. Lead nitrate (LN, 45 mg/kg b.w/day) and mercury chloride (MC, 0.02 mg/kg b.w/day) and their combination were administered orally for 28 days. Four groups of rats were used in the study: control, LN, MC and LN plus MC groups. Serum biochemical parameters, lipid peroxidation, antioxidant enzymes and histopathological changes in kidney tissues were investigated in all treatment groups. LN and MC caused severe histopathological changes. It was shown that LN, MC and also co-treatment with LN and MC exposure induced significant increase in serum urea, uric acid and creatinine levels. There were also statistically significant changes in antioxidant enzyme activities (SOD, CAT, GPx and GST) and lipid peroxidation (MDA) in all groups except control group. In this study, we showed that MC caused more harmful effects than LN in rats.

  1. Low-dose exposure to bisphenol A and replacement bisphenol S induces precocious hypothalamic neurogenesis in embryonic zebrafish

    PubMed Central

    Kinch, Cassandra D.; Ibhazehiebo, Kingsley; Jeong, Joo-Hyun; Habibi, Hamid R.; Kurrasch, Deborah M.

    2015-01-01

    Bisphenol A (BPA), a ubiquitous endocrine disruptor that is present in many household products, has been linked to obesity, cancer, and, most relevant here, childhood neurological disorders such as anxiety and hyperactivity. However, how BPA exposure translates into these neurodevelopmental disorders remains poorly understood. Here, we used zebrafish to link BPA mechanistically to disease etiology. Strikingly, treatment of embryonic zebrafish with very low-dose BPA (0.0068 μM, 1,000-fold lower than the accepted human daily exposure) and bisphenol S (BPS), a common analog used in BPA-free products, resulted in 180% and 240% increases, respectively, in neuronal birth (neurogenesis) within the hypothalamus, a highly conserved brain region involved in hyperactivity. Furthermore, restricted BPA/BPS exposure specifically during the neurogenic window caused later hyperactive behaviors in zebrafish larvae. Unexpectedly, we show that BPA-mediated precocious neurogenesis and the concomitant behavioral phenotype were not dependent on predicted estrogen receptors but relied on androgen receptor-mediated up-regulation of aromatase. Although human epidemiological results are still emerging, an association between high maternal urinary BPA during gestation and hyperactivity and other behavioral disturbances in the child has been suggested. Our studies here provide mechanistic support that the neurogenic period indeed may be a window of vulnerability and uncovers previously unexplored avenues of research into how endocrine disruptors might perturb early brain development. Furthermore, our results show that BPA-free products are not necessarily safer and support the removal of all bisphenols from consumer merchandise. PMID:25583509

  2. Subchronic exposure to low-doses of the nerve agent VX: physiological, behavioral, histopathological and neurochemical studies.

    PubMed

    Bloch-Shilderman, Eugenia; Rabinovitz, Ishai; Egoz, Inbal; Raveh, Lily; Allon, Nahum; Grauer, Ettie; Gilat, Eran; Weissman, Ben Avi

    2008-08-15

    The highly toxic organophosphorous compound VX [O-ethyl-S-(isoporopylaminoethyl) methyl phosphonothiolate] undergoes an incomplete decontamination by conventional chemicals and thus evaporates from urban surfaces, e.g., pavement, long after the initial insult. As a consequence to these characteristics of VX, even the expected low levels should be examined for their potential to induce functional impairments including those associated with neuronal changes. In the present study, we developed an animal model for subchronic, low-dose VX exposure and evaluated its effects in rats. Animals were exposed to VX (2.25 microg/kg/day, 0.05 LD(50)) for three months via implanted mini osmotic pumps. The rapidly attained continuous and marked whole-blood cholinesterase inhibition (approximately 60%), fully recovered 96 h post pump removal. Under these conditions, body weight, blood count and chemistry, water maze acquisition task, sensitivity to the muscarinic agonist oxotremorine, peripheral benzodiazepine receptors density and brain morphology as demonstrated by routine histopathology, remained unchanged. However, animals treated with VX showed abnormal initial response in an Open Field test and a reduction (approximately 30%) in the expression of the exocytotic synaptobrevin/vesicle associate membrane protein (VAMP) in hippocampal neurons. These changes could not be detected one month following termination of exposure. Our findings indicate that following a subchronic, low-level exposure to the chemical warfare agent VX some important processes might be considerably impaired. Further research should be addressed towards better understanding of its potential health ramifications and in search of optimal countermeasures.

  3. Assessment of the Technologies for Molecular Biodosimetry for Human Low-Dose Radiation Exposure Symposium: Agenda and Abstracts

    SciTech Connect

    Coleman, Matthew A.; Ramakrishnan, Narayani

    2009-11-16

    In the event of a radiological accident, the rapid evaluation of the individual absorbed dose is paramount to discriminate those individuals who must receive medical attention. New research with genomic- and proteomic-wide tools is showing that within minutes to hours after exposure to ionizing radiation the cellular machinery is modified. For example: large-scale changes occur in the gene expression profiles involving a broad variety of cellular pathways after a wide range of both low dose (<10 cGy) and high dose (>10 cGy) ionizing radiation exposures. Symposium 12 was organized to address a wide range of biological effects using the latest technologies. To address current models following ionizing radiation exposure, methods in biodosimetry and dose effects the symposia featured a general overview titled “Model Systems and Current Approaches in Biodosimetry” by Matthew A. Coleman, from Lawrence Livermore National Laboratory and a talk entitled “Brief Overview of Biodosimetry Projects in the NIH Rad/Nuc Program” by Dr. Narayani Ramakrishnan, National Institute of Allergy and Infectious Diseases. These two talk set the tone for issues in data and model integration as well as addressing the national need for robust technologies for biological dosimetry. The report continues with more description of the presentations, along with the agenda and abstracts of the papers presented.

  4. Absence of effects on the rat sperm quality after subacute exposure to low doses of fungicide prochloraz.

    PubMed

    Sanabria, Marciana; Pessin, Alessandra; Zanutto, Mirella Rossitto; Perobelli, Juliana Elaine; Guerra, Marina Trevizan; Banzato, Thais Petrochelli; Borges, Cibele dos Santos; Kempinas, Wilma De Grava

    2015-01-01

    Prochloraz (PCZ) is a fungicide and androgen-receptor antagonist used worldwide in horticulture and agriculture. Pre- and perinatal exposure to this pesticide during sexual differentiation is deleterious for male offspring. Since data on the effects of PCZ on epididymal functions are scarce, and because sperm maturation occurs in this organ, the present investigation aimed to determine whether low PCZ doses administered to rats during the phase of sperm transit through the epididymis might affect the morphophysiology of this organ and sperm quality. Adult male Wistar rats were assigned to 4 different groups: 0 (control, vehicle) or 10, 15, or 30 mg/kg bw/d PCZ diluted in corn oil administered orally for 4 consecutive days. Morphofunctional parameters of the male reproductive tract, hormone concentrations, sperm evaluations, and fertility and histopathologic analysis of testis and epididymis were assessed. There were no statistically significant differences between treated and control groups in relation to all evaluated parameters. Data demonstrated show that PCZ exposure for a brief 4-d exposure and low doses did not produce reproductive toxicity or compromise sperm quality in adult rats.

  5. Effects of low-dose exposure to pesticide mixture on physiological responses of the Pacific oyster, Crassostrea gigas.

    PubMed

    Geret, F; Burgeot, T; Haure, J; Gagnaire, B; Renault, T; Communal, P Y; Samain, J F

    2013-12-01

    This study investigated the effects on the physiology of Pacific oyster, Crassostrea gigas, of a mixture of pesticides containing 0.8 μg L(-1) alachlor, 0.6 μg L(-1) metolachlor, 0.7 μg L(-1) atrazine, 0.6 μg L(-1) terbuthylazine, 0.5 μg L(-1) diuron, 0.6 μg L(-1) fosetyl aluminum, 0.05 μg L(-1) carbaryl, and 0.7 μg L(-1) glyphosate for a total concentration of 4.55 μg L(-1) . The total nominal concentration of pesticides mixture corresponds to the pesticide concentrations in the shellfish culture area of the Marennes-Oleron basin. Two varieties of C. gigas were selected on the foreshore, based on their characteristics in terms of resistance to summer mortality, to assess the effects of the pesticide mixture after 7 days of exposure under controlled conditions. The early effects of the mixture were assessed using enzyme biomarkers of nitrogen metabolism (GS, glutamine synthetase), detoxification metabolism (GST, glutathione S-transferase), and oxidative stress (CAT, catalase). Sublethal effects on hemocyte parameters (phagocytosis and esterase activity) and DNA damages (DNA adducts) were also measured. Changes in metabolic activities were characterized by increases in GS, GST, and CAT levels on the first day of exposure for the "resistant" oysters and after 3-7 days of exposure for the "susceptible" oysters. The formation of DNA adducts was detected after 7 days of exposure. The percentage of hemocyte esterase-positive cells was reduced in the resistant oysters, as was the hemocyte phagocytic capacity in both oyster varieties after 7 days of exposure to the pesticide mixture. This study highlights the need to consider the low doses and the mixture of pesticides to evaluate the effects of these molecules on organisms.

  6. Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure

    PubMed Central

    Kundakovic, Marija; Gudsnuk, Kathryn; Franks, Becca; Madrid, Jesus; Miller, Rachel L.; Perera, Frederica P.; Champagne, Frances A.

    2013-01-01

    Bisphenol A (BPA) is an estrogenic endocrine disruptor widely used in the production of plastics. Increasing evidence indicates that in utero BPA exposure affects sexual differentiation and behavior; however, the mechanisms underlying these effects are unknown. We hypothesized that BPA may disrupt epigenetic programming of gene expression in the brain. Here, we provide evidence that maternal exposure during pregnancy to environmentally relevant doses of BPA (2, 20, and 200 µg/kg/d) in mice induces sex-specific, dose-dependent (linear and curvilinear), and brain region-specific changes in expression of genes encoding estrogen receptors (ERs; ERα and ERβ) and estrogen-related receptor-γ in juvenile offspring. Concomitantly, BPA altered mRNA levels of epigenetic regulators DNA methyltransferase (DNMT) 1 and DNMT3A in the juvenile cortex and hypothalamus, paralleling changes in estrogen-related receptors. Importantly, changes in ERα and DNMT expression in the cortex (males) and hypothalamus (females) were associated with DNA methylation changes in the ERα gene. BPA exposure induced persistent, largely sex-specific effects on social and anxiety-like behavior, leading to disruption of sexually dimorphic behaviors. Although postnatal maternal care was altered in mothers treated with BPA during pregnancy, the effects of in utero BPA were not found to be mediated by maternal care. However, our data suggest that increased maternal care may partially attenuate the effects of in utero BPA on DNA methylation. Overall, we demonstrate that low-dose prenatal BPA exposure induces lasting epigenetic disruption in the brain that possibly underlie enduring effects of BPA on brain function and behavior, especially regarding sexually dimorphic phenotypes. PMID:23716699

  7. In Utero Exposure to Low-Dose Alcohol Induces Reprogramming of Mammary Development and Tumor Risk in MMTV-erbB-2 Transgenic Mice

    PubMed Central

    Ma, Zhikun; Blackwelder, Amanda J.; Lee, Harry; Zhao, Ming; Yang, Xiaohe

    2015-01-01

    There is increasing evidence that prenatal exposure to environmental factors may modify breast cancer risk later in life. This study aimed to investigate the effects of in utero exposure to low-dose alcohol on mammary development and tumor risk. Pregnant MMTV-erbB-2 mice were exposed to alcohol (6 g/kg/day) between day 13 and day 19 of gestation, and the female offspring were examined for tumor risk. Whole mount analysis indicated that in utero exposure to low-dose alcohol induced significant increases in ductal extension at 10 weeks of age. Molecular analysis showed that in utero alcohol exposure induced upregulation of ERα signaling and activation of Akt and Erk1/2 in pubertal mammary glands. However, enhanced signaling in the EGFR/erbB-2 pathway appeared to be more prominent in 10-week-old glands than did signaling in the other pathways. Interestingly, tumor development in mice with in utero exposure to low-dose alcohol was slightly delayed compared to control mice, but tumor multiplicity was increased. The results indicate that in utero exposure to low-dose alcohol induces the reprogramming of mammary development by mechanisms that include altered signaling in the estrogen receptor (ER) and erbB-2 pathways. The intriguing tumor development pattern might be related to alcohol dose and exposure conditions, and warrants further investigation. PMID:25853264

  8. Maternal low-dose estradiol-17β exposure during pregnancy impairs postnatal progeny weight development and body composition

    SciTech Connect

    Werner Fürst, Rainer; Pistek, Veronika Leopoldine; Kliem, Heike; Skurk, Thomas; Hauner, Hans; Meyer, Heinrich Herman Dietrich; Ulbrich, Susanne Ernestine

    2012-09-15

    Endocrine disrupting chemicals with estrogenic activity play an important role as obesogens. However, studies investigating the most potent natural estrogen, estradiol-17β (E2), at low dose are lacking. We examined endocrine and physiological parameters in gilts receiving distinct concentrations of E2 during pregnancy. We then investigated whether adverse effects prevail in progeny due to a potential endocrine disruption. E2 was orally applied to gilts during the entire period of pregnancy. The concentrations represented a daily consumption at the recommended ADI level (0.05 μg/kg body weight/day), at the NOEL (10 μg/kg body weight/day) and at a high dosage (1000 μg/kg body weight/day). Plasma hormone concentrations were determined using enzyme immuno assays. Offspring body fat was assessed by dual-energy X-ray absorptiometry scanning. In treated gilts receiving 1000 μg E2/kg body weight/day we found significantly elevated plasma E2 levels during pregnancy, paralleled by an increased weight gain. While offspring showed similar weight at birth, piglets exhibited a significant reduction in weight at weaning even though their mothers had only received 0.05 μg E2/kg body weight/day. At 8 weeks of age, specifically males showed a significant increase in overall body fat percentage. In conclusion, prenatal exposure to low doses of E2 affected pig offspring development in terms of body weight and composition. In line with findings from other obesogens, our data suggest a programming effect during pregnancy for E2 causative for the depicted phenotypes. Therefore, E2 exposure may imply a possible contribution to childhood obesity. -- Highlights: ► We investigate the potential role of estradiol-17β (E2) as an obesogen. ► We orally apply E2 at the ADI, NOEL and a high dose to gilts during pregnancy. ► Offspring weight is similar at birth but reduced at weaning even after ADI treatment. ► Male offspring only exhibit an increase in overall body fat percentage

  9. Subchronic exposure to low-doses of the nerve agent VX: Physiological, behavioral, histopathological and neurochemical studies

    SciTech Connect

    Bloch-Shilderman, Eugenia Rabinovitz, Ishai; Egoz, Inbal; Raveh, Lily; Allon, Nahum; Grauer, Ettie; Gilat, Eran; Weissman, Ben Avi

    2008-08-15

    The highly toxic organophosphorous compound VX [O-ethyl-S-(isoporopylaminoethyl) methyl phosphonothiolate] undergoes an incomplete decontamination by conventional chemicals and thus evaporates from urban surfaces, e.g., pavement, long after the initial insult. As a consequence to these characteristics of VX, even the expected low levels should be examined for their potential to induce functional impairments including those associated with neuronal changes. In the present study, we developed an animal model for subchronic, low-dose VX exposure and evaluated its effects in rats. Animals were exposed to VX (2.25 {mu}g/kg/day, 0.05 LD{sub 50}) for three months via implanted mini osmotic pumps. The rapidly attained continuous and marked whole-blood cholinesterase inhibition ({approx} 60%), fully recovered 96 h post pump removal. Under these conditions, body weight, blood count and chemistry, water maze acquisition task, sensitivity to the muscarinic agonist oxotremorine, peripheral benzodiazepine receptors density and brain morphology as demonstrated by routine histopathology, remained unchanged. However, animals treated with VX showed abnormal initial response in an Open Field test and a reduction ({approx} 30%) in the expression of the exocytotic synaptobrevin/vesicle associate membrane protein (VAMP) in hippocampal neurons. These changes could not be detected one month following termination of exposure. Our findings indicate that following a subchronic, low-level exposure to the chemical warfare agent VX some important processes might be considerably impaired. Further research should be addressed towards better understanding of its potential health ramifications and in search of optimal countermeasures.

  10. [The effect of long-term exposure to low doses of endocrine disruptor ddt on serum levels of thyroid protein autoantigenes and antithyroid autoantibodies].

    PubMed

    Yaglova, N V; Yaglov, V V

    2016-01-01

    Changes in secretion of thyroid autoantigenes and production of antithyroid autoantibodies after long-term exposure to low doses of DDT were studied. Changes in serum levels of antithyroid peroxidase antibodies and thyroid peroxidase, attributed to disruption of thyroxine production by DDT were found. Long-term exposure of rats to low doses of DDT revealed no specific impact on serum autoantibodies to all thyroid autoantigenes studied. The increase of the ratio of autoantibody/autoantigen for thyroid peroxidase and thyroglobulin was rather small and thus could not be considered as a significant symptom of thyroid autoimmunity.

  11. Impact of low dose prenatal ethanol exposure on glucose homeostasis in Sprague-Dawley rats aged up to eight months.

    PubMed

    Probyn, Megan E; Parsonson, Kylie R; Gårdebjer, Emelie M; Ward, Leigh C; Wlodek, Mary E; Anderson, Stephen T; Moritz, Karen M

    2013-01-01

    Excessive exposure to alcohol prenatally has a myriad of detrimental effects on the health and well-being of the offspring. It is unknown whether chronic low-moderate exposure of alcohol prenatally has similar and lasting effects on the adult offspring's health. Using our recently developed Sprague-Dawley rat model of 6% chronic prenatal ethanol exposure, this study aimed to determine if this modest level of exposure adversely affects glucose homeostasis in male and female offspring aged up to eight months. Plasma glucose concentrations were measured in late fetal and postnatal life. The pancreas of 30 day old offspring was analysed for β-cell mass. Glucose handling and insulin action was measured at four months using an intraperitoneal glucose tolerance test and insulin challenge, respectively. Body composition and metabolic gene expression were measured at eight months. Despite normoglycaemia in ethanol consuming dams, ethanol-exposed fetuses were hypoglycaemic at embryonic day 20. Ethanol-exposed offspring were normoglycaemic and normoinsulinaemic under basal fasting conditions and had normal pancreatic β-cell mass at postnatal day 30. However, during a glucose tolerance test, male ethanol-exposed offspring were hyperinsulinaemic with increased first phase insulin secretion. Female ethanol-exposed offspring displayed enhanced glucose clearance during an insulin challenge. Body composition and hepatic, muscle and adipose tissue metabolic gene expression levels at eight months were not altered by prenatal ethanol exposure. Low-moderate chronic prenatal ethanol exposure has subtle, sex specific effects on glucose homeostasis in the young adult rat. As aging is associated with glucose dysregulation, further studies will clarify the long lasting effects of prenatal ethanol exposure.

  12. Differential Response and Priming Dose Effect on the Proteome of Human Fibroblast and Stem Cells Induced by Exposure to Low Doses of Ionizing Radiation.

    PubMed

    Hauptmann, Monika; Haghdoost, Siamak; Gomolka, Maria; Sarioglu, Hakan; Ueffing, Marius; Dietz, Anne; Kulka, Ulrike; Unger, Kristian; Babini, Gabriele; Harms-Ringdahl, Mats; Ottolenghi, Andrea; Hornhardt, Sabine

    2016-03-01

    It has been suggested that a mechanistic understanding of the cellular responses to low dose and dose rate may be valuable in reducing some of the uncertainties involved in current risk estimates for cancer- and non-cancer-related radiation effects that are inherited in the linear no-threshold hypothesis. In this study, the effects of low-dose radiation on the proteome in both human fibroblasts and stem cells were investigated. Particular emphasis was placed on examining: 1. the dose-response relationships for the differential expression of proteins in the low-dose range (40-140 mGy) of low-linear energy transfer (LET) radiation; and 2. the effect on differential expression of proteins of a priming dose given prior to a challenge dose (adaptive response effects). These studies were performed on cultured human fibroblasts (VH10) and human adipose-derived stem cells (ADSC). The results from the VH10 cell experiments demonstrated that low-doses of low-LET radiation induced unique patterns of differentially expressed proteins for each dose investigated. In addition, a low priming radiation dose significantly changed the protein expression induced by the subsequent challenge exposure. In the ADSC the number of differentially expressed proteins was markedly less compared to VH10 cells, indicating that ADSC differ in their intrinsic response to low doses of radiation. The proteomic results are further discussed in terms of possible pathways influenced by low-dose irradiation.

  13. Hepatic mitochondrial alteration in CD1 mice associated with prenatal exposures to low doses of perfluorooctanoic acid (PFOA)

    PubMed Central

    Quist, Erin M.; Filgo, Adam J.; Cummings, Connie A.; Kissling, Grace E.; Hoenerhoff, Mark J.; Fenton, Suzanne E.

    2014-01-01

    Perfluorooctanoic acid (PFOA) is a perfluoroalkyl acid primarily used as an industrial surfactant. It persists in the environment and has been linked to potentially toxic and/or carcinogenic effects in animals and people. As a known activator of peroxisome proliferator-activated receptors (PPARs), PFOA exposure can induce defects in fatty acid oxidation, lipid transport, and inflammation. Here, pregnant CD-1 mice were orally gavaged with 0, 0.01, 0.1, 0.3 and 1 mg/kg of PFOA from gestation days (GD) 1 through 17. On postnatal day (PND) 21, histopathologic changes in the livers of offspring included hepatocellular hypertrophy and periportal inflammation that increased in severity by PND 91 in an apparent dose-dependent response. Transmission electron microscopy (TEM) of selected liver sections from PND 91 mice revealed PFOA-induced cellular damage and mitochondrial abnormalities with no evidence of peroxisome proliferation. Within hypertrophied hepatocytes, mitochondria were not only increased in number, but also exhibited altered morphologies suggestive of increased and/or uncontrolled fission and fusion reactions. These findings suggest that peroxisome proliferation is not a component of PFOA-induced hepatic toxicity in animals that are prenatally exposed to low doses of PFOA. PMID:25326589

  14. Evidence for Radiation Hormesis After In Vitro Exposure of Human Lymphocytes to Low Doses of Ionizing Radiation§

    PubMed Central

    Rithidech, Kanokporn Noy; Scott, Bobby R.

    2008-01-01

    Previous research has demonstrated that adding a very small gamma-ray dose to a small alpha radiation dose can completely suppress lung cancer induction by alpha radiation (a gamma-ray hormetic effect). Here we investigated the possibility of gamma-ray hormesis during low-dose neutron irradiation, since a small contribution to the total radiation dose from neutrons involves gamma rays. Using binucleated cells with micronuclei (micronucleated cells) among in vitro monoenergetic-neutron-irradiated human lymphocytes as a measure of residual damage, we investigated the influence of the small gamma-ray contribution to the dose on suppressing residual damage. We used residual damage data from previous experiments that involved neutrons with five different energies (0.22-, 0.44-, 1.5-, 5.9-, and 13.7-million electron volts [MeV]). Corresponding gamma-ray contributions to the dose were approximately 1%, 1%, 2%, 6%, and 6%, respectively. Total absorbed radiation doses were 0, 10, 50, and 100 mGy for each neutron source. We demonstrate for the first time a protective effect (reduced residual damage) of the small gamma-ray contribution to the neutron dose. Using similar data for exposure to gamma rays only, we also demonstrate a protective effect of 10 mGy (but not 50 or 100 mGy) related to reducing the frequency of micronucleated cells to below the spontaneous level. PMID:18846261

  15. Long-term exposures to low doses of titanium dioxide nanoparticles induce cell transformation, but not genotoxic damage in BEAS-2B cells.

    PubMed

    Vales, Gerard; Rubio, Laura; Marcos, Ricard

    2015-01-01

    There is a great interest in a better knowledge of the health effects caused by nanomaterials exposures and, in particular to those induced by titanium dioxide nanoparticles (nano-TiO2) due to its high use and increasing presence in the environment. To add new information on its potential genotoxic/carcinogenic risk, we have carried out experiments using chronic exposures (up to 4 weeks), low doses, and the BEAS-2B cell line that, as a human bronchial epithelium cells, can be considered a good cell target. Cell uptake has been assessed by transmission electron microscopy (TEM) and flow cytometry (FC); genotoxicity was evaluated using the comet and the micronucleus (MN) assays; and cell-transforming ability was evaluated using the soft-agar assay to detect anchorage-independent cell growth. Results show an important cell uptake at all the tested doses and sampling times used (except for 1 µg/mL and 24-h exposure). Nevertheless, no genotoxic effects were observed in the comet and in the MN assays. This lack of genotoxic effect agrees with the FC results showing no induction of intracellular reactive oxygen species (ROS), the data from the comet assay with formamidopyrimidine DNA glycosylase (FPG) enzyme showing no induction of oxidized bases, and the lack of induction of expression of heme-oxygenase (HO-1) gene both at the RNA and protein level. On the contrary, significant increases in the number of clones growing in an anchorage-independent way were observed. This study would indicate a potential carcinogenic risk associated to nano-TiO2 exposure, not mediated by a genotoxic mechanism.

  16. Managing chronic whiplash associated pain with a combination of low-dose opioid (remifentanil) and NMDA-antagonist (ketamine).

    PubMed

    Lemming, Dag; Sörensen, Jan; Graven-Nielsen, Thomas; Lauber, Rolf; Arendt-Nielsen, Lars; Gerdle, Björn

    2007-10-01

    The aim was to investigate the efficacy of a combination of low-dose remifentanil (REMI) and ketamine (KET) compared to the single drugs and placebo (P) on whiplash associated pain (WAD) in a double-blind, randomized, placebo-controlled, cross-over study. Twenty patients with chronic (>1 year) WAD were included. Four different drug combinations were tested in four sessions: placebo/placebo (P/P), placebo/remifentanil (P/REMI), ketamine/placebo (KET/P) and ketamine/remifentanil (KET/REMI). Target concentrations were 1 and 2ng/ml (stepwise) for remifentanil and 100ng/ml for ketamine. Habitual pain intensity was assessed on a visual analogue scale (VAS). Experimental pain was assessed with electrical stimulation (single and repeated) of tibialis anterior (TA) muscle, pressure pain algometry applied over infraspinatus (IS) and TA muscles and VAS scores after intramuscular hypertonic saline infusion in TA. KET/REMI significantly reduced habitual pain. KET/REMI infused at low REMI target concentration (1ng/ml) significantly elevated electrical intramuscular pain thresholds (single and repeated). Pain thresholds to electrical stimulation were similarly increased by both P/REMI and KET/REMI at 2ng/ml target concentration. Pressure pain thresholds were increased by both KET/REMI and P/REMI. VAS-scores after intramuscular saline were also similarly decreased by both REMI combinations. Seven out of 20 subjects were non-responders (<50% pain relief). No correlation was found between effects on spontaneous pain and experimental pain. KET/REMI showed an analgesic effect on habitual pain. Experimental pain was attenuated by both combinations containing the opioid, however, KET seemed to enhance the effect of REMI on electrical pain thresholds when a low REMI target concentration was used.

  17. Low-dose BPA exposure alters the mesenchymal and epithelial transcriptomes of the mouse fetal mammary gland.

    PubMed

    Wadia, Perinaaz R; Cabaton, Nicolas J; Borrero, Michael D; Rubin, Beverly S; Sonnenschein, Carlos; Shioda, Toshi; Soto, Ana M

    2013-01-01

    Exposure of rodent fetuses to low doses of the endocrine disruptor bisphenol A (BPA) causes subtle morphological changes in the prenatal mammary gland and results in pre-cancerous and cancerous lesions during adulthood. To examine whether the BPA-induced morphological alterations of the fetal mouse mammary glands are a) associated with changes in mRNA expression reflecting estrogenic actions and/or b) dependent on the estrogen receptor α (ERα), we compared the transcriptomal effects of BPA and the steroidal estrogen ethinylestradiol (EE2) on fetal mammary tissues of wild type and ERα knock-out mice. Mammary glands from fetuses of dams exposed to vehicle, 250 ng BPA/kg BW/d or 10 ng EE2/kg BW/d from embryonic day (E) 8 were harvested at E19. Transcriptomal analyses on the ductal epithelium and periductal stroma revealed altered expression of genes involved in the focal adhesion and adipogenesis pathways in the BPA-exposed stroma while genes regulating the apoptosis pathway changed their expression in the BPA-exposed epithelium. These changes in gene expression correlated with previously reported histological changes in matrix organization, adipogenesis, and lumen formation resulting in enhanced maturation of the fat-pad and delayed lumen formation in the epithelium of BPA-exposed fetal mammary glands. Overall similarities in the transcriptomal effects of BPA and EE2 were more pronounced in the epithelium, than in the stroma. In addition, the effects of BPA and EE2 on the expression of various genes involved in mammary stromal-epithelial interactions were suppressed in the absence of ERα. These observations support a model whereby BPA and EE2 act directly on the stroma, which expresses ERα, ERβ and GPR30 in fetal mammary glands, and that the stroma, in turn, affects gene expression in the epithelium, where ERα and ERβ are below the level of detection at this stage of development.

  18. Exposure to Low-Dose Bisphenol A Impairs Meiosis in the Rat Seminiferous Tubule Culture Model: A Physiotoxicogenomic Approach

    PubMed Central

    Ali, Sazan; Steinmetz, Gérard; Montillet, Guillaume; Perrard, Marie-Hélène; Loundou, Anderson; Durand, Philippe

    2014-01-01

    Background Bisphenol A (BPA) is one of the most widespread chemicals in the world and is suspected of being responsible for male reproductive impairments. Nevertheless, its molecular mode of action on spermatogenesis is unclear. This work combines physiology and toxicogenomics to identify mechanisms by which BPA affects the timing of meiosis and induces germ-cell abnormalities. Methods We used a rat seminiferous tubule culture model mimicking the in vivo adult rat situation. BPA (1 nM and 10 nM) was added to the culture medium. Transcriptomic and meiotic studies were performed on the same cultures at the same exposure times (days 8, 14, and 21). Transcriptomics was performed using pangenomic rat microarrays. Immunocytochemistry was conducted with an anti-SCP3 antibody. Results The gene expression analysis showed that the total number of differentially expressed transcripts was time but not dose dependent. We focused on 120 genes directly involved in the first meiotic prophase, sustaining immunocytochemistry. Sixty-two genes were directly involved in pairing and recombination, some of them with high fold changes. Immunocytochemistry indicated alteration of meiotic progression in the presence of BPA, with increased leptotene and decreased diplotene spermatocyte percentages and partial meiotic arrest at the pachytene checkpoint. Morphological abnormalities were observed at all stages of the meiotic prophase. The prevalent abnormalities were total asynapsis and apoptosis. Transcriptomic analysis sustained immunocytological observations. Conclusion We showed that low doses of BPA alter numerous genes expression, especially those involved in the reproductive system, and severely impair crucial events of the meiotic prophase leading to partial arrest of meiosis in rat seminiferous tubule cultures. PMID:25181051

  19. Exposure to low doses (20 cGy) of Hze results in spatial memory impairment in rats.

    NASA Astrophysics Data System (ADS)

    Britten, Richard; Johnson, Angela; Davis, Leslie; Green-Mitchell, Shamina; Chabriol, Olivia; Sanford, Larry; Drake, Richard

    Escape hole over the 5 days of training. There was a suggestion that there may be some recovery in spatial memory performance by 6 months post exposure. Our preliminary data on Hze-induced exposure on sleep, suggests that within 4 weeks of Hze exposure there is a change in sleep latency, raising the possibility that some of the observed decline in neurocognitive performance may arise due to perturbed sleep patterns. We have used MALDI-IMS to determine the Hze-induced changes in the neuroproteome with a high degree of spatial resolution. Using this technique we have found that a peptide with a m/z of 14207 is differentially elevated in the Thalamus of irradiated rats that have good spatial memory. MALDI-MSI thus appears to be a powerful tool that can be used to identify radiation-induced changes in ancillary brain regions that correlate with neurocognitive impairment, and will ultimately be useful for identifying proteins whose expression changes in parallel with Hze-induced neurocognitive deficits. SUMMARY. We have found that mission-relevant Hze doses (20 cGy) lead to significant neu-rocognitive defects. Clearly such low doses of Hze are unlikely to lead to a significant loss of neuronal cells, and have not been reported to lead to gliosis etc. We take this as further evi-dence that neurocognitive impairment is not solely dependent upon radiation-induced changes in neurogenesis and neuronal cell death. FUNDING: The authors gratefully acknowledge grant support from NASA (NNJ06HD89D).

  20. Effects of six priority controlled phthalate esters with long-term low-dose integrated exposure on male reproductive toxicity in rats.

    PubMed

    Gao, Hai-Tao; Xu, Run; Cao, Wei-Xin; Qian, Liang-Liang; Wang, Min; Lu, Lingeng; Xu, Qian; Yu, Shu-Qin

    2017-03-01

    Human beings are inevitably exposed to ubiquitous phthalate esters (PEs) surroundings. The purposes of this study were to investigate the effects of long-term low-dose exposure to the mixture of six priority controlled phthalate esters (MIXPs): dimethyl phthalate (DMP), diethyl phthalate (DEP), di(n-butyl) phthalate (DBP), butyl benzyl phthalate (BBP), di(2-ethyhexyl) phthalate (DEHP) and di-n-octyl phthalate (DNOP), on male rat reproductive system and further to explore the underlying mechanisms of the reproductive toxicity. The male rats were orally exposed to either sodium carboxymethyl cellulose as controls or MIXPs at three different low-doses by gavage for 15 weeks. Testosterone and luteinizing hormone (LH) in serum were analyzed, and pathological examinations were performed for toxicity evaluation. Steroidogenic proteins (StAR, P450scc, CYP17A1 and 17β-HSD), cell cycle and apoptosis-related proteins (p53, Chk1, Cdc2, CDK6, Bcl-2 and Bax) were measured for mechanisms exploration. MIXPs with long-term low-dose exposure could cause male reproductive toxicity to the rats, including the decrease of both serum and testicular testosterone, and the constructional damage of testis. These effects were related to down-regulated steroidogenic proteins, arresting cell cycle progression and promoting apoptosis in rat testicular cells. The results indicate that MIXPs with long-term low-dose exposure may pose male reproductive toxicity in human.

  1. Long-Term Effects of Low-Dose Spironolactone on Chronic Dialysis Patients: A Randomized Placebo-Controlled Study.

    PubMed

    Lin, ChongTing; Zhang, Qing; Zhang, HuiFang; Lin, AiXia

    2016-02-01

    The purpose of this 2-year multicentric, randomized, placebo-controlled study was to evaluate the long-term effects and adverse effects of spironolactone on chronic dialysis patients. A total of 253 non-heart failure dialysis patients with end-stage renal disease were randomly assigned to 2-year treatment with spironolactone (25 mg once daily, n=125) or a matching placebo (n=128) as add-on therapy. The primary outcome was a composite of death from cardiocerebrovascular (CCV) events, aborted cardiac arrest, and sudden cardiac death, and the secondary outcome was death from all causes. Other CCV-related indexes such as left ventricular mass index, left ventricular ejection fraction, heart rate variability, vascular endothelial function, and blood pressure-lowering effect were analyzed for patients who completed the whole 2-year follow-up study. Sociodemographic, clinical, and relevant laboratory data were also collected. During the 2-year follow-up, the primary outcome occurred less frequently in the spironolactone group vs the control group (7.2% vs 18.0%; adjusted hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.26-0.78). Death from CCV events occurred in 4.0% of patients in the spironolactone group and in 11.7% of patients in the control group. Neither aborted cardiac arrest nor sudden cardiac death was significantly reduced by spironolactone treatment. The secondary outcome occurred less frequently in the spironolactone group vs the control group (9.6% vs 19.5%; adjusted HR, 0.52; 95% CI, 0.29-0.94). Other CCV-related indexes except for heart rate variability were significantly improved. This study demonstrates that use of low-dose spironolactone in non-heart failure dialysis patients can effectively reduce the risks of both CCV morbidity and mortality with few side effects. Moreover, the beneficial effect was mediated through improving the endothelial function or reducing left ventricular size independent of blood pressure changes, rather than mediation

  2. Non-Target Effect for Chromosome Aberrations in Human Lymphocytes and Fibroblasts After Exposure to Very Low Doses of High LET Radiation

    NASA Technical Reports Server (NTRS)

    Hada, Megumi; George, Kerry A.; Cucinotta, F. A.

    2011-01-01

    The relationship between biological effects and low doses of absorbed radiation is still uncertain, especially for high LET radiation exposure. Estimates of risks from low-dose and low-dose-rates are often extrapolated using data from Japanese atomic bomb survivor with either linear or linear quadratic models of fit. In this study, chromosome aberrations were measured in human peripheral blood lymphocytes and normal skin fibroblasts cells after exposure to very low dose (.01 - 0.2 Gy) of 170 MeV/u Si-28-ions or 600 MeV/u Fe-56-ions. Chromosomes were analyzed using the whole chromosome fluorescence in situ hybridization (FISH) technique during the first cell division after irradiation, and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving >2 breaks in 2 or more chromosomes). The curves for doses above 0.1 Gy were more than one ion traverses a cell showed linear dose responses. However, for doses less than 0.1 Gy, Si-28-ions showed no dose response, suggesting a non-targeted effect when less than one ion traversal occurs. Additional findings for Fe-56 will be discussed.

  3. Sex-specific enhanced behavioral toxicity induced by maternal exposure to a mixture of low dose endocrine-disrupting chemicals.

    PubMed

    Sobolewski, Marissa; Conrad, Katherine; Allen, Joshua L; Weston, Hiromi; Martin, Kyle; Lawrence, B Paige; Cory-Slechta, Deborah A

    2014-12-01

    Humans are increasingly and consistently exposed to a variety of endocrine disrupting chemicals (EDCs), chemicals that have been linked to neurobehavioral disorders such as ADHD and autism. Many of such EDCs have been shown to adversely influence brain mesocorticolimbic systems raising the potential for cumulative toxicity. As such, understanding the effects of developmental exposure to mixtures of EDCs is critical to public health protection. Consequently, this study compared the effects of a mixture of four EDCs to their effects alone to examine potential for enhanced toxicity, using behavioral domains and paradigms known to be mediated by mesocorticolimbic circuits (fixed interval (FI) schedule controlled behavior, novel object recognition memory and locomotor activity) in offspring of pregnant mice that had been exposed to vehicle or relatively low doses of four EDCs, atrazine (ATR - 10mg/kg), perfluorooctanoic acid (PFOA - 0.1mg/kg), bisphenol-A (BPA - 50 μg/kg), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD - 0.25 μg/kg) alone or combined in a mixture (MIX), from gestational day 7 until weaning. EDC-treated males maintained significantly higher horizontal activity levels across three testing sessions, indicative of delayed habituation, whereas no effects were found in females. Statistically significant effects of MIX were seen in males, but not females, in the form of increased FI response rates, in contrast to reductions in response rate with ATR, BPA and TCDD, and reduced short term memory in the novel object recognition paradigm. MIX also reversed the typically lower neophobia levels of males compared to females. With respect to individual EDCs, TCDD produced notable increases in FI response rates in females, and PFOA significantly increased ambulatory locomotor activity in males. Collectively, these findings show the potential for enhanced behavioral effects of EDC mixtures in males and underscore the need for animal studies to fully investigate mixtures

  4. Exposure to low doses of (137)cesium and nicotine during postnatal development modifies anxiety levels, learning, and spatial memory performance in mice.

    PubMed

    Bellés, Montserrat; Heredia, Luis; Serra, Noemí; Domingo, José L; Linares, Victoria

    2016-11-01

    Radiation therapy is a major cause of long-term complications observed in survivors of pediatric brain tumors. However, the effects of low-doses of ionizing radiation (IR) to the brain are less studied. On the other hand, tobacco is one of the most heavily abused drugs in the world. Tobacco is not only a health concern for adults. It has also shown to exert deleterious effects on fetuses, newborns, children and adolescents. Exposure to nicotine (Nic) from smoking may potentiate the toxic effects induced by IR on brain development. In this study, we evaluated in mice the cognitive effects of concomitant exposure to low doses of internal radiation ((137)Cs) and Nic during neonatal brain development. On postnatal day 10 (PND10), two groups of C57BL/6J mice were subcutaneously exposed to 137-Cesium ((137)Cs) (4000 and 8000 Bq/kg) and/or Nic (100 μg/ml). At the age of two months, neurobehavior of mice was assessed. Results showed that exposure to IR-alone or in combination with Nic-increased the anxiety-like of the animals without changing the activity levels. Moreover, exposure to IR impaired learning and spatial memory. However, Nic administration was able to reverse this effect, but only at the low dose of (137)Cs.

  5. Low-dose penicillin exposure in early life decreases Th17 and the susceptibility to DSS colitis in mice through gut microbiota modification.

    PubMed

    Jin, Shuang; Zhao, Di; Cai, Chenwen; Song, Dongjuan; Shen, Jun; Xu, Antao; Qiao, Yuqi; Ran, Zhihua; Zheng, Qing

    2017-03-08

    Antibiotic exposure in early life can lead to a significant change of the gut microbiota and may contribute to later onset of inflammatory bowel disease (IBD). However, the relationship between early-life antibiotic treatment and IBD is ambiguous, according to contradicting results of epidemiologic studies. In the present study, we demonstrated that low-dose penicillin pre-treatment had a unique protective effect against mouse colitis induced by dextran sodium sulfate (DSS). Low-dose penicillin also suppressed the expression of pro-inflammatory cytokine IL-17 in various intestinal tissues, and decreased the amount of Th17 cells in small-intestine lamina propria. Neither metronidazole nor enrofloxacin had a similar effect. We further confirmed that low-dose penicillin could cause specific changes of the gut microbiota, especially the eradication of segmented filamentous bacteria (SFB). Mice without SFB inoculation showed no disparity when treated with penicillin or water. Taken together, the results showed that low-dose penicillin can achieve a highly specific manipulation of sensitive bacteria and interfere with development of intestinal immune system in early life. The study may further indicate the possibility of achieving a favorable immune state among a certain group of patients with IBD, or other autoimmune diseases, by fine-tuning the gut microbiota.

  6. Low-dose penicillin exposure in early life decreases Th17 and the susceptibility to DSS colitis in mice through gut microbiota modification

    PubMed Central

    Jin, Shuang; Zhao, Di; Cai, Chenwen; Song, Dongjuan; Shen, Jun; Xu, Antao; Qiao, Yuqi; Ran, Zhihua; Zheng, Qing

    2017-01-01

    Antibiotic exposure in early life can lead to a significant change of the gut microbiota and may contribute to later onset of inflammatory bowel disease (IBD). However, the relationship between early-life antibiotic treatment and IBD is ambiguous, according to contradicting results of epidemiologic studies. In the present study, we demonstrated that low-dose penicillin pre-treatment had a unique protective effect against mouse colitis induced by dextran sodium sulfate (DSS). Low-dose penicillin also suppressed the expression of pro-inflammatory cytokine IL-17 in various intestinal tissues, and decreased the amount of Th17 cells in small-intestine lamina propria. Neither metronidazole nor enrofloxacin had a similar effect. We further confirmed that low-dose penicillin could cause specific changes of the gut microbiota, especially the eradication of segmented filamentous bacteria (SFB). Mice without SFB inoculation showed no disparity when treated with penicillin or water. Taken together, the results showed that low-dose penicillin can achieve a highly specific manipulation of sensitive bacteria and interfere with development of intestinal immune system in early life. The study may further indicate the possibility of achieving a favorable immune state among a certain group of patients with IBD, or other autoimmune diseases, by fine-tuning the gut microbiota. PMID:28272549

  7. Axon-reflex cutaneous vasodilatation is impaired in type 2 diabetic patients receiving chronic low-dose aspirin.

    PubMed

    Rousseau, Pascal; Mahé, Guillaume; Fromy, Bérengère; Ducluzeau, Pierre-Henri; Saumet, Jean-Louis; Abraham, Pierre

    2009-09-01

    Low-dose aspirin is largely but non-homogeneously used in primary prevention of cardiovascular complication in type-2 diabetic patients. We hypothesised that low-dose aspirin could interfere with the cutaneous neurovascular responses in type-2 diabetic patients. Galvanic current-induced vasodilatation (CIV) is an original non-noxious integrative model of neurovascular interaction and is impaired under low-dose aspirin in healthy subjects. Twenty type-2 diabetic patients (ten not receiving aspirin: D(-NA) and ten regularly receiving low-dose aspirin, while other macrovascular, microvascular and clinical-sensitivity investigations show no significant difference. Potential clinical markers for the impairment of the neurovascular interaction are still required in diabetes. Correlation of the CIV response with the risk of cutaneous complications in diabetic patients remains to be tested.

  8. Long-term low dose dietary resveratrol supplement reduces cardiovascular structural and functional deterioration in chronic heart failure in rats.

    PubMed

    Ahmet, Ismayil; Tae, Hyun-Jin; Lakatta, Edward G; Talan, Mark

    2017-03-01

    A short-term exposure to resveratrol at high dosages exerts a remarkable cardioprotective effect. Whether a long-term exposure to resveratrol at low dosages that can be obtained through consumption of a resveratrol-rich diet is beneficial to heart diseases is unknown. We tested the effects of a resveratrol-enriched diet on cardiovascular remodeling of chronic heart failure (CHF) in rats resulting from permanent ligation of left coronary artery. Two weeks after surgery, rats were started on either a resveratrol-enriched (R; 5 mg/kg per day; n = 23) or normal (Control; n = 23) diet for next 10 months. Serial echocardiography in Control showed a significant decline in LV ejection fraction, increases in LV end-systolic and end-diastolic volumes, and expansion in myocardial infarct from pre-treatment values. In R, compared with Control, there were substantial improvements in those parameters. End-point LV pressure-volume loop analysis showed a significantly improved LV systolic function and AV-coupling, an index of energy transfer efficacy between the heart and aortic tree, in R compared with Control (p < 0.05). Aortic pulse wave velocity, a measure of arterial stiffness, was significantly lower in R (389 ± 15 cm/s; p < 0.05) compared with Control (489 ± 38 cm/s). These results demonstrated that long-term dietary resveratrol supplement reduces cardiovascular structural and functional deterioration in CHF.

  9. Elevated mu-opioid receptor expression in the nucleus of the solitary tract accompanies attenuated withdrawal signs after chronic low dose naltrexone in opiate-dependent rats.

    PubMed

    Van Bockstaele, E J; Rudoy, C; Mannelli, P; Oropeza, V; Qian, Y

    2006-02-15

    We previously described a decrease in withdrawal behaviors in opiate-dependent rats that were chronically treated with very low doses of naltrexone in their drinking water. Attenuated expression of withdrawal behaviors correlated with decreased c-Fos expression and intracellular signal transduction elements [protein kinase A regulatory subunit II (PKA) and phosphorylated cAMP response element binding protein (pCREB)] in brainstem noradrenergic nuclei. In this study, to determine whether similar cellular changes occurred in forebrain nuclei associated with drug reward, expressions of PKA and pCREB were analyzed in the ventral tegmental area, frontal cortex, striatum, and amygdala of opiate-treated rats that received low doses of naltrexone in their drinking water. No significant difference in PKA or pCREB was detected in these regions following drug treatment. To examine further the cellular mechanisms in noradrenergic nuclei that could underlie attenuated withdrawal behaviors following low dose naltrexone administration, the nucleus of the solitary tract (NTS) and locus coeruleus (LC) were examined for opioid receptor (OR) protein expression. Results showed a significant increase in muOR expression in the NTS of morphine-dependent rats that received low doses of naltrexone in their drinking water, and increases in muOR expression were also found to be dose dependent. Protein expression of muOR in the LC and deltaOR in either brain region remained unchanged. In conclusion, our previously reported decreases in c-Fos and PKA expression in the NTS following pretreatment with low doses of naltrexone may be partially explained by a greater inhibition of NTS neurons resulting from increased muOR expression in this region.

  10. Modulation of DNA polymerase beta-dependent base excision repair in cultured human cells after low dose exposure to arsenite

    SciTech Connect

    Sykora, Peter; Snow, Elizabeth T.

    2008-05-01

    Base excision repair (BER) is crucial for development and for the repair of endogenous DNA damage. However, unlike nucleotide excision repair, the regulation of BER is not well understood. Arsenic, a well-established human carcinogen, is known to produce oxidative DNA damage, which is repaired primarily by BER, whilst high doses of arsenic can also inhibit DNA repair. However, the mechanism of repair inhibition by arsenic and the steps inhibited are not well defined. To address this question we have investigated the regulation of DNA polymerase {beta} (Pol {beta}) and AP endonuclease (APE1), in response to low, physiologically relevant doses of arsenic. GM847 lung fibroblasts and HaCaT keratinocytes were exposed to sodium arsenite, As(III), and mRNA, protein levels and BER activity were assessed. Both Pol {beta} and APE1 mRNA exhibited significant dose-dependant down regulation at doses of As(III) above 1 {mu}M. However, at lower doses Pol {beta} mRNA and protein levels, and consequently, BER activity were significantly increased. In contrast, APE1 protein levels were only marginally increased by low doses of As(III) and there was no correlation between APE1 and overall BER activity. Enzyme supplementation of nuclear extracts confirmed that Pol {beta} was rate limiting. These changes in BER correlated with overall protection against sunlight UV-induced toxicity at low doses of As(III) and produced synergistic toxicity at high doses. The results provide evidence that changes in BER due to low doses of arsenic could contribute to a non-linear, threshold dose response for arsenic carcinogenesis.

  11. Expression of genes involved in mouse lung cell differentiation/regulation after acute exposure to photons and protons with or without low-dose preirradiation.

    PubMed

    Tian, Jian; Zhao, WeiLing; Tian, Sisi; Slater, James M; Deng, Zhiyong; Gridley, Daila S

    2011-11-01

    The goal of this study was to compare the effects of acute 2 Gy irradiation with photons (0.8 Gy/min) or protons (0.9 Gy/min), both with and without pre-exposure to low-dose/low-dose-rate γ rays (0.01 Gy at 0.03 cGy/h), on 84 genes involved in stem cell differentiation or regulation in mouse lungs on days 21 and 56. Genes with a ≥1.5-fold difference in expression and P < 0.05 compared to 0 Gy controls are emphasized. Two proteins specific for lung stem cells/progenitors responsible for local tissue repair were also compared. Overall, striking differences were present between protons and photons in modulating the genes. More genes were affected by protons than by photons (22 compared to 2 and 6 compared to 2 on day 21 and day 56, respectively) compared to 0 Gy. Preirradiation with low-dose-rate γ rays enhanced the acute photon-induced gene modulation on day 21 (11 compared to 2), and all 11 genes were significantly downregulated on day 56. On day 21, seven genes (aldh2, bmp2, cdc2a, col1a1, dll1, foxa2 and notch1) were upregulated in response to most of the radiation regimens. Immunoreactivity of Clara cell secretory protein was enhanced by all radiation regimens. The number of alveolar type 2 cells positive for prosurfactant protein C in irradiated groups was higher on day 56 (12.4-14.6 cells/100) than on day 21 (8.5-11.2 cells/100) (P < 0.05). Taken together, these results showed that acute photons and protons induced different gene expression profiles in the lungs and that pre-exposure to low-dose-rate γ rays sometimes had modulatory effects. In addition, proteins associated with lung-specific stem cells/progenitors were highly sensitive to radiation.

  12. Subcutaneous injections of low doses of humanized anti-CD20 veltuzumab: a phase I study in chronic lymphocytic leukemia.

    PubMed

    Kalaycio, Matt E; George Negrea, O; Allen, Steven L; Rai, Kanti R; Abbasi, Rashid M; Horne, Heather; Wegener, William A; Goldenberg, David M

    2016-01-01

    To evaluate the potential of subcutaneous (SC) injections with anti-CD20 antibody veltuzumab in chronic lymphocytic leukemia (CLL), 21 patients received 80, 160, or 320 mg injections every 2 weeks × 4 doses (n = 11) or 160 or 320 mg twice-weekly × 16 doses (n = 10). Treatment was well tolerated with only occasional, mild-moderate, transient injection reactions. Lymphocytosis decreased in all patients (maximum decrease, 5-91%), with 12 patients obtaining >50% decreases. Of 14 patients with lymphadenopathy on CT imaging, 5 (36%) achieved 14-61% reductions (sum of perpendicular diameters). By NCI-WG criteria, two patients achieved partial responses (10%). SC veltuzumab appeared active in all dose groups, with no obvious exposure-response relationship, despite cumulative doses ranging from 320-5120 mg. Overall median progression-free survival was 7.7 months; three patients remained progression-free >1 year (2 ongoing at 2-year study completion). These data suggest further studies of SC veltuzumab in CLL are warranted.

  13. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: focus on the cancer hallmark of tumor angiogenesis.

    PubMed

    Hu, Zhiwei; Brooks, Samira A; Dormoy, Valérian; Hsu, Chia-Wen; Hsu, Hsue-Yin; Lin, Liang-Tzung; Massfelder, Thierry; Rathmell, W Kimryn; Xia, Menghang; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Amedei, Amedeo; Brown, Dustin G; Prudhomme, Kalan R; Colacci, Annamaria; Hamid, Roslida A; Mondello, Chiara; Raju, Jayadev; Ryan, Elizabeth P; Woodrick, Jordan; Scovassi, A Ivana; Singh, Neetu; Vaccari, Monica; Roy, Rabindra; Forte, Stefano; Memeo, Lorenzo; Salem, Hosni K; Lowe, Leroy; Jensen, Lasse; Bisson, William H; Kleinstreuer, Nicole

    2015-06-01

    One of the important 'hallmarks' of cancer is angiogenesis, which is the process of formation of new blood vessels that are necessary for tumor expansion, invasion and metastasis. Under normal physiological conditions, angiogenesis is well balanced and controlled by endogenous proangiogenic factors and antiangiogenic factors. However, factors produced by cancer cells, cancer stem cells and other cell types in the tumor stroma can disrupt the balance so that the tumor microenvironment favors tumor angiogenesis. These factors include vascular endothelial growth factor, endothelial tissue factor and other membrane bound receptors that mediate multiple intracellular signaling pathways that contribute to tumor angiogenesis. Though environmental exposures to certain chemicals have been found to initiate and promote tumor development, the role of these exposures (particularly to low doses of multiple substances), is largely unknown in relation to tumor angiogenesis. This review summarizes the evidence of the role of environmental chemical bioactivity and exposure in tumor angiogenesis and carcinogenesis. We identify a number of ubiquitous (prototypical) chemicals with disruptive potential that may warrant further investigation given their selectivity for high-throughput screening assay targets associated with proangiogenic pathways. We also consider the cross-hallmark relationships of a number of important angiogenic pathway targets with other cancer hallmarks and we make recommendations for future research. Understanding of the role of low-dose exposure of chemicals with disruptive potential could help us refine our approach to cancer risk assessment, and may ultimately aid in preventing cancer by reducing or eliminating exposures to synergistic mixtures of chemicals with carcinogenic potential.

  14. Cell Type-dependent Gene Transcription Profile in Three Dimensional Human Skin Tissue Model Exposed to Low Doses of Ionizing Radiation: Implications for Medical Exposures

    SciTech Connect

    Freiin von Neubeck, Claere H.; Shankaran, Harish; Karin, Norman J.; Kauer, Paula M.; Chrisler, William B.; Wang, Xihai; Robinson, Robert J.; Waters, Katrina M.; Tilton, Susan C.; Sowa, Marianne B.

    2012-04-17

    The concern over possible health risks from exposures to low doses of ionizing radiation has been driven largely by the increase in medical exposures, the routine implementation of X-ray backscatter devices for airport security screening, and, most recently, the nuclear incident in Japan. Due to a paucity of direct epidemiological data at very low doses, cancer risk must be estimated from high dose exposure scenarios. However, there is increasing evidence that low and high dose exposures result in different signaling events and may have different mechanisms of cancer induction. We have examined the radiation induced temporal response of an in vitro three dimensional (3D) human skin tissue model using microarray-based transcriptional profiling. Our data shows that exposure to 100 mGy of X-rays is sufficient to affect gene transcription. Cell type specific analysis showed significant changes in gene expression with the levels of > 1400 genes altered in the dermis and > 400 genes regulated in the epidermis. The two cell types rarely exhibited overlapping responses at the mRNA level. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) measurements validated the microarray data in both regulation direction and value. Key pathways identified relate to cell cycle regulation, immune responses, hypoxia, reactive oxygen signaling, and DNA damage repair. We discuss in particular the role of proliferation and emphasizing how the disregulation of cellular signaling in normal tissue may impact progression towards radiation induced secondary diseases.

  15. p53-Dependent Senescence in Mesenchymal Stem Cells under Chronic Normoxia Is Potentiated by Low-Dose γ-Irradiation.

    PubMed

    Höfig, Ines; Ingawale, Yashodhara; Atkinson, Michael J; Hertlein, Heidi; Nelson, Peter J; Rosemann, Michael

    2016-01-01

    Mesenchymal stem cells (MSCs) are a source of adult multipotent cells important in tissue regeneration. Murine MSCs are known to proliferate poorly in vitro under normoxia. The aim of this study is to analyze the interaction of nonphysiological high oxygen and low-dose γ-irradiation onto growth, senescence, and DNA damage. Tri-potent bone marrow-derived MSCs from p53 wildtype and p53-/- mice were cultured under either 21% or 2% O2. Long-term observations revealed a decreasing ability of wildtype mMSCs to proliferate and form colonies under extended culture in normoxia. This was accompanied by increased senescence under normoxia but not associated with telomere shortening. After low-dose γ-irradiation, the normoxic wildtype cells further increased the level of senescence. The number of radiation-induced γH2AX DNA repair foci was higher in mMSCs kept under normoxia but not in p53-/- cells. P53-deficient MSCs additionally showed higher clonogeneity, lower senescence levels, and fewer γH2AX repair foci per cell as compared to their p53 wildtype counterparts irrespective of oxygen levels. These results reveal that oxygen levels together with γ-irradiation and p53 status are interconnected factors modulating growth capacity of BM MSCs in long-term culture. These efforts help to better understand and optimize handling of MSCs prior to their therapeutic use.

  16. p53-Dependent Senescence in Mesenchymal Stem Cells under Chronic Normoxia Is Potentiated by Low-Dose γ-Irradiation

    PubMed Central

    Ingawale, Yashodhara; Hertlein, Heidi; Nelson, Peter J.

    2016-01-01

    Mesenchymal stem cells (MSCs) are a source of adult multipotent cells important in tissue regeneration. Murine MSCs are known to proliferate poorly in vitro under normoxia. The aim of this study is to analyze the interaction of nonphysiological high oxygen and low-dose γ-irradiation onto growth, senescence, and DNA damage. Tri-potent bone marrow-derived MSCs from p53 wildtype and p53−/− mice were cultured under either 21% or 2% O2. Long-term observations revealed a decreasing ability of wildtype mMSCs to proliferate and form colonies under extended culture in normoxia. This was accompanied by increased senescence under normoxia but not associated with telomere shortening. After low-dose γ-irradiation, the normoxic wildtype cells further increased the level of senescence. The number of radiation-induced γH2AX DNA repair foci was higher in mMSCs kept under normoxia but not in p53−/− cells. P53-deficient MSCs additionally showed higher clonogeneity, lower senescence levels, and fewer γH2AX repair foci per cell as compared to their p53 wildtype counterparts irrespective of oxygen levels. These results reveal that oxygen levels together with γ-irradiation and p53 status are interconnected factors modulating growth capacity of BM MSCs in long-term culture. These efforts help to better understand and optimize handling of MSCs prior to their therapeutic use. PMID:26788069

  17. [Genomic instability after exposure to radiation at low doses (in the 10-kilometer zone of the accident at the Chernobyl Atomic Electric Power Station and under laboratory conditions)].

    PubMed

    Pelevina, I I; Gotlib, V Ia; Kudriashova, O V; Serebrianyĭ, A M; Afanas'ev, G G

    1996-01-01

    The results of series investigations of late effects after Chernobyl accident are discussed. Genomic instability induced by chronic irradiation of cultural cells in Chernobyl zone and in laboratory conditions have been studied. It was shown that low level prolonged irradiation result in increase of frequency of cells with micronuclei, giant cells, enhancement of radiosensitivity in descendents of early irradiated cells. Chronic low doses irradiation doesn't induce the adaptive response. Comparative investigation of adaptive response in blood lymphocytes of people (adults and children) living in Moscow and in regions polluted with radionuclides (5-40 ci/km2) after Chernobyl disaster have been conducted. In population from contaminated areas the frequency of individuals with definite adaptive response is decreased and there are individuals with increasing radiosensitivity after irradiation in conditioned dose. Chronic irradiation during living on contaminated areas don't induce the adaptive response.

  18. Low-dose and combined effects of oral exposure to bisphenol A and diethylstilbestrol on the male reproductive system in adult Sprague-Dawley rats.

    PubMed

    Jiang, Xiao; Chen, Hong-Qiang; Cui, Zhi-Hong; Yin, Li; Zhang, Wen-Long; Liu, Wen-Bin; Han, Fei; Ao, Lin; Cao, Jia; Liu, Jin-Yi

    2016-04-01

    Study of the joint action of xenobiotics is important to fully explore their toxicity and complete risk analysis. In this study, we investigated the effects of low-dose and combined exposure of bisphenol A (BPA) and diethylstilbestrol (DES) on the reproductive system in adult male rats. The results showed that the sperm motility decreased in the BPA/DES and combined groups. Sperm deformity ratios and histological lesions of the testes were significantly higher and more significant, respectively, in the combined group compared with the single treated groups. No dose-effect relationship or significant additive effect on serum hormone levels was observed after combined exposure to BPA/DES. Ultrastructural results showed lesions of the Sertoli and Leydig cells, mainly in the endoplasmic reticulum (ER), in all treated groups. ER stress molecular sensor IRE1 was phosphorylated and activated after BPA and DES treatment in this study. The protein levels of ES stress molecular marker CHOP were significantly up-regulated after exposure to BPA, DES, and BPA and DES combined. These findings indicate that ER stress is important in BPA/DES-induced damage in rat testes. Low-dose and combined exposure to BPA and DES may have toxic effects on male fertility in the adult population.

  19. Sublinear response in lacZ mutant frequency of Muta™ Mouse spermatogonial stem cells after low dose subchronic exposure to N-ethyl-N-nitrosourea.

    PubMed

    O'Brien, Jason M; Walker, Mike; Sivathayalan, Ahalya; Douglas, George R; Yauk, Carole L; Marchetti, Francesco

    2015-05-01

    The transgenic rodent mutation assay was used to compare the dose-response relationship of lacZ mutant frequency (MF) in spermatogonial stem cells exposed acutely or subchronically to N-ethyl-N-nitrosourea (ENU). Muta(™) Mouse males were exposed orally to 0, 25, 50, or 100 mg/kg ENU for acute exposures and 0, 1, 2, or 5 mg/(kg day) for 28-day subchronic exposures. LacZ MF was measured in sperm collected 70 days post-exposure to target spermatogonial stem cells. Dose-response data were fit to linear, quadratic, exponential, or power models. Acute exposure resulted in a dose-dependent increase in MF that was significant (P < 0.05) at all doses tested and was best described by a quadratic dose-response model that was linear in the low dose range. In contrast, similar total doses fragmented over a 28-day subchronic exposure only resulted in a significant increase in lacZ MF at the highest dose tested. Therefore, the subchronic no observable genotoxic effect level (NOGEL) was 2 mg/(kg day) (or 56 mg/kg total dose). The subchronic dose-response was best described by the exponential and power models, which were sublinear in the low dose range. Benchmark dose lower confidence limits (BMDLs) for acute and subchronic exposure were 3.0 and 1.0 mg/(kg day) (or 27.4 mg/kg total dose), respectively. These findings are supportive of a saturable DNA repair mechanism as the mutagenic mode of action for ENU in spermatogonia and imply that sufficiently low exposures would not cause appreciable genotoxic effects over background. This may have important implications for the quantitative risk assessment of germ cell mutagens.

  20. Comparison between Calcitriol and Calcitriol Plus Low-Dose Cinacalcet for the Treatment of Moderate to Severe Secondary Hyperparathyroidism in Chronic Dialysis Patients

    PubMed Central

    Lee, Yueh-Ting; Ng, Hwee-Yeong; Kuo, Chien-Chun; Chen, Te-Chuan; Wu, Chien-Shing; Chiu, Terry Ting-Yu; Lee, Wen-Chin; Lee, Chien-Te

    2013-01-01

    Aim: Uremic hyperparathyroidism (UHPT) has been shown to contribute to the development and progression of chronic kidney disease—mineral bone disorder. UHPT is frequently observed in chronic dialysis patients, and patients with UHPT are associated with increased risk of all-cause and cardiovascular mortality. Cinacalcet is a novel agent that increases sensitivity to the calcium-sensing receptor and is approved for control of UHPT. Nevertheless, cinacalcet is costly and information regarding efficacy of low-dose cinacalcet on UHPT is limited. Methods: We conducted a retrospective study to evaluate treatment with either low-dose calcitriol combined with low-dose cinacalcet (25 mg) (d-Cinacalcet) or calcitriol alone (VitD) in dialysis patients with moderate to severe UHPT. A total of 81 dialysis patients were enrolled (40 subjects in d-Cinacalcet group and 41 subjects in VitD group). Demographic data including age, gender, duration on dialysis and biochemical data were reviewed and recorded. Results: At the end of the study, the intact parathyroid hormone (iPTH) levels of the d-Cinacalcet group declined significantly (from 1166.0 ± 469.3 pg/mL to 679.8 ± 421.6 pg/mL, p < 0.0001), while there was no significant change in the VitD group. Significant decrease of serum calcium (Ca: 9.9 ± 0.6 mg/dL vs. 9.6 ± 0.8 mg/dL, p = 0.002), phosphorus (P: 5.9 ± 1.3 mg/dL vs. 4.9 ± 0.9 mg/dL, p < 0.0001) and calcium phosphate product (Ca × P: 58.7 ± 15.0 mg2/dL2 vs. 46.9 ± 8.9 mg2/dL2, p < 0.0001) were observed in the d-Cinacalcet group. In addition, the subjects in the d-Cinacalcet group had a greater proportion to achieve Kidney Disease Outcomes Quality Initiative (KDOQI)-recommended biochemical targets than the subjects in the VitD group (Ca: 48% vs. 24%; P: 78% vs. 32%; Ca × P: 85% vs. 37%; iPTH: 15% vs. 0%). Conclusions: We conclude that combination therapy of low-dose cinacalcet and calcitriol is more effective than calcitriol alone as a treatment for moderate and

  1. Deoxynivalenol Impairs Weight Gain and Affects Markers of Gut Health after Low-Dose, Short-Term Exposure of Growing Pigs

    PubMed Central

    Alizadeh, Arash; Braber, Saskia; Akbari, Peyman; Garssen, Johan; Fink-Gremmels, Johanna

    2015-01-01

    Deoxynivalenol (DON) is one of the major mycotoxins produced by Fusarium fungi, and exposure to this mycotoxin requires an assessment of the potential adverse effects, even at low toxin levels. The aim of this study was to investigate the effects of a short-term, low-dose DON exposure on various gut health parameters in pigs. Piglets received a commercial feed or the same feed contaminated with DON (0.9 mg/kg feed) for 10 days, and two hours after a DON bolus (0.28 mg/kg BW), weight gain was determined and samples of different segments of the intestine were collected. Even the selected low dose of DON in the diet negatively affected weight gain and induced histomorphological alterations in the duodenum and jejunum. The mRNA expression of different tight junction (TJ) proteins, especially occludin, of inflammatory markers, like interleukin-1 beta and interleukin-10 and the oxidative stress marker heme-oxigenase1, were affected along the intestine by low levels of DON in the diet. Taken together, our results indicate that even after low-level exposure to DON, which has been generally considered as acceptable in animal feeds, clinically-relevant changes are measurable in markers of gut health and integrity. PMID:26067367

  2. Comparison between two FISH techniques in the in vitro study of cytogenetic markers for low-dose X-ray exposure in human primary fibroblasts

    PubMed Central

    Nieri, D.; Berardinelli, F.; Antoccia, A.; Tanzarella, C.; Sgura, Antonella

    2013-01-01

    This work is about the setup of an in vitro system to report low-dose of X-rays as measured as cytogenetic damage. Q- and multicolor FISH (m-FISH), for telomere length and chromosome instability analysis, respectively, were compared to evaluate their sensitivity in the low-dose range in human primary fibroblasts. No telomere length modulation was observed up to 1 Gy in cycling fibroblasts, though reported for high doses, by that frustrating the purpose of using it as a low-exposure marker. To date the m-FISH is the best setup for the assessment of the chromosome structural damage: it allows stable and instable aberrations to be detected all over the karyotype. Stable ones such as balanced translocations, are not eliminated due to cell-cycle as unstable ones, so they are considered transmissible markers for retrospective dosimetry. The induction of chromosome damage showed a clear dependence on dose delivered; unstable aberrations were demonstrated after doses of 0.1 Gy, and stable aberrations after doses higher than 0.5 Gy. Summarizing, q-FISH is unfit to report low exposures while m-FISH provides better results: unstable aberrations are sensible short-term reporters, while stable ones long report exposures but with a higher induction threshold. PMID:23908663

  3. Effectiveness of subcutaneous low-dose alemtuzumab and rituximab combination therapy for steroid-resistant chronic graft-versus-host disease

    PubMed Central

    Gutiérrez-Aguirre, Cesar Homero; Cantú-Rodríguez, Olga Graciela; Borjas-Almaguer, Omar David; González-Llano, Oscar; Jaime-Pérez, José Carlos; Solano-Genesta, Manuel; Gómez-Guijosa, Miguel; Mancias-Guerra, Consuelo; Tarin, Luz; Gómez-Almaguer, David

    2012-01-01

    Background Chronic graft-versus-host disease is a common late complication of allogeneic hematopoietic stem cell transplantation. Corticosteroids are the standard initial treatment. Second-line treatment has not been well defined. We evaluated the effectiveness and safety of low doses of alemtuzumab plus low doses of rituximab in the treatment of steroid-refractory chronic graft-versus-host disease. Design and Methods Ten men and 5 women were prospectively included in the study. All patients received one cycle of subcutaneous alemtuzumab 10 mg/day/3 days and intravenous rituximab 100 mg on Days +4, +11, +18 and +25. The therapeutic response was measured on Days +30, +90 and +365 of the protocol. Results Median age was 41 years. The main site involved was the oral mucosa (86.7%) followed by the eyes (66.7%), liver (60%), skin (53%), lungs (13.3%) and intestinal tract (6.7%). The overall response was 100% at Day +30 evaluation: 10 patients (67%) had partial remission, 5 (33%) had complete remission. At Day +90 evaluation, 7 (50%) patients had partial remission, 4 (28%) had complete remission; 3 (21%) had relapsed chronic graft-versus-host disease and one patient did not reach the evaluation time point. So far, 5 patients have reached the Day +365 follow-up evaluation; 2 (40%) had partial remission, 2 had complete remission and one experienced chronic graft-versus-host disease progression. Adverse effects were mainly infections in 67% of patients; these were all quickly solved, except for one patient who died from pneumonia. Conclusions This combination therapy appears to be an efficacious and safe treatment for steroid-refractory chronic graft-versus-host disease. Longer follow up to determine the durability of response and survival is required. PMID:22133770

  4. Investigation of sinonasal anatomy via low-dose multidetector CT examination in chronic rhinosinusitis patients with higher risk for perioperative complications.

    PubMed

    Fraczek, Marcin; Guzinski, Maciej; Morawska-Kochman, Monika; Krecicki, Tomasz

    2017-02-01

    The aim of the study was to compare visualisation of the surgically relevant anatomical structures via low- and standard-dose multidetector CT protocol in patients with chronic rhinosinusitis (CRS) and higher risk for perioperative complications (i.e. presence of bronchial asthma, history of sinus surgery and advanced nasal polyposis). 135 adult CRS patients were divided randomly into standard-dose (120 kVp, 100 mAs) or low-dose CT groups (120 kVp, 45 mAs). The detectability of the vital anatomical structures (anterior ethmoid artery, optic nerve, cribriform plate and lamina papyracea) was scored using a five-point scale (from excellent to unacceptable) by a radiologist and sinus surgeon. Polyp sizes were quantified endoscopically according to the Lildholdt's scale (LS). Olfactory function was tested with the "Sniffin' Sticks" test. On the low-dose CT images, detectability ranged from 2.42 (better than poor) for cribriform plate among anosmic cases to 4.11 (better than good) for lamina papyracea in cases without nasal polyps. Identification of lamina papyracea on low-dose scans was significantly worse in each group and the same was the case with cribriform plates in patients with advanced polyposis and anosmia. Cribriform plates were the most poorly identified (between poor and average) among all the structures on low-dose images. Identification of anterior ethmoid artery (AEA) with reduced dose was insignificantly worse than with standard-dose examination. The AEA was scored as an average-defined structure and was the second weakest visualised. In conclusion, preoperatively, low-dose protocols may not sufficiently visualise the surgically relevant anatomical structures in patients with CRS and bronchial asthma, advanced nasal polyps (LS > 2) and history of sinus surgery. Low mAs value enables comparable detectability of sinonasal landmarks with standard-dose protocols in patients without analysed risk factors. In the context of planned surgery, the current

  5. Low Dose Risk, Decisions, and Risk Communication

    SciTech Connect

    Flynn, James

    2002-09-14

    The overall research objective was to establish new levels of information about how people, groups, and communities respond to low dose radiation exposure. This is basic research into the social psychology of individual, group, and community responses to radiation exposures. The results of this research are directed to improving risk communication and public participation in management of environmental problems resulting from low dose radiation.

  6. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: focus on the cancer hallmark of tumor angiogenesis

    PubMed Central

    Hu, Zhiwei; Brooks, Samira A.; Dormoy, Valérian; Hsu, Chia-Wen; Hsu, Hsue-Yin; Lin, Liang-Tzung; Massfelder, Thierry; Rathmell, W. Kimryn; Xia, Menghang; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Amedei, Amedeo; Brown, Dustin G.; Prudhomme, Kalan R.; Colacci, Annamaria; Hamid, Roslida A.; Mondello, Chiara; Raju, Jayadev; Ryan, Elizabeth P.; Woodrick, Jordan; Scovassi, A. Ivana; Singh, Neetu; Vaccari, Monica; Roy, Rabindra; Forte, Stefano; Memeo, Lorenzo; Salem, Hosni K.; Lowe, Leroy; Jensen, Lasse; Bisson, William H.; Kleinstreuer, Nicole

    2015-01-01

    One of the important ‘hallmarks’ of cancer is angiogenesis, which is the process of formation of new blood vessels that are necessary for tumor expansion, invasion and metastasis. Under normal physiological conditions, angiogenesis is well balanced and controlled by endogenous proangiogenic factors and antiangiogenic factors. However, factors produced by cancer cells, cancer stem cells and other cell types in the tumor stroma can disrupt the balance so that the tumor microenvironment favors tumor angiogenesis. These factors include vascular endothelial growth factor, endothelial tissue factor and other membrane bound receptors that mediate multiple intracellular signaling pathways that contribute to tumor angiogenesis. Though environmental exposures to certain chemicals have been found to initiate and promote tumor development, the role of these exposures (particularly to low doses of multiple substances), is largely unknown in relation to tumor angiogenesis. This review summarizes the evidence of the role of environmental chemical bioactivity and exposure in tumor angiogenesis and carcinogenesis. We identify a number of ubiquitous (prototypical) chemicals with disruptive potential that may warrant further investigation given their selectivity for high-throughput screening assay targets associated with proangiogenic pathways. We also consider the cross-hallmark relationships of a number of important angiogenic pathway targets with other cancer hallmarks and we make recommendations for future research. Understanding of the role of low-dose exposure of chemicals with disruptive potential could help us refine our approach to cancer risk assessment, and may ultimately aid in preventing cancer by reducing or eliminating exposures to synergistic mixtures of chemicals with carcinogenic potential. PMID:26106137

  7. Perinatal Exposure to a Low Dose of Bisphenol A Impaired Systemic Cellular Immune Response and Predisposes Young Rats to Intestinal Parasitic Infection

    PubMed Central

    Ménard, Sandrine; Guzylack-Piriou, Laurence; Lencina, Corinne; Leveque, Mathilde; Naturel, Manon; Sekkal, Soraya; Harkat, Cherryl; Gaultier, Eric; Olier, Maïwenn; Garcia-Villar, Raphael; Theodorou, Vassilia; Houdeau, Eric

    2014-01-01

    Perinatal exposure to the food contaminant bisphenol A (BPA) in rats induces long lasting adverse effects on intestinal immune homeostasis. This study was aimed at examining the immune response to dietary antigens and the clearance of parasites in young rats at the end of perinatal exposure to a low dose of BPA. Female rats were fed with BPA [5 µg/kg of body weight/day] or vehicle from gestational day 15 to pup weaning. Juvenile female offspring (day (D)25) were used to analyze immune cell populations, humoral and cellular responses after oral tolerance or immunization protocol to ovalbumin (OVA), and susceptibility to infection by the intestinal nematode Nippostrongylus brasiliensis (N. brasiliensis). Anti-OVA IgG titers following either oral tolerance or immunization were not affected after BPA perinatal exposure, while a sharp decrease in OVA-induced IFNγ secretion occurred in spleen and mesenteric lymph nodes (MLN) of OVA-immunized rats. These results are consistent with a decreased number of helper T cells, regulatory T cells and dendritic cells in spleen and MLN of BPA-exposed rats. The lack of cellular response to antigens questioned the ability of BPA-exposed rats to clear intestinal infections. A 1.5-fold increase in N. brasiliensis living larvae was observed in the intestine of BPA-exposed rats compared to controls due to an inappropriate Th1/Th2 cytokine production in infected jejunal tissues. These results show that perinatal BPA exposure impairs cellular response to food antigens, and increases susceptibility to intestinal parasitic infection in the juveniles. This emphasized the maturing immune system during perinatal period highly sensitive to low dose exposure to BPA, altering innate and adaptative immune response capacities in early life. PMID:25415191

  8. What Have "Omics" Taught Us about the Health Risks Associated with Exposure to Low Doses of Ionizing Radiation

    SciTech Connect

    Morgan, William F.; Sowa, Marianne B.

    2011-04-27

    There is a plethora of data available on the DNA damages associated with exposures to ionizing radiation and the subsequent cellular responses. Indeed, much of radiation research has focused on these initial insults and induced responses, particularly DNA repair, cell signaling pathways, cell cycle checkpoint control, mutation induction, chromosomal rearrangements, transformation and apoptosis etc. While many of these endpoints correlate with exposure dose, few, if any, provide substantive information on human health risk(s) associated with radiation exposure. Here the contribution of recent advances in high throughput ‘omics technologies are evaluated to examine what they have taught us about health risk(s) to humans associated with exposure to ionizing radiation.

  9. [The status of the progeny of male rats subjected to low-dose external gamma irradiation exposure].

    PubMed

    Ovcharenko, E P; Kononenko, V V; Galian, S P; Vernidub, I V; Topchiĭ, I G

    1996-01-01

    In studies on 120 mature males of Wistar rats and 252 female rats of the same line, 20-day-old fetuses and 974 young rats of the first generation, anomalies of antenatal and postnatal development were found after exposure of spermatids and spermatozoa to gamma-radiation in doses 0.25-1.0 Gy. After exposure of male rats to radiation in dose 0.25 Gy, reliable delay of pelvic bone ossification was observed as compared to the control.

  10. Arsenic exposure and bladder cancer: quantitative assessment of studies in human populations to detect risks at low doses.

    PubMed

    Tsuji, Joyce S; Alexander, Dominik D; Perez, Vanessa; Mink, Pamela J

    2014-03-20

    While exposures to high levels of arsenic in drinking water are associated with excess cancer risk (e.g., skin, bladder, and lung), exposures at lower levels (e.g., <100-200 µg/L) generally are not. Lack of significant associations may result from methodological issues (e.g., inadequate statistical power, exposure misclassification), or a different dose-response relationship at low exposures, possibly associated with a toxicological mode of action that requires a sufficient dose for increased tumor formation. The extent to which bladder cancer risk for low-level arsenic exposure can be statistically measured by epidemiological studies was examined using an updated meta-analysis of bladder cancer risk with data from two new publications. The summary relative risk estimate (SRRE) for all nine studies was elevated slightly, but not significantly (1.07; 95% confidence interval [CI]: 0.95-1.21, p-Heterogeneity [p-H]=0.543). The SRRE among never smokers was 0.85 (95% CI: 0.66-1.08, p-H=0.915), whereas the SRRE was positive and more heterogeneous among ever smokers (1.18; 95% CI: 0.97-1.44, p-H=0.034). The SRRE was statistically significantly lower than relative risks predicted for never smokers in the United States based on linear extrapolation of risks from higher doses in southwest Taiwan to arsenic water exposures >10 µg/L for more than one-third of a lifetime. By contrast, for all study subjects, relative risks predicted for one-half of lifetime exposure to 50 µg/L were just above the upper 95% CI on the SRRE. Thus, results from low-exposure studies, particularly for never smokers, were statistically inconsistent with predicted risk based on high-dose extrapolation. Additional studies that better characterize tobacco use and stratify analyses of arsenic and bladder cancer by smoking status are necessary to further examine risks of arsenic exposure for smokers.

  11. Immune potentiation after fractionated exposure to very low doses of ionizing radiation and/or caloric restriction in autoimmune-prone and normal C57Bl/6 mice

    SciTech Connect

    James, S.J.; Enger, S.M.; Peterson, W.J.; Makinodan, T. )

    1990-06-01

    Very low doses of ionizing radiation can enhance immune responsiveness and extend life span in normal mice. Total lymphoid irradiation at relatively high doses of radiation can retard autoimmune disease in genetically susceptible mice, but may impair immune function. In order to determine whether fractionated low dose exposure would enhance immune response and retard lymphadenopathy in autoimmune-prone mice, groups of C57B1/6 lpr/lpr mice were sham irradiated, exposed 5 days/week for 4 weeks to 0.04 Gy/day, or to 0.1 Gy/day. After the radiation protocol, the mice were evaluated for splenic T cell proliferative capacity, T cell subset distribution, and total spleen cell numbers. The independent and additive effect of caloric restriction was additionally assessed since this intervention has been shown to increase immune responsiveness and retard disease progression in autoimmune-prone mice. The congenic C57B1/6 +/+ immunologically normal strain was evaluated in parallel as congenic control. The results indicated that mitogen-stimulated proliferation was up-regulated in both strains of mice after exposure to 0.04 Gy/day. The proliferative capacity was additively enhanced when radiation at this dose level was combined with caloric restriction. Exposure to 0.1 Gy/day resulted in further augmentation of proliferative response in the lpr/lpr mice, but was depressive in the +/+ mice. Although the proportions of the various T cell subpopulations were altered in both strains after exposure to LDR, the specific subset alterations were different within each strain. Additional experiments were subsequently performed to assess whether the thymus is required for LDR-induced immune potentiation. Thymectomy completely abrogated the LDR effect in the +/+ mice, suggesting that thymic processing and/or trafficking is adaptively altered with LDR in this strain.

  12. Nuclear accumulation of cyclin D1 following long-term fractionated exposures to low-dose ionizing radiation in normal human diploid cells.

    PubMed

    Shimura, Tsutomu; Hamada, Nobuyuki; Sasatani, Megumi; Kamiya, Kenji; Kunugita, Naoki

    2014-01-01

    Cyclin D1 is a mitogenic sensor that responds to growth signals from the extracellular environment and regulates the G 1-to-S cell cycle transition. When cells are acutely irradiated with a single dose of 10 Gy, cyclin D1 is degraded, causing cell cycle arrest at the G 1/S checkpoint. In contrast, cyclin D1 accumulates in human tumor cells that are exposed to long-term fractionated radiation (0.5 Gy/fraction of X-rays). In this study we investigated the effect of fractionated low-dose radiation exposure on cyclin D1 localization in 3 strains of normal human fibroblasts. To specifically examine the nuclear accumulation of cyclin D1, cells were treated with a hypotonic buffer containing detergent to remove cytoplasmic cyclin D1. Proliferating cell nuclear antigen (PCNA) immunofluorescence was used to identify cells in S phase. With this approach, we observed S-phase nuclear retention of cyclin D1 following low-dose fractionated exposures, and found that cyclin D1 nuclear retention increased with exposure time. Cells that retained nuclear cyclin D1 were more likely to have micronuclei than non-retaining cells, indicating that the accumulation of nuclear cyclin D1 was associated with genomic instability. Moreover, inhibition of the v-akt murine thymoma viral oncogene homolog (AKT) pathway facilitated cyclin D1 degradation and eliminated cyclin D1 nuclear retention in cells exposed to fractionated radiation. Thus, cyclin D1 may represent a useful marker for monitoring long-term effects associated with exposure to low levels of radiation.

  13. [Methodological aspects in environmental and biological monitoring of exposure to low doses of benzene: problems and possible solutions].

    PubMed

    Tranfo, Giovanna; Paci, Enrico; Fustinoni, Silvia; Barbieri, Anna; Carrieri, Mariella

    2013-01-01

    This paper aims to examine some methods to measure human exposure to benzene, both in life and occupational environments, through environmental and biological monitoring, examining the critical issues and optimal conditions of use. The overall performance of environmental monitoring, from the analytical point of view, strongly depend on the choice of an appropriate method of sampling and analysis. Urinary SPMA and t, t-MA are the biomarkers listed by ACGIH to evaluate occupational exposure: most of the recent studies use HPLC with tandem mass spectrometry, but since t, t-MA is present in the urine in larger quantities it is also determinable with UV detectors. The urinary benzene is an index not officially included in the list of the ACGIH BEIs, but it is useful to assess exposure and benzene at low concentrations, that most frequently are found today in the occupational and life environments.

  14. Peripubertal exposure to low doses of tributyltin chloride affects the homeostasis of serum T, E2, LH, and body weight of male mice.

    PubMed

    Si, Jiliang; Wu, Xuesen; Wan, Chengen; Zeng, Tao; Zhang, Miao; Xie, Keqin; Li, Jie

    2011-06-01

    Previous studies have shown that tributyltin could act as an endocrine disruptor in mammals. However, the data on the low-dose effect of tributyltin in animals are still lacking. The objective of this study was to demonstrate the endocrine disruption induced by low levels of tributyltin chloride (TBTCl) in male KM mice. The animals were treated with 0.05 or 0.5 mg TBTCl/kg body weight/3 days from postnatal days (PNDs) 24 to 45, and killed on PNDs 49 and 84, respectively. Mice treated with 0.5 mg TBTCl/kg exhibited decreased serum and intratesticular testosterone (T) levels on PND 49 and then followed by an obvious recovery on PND 84. Furthermore, mice treated with 0.05 mg TBTCl/kg showed reduced serum 17β-estradiol (E2) levels on PND 49. However, treatments with TBTCl resulted in a dose-dependent increase in serum E2 concentration of the mice on PND 84. Administration of TBTCl also decreased levels of serum luteinizing hormone and intratesticular E2 on PND 84. In addition, mice exposed to 0.05 mg/kg TBTCl exhibited an increase in body weight in the late stage of the experiment. These results indicate that treatment with low doses of TBTCl could disturb hormone homeostasis and body weight gain in rodents, and exposure to different levels of TBTCl might have different effects on changing some physiologic parameters.

  15. Repetitive exposure to low-dose X-irradiation attenuates testicular apoptosis in type 2 diabetic rats, likely via Akt-mediated Nrf2 activation

    PubMed Central

    Zhao, Yuguang; Kong, Chuipeng; Chen, Xiao; Wang, Zhenyu; Wan, Zhiqiang; Jia, Lin; Liu, Qiuju; Wang, Yuehui; Li, Wei; Cui, Jiuwei; Han, Fujun; Cai, Lu

    2017-01-01

    To determine whether repetitive exposure to low-dose radiation (LDR) attenuates type 2 diabetes (T2DM)-induced testicular apoptotic cell death in a T2DM rat model, we examined the effects of LDR exposure on diabetic and age-matched control rats. We found that testicular apoptosis and oxidative stress levels were significantly higher in T2DM rats than in control rats. In addition, glucose metabolism-related Akt and GSK-3β function was downregulated and Akt negative regulators PTP1B and TRB3 were upregulated in the T2DM group. Superoxide dismutase (SOD) activity and catalase content were also found to be decreased in T2DM rats. These effects were partially prevented or reversed by repetitive LDR exposure. Nrf2 and its downstream genes NQO1, SOD, and catalase were significantly upregulated by repetitive exposure to LDR, suggesting that the reduction of T2DM-induced testicular apoptosis due to repetitive LDR exposure likely involves enhancement of testicular Akt-mediated glucose metabolism and anti-oxidative defense mechanisms. PMID:26704079

  16. Enhancement of regulatory T cell-like suppressive function in MT-2 by long-term and low-dose exposure to asbestos.

    PubMed

    Ying, Chen; Maeda, Megumi; Nishimura, Yasumitsu; Kumagai-Takei, Naoko; Hayashi, Hiroaki; Matsuzaki, Hidenori; Lee, Suni; Yoshitome, Kei; Yamamoto, Shoko; Hatayama, Tamayo; Otsuki, Takemi

    2015-12-02

    Asbestos exposure causes lung fibrosis and various malignant tumors such as lung cancer and malignant mesothelioma. The effects of asbestos on immune cells have not been thoroughly investigated, although our previous reports showed that asbestos exposure reduced anti-tumor immunity. The effects of continuous exposure of regulatory T cells (Treg) to asbestos were examined using the HTLV-1 immortalized human T cell line MT-2, which possesses a suppressive function and expresses the Treg marker protein, Foxp3. Sublines were generated by the continuous exposure to low doses of asbestos fibers for more than one year. The sublines exposed to asbestos showed enhanced suppressive Treg function via cell-cell contact, and increased production of soluble factors such as IL-10 and transforming growth factor (TGF)-β1. These results also indicated that asbestos exposure induced the reduction of anti-tumor immunity, and efforts to develop substances to reverse this reduction may be helpful in preventing the occurrence of asbestos-induced tumors.

  17. Exposure to a low dose of bisphenol A during fetal life or in adulthood alters maternal behavior in mice.

    PubMed Central

    Palanza, Paola L; Howdeshell, Kembra L; Parmigiani, Stefano; vom Saal, Frederick S

    2002-01-01

    Maternal behavior in mammals is the result of a complex interaction between the lactating dam and her developing offspring. Slight perturbations of any of the components of the mother-infant interaction may result in alterations of the behavior of the mother and/or of the offspring. We studied the effects of exposure of female CD-1 mice to the estrogenic chemical bisphenol A (BPA) during fetal life and/or in adulthood during the last part of pregnancy on subsequent maternal behavior. Pregnant females were fed daily doses of corn oil (controls) or 10 microg/kg body weight BPA during gestation days 14-18. As adults, the prenatally treated female offspring were time-mated and again fed either corn oil (controls) or the same doses of BPA on gestation days 14-18, resulting in four treatment groups: controls, prenatal BPA exposure, adult BPA exposure, and both prenatal and adult BPA exposure. Maternal behavior was then observed on postnatal days 2-15 and reflex responses were examined in the offspring. Dams exposed to BPA either as fetuses or in adulthood spent less time nursing their pups and more time out of the nest compared with the control group. Females exposed to BPA both as fetuses and in adulthood did not significantly differ from controls. No alterations in postnatal reflex development were observed in the offspring of the females exposed to BPA. The changes seen in maternal behavior may be the result of a direct effect of BPA on the neuroendocrine substrates underlying the initiation of maternal behavior. PMID:12060838

  18. Acute and chronic administration of a low-dose combination of topiramate and ondansetron reduces ethanol's reinforcing effects in male alcohol preferring (P) rats.

    PubMed

    Moore, Catherine F; Lycas, Matthew D; Bond, Colin W; Johnson, Bankole A; Lynch, Wendy J

    2014-02-01

    Topiramate (a GABA/glutamate modulator) and ondansetron (a serotonin-3 antagonist) have shown promise as treatments for alcohol use disorders (AUDs), although efficacy is modest/variable for both medications. We recently showed in animal models of consumption and relapse that acute treatment with a combination of these medications was more efficacious than either alone. To determine whether the mechanism for its beneficial effects is through modulation of ethanol's reinforcing effects, we measured the effect of this combination in male alcohol preferring (P) rats (N = 22) responding for ethanol under a progressive-ratio (PR) schedule. Low doses, which either do not affect (ondansetron; 0.001 mg/kg) or only modestly affect (topiramate; 10 mg/kg) alcohol-related behaviors on their own, were selected in an attempt to maximize their combined efficacy while minimizing potential side effects. In addition to acute treatment (1 day), the effects of chronic administration (10 days) were examined in an attempt to model human treatment approaches. The effects of the combination were compared with the low dose of topiramate alone hypothesizing that the combination would be more efficacious than topiramate alone. Although both topiramate and the combination similarly reduced PR responding for ethanol following acute treatment and during the initial phase of chronic treatment (Days 1-5), after repeated administration (Days 6-10), only the combination produced a sustained reduction in ethanol-maintained responding. These results suggest an advantage of the combination over topiramate alone at producing a sustained reduction in ethanol's reinforcing effects following prolonged treatment, and lend further support for its use as a potential treatment for AUDs.

  19. Effects of low dose endosulfan exposure on brain neurotransmitter levels in the African clawed frog Xenopus laevis.

    PubMed

    Preud'homme, Valérie; Milla, Sylvain; Gillardin, Virginie; De Pauw, Edwin; Denoël, Mathieu; Kestemont, Patrick

    2015-02-01

    Understanding the impact of pesticides in amphibians is of growing concern to assess the causes of their decline. Among pesticides, endosulfan belongs to one of the potential sources of danger because of its wide use and known effects, particularly neurotoxic, on a variety of organisms. However, the effect of endosulfan was not yet evaluated on amphibians at levels encompassing simultaneously brain neurotransmitters and behavioural endpoints. In this context, tadpoles of the African clawed frog Xenopus laevis were submitted to four treatments during 27 d: one control, one ethanol control, and two low environmental concentrations of endosulfan (0.1 and 1 μg L(-1)). Endosulfan induced a significant increase of brain serotonin level at both concentrations and a significant increase of brain dopamine and GABA levels at the lower exposure but acetylcholinesterase activity was not modified by the treatment. The gene coding for the GABA transporter 1 was up-regulated in endosulfan contaminated tadpoles while the expression of other genes coding for the neurotransmitter receptors or for the enzymes involved in their metabolic pathways was not significantly modified by endosulfan exposure. Endosulfan also affected foraging, and locomotion in links with the results of the physiological assays, but no effects were seen on growth. These results show that low environmental concentrations of endosulfan can induce adverse responses in X. laevis tadpoles. At a broader perspective, this suggests that more research using and linking multiple markers should be used to understand the complex mode of action of pollutants.

  20. Association of Chromosome Translocation Rate with Low Dose Occupational Radiation Exposures in U.S. Radiologic Technologists

    PubMed Central

    Little, Mark P.; Kwon, Deukwoo; Doi, Kazataka; Simon, Steven L.; Preston, Dale L.; Doody, Michele M.; Lee, Terrence; Miller, Jeremy S.; Kampa, Diane M.; Bhatti, Parveen; Tucker, James D.; Linet, Martha S.; Sigurdson, Alice J.

    2016-01-01

    Chromosome translocations are a well-recognized biological marker of radiation exposure and cancer risk. However, there is uncertainty about the lowest dose at which excess translocations can be detected, and whether there is temporal decay of induced translocations in radiation-exposed populations. Dosimetric uncertainties can substantially alter the shape of dose-response relationships; although regression-calibration methods have been used in some datasets, these have not been applied in radio-occupational studies, where there are also complex patterns of shared and unshared errors that these methods do not account for. In this article we evaluated the relationship between estimated occupational ionizing radiation doses and chromosome translocation rates using fluorescent in situ hybridization in 238 U.S. radiologic technologists selected from a large cohort. Estimated cumulative red bone marrow doses (mean 29.3 mGy, range 0–135.7 mGy) were based on available badge–dose measurement data and on questionnaire-reported work history factors. Dosimetric assessment uncertainties were evaluated using regression calibration, Bayesian and Monte Carlo maximum likelihood methods, taking account of shared and unshared error and adjusted for overdispersion. There was a significant dose response for estimated occupational radiation exposure, adjusted for questionnaire-based personal diagnostic radiation, age, sex and study group (5.7 translocations per 100 whole genome cell equivalents per Gy, 95% CI 0.2, 11.3, P = 0.0440). A significant increasing trend with dose continued to be observed for individuals with estimated doses <100 mGy. For combined estimated occupational and personal-diagnostic-medical radiation exposures, there was a borderline-significant modifying effect of age (P 0.0704), but little evidence (P > 0.5) of temporal decay of induced translocations. The three methods of analysis to adjust for dose uncertainty gave similar results. In summary, chromosome

  1. Association of chromosome translocation rate with low dose occupational radiation exposures in U.S. radiologic technologists.

    PubMed

    Little, Mark P; Kwon, Deukwoo; Doi, Kazataka; Simon, Steven L; Preston, Dale L; Doody, Michele M; Lee, Terrence; Miller, Jeremy S; Kampa, Diane M; Bhatti, Parveen; Tucker, James D; Linet, Martha S; Sigurdson, Alice J

    2014-07-01

    Chromosome translocations are a well-recognized biological marker of radiation exposure and cancer risk. However, there is uncertainty about the lowest dose at which excess translocations can be detected, and whether there is temporal decay of induced translocations in radiation-exposed populations. Dosimetric uncertainties can substantially alter the shape of dose-response relationships; although regression-calibration methods have been used in some datasets, these have not been applied in radio-occupational studies, where there are also complex patterns of shared and unshared errors that these methods do not account for. In this article we evaluated the relationship between estimated occupational ionizing radiation doses and chromosome translocation rates using fluorescent in situ hybridization in 238 U.S. radiologic technologists selected from a large cohort. Estimated cumulative red bone marrow doses (mean 29.3 mGy, range 0-135.7 mGy) were based on available badge-dose measurement data and on questionnaire-reported work history factors. Dosimetric assessment uncertainties were evaluated using regression calibration, Bayesian and Monte Carlo maximum likelihood methods, taking account of shared and unshared error and adjusted for overdispersion. There was a significant dose response for estimated occupational radiation exposure, adjusted for questionnaire-based personal diagnostic radiation, age, sex and study group (5.7 translocations per 100 whole genome cell equivalents per Gy, 95% CI 0.2, 11.3, P = 0.0440). A significant increasing trend with dose continued to be observed for individuals with estimated doses <100 mGy. For combined estimated occupational and personal-diagnostic-medical radiation exposures, there was a borderline-significant modifying effect of age (P = 0.0704), but little evidence (P > 0.5) of temporal decay of induced translocations. The three methods of analysis to adjust for dose uncertainty gave similar results. In summary, chromosome

  2. Effects of repeated low-dose exposure of the nerve agent VX on monoamine levels in different brain structures in mice.

    PubMed

    Graziani, S; Christin, D; Daulon, S; Breton, P; Perrier, N; Taysse, L

    2014-05-01

    In a previous report, alterations of the serotonin metabolism were previously reported in mice intoxicated with repeated low doses of soman. In order to better understand the effects induced by repeated low-dose exposure to organophosphorus compounds on physiological and behavioural functions, the levels of endogenous monoamines (serotonin and dopamine) in different brain areas in mice intoxicated with sublethal dose of (O-ethyl-S-[2(di-isopropylamino) ethyl] methyl phosphonothioate) (VX) were analysed by HPLC method with electrochemical detection. Animals were injected once a day for three consecutive days with 0.10 LD50 of VX (5 μg/kg, i.p). Neither severe signs of cholinergic toxicity nor pathological changes in brain tissue of exposed animals were observed. Cholinesterase (ChE) activity was only inhibited in plasma (a maximum of 30% inhibition 24 h after the last injection of VX), but remained unchanged in the brain. Serotonin and dopamine (DA) metabolism appeared significantly modified. During the entire period of investigation, at least one of the three parameters investigated (i.e. DA and DOPAC levels and DOPAC/DA ratio) was modified. During the toxic challenge, an increase of the serotonin metabolism was noted in hippocampus (HPC), hypothalamus/thalamus, pons medulla and cerebellum (CER). This increase was maintained 4 weeks after exposure in HPC, pons medulla and CER whereas a decrease in cortex 3 weeks after the toxic challenge was observed. The lack of correlation between brain ChE activity and neurochemical outcomes points out to independent mechanisms. The involvement in possibly long-lasting behavioural disorders is discussed.

  3. Low-dose exposure to bisphenol A in combination with fructose increases expression of genes regulating angiogenesis and vascular tone in juvenile Fischer 344 rat cardiac tissue

    PubMed Central

    Klint, Helén; Karimullina, Elina; Rönn, Monika; Lind, Lars; Lind, P. Monica

    2017-01-01

    Objectives Epidemiological studies report associations between exposure to the high-volume chemical and endocrine disruptor bisphenol A (BPA) and cardiovascular disorders, but there is a lack of experimental studies addressing the mechanisms of action of BPA on the cardiovascular system. In the present study, effects on markers for cardiovascular function of exposure to BPA and fructose in vivo in rat cardiac tissues, and of BPA exposure in human cardiomyocytes in vitro, were investigated. Materials Juvenile female Fischer 344 rats were exposed to 5, 50, and 500 μg BPA/kg bodyweight/day in their drinking water from 5 to 15 weeks of age, in combination with 5% fructose. Further, cultured human cardiomyocytes were exposed to 10 nM BPA to 1 × 104 nM BPA for six hours. Expression of markers for cardiovascular function and BPA target receptors was investigated using qRT-PCR. Results Exposure to 5 μg BPA/kg bodyweight/day plus fructose increased mRNA expression of Vegf, Vegfr2, eNos, and Ace1 in rat heart. Exposure of human cardiomyocytes to 1 × 104 nM BPA increased mRNA expression of eNOS and ACE1, as well as IL-8 and NFκβ known to regulate inflammatory response. Conclusions:. Low-dose exposure of juvenile rats to BPA and fructose induced up-regulation of expression of genes controlling angiogenesis and vascular tone in cardiac tissues. The observed effects of BPA in rat heart were in line with our present and previous studies of BPA in human endothelial cells and cardiomyocytes. These findings may aid in understanding the mechanisms of the association between BPA exposure and cardiovascular disorders reported in epidemiological studies. PMID:27622962

  4. Low-dose and short-term cyclosporine treatment in patients with chronic idiopathic urticaria: a clinical and immunological evaluation.

    PubMed

    Serhat Inaloz, H; Ozturk, Savas; Akcali, Cenk; Kirtak, Necmettin; Tarakcioglu, Mehmet

    2008-05-01

    The present study aimed to evaluate the effectiveness of 2.5 mg/kg/day cyclosporin (CsA) treatment in patients with severe chronic idiopathic urticaria (CIU) and the impact of CsA treatment on several cytokines involved in the etiopathogenesis of CIU. Twenty-seven CIU patients and 24 healthy control subjects were included in the study. The autologous serum skin test (ASST) for autoantibodies and urticaria activity scoring (UAS) were measured for the evaluation of the clinical severity and the response to therapy, and the serum levels of interleukin (IL)-6, IL-8, IL-2 receptor, IL-1beta, tumor necrosis factor (TNF)-alpha and IL-5 were measured. The mean UAS score was 32.07 +/- 7.05 and 6.22 +/- 3.84 before and after CsA treatment, respectively. The serum IL-2 receptor, TNF-alpha and IL-5 levels of patients before CsA treatment were statistically higher than those of the control group (P = 0.001), and after 4 weeks of CsA therapy the mean IL-2R, TNF-alpha and IL-5 levels were significantly decreased. The data from this study demonstrate that CsA therapy is efficient and safe for CIU patients. Increase in clinical efficacy and marked decreases in serum cytokine levels suggest that inhibition of cytokine generation is involved in the action of the drug in this clinical setting.

  5. Nanoscale-Barrier Formation Induced by Low-Dose Electron-Beam Exposure in Ultrathin MoS2 Transistors.

    PubMed

    Matsunaga, Masahiro; Higuchi, Ayaka; He, Guanchen; Yamada, Tetsushi; Krüger, Peter; Ochiai, Yuichi; Gong, Yongji; Vajtai, Robert; Ajayan, Pulickel M; Bird, Jonathan P; Aoki, Nobuyuki

    2016-10-05

    Utilizing an innovative combination of scanning-probe and spectroscopic techniques, supported by first-principles calculations, we demonstrate how electron-beam exposure of field-effect transistors, implemented from ultrathin molybdenum disulfide (MoS2), may cause nanoscale structural modifications that in turn significantly modify the electrical operation of these devices. Quite surprisingly, these modifications are induced by even the relatively low electron doses used in conventional electron-beam lithography, which are found to induce compressive strain in the atomically thin MoS2. Likely arising from sulfur-vacancy formation in the exposed regions, the strain gives rise to a local widening of the MoS2 bandgap, an idea that is supported both by our experiment and by the results of first-principles calculations. A nanoscale potential barrier develops at the boundary between exposed and unexposed regions and may cause extrinsic variations in the resulting electrical characteristics exhibited by the transistor. The widespread use of electron-beam lithography in nanofabrication implies that the presence of such strain must be carefully considered when seeking to harness the potential of atomically thin transistors. At the same time, this work also promises the possibility of exploiting the strain as a means to achieve "bandstructure engineering" in such devices.

  6. Enhancing acupuncture by low dose naltrexone.

    PubMed

    Hesselink, Jan M Keppel; Kopsky, David J

    2011-06-01

    To find appropriate and effective treatment options for chronic pain syndromes is a challenging task. Multimodal treatment approach has been gaining acceptance for chronic pain. However, combining treatments, such as acupuncture, with rational pharmacology is still in its infancy. Acupuncture influences the opioid and cannabinoid system through releasing endogenous receptor ligands. Low dose naltrexone also acts on both these systems, and upregulates the opioid and cannabinoid receptors. The authors hypothesise that low dose naltrexone could enhance the pain-relieving effect of acupuncture.

  7. [Functional and morphological characterization of rat thyroid gland at remote periods following single high and low dose radiation exposure].

    PubMed

    Nadol'nik, L I; Netsetskaia, Z V; Kardash, N A; Martynchik, D I; Kravchuk, R I; Basinskiĭ, V A; Vinogradov, V V

    2004-01-01

    A study of the morphological structure and functional activity of the rat thyroid gland was carried out after 22 months following a single exposure to external radiation. The 3-month-old animals were irradiated with doses of 0.25, 0.5, 1.0, 2.0 and 5.0 Gy. Blood was assayed for thyroxin (T4) and triiodothyronine (T3) levels, while liver tissue--for NADP-MDH activity and thyroid tissue--for thyroperoxidase activity. The thyroid was studied histologically, morphometrically and by electron microscope. The decreased T4 concentrations 2.59-fold in the 5.0 Gy group, the increased T3/T4 in the 2.0 and 0.25 Gy groups, the reduced diameter of cellular nuclei and follicles, the flat follicular epithelium and diminished number of thyrocyte ultrastructures indicate thyroid hypofunction in the irradiated animals. The morphological changes are characterized by enhanced diffuse and focal sclerotic changes in thyroid, most pronounced at high irradiation doses (1.0-5.0 Gy), whereas the hemosiderosis foci suggest that the structural changes are consequences of radiation-induced destructive injuries in the gland parenchyma. Two of the thyroids (0.5 Gy) demonstrate foci with pronounced lymphoid infiltration, while follicular carcinomas were detected in 4 thyroids (2.0 Gy), and in one thyroid (0.5 Gy) in one thyroid (5.0 Gy). The remote effects of radiation were dose-dependent destructive, sclerotic and atrophic processes, decreased functional activity, stimulation of development of autoimmune aggression and carcinogenesis in thyroid.

  8. Life-Span Exposure to Low Doses of Aspartame Beginning during Prenatal Life Increases Cancer Effects in Rats

    PubMed Central

    Soffritti, Morando; Belpoggi, Fiorella; Tibaldi, Eva; Esposti, Davide Degli; Lauriola, Michelina

    2007-01-01

    Background In a previous study conducted at the Cesare Maltoni Cancer Research Center of the European Ramazzini Foundation (CMCRC/ERF), we demonstrated for the first time that aspartame (APM) is a multipotent carcinogenic agent when various doses are administered with feed to Sprague-Dawley rats from 8 weeks of age throughout the life span. Objective The aim of this second study is to better quantify the carcinogenic risk of APM, beginning treatment during fetal life. Methods We studied groups of 70–95 male and female Sprague-Dawley rats administered APM (2,000, 400, or 0 ppm) with feed from the 12th day of fetal life until natural death. Results Our results show a) a significant dose-related increase of malignant tumor–bearing animals in males (p < 0.01), particularly in the group treated with 2,000 ppm APM (p < 0.01); b) a significant increase in incidence of lymphomas/leukemias in males treated with 2,000 ppm (p < 0.05) and a significant dose-related increase in incidence of lymphomas/leukemias in females (p < 0.01), particularly in the 2,000-ppm group (p < 0.01); and c) a significant dose-related increase in incidence of mammary cancer in females (p < 0.05), particularly in the 2,000-ppm group (p < 0.05). Conclusions The results of this carcinogenicity bioassay confirm and reinforce the first experimental demonstration of APM’s multipotential carcinogenicity at a dose level close to the acceptable daily intake for humans. Furthermore, the study demonstrates that when life-span exposure to APM begins during fetal life, its carcinogenic effects are increased. PMID:17805418

  9. Directed Differentiation of Human Embryonic Stem Cells into Prostate Organoids In Vitro and its Perturbation by Low-Dose Bisphenol A Exposure.

    PubMed

    Calderon-Gierszal, Esther L; Prins, Gail S

    2015-01-01

    Studies using rodent and adult human prostate stem-progenitor cell models suggest that developmental exposure to the endocrine disruptor Bisphenol-A (BPA) can predispose to prostate carcinogenesis with aging. Unknown at present is whether the embryonic human prostate is equally susceptible to BPA during its natural developmental window. To address this unmet need, we herein report the construction of a pioneer in vitro human prostate developmental model to study the effects of BPA. The directed differentiation of human embryonic stem cells (hESC) into prostatic organoids in a spatial system was accomplished with precise temporal control of growth factors and steroids. Activin-induced definitive endoderm was driven to prostate specification by combined exposure to WNT10B and FGF10. Matrigel culture for 20-30 days in medium containing R-Spondin-1, Noggin, EGF, retinoic acid and testosterone was sufficient for mature prostate organoid development. Immunofluorescence and gene expression analysis confirmed that organoids exhibited cytodifferentiation and functional properties of the human prostate. Exposure to 1 nM or 10 nM BPA throughout differentiation culture disturbed early morphogenesis in a dose-dependent manner with 1 nM BPA increasing and 10 nM BPA reducing the number of branched structures formed. While differentiation of branched structures to mature organoids seemed largely unaffected by BPA exposure, the stem-like cell population increased, appearing as focal stem cell nests that have not properly entered lineage commitment rather than the rare isolated stem cells found in normally differentiated structures. These findings provide the first direct evidence that low-dose BPA exposure targets hESC and perturbs morphogenesis as the embryonic cells differentiate towards human prostate organoids, suggesting that the developing human prostate may be susceptible to disruption by in utero BPA exposures.

  10. Identification of Differential Gene Expression Patterns after Acute Exposure to High and Low Doses of Low-LET Ionizing Radiation in a Reconstituted Human Skin Tissue

    SciTech Connect

    Tilton, Susan C.; Markillie, Lye Meng; Hays, Spencer; Taylor, Ronald C.; Stenoien, David L.

    2016-11-01

    Our goal here was to identify dose and temporal dependent radiation responses in a complex tissue, reconstituted human skin. Direct sequencing of RNA (RNA-seq) was used to quantify altered transcripts following exposure to 0.1, 2 and 10 Gy of ionizing radiation at 3 and 8 hours. These doses include a low dose in the range of some medical diagnostic procedures (0.1 Gy), a dose typically received during radiotherapy (2.0 Gy) and a lethal dose (10 Gy). These doses could be received after an intentional or accidental radiation exposure and biomarkers are needed to rapidly and accurately triage exposed individuals. A total of 1701 genes were deemed to be significantly affected by high dose radiation exposure with the majority of genes affected at 10 Gy. A group of 29 genes including GDF15, BBC3, PPM1D, FDXR, GADD45A, MDM2, CDKN1A, TP53INP1, CYCSP27, SESN1, SESN2, PCNA, and AEN were similarly altered at both 2 and 10 Gy, but not 0.1 Gy, at multiple time points. A much larger group of up regulated genes, including those involved in inflammatory responses, was significantly altered only after a 10 Gy exposure. At high doses, down regulated genes were associated with cell cycle regulation and exhibited an apparent linear response between 2 and 10 Gy. While only a handful of genes were significantly affected by 0.1 Gy exposure using stringent statistical filters, groups of related genes regulating cell cycle progression and inflammatory responses consistently exhibited opposite trends in their regulation compared to the high dose exposures. Differential regulation of PLK1 signaling at low and high doses was confirmed using qRT-PCR. These results indicate that some alterations in gene expression are qualitatively different at low and high doses of radiation in this model system.

  11. The Fukushima nuclear accident and the pale grass blue butterfly: evaluating biological effects of long-term low-dose exposures

    PubMed Central

    2013-01-01

    Background On August 9th 2012, we published an original research article in Scientific Reports, concluding that artificial radionuclides released from the Fukushima Dai-ichi Nuclear Power Plant exerted genetically and physiologically adverse effects on the pale grass blue butterfly Zizeeria maha in the Fukushima area. Immediately following publication, many questions and comments were generated from all over the world. Here, we have clarified points made in the original paper and answered questions posed by the readers. Results The following points were clarified. (1) There are many advantages to using the pale grass blue butterfly as an indicator species. (2) The forewings of the individuals collected in Fukushima were significantly smaller than in the northern and southern localities. (3) We observed growth retardation in the butterflies from the Fukushima area. (4) The aberrant colour patterns in the butterflies obtained in the Fukushima area were different from the colour patterns induced by temperature and sibling crosses but similar to those induced by external and internal exposures to the artificial radionuclides and by a chemical mutagen, suggesting that genetic mutations caused the aberrations. (5) This species of butterfly has been plentiful in Fukushima area for at least half a century. We here present specimens collected from Fukushima Prefecture before the accident. (6) Mutation accumulation was detected by the increase in the abnormality rates from May 2011 to September 2011. (7) The abnormal traits were heritable. (8) Our sampling localities were not affected by the tsunami. (9) We used a high enough number of samples to obtain statistically significant results. (10) The standard rearing method was followed, producing normal adults in the control groups. (11) The exposure experiments successfully reproduced the results of the field work. This species of butterfly is vulnerable to long-term low-dose internal and external exposures; however, insect

  12. The potential benefits of nicaraven to protect against radiation-induced injury in hematopoietic stem/progenitor cells with relative low dose exposures

    SciTech Connect

    Ali, Haytham; Galal, Omima; Urata, Yoshishige; Goto, Shinji; Guo, Chang-Ying; Luo, Lan; Abdelrahim, Eman; Ono, Yusuke; Mostafa, Emtethal; Li, Tao-Sheng

    2014-09-26

    Highlights: • Nicaraven mitigated the radiation-induced reduction of c-kit{sup +} stem cells. • Nicaraven enhanced the function of hematopoietic stem/progenitor cells. • Complex mechanisms involved in the protection of nicaraven to radiation injury. - Abstract: Nicaraven, a hydroxyl radical-specific scavenger has been demonstrated to attenuate radiation injury in hematopoietic stem cells with 5 Gy γ-ray exposures. We explored the effect and related mechanisms of nicaraven for protecting radiation injury induced by sequential exposures to a relatively lower dose γ-ray. C57BL/6 mice were given nicaraven or placebo within 30 min before exposure to 50 mGy γ-ray daily for 30 days in sequences (cumulative dose of 1.5 Gy). Mice were victimized 24 h after the last radiation exposure, and the number, function and oxidative stress of hematopoietic stem cells were quantitatively estimated. We also compared the gene expression in these purified stem cells from mice received nicaraven and placebo treatment. Nicaraven increased the number of c-kit{sup +} stem/progenitor cells in bone marrow and peripheral blood, with a recovery rate around 60–90% of age-matched non-irradiated healthy mice. The potency of colony forming from hematopoietic stem/progenitor cells as indicator of function was completely protected with nicaraven treatment. Furthermore, nicaraven treatment changed the expression of many genes associated to DNA repair, inflammatory response, and immunomodulation in c-kit{sup +} stem/progenitor cells. Nicaraven effectively protected against damages of hematopoietic stem/progenitor cells induced by sequential exposures to a relatively low dose radiation, via complex mechanisms.

  13. Exposure to low-dose (56)Fe-ion radiation induces long-term epigenetic alterations in mouse bone marrow hematopoietic progenitor and stem cells.

    PubMed

    Miousse, Isabelle R; Shao, Lijian; Chang, Jianhui; Feng, Wei; Wang, Yingying; Allen, Antiño R; Turner, Jennifer; Stewart, Blair; Raber, Jacob; Zhou, Daohong; Koturbash, Igor

    2014-07-01

    There is an increasing need to better understand the long-term health effects of high-linear energy transfer (LET) radiation due to exposure during space missions, as well as its increasing use in clinical treatments. Previous studies have indicated that exposure to (56)Fe heavy ions increases the incidence of acute myeloid leukemia (AML) in mice but the underlying molecular mechanisms remain elusive. Epigenetic alterations play a role in radiation-induced genomic instability and the initiation and progression of AML. In this study, we assessed the effects of low-dose (56)Fe-ion irradiation on epigenetic alterations in bone marrow mononuclear cells (BM-MNCs) and hematopoietic progenitor and stem cells (HPSCs). Exposure to (56)Fe ions (600 MeV, 0.1, 0.2 and 0.4 Gy) resulted in significant epigenetic alterations involving methylation of DNA, the DNA methylation machinery and expression of repetitive elements. Four weeks after irradiation, these changes were primarily confined to HPSCs and were exhibited as dose-dependent hypermethylation of LINE1 and SINE B1 repetitive elements [4.2-fold increase in LINE1 (P < 0.001) and 7.6-fold increase in SINE B1 (P < 0.01) after exposure to 0.4 Gy; n = 5]. Epigenetic alterations were persistent and detectable for at least 22 weeks after exposure, when significant loss of global DNA hypomethylation (1.9-fold, P < 0.05), decreased expression of Dnmt1 (1.9-fold, P < 0.01), and increased expression of LINE1 and SINE B1 repetitive elements (2.8-fold, P < 0.001 for LINE1 and 1.9-fold, P < 0.05 for SINE B1; n = 5) were observed after exposure to 0.4 Gy. In contrast, exposure to (56)Fe ions did not result in accumulation of increased production of reactive oxygen species (ROS) and DNA damage, exhibited as DNA strand breaks. Furthermore, no significant alterations in cellular senescence and apoptosis were detected in HPSCs after exposure to (56)Fe-ion radiation. These findings suggest that epigenetic reprogramming is possibly involved in

  14. Altered gene expression by low-dose arsenic exposure in humans and cultured cardiomyocytes: Assessment by real-time PCR array

    EPA Science Inventory

    Arsenic contamination in drinking water has become a great public health concern worldwide. Chronic arsenic exposure results in higher risk of skin, lung and bladder cancer, as well as cardiovascular disease and diabetes. The purpose of this study was to investigate the effects o...

  15. Induction of reciprocal translocations in rhesus monkey stem-cell spermatogonia: effects of low doses and low dose rates

    SciTech Connect

    van Buul, P.P.; Richardson, J.F. Jr.; Goudzwaard, J.H.

    1986-01-01

    The induction of reciprocal translocation in rhesus monkey spermatogonial stem cells was studied following exposure to low doses of acute X rays (0.25 Gy, 300 mGy/min) or to low-dose-rate X rays (1 Gy, 2 mGy/min) and gamma rays (1 Gy, 0.2 mGy/min). The results obtained at 0.25 Gy of X rays fitted exactly the linear extrapolation down from the 0.5 and 1.0 Gy points obtained earlier. Extension of X-ray exposure reduced the yield of translocations similar to that in the mouse by about 50%. The reduction to 40% of translocation rate after chronic gamma exposure was clearly less than the value of about 80% reported for the mouse over the same range of dose rates. Differential cell killing with ensuing differential elimination of aberration-carrying cells is the most likely explanation for the differences between mouse and monkey.

  16. Low-Dose Carcinogenicity Studies

    EPA Science Inventory

    One of the major deficiencies of cancer risk assessments is the lack of low-dose carcinogenicity data. Most assessments require extrapolation from high to low doses, which is subject to various uncertainties. Only 4 low-dose carcinogenicity studies and 5 low-dose biomarker/pre-n...

  17. High susceptibility to repeated, low-dose, vaginal SHIV exposure late in the luteal phase of the menstrual cycle of pigtail macaques.

    PubMed

    Vishwanathan, Sundaram A; Guenthner, Patricia C; Lin, Carol Y; Dobard, Charles; Sharma, Sunita; Adams, Debra R; Otten, Ron A; Heneine, Walid; Hendry, R Michael; McNicholl, Janet M; Kersh, Ellen N

    2011-08-01

    Fluctuations in susceptibility to HIV or SHIV during the menstrual cycle are currently not fully documented. To address this, the time point of infection was determined in 19 adult female pigtail macaques vaginally challenged during their undisturbed menstrual cycles with repeated, low-dose SHIV(SF162P3) exposures. Eighteen macaques (95%) first displayed viremia in the follicular phase, as compared with 1 macaque (5%) in the luteal phase (P < 0.0001). Due to a viral eclipse phase, we estimated a window of most frequent virus transmission between days 24 and 31 of the menstrual cycle, in the late luteal phase. Thus, susceptibility to vaginal SHIV infection is significantly elevated in the second half of the menstrual cycle when progesterone levels are high and when local immunity may be low. Such susceptibility windows have been postulated before but not definitively documented. Our data support the findings of higher susceptibility to HIV in women during progesterone-dominated periods including pregnancy and contraceptive use.

  18. Chronic oral administration of low-dose combination of fenofibrate and rosuvastatin protects the rat heart against experimentally induced acute myocardial infarction.

    PubMed

    Garg, Monika; Khanna, Deepa; Kalra, Sanjeev; Balakumar, Pitchai

    2016-10-01

    Fenofibrate and rosuvastatin at low doses might have experimental pleiotropic benefits. This study investigated the combined effect of low doses of fenofibrate and rosuvastatin in isoproterenol-induced experimental myocardial infarction. Rats administered isoproterenol (85 mg/kg/day, s.c.) for 2 days (day 29 and day 30) of 30 days experimental protocol developed significant myocardial infarction that was accompanied with high myocardial oxidative stress and lipid peroxidation, elevated serum markers of cardiac injury, lipid abnormalities, and elevated circulatory levels of C-reactive protein. Pretreatment with low doses of fenofibrate (30 mg/kg/day p.o., 30 days) and rosuvastatin (2 mg/kg/day p.o., 30 days) both alone or in combination markedly prevented isoproterenol-induced myocardial infarction and associated abnormalities while the low-dose combination of fenofibrate and rosuvastatin was more effective. Histopathological study in isoproterenol control rat heart showed necrosis with edema and acute inflammation at the margins of necrotic area. The rat heart from low-dose fenofibrate and rosuvastatin pretreated group showed scanty inflammation and no ischemia. In conclusion, fenofibrate and rosuvastatin pretreatment in low doses might have a therapeutic potential to prevent the pathogenesis of myocardial infarction. Moreover, their combined treatment option might offer superior therapeutic benefits via a marked reduction in myocardial infarct size and oxidative stress, suggesting a possibility of their pleiotropic cardioprotective action at low doses.

  19. Radiation Leukemogenesis at Low Dose Rates

    SciTech Connect

    Weil, Michael; Ullrich, Robert

    2013-09-25

    The major goals of this program were to study the efficacy of low dose rate radiation exposures for the induction of acute myeloid leukemia (AML) and to characterize the leukemias that are caused by radiation exposures at low dose rate. An irradiator facility was designed and constructed that allows large numbers of mice to be irradiated at low dose rates for protracted periods (up to their life span). To the best of our knowledge this facility is unique in the US and it was subsequently used to study radioprotectors being developed for radiological defense (PLoS One. 7(3), e33044, 2012) and is currently being used to study the role of genetic background in susceptibility to radiation-induced lung cancer. One result of the irradiation was expected; low dose rate exposures are ineffective in inducing AML. However, another result was completely unexpected; the irradiated mice had a very high incidence of hepatocellular carcinoma (HCC), approximately 50%. It was unexpected because acute exposures are ineffective in increasing HCC incidence above background. This is a potential important finding for setting exposure limits because it supports the concept of an 'inverse dose rate effect' for some tumor types. That is, for the development of some tumor types low dose rate exposures carry greater risks than acute exposures.

  20. IL6-174 G>C Polymorphism (rs1800795) Association with Late Effects of Low Dose Radiation Exposure in the Portuguese Tinea Capitis Cohort.

    PubMed

    Boaventura, Paula; Durães, Cecília; Mendes, Adélia; Costa, Natália Rios; Chora, Inês; Ferreira, Sara; Araújo, Emanuel; Lopes, Pedro; Rosa, Gilberto; Marques, Pedro; Bettencourt, Paulo; Oliveira, Inês; Costa, Francisco; Ramos, Isabel; Teles, Maria José; Guimarães, João Tiago; Sobrinho-Simões, Manuel; Soares, Paula

    Head and neck cancers, and cardiovascular disease have been described as late effects of low dose radiation (LDR) exposure, namely in tinea capitis cohorts. In addition to radiation dose, gender and younger age at exposure, the genetic background might be involved in the susceptibility to LDR late effects. The -174 G>C (rs1800795) SNP in IL6 has been associated with cancer and cardiovascular disease, nevertheless this association is still controversial. We assessed the association of the IL6-174 G>C SNP with LDR effects such as thyroid carcinoma, basal cell carcinoma and carotid atherosclerosis in the Portuguese tinea capitis cohort. The IL6-174 G>C SNP was genotyped in 1269 individuals formerly irradiated for tinea capitis. This sampling group included thyroid cancer (n = 36), basal cell carcinoma (n = 113) and cases without thyroid or basal cell carcinoma (1120). A subgroup was assessed for atherosclerosis by ultrasonography (n = 379) and included matched controls (n = 222). Genotypes were discriminated by real-time PCR using a TaqMan SNP genotyping assay. In the irradiated group, we observed that the CC genotype was significantly associated with carotid plaque risk, both in the genotypic (OR = 3.57, CI = 1.60-7.95, p-value = 0.002) and in the recessive (OR = 3.02, CI = 1.42-6.42, p-value = 0.004) models. Irradiation alone was not a risk factor for carotid atherosclerosis. We did not find a significant association of the IL6-174 C allele with thyroid carcinoma or basal cell carcinoma risk. The IL6-174 CC genotype confers a three-fold risk for carotid atherosclerotic disease suggesting it may represent a genetic susceptibility factor in the LDR context.

  1. IL6-174 G>C Polymorphism (rs1800795) Association with Late Effects of Low Dose Radiation Exposure in the Portuguese Tinea Capitis Cohort

    PubMed Central

    Mendes, Adélia; Costa, Natália Rios; Chora, Inês; Ferreira, Sara; Araújo, Emanuel; Lopes, Pedro; Rosa, Gilberto; Marques, Pedro; Bettencourt, Paulo; Oliveira, Inês; Costa, Francisco; Ramos, Isabel; Teles, Maria José; Guimarães, João Tiago; Sobrinho-Simões, Manuel; Soares, Paula

    2016-01-01

    Head and neck cancers, and cardiovascular disease have been described as late effects of low dose radiation (LDR) exposure, namely in tinea capitis cohorts. In addition to radiation dose, gender and younger age at exposure, the genetic background might be involved in the susceptibility to LDR late effects. The -174 G>C (rs1800795) SNP in IL6 has been associated with cancer and cardiovascular disease, nevertheless this association is still controversial. We assessed the association of the IL6-174 G>C SNP with LDR effects such as thyroid carcinoma, basal cell carcinoma and carotid atherosclerosis in the Portuguese tinea capitis cohort. The IL6-174 G>C SNP was genotyped in 1269 individuals formerly irradiated for tinea capitis. This sampling group included thyroid cancer (n = 36), basal cell carcinoma (n = 113) and cases without thyroid or basal cell carcinoma (1120). A subgroup was assessed for atherosclerosis by ultrasonography (n = 379) and included matched controls (n = 222). Genotypes were discriminated by real-time PCR using a TaqMan SNP genotyping assay. In the irradiated group, we observed that the CC genotype was significantly associated with carotid plaque risk, both in the genotypic (OR = 3.57, CI = 1.60–7.95, p-value = 0.002) and in the recessive (OR = 3.02, CI = 1.42–6.42, p-value = 0.004) models. Irradiation alone was not a risk factor for carotid atherosclerosis. We did not find a significant association of the IL6-174 C allele with thyroid carcinoma or basal cell carcinoma risk. The IL6-174 CC genotype confers a three-fold risk for carotid atherosclerotic disease suggesting it may represent a genetic susceptibility factor in the LDR context. PMID:27662210

  2. MAMMARY GLAND DEVELOPMENT AS A SENSITIVE END-POINT FOLLOWING ACUTE PERNATAL EXPOSURE TO A LOW DOSE ATRAZINE METABOLITE MIXTURE IN FEMALE LONG EVANS RATS

    EPA Science Inventory

    In order to characterize the potential developmental effects of atrazine (ATR) metabolites at low doses, an environmentally-based mixture (EBM) of ATR and its metabolites hydroxyatrazine, diaminochlorotriazine, deethylatrazine, and deisopropylatrazine was formulated based on surv...

  3. Identification of Differential Gene Expression Patterns after Acute Exposure to High and Low Doses of Low-LET Ionizing Radiation in a Reconstituted Human Skin Tissue.

    PubMed

    Tilton, Susan C; Markillie, Lye Meng; Hays, Spencer; Taylor, Ronald C; Stenoien, David L

    2016-11-01

    In this study we utilized a systems biology approach to identify dose- (0.1, 2.0 and 10 Gy) and time- (3 and 8 h) dependent responses to acute ionizing radiation exposure in a complex tissue, reconstituted human skin. The low dose used here (0.1 Gy) falls within the range of certain medical diagnostic procedures. Of the two higher doses used, 2.0 Gy is typically administered for radiotherapy, while 10 Gy is lethal. Because exposure to any of these doses is possible after an intentional or accidental radiation events, biomarkers are needed to rapidly and accurately triage potentially exposed individuals. Here, tissue samples were acutely exposed to X-ray-generated low-linear-energy transfer (LET) ionizing radiation, and direct RNA sequencing (RNA-seq) was used to quantify altered transcripts. The time points used for this study aid in assessing early responses to exposure, when key signaling pathways and biomarkers can be identified, which precede and regulate later phenotypic alterations that occur at high doses, including cell death. We determined that a total of 1,701 genes expressed were significantly affected by high-dose radiation, with the majority of genes affected at 10 Gy. Expression levels of a group of 29 genes, including GDF15, BBC3, PPM1D, FDXR, GADD45A, MDM2, CDKN1A, TP53INP1, CYCSP27, SESN1, SESN2, PCNA and AEN, were similarly altered at both 2 and 10 Gy, but not 0.1 Gy, at both time points. A much larger group of upregulated genes, including those involved in inflammatory responses, was significantly altered only after 10 Gy irradiation. At high doses, downregulated genes were associated with cell cycle regulation and exhibited an apparent linear response between 2 and 10 Gy. While only a few genes were significantly affected by 0.1 Gy irradiation, using stringent statistical filters, groups of related genes regulating cell cycle progression and inflammatory responses consistently exhibited opposite trends in their regulation compared to high

  4. State of the art in research into the risk of low dose radiation exposure--findings of the fourth MELODI workshop.

    PubMed

    Salomaa, Sisko; Prise, Kevin M; Atkinson, Michael J; Wojcik, Andrzej; Auvinen, Anssi; Grosche, Bernd; Sabatier, Laure; Jourdain, Jean-René; Salminen, Eeva; Baatout, Sarah; Kulka, Ulrike; Rabus, Hans; Blanchardon, Eric; Averbeck, Dietrich; Weiss, Wolfgang

    2013-09-01

    The fourth workshop of the Multidisciplinary European Low Dose Initiative (MELODI) was organised by STUK-Radiation and Nuclear Safety Authority of Finland. It took place from 12 to 14 September 2012 in Helsinki, Finland. The meeting was attended by 179 scientists and professionals engaged in radiation research and radiation protection. We summarise the major scientific findings of the workshop and the recommendations for updating the MELODI Strategic Research Agenda and Road Map for future low dose research activities.

  5. Genome Wide Evaluation of Normal Human Tissue in Response to Controlled, In vivo Low-Dose Low LET Ionizing Radiation Exposure: Pathways and Mechanisms Final Report, September 2013

    SciTech Connect

    Rocke, David M.

    2013-09-09

    During course of this project, we have worked in several areas relevant to low-dose ionizing radiation. Using gene expression to measure biological response, we have examined the response of human skin exposed in-vivo to radation, human skin exposed ex-vivo to radiation, and a human-skin model exposed to radiation. We have learned a great deal about the biological response of human skin to low-dose ionizing radiation.

  6. Treating Concurrent Chronic Low Back Pain and Depression with Low-Dose Venlafaxine: An Initial Identification of “Easy-to-Use” Clinical Predictors of Early Response

    PubMed Central

    Rej, Soham; Dew, Mary Amanda; Karp, Jordan F.

    2014-01-01

    Objective Depression and Chronic Low Back Pain (CLBP) are both frequent and commonly comorbid in older adults seeking primary care. Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) such as venlafaxine may be effective in treating comorbid depression and CLBP. For patients with comorbid depression and CLBP, our goal was to identify “easy-to-use” early clinical variables associated with response to 6 weeks of low-dose venlafaxine pharmacotherapy that could be used to construct a clinically-useful predictive model in future studies. Methods We report data from the first 140 patients completing phase 1 of the ADAPT clinical trial. Patients aged ≥60 with concurrent depression and CLBP received 6-weeks of open-label venlafaxine 150mg/day and supportive management. Using univariate and multivariate methods, we examined a variety of clinical predictors and their association with response to both depression and CLBP; change in depression; and change in pain scores at 6 weeks. Results 26.4% of patients responded for both depression and pain with venlafaxine. Early improvement in pain at 2 weeks predicted improved response rates (p=0.027). Similarly, positive changes in depression and pain at 2 weeks independently predicted continued improvement at 6 weeks in depression and pain, respectively (p<0.001). Conclusions An important minority of patients benefitted from 6 weeks of venlafaxine 150mg/day. Early improvement in depression and pain at 2 weeks may predict continued improvement at week 6. Future studies must examine whether patients who have a poor initial response may benefit from increasing the SNRI dose, switching, or augmenting with other treatments after 2 weeks of pharmacotherapy. PMID:25040462

  7. Low-Dose Treatment with Erythropoiesis-Stimulating Agents and Cardiovascular Geometry in Chronic Kidney Disease: Is Darbepoetin-α More Effective than Expected?

    PubMed

    Di Lullo, Luca; Floccari, Fulvio; Granata, Antonio; Malaguti, Moreno

    2012-02-01

    INTRODUCTION: Chronic kidney disease (CKD) is a widespread invalidating condition, leading to erythropoietin deficiency and decreased cardiovascular performance. Darbepoetin-α and epoetin-α are extensively used to correct renal anemia. The aim of this study was to evaluate cardiological outcomes in two groups of CKD patients treated with erythropoiesis-stimulating agents (ESA: 20 μg darbepoetin-α weekly vs. 2,000 IU epoetin-α thrice weekly) with an unconventional 1:300 conversion ratio. METHODS: The study was designed as a single center, retrospective, observational study. One hundred stage IV CKD patients were selected. Hemoglobin (Hb), hematocrit, C-reactive protein, pro-brain natriuretic peptide (BNP) and basal echocardiograms were monitored every 3 months. RESULTS: Darbepoetin-α was significantly more effective in increasing Hb levels after 3 (p < 0.0001), 6 (p < 0.0001), 9 (p < 0.01) and 12 months (p < 0.01) compared to epoetin-α. The optimal Hb target level (11 g/dl < Hb < 12 g/dl) was completely reached after 1 year of treatment with darbepoetin-α and in 70% of the patients treated with epoetin-α (p < 0.01). Cardiovascular performance (left ventricular end-diastolic volume, ejection fraction and pro-BNP) was significantly improved after darbepoetin-α treatment at the 6- and 12-month follow-ups compared to epoetin-α. Discussion: Despite the limitations of a retrospective observational study, these results encourage nephrologists to test the 1:300 darbepoetin/epoetin conversion ratio in 'easy' patients, and aggressive protocols for the treatment of anemia in CKD patients are avoided. Darbepoetin-α appeared effective in anemia correction, improving cardiovascular performance in a significantly higher proportion than epoetin. At low doses, on the other hand, it has to be borne in mind that a treatment regimen with only one submaximal administration per week may increase patient compliance and adherence to therapy, explaining in part the observed

  8. Low-Dose Treatment with Erythropoiesis-Stimulating Agents and Cardiovascular Geometry in Chronic Kidney Disease: Is Darbepoetin-α More Effective than Expected?

    PubMed Central

    Di Lullo, Luca; Floccari, Fulvio; Granata, Antonio; Malaguti, Moreno

    2012-01-01

    Introduction Chronic kidney disease (CKD) is a widespread invalidating condition, leading to erythropoietin deficiency and decreased cardiovascular performance. Darbepoetin-α and epoetin-α are extensively used to correct renal anemia. The aim of this study was to evaluate cardiological outcomes in two groups of CKD patients treated with erythropoiesis-stimulating agents (ESA: 20 μg darbepoetin-α weekly vs. 2,000 IU epoetin-α thrice weekly) with an unconventional 1:300 conversion ratio. Methods The study was designed as a single center, retrospective, observational study. One hundred stage IV CKD patients were selected. Hemoglobin (Hb), hematocrit, C-reactive protein, pro-brain natriuretic peptide (BNP) and basal echocardiograms were monitored every 3 months. Results Darbepoetin-α was significantly more effective in increasing Hb levels after 3 (p < 0.0001), 6 (p < 0.0001), 9 (p < 0.01) and 12 months (p < 0.01) compared to epoetin-α. The optimal Hb target level (11 g/dl < Hb < 12 g/dl) was completely reached after 1 year of treatment with darbepoetin-α and in 70% of the patients treated with epoetin-α (p < 0.01). Cardiovascular performance (left ventricular end-diastolic volume, ejection fraction and pro-BNP) was significantly improved after darbepoetin-α treatment at the 6- and 12-month follow-ups compared to epoetin-α. Discussion: Despite the limitations of a retrospective observational study, these results encourage nephrologists to test the 1:300 darbepoetin/epoetin conversion ratio in ‘easy’ patients, and aggressive protocols for the treatment of anemia in CKD patients are avoided. Darbepoetin-α appeared effective in anemia correction, improving cardiovascular performance in a significantly higher proportion than epoetin. At low doses, on the other hand, it has to be borne in mind that a treatment regimen with only one submaximal administration per week may increase patient compliance and adherence to therapy, explaining in part the observed

  9. Altered Gene Expression by Low-Dose Arsenic Exposure in Humans and Cultured Cardiomyocytes: Assessment by Real-Time PCR Arrays

    PubMed Central

    Mo, Jinyao; Xia, Yajuan; Wade, Timothy J.; DeMarini, David M.; Davidson, Mercy; Mumford, Judy

    2011-01-01

    Chronic arsenic exposure results in higher risk of skin, lung, and bladder cancer, as well as cardiovascular disease and diabetes. The purpose of this study was to investigate the effects on expression of selected genes in the blood lymphocytes from 159 people exposed chronically to arsenic in their drinking water using a novel RT-PCR TaqMan low-density array (TLDA). We found that expression of tumor necrosis factor-α (TNF-α), which activates both inflammation and NF-κB-dependent survival pathways, was strongly associated with water and urinary arsenic levels. Expression of KCNA5, which encodes a potassium ion channel protein, was positively associated with water and toe nail arsenic levels. Expression of 2 and 11 genes were positively associated with nail and urinary arsenic, respectively. Because arsenic exposure has been reported to be associated with long QT intervals and vascular disease in humans, we also used this TLDA for analysis of gene expression in human cardiomyocytes exposed to arsenic in vitro. Expression of the ion-channel genes CACNA1, KCNH2, KCNQ1 and KCNE1 were down-regulated by 1-μM arsenic. Alteration of some common pathways, including those involved in oxidative stress, inflammatory signaling, and ion-channel function, may underlay the seemingly disparate array of arsenic-associated diseases, such as cancer, cardiovascular disease, and diabetes. PMID:21776218

  10. Aberrant cell divisions in root meristeme of maize following exposure to X-rays low doses compared to similar effects of 50 Hz electromagnetic exposure

    NASA Astrophysics Data System (ADS)

    Focea, R.; Capraru, G.; Racuciu, M.; Creanga, D.; Luchian, T.

    2012-04-01

    The response of maize to radiation exposure was investigated by two cytogenetic methods considering the importance of the geno-toxic effect for environmental and agricultural purposes. Uniform genophond seeds, freshly germinated, were exposed to relatively low radiation doses using a radiotherapy X-ray applicator from a hospital irradiation device and to a 50 Hz electromagnetic field with about 10 mT magnetic induction (generated within laboratory assembled electromagnetic coils). Radicular meristeme tissue aliquots were prevailed for cytogenetic investigation based on microscopic observations and cell counting. Microscope slides were prepared following a specific procedure (squash technique and Feulgen method based on modified Carr reactive coloration). Mitotic index as well as chromosomal aberration percentage were calculated for more than 30,000 cells taken into account. From a qualitative viewpoint, chromosomal aberrations such as interchromatidian bridges, lagging and expelled chromosomes and multipolar divisions were evidenced - no distinct situation for either ionizing radiation or electromagnetic field being identified. The main quantitative difference consisted in the increased mitotic index for electromagnetic exposure increased times compared with the diminished mitotic index in the case of low X-ray doses.

  11. An innovative in vitro device providing continuous low doses of gamma-rays and altered gravity mimicking spatial exposure: dosimetry study

    NASA Astrophysics Data System (ADS)

    Collin, Laetitia; Courtade-Saidi, Monique; Pereda Loth, Veronica; Franceries, Xavier; Afonso, Anne Sophie; Ayala, Alicia; Bardies, Manuel

    Astronauts are exposed to microgravity and chronic irradiation. Experimental conditions combining these two factors are difficult to reproduce on earth. The aim of our study was to create an experimental device able to combine chronic irradiation and altered gravity that may be used for cell cultures or plant models. Irradiation was provided with Thorium nitrate powder, conditioned in several bags in order to obtain a sealed source. This source was placed in an incubator. Lead leafs covered the internal walls of the incubator in order to protect people outside from radiations. Cell plates or plants seeds could be placed on direct contact with the source or at different distances above the source. Moreover, a random positioning machine (RPM) was placed inside the incubator and positioned on the source. The dosimetry was performed for different experimental conditions. The activity of the source was established considering all the decay chain of thorium. The spectrum of the source calculated according to the natural decrease of radioactivity was compared with gamma spectrometry (InterceptorTM) and showed a very good adequacy. The fluence evaluated with a gamma detector was closed to the theoretical fluence evaluated with our model, attesting that the source was uniformly distributed. Dosimetry was performed with radiophotoluminescent dosimeters (RPL) placed for one month exposition in different locations (x and y axis) inside cell culture dishes. When the dishes were placed directly on the source, we obtained a dose rate from 660 to 983 mSv/year, while it was between 80 to 127 mSv/year at a distance of 14.5 cm above the source. Using the RPM placed on the source we reached median dose rate levels of 140 mSv/year. In conclusion, we have elaborated a new device allowing the combination of chronic radiation exposure and altered gravity. This device can be used by researchers interested in the field of space biology.

  12. Effects of prenatal exposure to a low dose atrazine metabolite mixture on pubertal timing and prostate development of male Long-Evans rats

    SciTech Connect

    Stanko, Jason; Enoch, Rolondo; Rayner, Jennifer L; Davis, Christine; Wolf, Douglas; Malarkey, David; Fenton, Suzanne

    2010-12-01

    The present study examines the postnatal reproductive development of male rats following prenatal exposure to an atrazine metabolite mixture (AMM) consisting of the herbicide atrazine and its environmental metabolites diaminochlorotriazine, hydroxyatrazine, deethylatrazine, and deisopropylatrazine. Pregnant Long-Evans rats were treated by gavage with 0.09, 0.87, or 8.73 mg AMM/kg body weight (BW), vehicle, or 100 mg ATR/kg BW positive control, on gestation days 15 19. Preputial separation was significantly delayed in 0.87 mg and 8.73 mg AMM-exposed males. AMM-exposed males demonstrated a significant treatment-related increase in incidence and severity of inflammation in the prostate on postnatal day (PND) 120. A dose-dependent increase in epididymal fat masses and prostate foci were grossly visible in AMM-exposed offspring. These results indicate that a short, late prenatal exposure to mixture of chlorotriazine metabolites can cause chronic prostatitis in male LE rats. The mode of action for these effects is presently unclear.

  13. Effects of prenatal exposure to a low dose atrazine metabolite mixture on pubertal timing and prostate development of male Long-Evans rats.

    PubMed

    Stanko, Jason P; Enoch, Rolondo R; Rayner, Jennifer L; Davis, Christine C; Wolf, Douglas C; Malarkey, David E; Fenton, Suzanne E

    2010-12-01

    The present study examines the postnatal reproductive development of male rats following prenatal exposure to an atrazine metabolite mixture (AMM) consisting of the herbicide atrazine and its environmental metabolites diaminochlorotriazine, hydroxyatrazine, deethylatrazine, and deisopropylatrazine. Pregnant Long-Evans rats were treated by gavage with 0.09, 0.87, or 8.73mg AMM/kg body weight (BW), vehicle, or 100mg ATR/kg BW positive control, on gestation days 15-19. Preputial separation was significantly delayed in 0.87 mg and 8.73mg AMM-exposed males. AMM-exposed males demonstrated a significant treatment-related increase in incidence and severity of inflammation in the prostate on postnatal day (PND) 120. A dose-dependent increase in epididymal fat masses and prostate foci were grossly visible in AMM-exposed offspring. These results indicate that a short, late prenatal exposure to mixture of chlorotriazine metabolites can cause chronic prostatitis in male LE rats. The mode of action for these effects is presently unclear.

  14. ADVANCE: Study to Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Hemodialysis

    ClinicalTrials.gov

    2014-07-14

    Chronic Kidney Disease; End Stage Renal Disease; Coronary Artery Calcification; Vascular Calcification; Calcification; Cardiovascular Disease; Chronic Renal Failure; Hyperparathyroidism; Kidney Disease; Nephrology; Secondary Hyperparathyroidism

  15. Health benefits from low-dose irradiation

    SciTech Connect

    Luckey, T.D.

    1996-12-31

    Whole-body exposures of mice and humans show no harm from low doses of ionizing radiation. Forty reports show statistically significant, p < 0.01, beneficial effects when cancer and total mortality rates were examined in mice. In vitro experiments indicate that radiogenic metabolism, adaptive repair mechanisms, such as DNA repair enzymes, and the essential nature of ionizing radiation are responsible for part of this activity. However, overwhelming evidence shows that low-dose irradiation increases immune competence. Such data negate the linear concept, which has no reliable whole-animal data to support it in the low-dose range. Cell culture data are not pertinent; such cells do not have a complete immune system.

  16. Repeated exposure of male mice to low doses of lipopolysaccharide: dose and time dependent development of behavioral sensitization and tolerance in an automated light-dark anxiety test.

    PubMed

    Banasikowski, Tomek J; Cloutier, Caylen J; Ossenkopp, Klaus-Peter; Kavaliers, Martin

    2015-06-01

    Although lipopolysaccharide (LPS) is widely used to examine immune behavior relationships there has been little consideration of the effects of low doses and the roles of sensitization and, or tolerance. Here low doses of LPS (1.0, 5.0 and 25.0 μg/kg) were peripherally administered to male mice on Days 1, 4, 28 and 32 after a baseline recording of anxiety-like behaviors in an automated light-dark apparatus (total time in the light chamber, number of light-dark transitions, nose pokes into the light chamber). LPS at 1.0 μg/kg, while having no significant effects on anxiety-like behaviors in the light-dark test on Days 1 and 4, displayed sensitization with the mice exhibiting significantly enhanced anxiety-like responses on Days 28 and 32. LPS at 5.0 μg/kg had no consistent significant effects on anxiety-like behavior on Days 1 and 4, with sensitization and enhanced anxiety-like behaviors on Day 28 followed by tolerance on Day 32. LPS at 25 μg/kg significantly enhanced anxiety-like behaviors on Day 1, followed by tolerance on Day 4, which was not evident by Day 28 and re-emerged on Day 32. There was a similar overall pattern of sensitization and tolerance for LPS-induced decreases in locomotor activity in the safe dark chamber, without, however, any significant effects on activity in the riskier light chamber. This shows that low doses of LPS induce anxiety-like behavior and these effects are subject to sensitization and tolerance in a dose, context, and time related manner.

  17. Short communication: Survival of Mycobacterium avium ssp. paratuberculosis in tissues of cows following low-dose exposure to electron beam irradiation.

    PubMed

    Bode, John F; Thoen, Charles O

    2016-08-01

    This investigation was designed to determine the effects of low-dose electron beam irradiation on the survival of Mycobacterium avium ssp. paratuberculosis in tissue samples collected at necropsy from clinically affected cows. Mycobacterium avium ssp. paratuberculosis was isolated from the ileum and ileocecal valve of one cow and from the ileum of another cow irradiated at 4.0 kGy, but was not isolated from the ileum, ileocecal valve, or mesenteric lymph node of 11 other cows irradiated at 4 kGy.

  18. LINE-1 gene hypomethylation and p16 gene hypermethylation in HepG2 cells induced by low-dose and long-term triclosan exposure: The role of hydroxyl group.

    PubMed

    Zeng, Liudan; Ma, Huimin; Pan, Shangxia; You, Jing; Zhang, Gan; Yu, Zhiqing; Sheng, Guoying; Fu, Jiamo

    2016-08-01

    Triclosan (TCS), a frequently used antimicrobial agent in pharmaceuticals and personal care products, exerts liver tumor promoter activities in mice. Previous work showed high-dose TCS (1.25-10μM) induced global DNA hypomethylation in HepG2 cells. However, whether or how tumor suppressor gene methylation changed in HepG2 cells after low-dose and long-term TCS exposure is still unknown. We investigate here the effects and mechanisms of DNA methylation of global DNA(GDM), repetitive genes, and liver tumor suppressor gene (p16) after exposing HepG2 cells to low-dose TCS (0.625-5nM)for two weeks using HPLC-MS/MS, Methylight, Q-MSP, Pyrosequencing, and Massarray methods. We found that low-dose TCS exposure decreased repetitive elements LINE-1 methylation levels, but not global DNA methylation, through down-regulating DNMT1 (DNA methyltransferase 1) and MeCP2 (methylated DNA binding domain) expression, and up-regulating 8-hydroxy-2-deoxyguanosine (8-OHdG) levels. Interestingly, low-dose TCS elevated p16 gene methylation and inhibited p16 expression, which were not observed in high-dose (10μM) group. Meanwhile, methyl-triclosan could not induce these two types of DNA methylation changes, suggesting the involvement of hydroxyl in TCS-mediated DNA methylation changes. Collectively, our results suggested low concentrations of TCS adversely affected HepG2 cells through DNA methylation dysregulation, and hydroxyl group in TCS played an important role in the effects. This study provided a better understanding on hepatotoxicity of TCS at environmentally relevant concentrations through epigenetic pathway.

  19. Changes in fibrinopeptide A peptides in the sera of rats chronically exposed to low doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

    PubMed

    Chen, Xi; Ma, Shi-wei; Ma, Xiao-ming; Xu, Yuan-jing; Tang, Nai-jun

    2012-03-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitously distributed endocrine disruptors. To investigate peptide changes in the sera of rats chronically exposed to TCDD and to explore the association of these changes with liver morphology, TCDD was administrated to male rats at doses of 140, 350, and 875 ng/kg/week for 29 weeks. Serum was collected and proteomic analysis was performed using automated Bruker Daltonics ClinProt with matrix-assisted laser desorption/ionization time-of-flight mass spectrometer. One peptide at 1740.89 was found to be significantly decreased and further identified with nano LC-MS/MS system. The MS BLAST homology search engine reported the peptide to be a partial sequence of fibrinopeptide A. Liver fatty degeneration and necrosis were assessed by hematoxylin and eosin staining. Liver fatty degeneration and necrosis were both found to be significantly increased after TCDD exposure. Levels of fibrinopeptide A were significantly correlated with liver fatty degeneration and necrosis.

  20. Biology Based Lung Cancer Model for Chronic Low Radon Exposures

    NASA Astrophysics Data System (ADS)

    TruÅ£ǎ-Popa, Lucia-Adina; Hofmann, Werner; Fakir, Hatim; Cosma, Constantin

    2008-08-01

    Low dose effects of alpha particles at the tissue level are characterized by the interaction of single alpha particles, affecting only a small fraction of the cells within that tissue. Alpha particle intersections of bronchial target cells during a given exposure period were simulated by an initiation-promotion model, formulated in terms of cellular hits within the cycle time of the cell (dose-rate) and then integrated over the whole exposure period (dose). For a given average number of cellular hits during the lifetime of bronchial cells, the actual number of single and multiple hits was selected from a Poisson distribution. While oncogenic transformation is interpreted as the primary initiation step, stimulated mitosis by killing adjacent cells is assumed to be the primary radiological promotion event. Analytical initiation and promotion functions were derived from experimental in vitro data on oncogenic transformation and cellular survival. To investigate the shape of the lung cancer risk function at chronic, low level exposures in more detail, additional biological factors describing the tissue response and operating specifically at low doses were incorporated into the initiation-promotion model. These mechanisms modifying the initial response at the cellular level were: adaptive response, genomic instability, induction of apoptosis by surrounding cells, and detrimental as well as protective bystander mechanisms. To quantify the effects of these mechanisms as functions of dose, analytical functions were derived from the experimental evidence presently available. Predictions of lung cancer risk, including these mechanisms, exhibit a distinct sublinear dose-response relationship at low exposures, particularly for very low exposure rates.

  1. Epigenomic Adaptation to Low Dose Radiation

    SciTech Connect

    Gould, Michael N.

    2015-06-30

    The overall hypothesis of this grant application is that the adaptive responses elicited by low dose ionizing radiation (LDIR) result in part from heritable DNA methylation changes in the epigenome. In the final budget period at the University of Wisconsin-Madison, we will specifically address this hypothesis by determining if the epigenetically labile, differentially methylated regions (DMRs) that regulate parental-specific expression of imprinted genes are deregulated in agouti mice by low dose radiation exposure during gestation. This information is particularly important to ascertain given the 1) increased human exposure to medical sources of radiation; 2) increased number of people predicted to live and work in space; and 3) enhanced citizen concern about radiation exposure from nuclear power plant accidents and terrorist ‘dirty bombs.’

  2. Harderian Gland Tumorigenesis: Low-Dose and LET Response.

    PubMed

    Chang, Polly Y; Cucinotta, Francis A; Bjornstad, Kathleen A; Bakke, James; Rosen, Chris J; Du, Nicholas; Fairchild, David G; Cacao, Eliedonna; Blakely, Eleanor A

    2016-05-01

    Increased cancer risk remains a primary concern for travel into deep space and may preclude manned missions to Mars due to large uncertainties that currently exist in estimating cancer risk from the spectrum of radiations found in space with the very limited available human epidemiological radiation-induced cancer data. Existing data on human risk of cancer from X-ray and gamma-ray exposure must be scaled to the many types and fluences of radiations found in space using radiation quality factors and dose-rate modification factors, and assuming linearity of response since the shapes of the dose responses at low doses below 100 mSv are unknown. The goal of this work was to reduce uncertainties in the relative biological effect (RBE) and linear energy transfer (LET) relationship for space-relevant doses of charged-particle radiation-induced carcinogenesis. The historical data from the studies of Fry et al. and Alpen et al. for Harderian gland (HG) tumors in the female CB6F1 strain of mouse represent the most complete set of experimental observations, including dose dependence, available on a specific radiation-induced tumor in an experimental animal using heavy ion beams that are found in the cosmic radiation spectrum. However, these data lack complete information on low-dose responses below 0.1 Gy, and for chronic low-dose-rate exposures, and there are gaps in the LET region between 25 and 190 keV/μm. In this study, we used the historical HG tumorigenesis data as reference, and obtained HG tumor data for 260 MeV/u silicon (LET ∼70 keV/μm) and 1,000 MeV/u titanium (LET ∼100 keV/μm) to fill existing gaps of data in this LET range to improve our understanding of the dose-response curve at low doses, to test for deviations from linearity and to provide RBE estimates. Animals were also exposed to five daily fractions of 0.026 or 0.052 Gy of 1,000 MeV/u titanium ions to simulate chronic exposure, and HG tumorigenesis from this fractionated study were compared to the

  3. Adaptive hormetic response of pre-exposure of mouse brain with low-dose 12C 6+ ion or 60Co γ-ray on growth hormone (GH) and body weight induced by subsequent high-dose irradiation

    NASA Astrophysics Data System (ADS)

    Zhang, Hong; Xie, Yi; Zhou, Qingming; Liu, Bing; Li, Wenjian; Li, Xiaoda; Duan, Xin; Yuan, Zhigang; Zhou, Guangming; Min, Fengling

    2006-01-01

    The brain of the Kun-Ming strain mice were irradiated with 0.05 Gy of 12C 6+ ion or 60Co γ-ray as the pre-exposure dose, and were then irradiated with 2 Gy of 12C 6+ ion or 60Co γ-ray as challenging irradiation dose at 4 h after per-exposure. Body weight and serum growth hormone (GH) concentration were measured at 35th day after irradiation. The results showed that irradiation of mouse brain with 2 Gy of 12C 6+ ion or 60Co γ-ray significantly diminished mouse body weight and level of serum GH. The relative biological effectiveness values of a 2 Gy dose of 12C 6+ ion calculated with respect to 60Co γ-ray were 1.47 and 1.34 for body weight and serum GH concentration, respectively. Pre-exposure with a low-dose (0.05 Gy) of 12C 6+ ion or 60Co γ-ray significantly alleviated reductions of mouse body weight and level of serum GH induced by a subsequent high-dose (2 Gy) irradiation. The data suggested that low-dose ionizing irradiation can induce adaptive hormetic responses to the harmful effects of pituitary by subsequent high-dose exposure.

  4. Neonatal exposure to low dose corticosterone persistently modulates hippocampal mineralocorticoid receptor expression and improves locomotor/exploratory behaviour in a mouse model of Rett syndrome.

    PubMed

    De Filippis, Bianca; Ricceri, Laura; Fuso, Andrea; Laviola, Giovanni

    2013-05-01

    Rett syndrome (RTT) is a pervasive neurodevelopmental disorder, primarily affecting girls. RTT causes a wide variety of debilitating symptoms and no cure currently exists. Mouse models bearing mutations in the Mecp2 gene recapitulate most physiological and behavioural RTT-related abnormalities. Stimulating neonatal environments (e.g. brief maternal separations or maternal low-dose corticosterone supplementation) reduce stress and fear responses at adulthood. The present study investigated whether impacting early in development the hypothalamic-pituitary-adrenal axis, by exposing Mecp2-308 mutant pups to a low dose of corticosterone (50 µg/ml, during the 1st week of life) may contrast RTT-related abnormalities in neuroendocrine regulation and behavioural adaptation at adulthood. In line with previous reports, when fully symptomatic, MeCP2-308 mice showed a reduction in the regular nocturnal hyperactivity in the home-cage and increased anxiety-like behaviours and plasma corticosterone (CORT) levels in response to restraint stress. An abnormal elevation in mRNA levels of mineralocorticoid receptors (MR) and BDNF gene was also evident in the hippocampus of fully symptomatic mutant mice. Neonatal CORT modulated MR gene expression and behavioural reactivity towards a novel object, also restoring wt-like levels of locomotor/exploratory behaviour in mutant mice. Enhanced sensitivity to the neonatal treatment (in terms of increase in GR and MR mRNA levels), was also evident in the hippocampus of MeCP2-308 mice compared to wt littermates. Present results corroborate the hypothesis that targeting the glucocorticoid system may prove valid in contrasting at least some of the RTT-related symptoms and provide evidence that pharmacological interventions during critical early time windows can persistently improve the behavioural phenotype of RTT mice. Current data also support the emerging role played by Mecp2 in mediating the epigenetic programming induced by early life events

  5. EARLY INDICATORS OF NITRATE STRESS; EFFECTS TO ECOSYSTEMS OF CHRONIC EXPOSURE TO LOW DOSES OF BIOAVAILABLE NITROGEN

    EPA Science Inventory

    Throughout the eastern United States, from the Front Range of the Rocky Mountains to the Atlantic Ocean, bioavailable nitrogen has been falling in the rain since the industrial revolution. Bioavailable nitrogen is a limiting nutrient throughout this region. While long-term rese...

  6. EARLY INDICATORS OF NITRATE STRESS; EFFECTS TO ECOSYSTEMS OF CHRONIC EXPOSURE TO LOW DOSES OF BIOAVAILABE NITROGEN

    EPA Science Inventory

    Throughout the eastern United States, from the Front Range of the Rocky Mountains to the Atlantic Ocean, bioavailable nitrogen has been falling in the rain since the industrial revolution. Bioavailable nitrogen is a limiting nutrient throughout this region. While long-term rese...

  7. Digital Tomosynthesis of the Chest: Comparison of Patient Exposure Dose and Image Quality between Standard Default Setting and Low Dose Setting

    PubMed Central

    Hwang, Hye Sun; Lee, Kyung Soo

    2013-01-01

    Objective To determine the optimum low dose (LD) digital tomosynthesis (DT) setting, and to compared the image quality of the LD DT with that of the standard default (SD) DT. Materials and Methods Nine DT settings, by changing tube voltage, copper filter, and dose ratio, were performed for determining the LD setting. Among combinations of DT setting, a condition providing the lowest radiation dose was determined. Eighty artificial nodules less than 1 cm in diameter (subcentimeter nodules: 40, micronodules less than 4 mm: 40) were attached to a Styrofoam and a diaphragm of the phantom. Among these, 38 nodules were located at the periphery of the lung (thin area) and 42 nodules were located at the paravertebral or sub-diaphragmatic area (thick area). Four observers counted the number of nodules detected in the thick and thin areas. The detection sensitivity in SD and LD settings were calculated separately. Data were analyzed statistically. Results The lowest LD setting was a combination of 100 kVp, 0.3 mm additional copper filter, and a 1 : 5 dose ratio. The effective dose for the LD and SD settings were 62 µSv and 140 µSv, separately. A 56.7% dose reduction was achieved in the LD setting compared with the SD setting. Detection sensitivities were not different between the SD and the LD settings except between observers 1 and 2 for the detection of micronodules in the thick area. Conclusion LD DT can be effective in nodule detection bigger than 4 mm without a significant decrease in image quality compared with SD DT. PMID:23690724

  8. The effect of low-dose exposure on germline microsatellite mutation rates in humans accidentally exposed to caesium-137 in Goiânia.

    PubMed

    Costa, Emília Oliveira Alves; de Melo e Silva, Daniela; de Melo, Aldaires Vieira; Godoy, Fernanda Ribeiro; Nunes, Hugo Freire; Pedrosa, Eduardo Rocha; Flores, Braúlio Cançado; Rodovalho, Ricardo Goulart; da Silva, Cláudio Carlos; da Cruz, Aparecido Divino

    2011-09-01

    A serious radiological accident occurred in 1987 in Goiânia, Brazil, which lead to extensive human and environmental contamination as a result of ionising radiation (IR) from caesium-137. Among the exposed were those in direct contact with caesium-137, their relatives, neighbours, liquidators and health personnel involved in the handling of the radioactive material and the clean-up of the radioactive sites. The exposed group consisted of 10 two-generation families, totalling 34 people. For each exposed family, at least one of the progenitors was directly exposed to very low doses of γ-IR. The control group consisted of 215 non-irradiated families, composed of a father, mother and child, all of them from Goiânia, Brazil. Genomic DNA was purified using 100 μl of whole blood. The amplification reactions were prepared according to PowerPlex® 16, following the manufacturer's instructions. Genetic profiles were obtained from a single polymerase chain reaction amplification. The exposed group had only one germline mutation of a paternal origin in the 'locus' D8S1179 and the observed mutation presented a gain of only one repeat unit. In the control group, 11 mutations were observed and the mutational events were distributed in five loci D16S539, D3S1358, FGA, Penta E and D21S11. The mutation rates for the exposed and control groups were 0.006 and 0.002, respectively. There was no statistically significant difference (P = 0.09) between the mutation rate of the exposed and control groups. In conclusion, the quantification of mutational events in short tandem repeats can provide a useful system for detecting induced mutations in a relatively small population.

  9. Role of DNA methylation in the adaptive responses induced in a human B lymphoblast cell line by long-term low-dose exposures to γ-rays and cadmium.

    PubMed

    Ye, Shuang; Yuan, Dexiao; Xie, Yuexia; Pan, Yan; Shao, Chunlin

    2014-10-01

    The possible involvement of epigenetic factors in health risks due to exposures to environmental toxicants and ionizing radiation is poorly understood. We have tested the hypothesis that DNA methylation contributes to the adaptive response (AR) to ionizing radiation or Cd. Human B lymphoblast cells HMy2.CIR were irradiated (0.032 Gy γ-rays) three times per week for 4 weeks or exposed to CdCl2 (0.005, 0.01, or 0.1 μM) for 3 months, and then challenged with a high dose of Cd (50 or 100 μM) or γ-rays (2 Gy). Long-term low-dose radiation (LDR) or long-term low-dose Cd exposure induced AR against challenging doses of Cd and irradiation, respectively. When the primed cells were treated with 5-aza-2'-deoxycytidine (5-aza-dC), a DNA methyltransferase inhibitor, the ARs were eliminated. These results indicate that DNA methylation is involved in the induction of AR in HMy2.CIR cells.

  10. Effects of Prenatal Exposure to a Low Dose Atrazine Metabolite Mixture on pubertal timing and prostrate Development of Male Long Evans Rats.

    EPA Science Inventory

    The present study examines the postnatal reproductive development of male rats following prenatal exposure to an atrazine metabolite mixture (AMM) consisting of the herbicide atrazine and its environmental metabolites diaminochlorotriazine, hydroxyatrazine, deethylatrazine, and d...

  11. Breast cancer risk from low-dose exposures to ionizing radiation: results of parallel analysis of three exposed populations of women

    SciTech Connect

    Land, C.E.; Boice, J.D. Jr.; Shore, R.E.; Norman, J.E.; Tokunaga, M.

    1980-08-01

    Breast cancer incidence data were analyzed from three populations of women exposed to ionizing radiation: survivors of the Hiroshima and Nagasaki atomic bombs, patients in Massachusetts tuberculosis sanitoria who were exposed to multiple chest fluoroscopies, and patients treated by X-rays for acute postpartum mastitis in Rochester, New York. Parallel analyses by radiation dose, age at exposure, and time after exposure suggested that risk of radiation-induced cancer increased approximately linearly with increasing dose and was heavily dependent on age at exposure; however, the risk was otherwise remarkably similar among the three populations, at least for ages 10 to 40 years at exposure, and followed the same temporal pattern of occurrence as did breast cancer incidence in nonexposed women of similar ages.

  12. Genomic Instability Induced by Low Dose Irradiation

    SciTech Connect

    Evans, Helen H. Sedwick, David W. Veigl, Martina L.

    2006-07-15

    The goal of this project was to determine if genomic instability could be initiated by poorly repaired DNA damage induced by low doses of ionizing radiation leading to a mutator phenotype. Human cells were irradiated, then transfected with an unirradiated reporter gene at various times AFTER exposure. The vector carried an inactive GFP gene that fluoresced when the gene was activated by a delayed mutation. Fluorescent cells were measured in the interval of 50 hours to four days after transfection. The results showed that delayed mutations occurred in these cells after exposure to relatively low doses (0.3-1.0 Gy) of low or high ionizing radiation, as well as after treatment with hyrodgen peroxide (30-100 micromolar). The occurrence was both dose and time dependent, often decreasing at higher doses and later times. No marked difference was observed between the response of mis-match repair-proficient and -deficient cell lines. Although the results were quite reproducible within single experiments, difficulties were observed from experiment to experiment. Different reagents and assays were tested, but no improvement resulted. We concluded that this method is not sufficiently robust or consisent to be useful in the assay of the induction of genomic instability by low doses of radiation, at least in these cell lines under our conditions.

  13. Short-term chamber exposure to low doses of two kinds of wood smoke does not induce systemic inflammation, coagulation or oxidative stress in healthy humans

    PubMed Central

    Sallsten, Gerd; Almerud, Pernilla; Basu, Samar; Barregard, Lars

    2013-01-01

    Introduction: Air pollution increases the risk of cardiovascular diseases. A proposed mechanism is that local airway inflammation leads to systemic inflammation, affecting coagulation and the long-term risk of atherosclerosis. One major source of air pollution is wood burning. Here we investigate whether exposure to two kinds of wood smoke, previously shown to cause airway effects, affects biomarkers of systemic inflammation, coagulation and lipid peroxidation. Methods: Thirteen healthy adults were exposed to filtered air followed by two sessions of wood smoke for three hours, one week apart. One session used smoke from the start-up phase of the wood-burning cycle, and the other smoke from the burn-out phase. Mean particle mass concentrations were 295 µg/m3 and 146 µg/m3, and number concentrations were 140 000/cm3 and 100 000/cm3, respectively. Biomarkers were analyzed in samples of blood and urine taken before and several times after exposure. Results after wood smoke exposure were adjusted for exposure to filtered air. Results: Markers of systemic inflammation and soluble adhesion molecules did not increase after wood smoke exposure. Effects on markers of coagulation were ambiguous, with minor decreases in fibrinogen and platelet counts and mixed results concerning the coagulation factors VII and VIII. Urinary F2-isoprostane, a consistent marker of in vivo lipid peroxidation, unexpectedly decreased after wood smoke exposure. Conclusions: The effects on biomarkers of inflammation, coagulation and lipid peroxidation do not indicate an increased risk of cardiovascular diseases in healthy adults by short-term exposure to wood smoke at these moderate doses, previously shown to cause airway effects. PMID:23808634

  14. Mammography-oncogenecity at low doses.

    PubMed

    Heyes, G J; Mill, A J; Charles, M W

    2009-06-01

    dose exposure, it is not a low dose rate examination, and protraction of dose should not be confused with fractionation. Although there is potential for a suppressive effect at low doses, recent epidemiological data, and several international radiation risk assessments, continue to promote the linear no-threshold (LNT) model. Finally, recent studies have shown that magnetic resonance imaging (MRI) is more sensitive than mammography in detecting invasive breast cancer in women with a genetic sensitivity. Since an increase in the risk associated with mammographic screening would blur the justification of exposure for this high risk subgroup, the use of other (non-ionising) screening modalities is preferable.

  15. Quantification of damage due to low-dose radiation exposure in mice: construction and application of a biodosimetric model using mRNA indicators in circulating white blood cells

    PubMed Central

    Ishihara, Hiroshi; Tanaka, Izumi; Yakumaru, Haruko; Tanaka, Mika; Yokochi, Kazuko; Fukutsu, Kumiko; Tajima, Katsushi; Nishimura, Mayumi; Shimada, Yoshiya; Akashi, Makoto

    2016-01-01

    Biodosimetry, the measurement of radiation damage in a biologic sample, is a reliable tool for increasing the accuracy of dose estimation. Although established chromosome analyses are suitable for estimating the absorbed dose after high-dose irradiation, biodosimetric methodology to measure damage following low-dose exposure is underdeveloped. RNA analysis of circulating blood containing radiation-sensitive cells is a candidate biodosimetry method. Here we quantified RNA from a small amount of blood isolated from mice following low-dose body irradiation (<0.5 Gy) aimed at developing biodosimetric tools for situations that are difficult to study in humans. By focusing on radiation-sensitive undifferentiated cells in the blood based on Myc RNA expression, we quantified the relative levels of RNA for DNA damage-induced (DDI) genes, such as Bax, Bbc3 and Cdkn1a. The RNA ratios of DDI genes/Myc in the blood increased in a dose-dependent manner 4 h after whole-body irradiation at doses ranging from 0.1 to 0.5 Gy (air-kerma) of X-rays, regardless of whether the mice were in an active or resting state. The RNA ratios were significantly increased after 0.014 Gy (air-kerma) of single X-ray irradiation. The RNA ratios were directly proportional to the absorbed doses in water ranging from 0.1 to 0.5 Gy, based on gamma-irradiation from 137Cs. Four hours after continuous irradiation with gamma-rays or by internal contamination with a beta-emitter, the increased RNA ratios resembled those following single irradiation. These findings indicate that the RNA status can be utilized as a biodosimetric tool to estimate low-dose radiation when focusing on undifferentiated cells in blood. PMID:26589759

  16. Quantification of damage due to low-dose radiation exposure in mice: construction and application of a biodosimetric model using mRNA indicators in circulating white blood cells.

    PubMed

    Ishihara, Hiroshi; Tanaka, Izumi; Yakumaru, Haruko; Tanaka, Mika; Yokochi, Kazuko; Fukutsu, Kumiko; Tajima, Katsushi; Nishimura, Mayumi; Shimada, Yoshiya; Akashi, Makoto

    2016-01-01

    Biodosimetry, the measurement of radiation damage in a biologic sample, is a reliable tool for increasing the accuracy of dose estimation. Although established chromosome analyses are suitable for estimating the absorbed dose after high-dose irradiation, biodosimetric methodology to measure damage following low-dose exposure is underdeveloped. RNA analysis of circulating blood containing radiation-sensitive cells is a candidate biodosimetry method. Here we quantified RNA from a small amount of blood isolated from mice following low-dose body irradiation (<0.5 Gy) aimed at developing biodosimetric tools for situations that are difficult to study in humans. By focusing on radiation-sensitive undifferentiated cells in the blood based on Myc RNA expression, we quantified the relative levels of RNA for DNA damage-induced (DDI) genes, such as Bax, Bbc3 and Cdkn1a. The RNA ratios of DDI genes/Myc in the blood increased in a dose-dependent manner 4 h after whole-body irradiation at doses ranging from 0.1 to 0.5 Gy (air-kerma) of X-rays, regardless of whether the mice were in an active or resting state. The RNA ratios were significantly increased after 0.014 Gy (air-kerma) of single X-ray irradiation. The RNA ratios were directly proportional to the absorbed doses in water ranging from 0.1 to 0.5 Gy, based on gamma-irradiation from (137)Cs. Four hours after continuous irradiation with gamma-rays or by internal contamination with a beta-emitter, the increased RNA ratios resembled those following single irradiation. These findings indicate that the RNA status can be utilized as a biodosimetric tool to estimate low-dose radiation when focusing on undifferentiated cells in blood.

  17. Effects of prenatal exposure to a low dose atrazine metabolite mixture onpubertal timing and prostate development of male Long-Evans rats

    EPA Science Inventory

    Atrazine (ATR) is a chlorotriazine herbicide extensively used in the US and other countries. Studies examining the effects of adult or developmental ATR exposure on the mammary gland (MG) have used either the Sprague Dawley (SD) or Long-Evans (LE) rat, but no strain comparisons h...

  18. Granzyme B mediates both direct and indirect cleavage of extracellular matrix in skin after chronic low-dose ultraviolet light irradiation

    PubMed Central

    Parkinson, Leigh G; Toro, Ana; Zhao, Hongyan; Brown, Keddie; Tebbutt, Scott J; Granville, David J

    2015-01-01

    Extracellular matrix (ECM) degradation is a hallmark of many chronic inflammatory diseases that can lead to a loss of function, aging, and disease progression. Ultraviolet light (UV) irradiation from the sun is widely considered as the major cause of visible human skin aging, causing increased inflammation and enhanced ECM degradation. Granzyme B (GzmB), a serine protease that is expressed by a variety of cells, accumulates in the extracellular milieu during chronic inflammation and cleaves a number of ECM proteins. We hypothesized that GzmB contributes to ECM degradation in the skin after UV irradiation through both direct cleavage of ECM proteins and indirectly through the induction of other proteinases. Wild-type and GzmB-knockout mice were repeatedly exposed to minimal erythemal doses of solar-simulated UV irradiation for 20 weeks. GzmB expression was significantly increased in wild-type treated skin compared to nonirradiated controls, colocalizing to keratinocytes and to an increased mast cell population. GzmB deficiency significantly protected against the formation of wrinkles and the loss of dermal collagen density, which was related to the cleavage of decorin, an abundant proteoglycan involved in collagen fibrillogenesis and integrity. GzmB also cleaved fibronectin, and GzmB-mediated fibronectin fragments increased the expression of collagen-degrading matrix metalloproteinase-1 (MMP-1) in fibroblasts. Collectively, these findings indicate a significant role for GzmB in ECM degradation that may have implications in many age-related chronic inflammatory diseases. PMID:25495009

  19. Impact of Low Dose Oral Exposure to Bisphenol A (BPA) on the Neonatal Rat Hypothalamic and Hippocampal Transcriptome: A CLARITY-BPA Consortium Study.

    PubMed

    Arambula, Sheryl E; Belcher, Scott M; Planchart, Antonio; Turner, Stephen D; Patisaul, Heather B

    2016-10-01

    Bisphenol A (BPA) is an endocrine disrupting, high volume production chemical found in a variety of products. Evidence of prenatal exposure has raised concerns that developmental BPA may disrupt sex-specific brain organization and, consequently, induce lasting changes on neurophysiology and behavior. We and others have shown that exposure to BPA at doses below the no-observed-adverse-effect level can disrupt the sex-specific expression of estrogen-responsive genes in the neonatal rat brain including estrogen receptors (ERs). The present studies, conducted as part of the Consortium Linking Academic and Regulatory Insights of BPA Toxicity program, expanded this work by examining the hippocampal and hypothalamic transcriptome on postnatal day 1 with the hypothesis that genes sensitive to estrogen and/or sexually dimorphic in expression would be altered by prenatal BPA exposure. NCTR Sprague-Dawley dams were gavaged from gestational day 6 until parturition with BPA (0-, 2.5-, 25-, 250-, 2500-, or 25 000-μg/kg body weight [bw]/d). Ethinyl estradiol was used as a reference estrogen (0.05- or 0.5-μg/kg bw/d). Postnatal day 1 brains were microdissected and gene expression was assessed with RNA-sequencing (0-, 2.5-, and 2500-μg/kg bw BPA groups only) and/or quantitative real-time PCR (all exposure groups). BPA-related transcriptional changes were mainly confined to the hypothalamus. Consistent with prior observations, BPA induced sex-specific effects on hypothalamic ERα and ERβ (Esr1 and Esr2) expression and hippocampal and hypothalamic oxytocin (Oxt) expression. These data demonstrate prenatal BPA exposure, even at doses below the current no-observed-adverse-effect level, can alter gene expression in the developing brain.

  20. Long- and short-term changes in the neuroimmune-endocrine parameters following inhalation exposures of F344 rats to low-dose sarin.

    PubMed

    Peña-Philippides, Juan Carlos; Razani-Boroujerdi, Seddigheh; Singh, Shashi P; Langley, Raymond J; Mishra, Neerad C; Henderson, Rogene F; Sopori, Mohan L

    2007-05-01

    Inhalation of subclinical doses of sarin suppresses the antibody-forming cell (AFC) response, T-cell mitogenesis, and serum corticosterone (CORT) levels, and high doses of sarin cause lung inflammation. However, the duration of these changes is not known. In these studies, rats were exposed to a subclinical dose of sarin (0.4 mg/m3/h/day) for 1 or 5 days, and immune and inflammatory parameters were assayed up to 8 weeks before sarin exposure. Our results showed that the effects of a 5-day sarin exposure on the AFC response and T-cell receptor (TCR)-mediated Ca2+ response disappeared within 2-4 weeks after sarin exposure, whereas the CORT and adrenocorticotropin hormone (ACTH) levels remained significantly decreased. Pretreatment of rats with chlorisondamine attenuated the effects of sarin on the AFC and the TCR-mediated Ca2+ response, implicating the autonomic nervous system (ANS) in the sarin-induced changes in T-cell function. Moreover, exposure to a single or five repeated subclinical doses of sarin upregulated the mRNA expression of proinflammatory cytokines in the lung, which is associated with the activation of NFkappaB in bronchoalveolar lavage cells. These effects were lost within 2 weeks of sarin inhalation. Our results suggest that while sarin-induced changes in T cells and cytokine gene expression were short lived, suppression of CORT and ACTH levels were relatively long lived and might represent biomarkers of sarin exposure. Moreover, while the effects of sarin on T-cell function were regulated by the ANS, the decreased CORT levels by sarin might result from its effects on the hypothalamus-pituitary-adrenal axis.

  1. The cessation of the long-term exposure to low doses of mercury ameliorates the increase in systolic blood pressure and vascular damage in rats.

    PubMed

    Rizzetti, Danize Aparecida; Torres, João Guilherme Dini; Escobar, Alyne Goulart; da Silva, Taiz Martins; Moraes, Paola Zambelli; Hernanz, Raquel; Peçanha, Franck Maciel; Castro, Marta Miguel; Vassallo, Dalton Valentim; Salaices, Mercedes; Alonso, Maria Jesús; Wiggers, Giulia Alessandra

    2017-02-18

    This study aimed to verify whether a prolonged exposure to low-level mercury promotes haemodynamic disorders and studied the reversibility of this vascular damage. Rats were divided into seven groups: three control groups received saline solution (im) for 30, 60 or 90 days; two groups received HgCl2 (im, first dose, 4.6μg/kg, subsequent doses 0.07μg/kg/day) for 30 or 60 days; two groups received HgCl2 for 30 or 60 days (im, same doses) followed by a 30-day washout period. Systolic blood pressure (SBP) was measured, along with analysis of vascular response to acetylcholine (ACh) and phenylephrine (Phe) in the absence and presence of endothelium, a nitric oxide (NO) synthase inhibitor, an NADPH oxidase inhibitor, superoxide dismutase, a non-selective cyclooxygenase (COX) inhibitor and an AT1 receptor blocker. Reactive oxygen species (ROS) levels and antioxidant power were measured in plasma. HgCl2 exposure for 30 and 60 days: a) reduced the endothelium-dependent relaxation; b) increased the Phe-induced contraction and the contribution of ROS, COX-derived vasoconstrictor prostanoids and angiotensin II acting on AT1 receptors to this response while the NO participation was reduced; c) increased the oxidative stress in plasma; d) increased the SBP only after 60 days of exposure. After the cessation of HgCl2 exposure, SBP, endothelium-dependent relaxation, Phe-induced contraction and the oxidative stress were normalised, despite the persistence of the increased COX-derived prostanoids. These results demonstrated that long-term HgCl2 exposure increases SBP as a consequence of vascular dysfunction; however, after HgCl2 removal from the environment the vascular function ameliorates.

  2. Impact of Low-Dose Oral Exposure to Bisphenol A (BPA) on Juvenile and Adult Rat Exploratory and Anxiety Behavior: A CLARITY-BPA Consortium Study.

    PubMed

    Rebuli, Meghan E; Camacho, Luísa; Adonay, Maria E; Reif, David M; Aylor, David L; Patisaul, Heather B

    2015-12-01

    Bisphenol A (BPA) is a high volume production chemical and has been identified as an endocrine disruptor, prompting concern that developmental exposure could impact brain development and behavior. Rodent and human studies suggest that early life BPA exposure may result in an anxious, hyperactive phenotype but results are conflicting and data from studies using multiple doses below the no-observed-adverse-effect level are limited. To address this, the present studies were conducted as part of the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) program. The impact of perinatal BPA exposure (2.5, 25, or 2500 µg/kg body weight (bw)/day) on behaviors related to anxiety and exploratory activity was assessed in juvenile (prepubertal) and adult NCTR Sprague-Dawley rats of both sexes. Ethinyl estradiol (0.5 µg/kg bw/day) was used as a reference estrogen. Exposure spanned gestation and lactation with dams gavaged from gestational day 6 until birth and then the offspring gavaged directly through weaning (n = 12/sex/group). Behavioral assessments included open field, elevated plus maze, and zero maze. Anticipated sex differences in behavior were statistically identified or suggested in most cases. No consistent effects of BPA were observed for any endpoint, in either sex, at either age compared to vehicle controls; however, significant differences between BPA-exposed and ethinyl estradiol-exposed groups were identified for some endpoints. Limitations of this study are discussed and include suboptimal statistical power and low concordance across behavioral tasks. These data do not indicate BPA-related effects on anxiety or exploratory activity in these developmentally exposed rats.

  3. Impact of Low-Dose Oral Exposure to Bisphenol A (BPA) on Juvenile and Adult Rat Exploratory and Anxiety Behavior: A CLARITY-BPA Consortium Study

    PubMed Central

    Rebuli, Meghan E.; Camacho, Luísa; Adonay, Maria E.; Reif, David M.; Aylor, David L.; Patisaul, Heather B.

    2015-01-01

    Bisphenol A (BPA) is a high volume production chemical and has been identified as an endocrine disruptor, prompting concern that developmental exposure could impact brain development and behavior. Rodent and human studies suggest that early life BPA exposure may result in an anxious, hyperactive phenotype but results are conflicting and data from studies using multiple doses below the no-observed-adverse-effect level are limited. To address this, the present studies were conducted as part of the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) program. The impact of perinatal BPA exposure (2.5, 25, or 2500 µg/kg body weight (bw)/day) on behaviors related to anxiety and exploratory activity was assessed in juvenile (prepubertal) and adult NCTR Sprague-Dawley rats of both sexes. Ethinyl estradiol (0.5 µg/kg bw/day) was used as a reference estrogen. Exposure spanned gestation and lactation with dams gavaged from gestational day 6 until birth and then the offspring gavaged directly through weaning (n = 12/sex/group). Behavioral assessments included open field, elevated plus maze, and zero maze. Anticipated sex differences in behavior were statistically identified or suggested in most cases. No consistent effects of BPA were observed for any endpoint, in either sex, at either age compared to vehicle controls; however, significant differences between BPA-exposed and ethinyl estradiol-exposed groups were identified for some endpoints. Limitations of this study are discussed and include suboptimal statistical power and low concordance across behavioral tasks. These data do not indicate BPA-related effects on anxiety or exploratory activity in these developmentally exposed rats. PMID:26209558

  4. Effects of gestational and lactational exposure to low dose mercury chloride (HgCl2) on behaviour, learning and hearing thresholds in WAG/Rij rats

    PubMed Central

    Sahin, Deniz; Erdolu, Cem Onur; Karadenizli, Sabriye; Kara, Ahmet; Bayrak, Gunce; Beyaz, Sumeyye; Demir, Buse; Ates, Nurbay

    2016-01-01

    We investigated the effects of inorganic mercury exposure during gestational/lactational periods on the behaviour, learning and hearing functions in a total of 32, 5-week-old and 5-month-old WAG/Rij rats (equally divided into 4 groups as 5-week and 5-month control mercury exposure groups). We evaluated the rats in terms of locomotor activity (LA), the Morris-water-maze (MWM) test and the passive avoidance (PA) test to quantify learning and memory performance; we used distortion product otoacoustic emission (DPOAE) tests to evaluate hearing ability. There were no significant differences between the 5-week-old rat groups in LA, and we detected a significant difference (p < 0.05) in the HgCl2-treated group in PA, MWM and DPOAE tests compared with the control group. The HgCl2-treated 5-week-old group exhibited worse emotional memory performance in PA, worse spatial learning and memory performances in MWM. There were no significant differences between the groups of 5-month-old rats in LA, MWM or PA. However, the DPOAE tests worsened in the mid- and high-frequency hearing thresholds. The HgCl2-treated 5-month-old group exhibited the most hearing loss of all groups. Our results convey that mercury exposure in young rats may worsen learning and memory performances as well as hearing at high-frequency levels. While there was no statistically significant difference in the behavior and learning tests in adult rats, the DPOAE test produced poorer results. Early detection of effects of mercury exposure provides medicals team with an opportunity to determinate treatment regimens and mitigate ototoxicity. DPOAE test can be used in clinical and experimental research investigating heavy metal ototoxicity. PMID:27540351

  5. Effect of treatment with cyclophosphamide in low doses upon the onset of delayed type hypersensitivity in mice chronically infected with Trypanosoma cruzi: involvement of heart interstitial dendritic cells.

    PubMed

    Thé, Torriceli Souza; Portella, Renata Siqueira; Guerreiro, Marcos Lázaro; Andrade, Sonia Gumes

    2013-09-01

    Acute infection with Trypanosoma cruzi results in intense myocarditis, which progresses to a chronic, asymptomatic indeterminate form. The evolution toward this chronic cardiac form occurs in approximately 30% of all cases of T. cruzi infection. Suppression of delayed type hypersensitivity (DTH) has been proposed as a potential explanation of the indeterminate form. We investigated the effect of cyclophosphamide (CYCL) treatment on the regulatory mechanism of DTH and the participation of heart interstitial dendritic cells (IDCs) in this process using BALB/c mice chronically infected with T. cruzi. One group was treated with CYCL (20 mg/kg body weight) for one month. A DTH skin test was performed by intradermal injection of T. cruzi antigen (3 mg/mL) in the hind-footpad and measured the skin thickness after 24 h, 48 h and 72 h. The skin test revealed increased thickness in antigen-injected footpads, which was more evident in the mice treated with CYCL than in those mice that did not receive treatment. The thickened regions were characterised by perivascular infiltrates and areas of necrosis. Intense lesions of the myocardium were present in three/16 cases and included large areas of necrosis. Morphometric evaluation of lymphocytes showed a predominance of TCD8 cells. Heart IDCs were immunolabelled with specific antibodies (CD11b and CD11c) and T. cruzi antigens were detected using a specific anti-T. cruzi antibody. Identification of T. cruzi antigens, sequestered in these cells using specific anti-T. cruzi antibodies was done, showing a significant increase in the number of these cells in treated mice. These results indicate that IDCs participate in the regulatory mechanisms of DTH response to T. cruzi infection.

  6. Effects of embryonic ethanol exposure at low doses on neuronal development, voluntary ethanol consumption and related behaviors in larval and adult zebrafish: Role of hypothalamic orexigenic peptides.

    PubMed

    Sterling, M E; Chang, G-Q; Karatayev, O; Chang, S Y; Leibowitz, S F

    2016-05-01

    Embryonic exposure to ethanol is known to affect neurochemical systems in rodents and increase alcohol drinking and related behaviors in humans and rodents. With zebrafish emerging as a powerful tool for uncovering neural mechanisms of numerous diseases and exhibiting similarities to rodents, the present report building on our rat studies examined in zebrafish the effects of embryonic ethanol exposure on hypothalamic neurogenesis, expression of orexigenic neuropeptides, and voluntary ethanol consumption and locomotor behaviors in larval and adult zebrafish, and also effects of central neuropeptide injections on these behaviors affected by ethanol. At 24h post-fertilization, zebrafish embryos were exposed for 2h to ethanol, at low concentrations of 0.25% and 0.5%, in the tank water. Embryonic ethanol compared to control dose-dependently increased hypothalamic neurogenesis and the proliferation and expression of the orexigenic peptides, galanin (GAL) and orexin (OX), in the anterior hypothalamus. These changes in hypothalamic peptide neurons were accompanied by an increase in voluntary consumption of 10% ethanol-gelatin and in novelty-induced locomotor and exploratory behavior in adult zebrafish and locomotor activity in larvae. After intracerebroventricular injection, these peptides compared to vehicle had specific effects on these behaviors altered by ethanol, with GAL stimulating consumption of 10% ethanol-gelatin more than plain gelatin food and OX stimulating novelty-induced locomotor behavior while increasing intake of food and ethanol equally. These results, similar to those obtained in rats, suggest that the ethanol-induced increase in genesis and expression of these hypothalamic peptide neurons contribute to the behavioral changes induced by embryonic exposure to ethanol.

  7. Life-span exposure to sinusoidal-50 Hz magnetic field and acute low-dose γ radiation induce carcinogenic effects in Sprague-Dawley rats.

    PubMed

    Soffritti, Morando; Tibaldi, Eva; Padovani, Michela; Hoel, David G; Giuliani, Livio; Bua, Luciano; Lauriola, Michelina; Falcioni, Laura; Manservigi, Marco; Manservisi, Fabiana; Panzacchi, Simona; Belpoggi, Fiorella

    2016-01-01

    Background In 2002 the International Agency for Research on Cancer classified extremely low frequency magnetic fields (ELFMF) as a possible carcinogen on the basis of epidemiological evidence. Experimental bioassays on rats and mice performed up to now on ELFMF alone or in association with known carcinogens have failed to provide conclusive confirmation. Objectives To study the carcinogenic effects of combined exposure to sinusoidal-50 Hz (S-50 Hz) magnetic fields and acute γ radiation in Sprague-Dawley rats. Methods We studied groups of male and female Sprague-Dawley rats exposed from prenatal life until natural death to 20 or 1000 μT S-50 Hz MF and also to 0.1 Gy γ radiation delivered as a single acute exposure at 6 weeks of age. Results The results of the study showed significant carcinogenic effects for the mammary gland in males and females and a significant increased incidence of malignant schwannomas of the heart as well as increased incidence of lymphomas/leukemias in males. Conclusions These results call for a re-evaluation of the safety of non-ionizing radiation.

  8. Measurement of brevetoxin levels by radioimmunoassay of blood collection cards after acute, long-term, and low-dose exposure in mice.

    PubMed Central

    Woofter, Ricky; Dechraoui, M-Yasmine Bottein; Garthwaite, Ian; Towers, Neale R; Gordon, Christopher J; Córdova, José; Ramsdell, John S

    2003-01-01

    We developed a radioimmunoassay (RIA) using a sheep anti-brevetoxin antiserum to evaluate detection of brevetoxin on blood collection cards from mice treated with the brevetoxin congener PbTx-3. The RIA has high affinity for PbTx-3 [half-maximal effective concentration (EC(50)) +/- SE = 1.2 +/- 0.2 nM; n = 10] and recognizes both type 1 and type 2 brevetoxins, but not ciguatoxin. Direct comparison of the RIA with a radiolabeled [(3)H]-PbTx-3 receptor-binding assay (RBA) revealed excellent sensitivity, congener selectivity, and minimal interference from blood matrix. We first analyzed blood samples from an acute time course exposure, using a maximal nonlethal dose [180 microg/kg body weight (bw)] for 0.5, 1, 2, 4, and 24 hr. Mean blood brevetoxin levels were 36 nM at 30 min and stayed above 20 nM during the 1-4 hr time points. We next analyzed blood brevetoxin levels after longer exposure (0.5, 1, 2, 3, 4, or 7 days). Mean blood brevetoxin levels were 26.0 nM at 0.5 days, decreased to 8.2 nM at 1.0 day, and maintained a significant level (p < 0.05) of 1.3 nM at day 2. We next determined the lowest measurable dose using increasing concentrations of PbTx-3 (10-300 micro g/kg bw). Analysis of the blood samples at 60 min revealed a linear relationship between administered and internal doses (r(2) = 0.993). All doses of brevetoxin administered were detectable at 1 hr, with significant levels found for the lowest administered dose of 10 micro g/kg bw--a dose that was 10-fold lower than the lowest observable effect level. This RIA provides an optimal first-tier detection of brevetoxin from blood collection cards and, used in combination with the RBA and liquid chromatography-mass spectrometry, should provide a complete panel of methods to biomonitor brevetoxin exposure. PMID:14527838

  9. Basic studies on epigenetic carcinogenesis of low-dose exposure to 1-trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo) in vitro.

    PubMed

    Wang, Renjie; Cui, Yi; Xu, Yi; Irudayaraj, Joseph

    2017-01-01

    1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo) has been widely studied as a neurotoxic substance, however, only few reports have explored its effect on carcinogenicity. Since the aberrant modification of DNA methylation occurs very early in almost all human cancers, the focus of this study is to assess the carcinogenicity of TaClo by characterizing alterations of the epigenetic state, specifically, DNA methylation, upon exposure to TaClo in a HEK 293 model cell line. Our results suggest that TaClo could induce global DNA hypomethylation and transcriptional repression of critical tumor suppressor genes by increasing their promoter methylation. Enhanced cell proliferation, migration and anchorage independent growth were observed in cells exposed to TaClo. Our study highlights the epigenetic toxicity of TaClo, which contributes to its carcinogenicity by altering the DNA methylation status.

  10. Basic studies on epigenetic carcinogenesis of low-dose exposure to 1-trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo) in vitro

    PubMed Central

    Wang, Renjie; Cui, Yi; Xu, Yi; Irudayaraj, Joseph

    2017-01-01

    1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo) has been widely studied as a neurotoxic substance, however, only few reports have explored its effect on carcinogenicity. Since the aberrant modification of DNA methylation occurs very early in almost all human cancers, the focus of this study is to assess the carcinogenicity of TaClo by characterizing alterations of the epigenetic state, specifically, DNA methylation, upon exposure to TaClo in a HEK 293 model cell line. Our results suggest that TaClo could induce global DNA hypomethylation and transcriptional repression of critical tumor suppressor genes by increasing their promoter methylation. Enhanced cell proliferation, migration and anchorage independent growth were observed in cells exposed to TaClo. Our study highlights the epigenetic toxicity of TaClo, which contributes to its carcinogenicity by altering the DNA methylation status. PMID:28199384

  11. Low-dose energetic protons induce adaptive and bystander effects that protect human cells against DNA damage caused by a subsequent exposure to energetic iron ions.

    PubMed

    Buonanno, Manuela; De Toledo, Sonia M; Howell, Roger W; Azzam, Edouard I

    2015-05-01

    During interplanetary missions, astronauts are exposed to mixed types of ionizing radiation. The low 'flux' of the high atomic number and high energy (HZE) radiations relative to the higher 'flux' of low linear energy transfer (LET) protons makes it highly probable that for any given cell in the body, proton events will precede any HZE event. Whereas progress has been made in our understanding of the biological effects of low-LET protons and high-LET HZE particles, the interplay between the biochemical processes modulated by these radiations is unclear. Here we show that exposure of normal human fibroblasts to a low mean absorbed dose of 20 cGy of 0.05 or 1-GeV protons (LET ∼ 1.25 or 0.2 keV/μm, respectively) protects the irradiated cells (P < 0.0001) against chromosomal damage induced by a subsequent exposure to a mean absorbed dose of 50 cGy from 1 GeV/u iron ions (LET ∼ 151 keV/μm). Surprisingly, unirradiated (i.e. bystander) cells with which the proton-irradiated cells were co-cultured were also significantly protected from the DNA-damaging effects of the challenge dose. The mitigating effect persisted for at least 24 h. These results highlight the interactions of biological effects due to direct cellular traversal by radiation with those due to bystander effects in cell populations exposed to mixed radiation fields. They show that protective adaptive responses can spread from cells targeted by low-LET space radiation to bystander cells in their vicinity. The findings are relevant to understanding the health hazards of space travel.

  12. Changes in the Subpopulations of Porcine Peripheral Blood Lymphocytes Induced by Exposure to Low Doses of Zearalenone (ZEN) and Deoxynivalenol (DON).

    PubMed

    Dąbrowski, Michał; Obremski, Kazimierz; Gajęcka, Magdalena; Gajęcki, Maciej Tadeusz; Zielonka, Łukasz

    2016-04-27

    Zearalenone and deoxynivalenol are secondary metabolites of fungi of the genus Fusarium. The presence of mycotoxins in cereals and the resulting contamination of feeds and foods pose health risks for animals and humans. The dangers associated with high doses of mycotoxins have been extensively researched but very little is known about NOAEL (No Observed Adverse Effect Level) doses or exposure to a combination of mycotoxins (mixed mycotoxicoses). The aim of this study was to determine the effects of six-week exposure to NOAEL doses of individual and combined mycotoxins on the subpopulations of CD4⁺8(-), CD4(-)8⁺ and CD4⁺8⁺ lymphocytes in the peripheral blood of pigs. The experiment was performed on 72 gilts with average body weight of 25 kg, divided into three experimental groups (E1, E2 and E3, administered zearalenone (ZEN), deoxynivalenol (DON) and ZEN + DON, respectively, on a daily basis) and a control group (C) receiving placebo. Changes in lymphocyte subpopulations were evaluated by flow cytometry at weekly intervals (experimental days 7, 14, 21, 28, 35 and 42). A linear increase in the percentage of CD4⁺8⁺ lymphocytes was highly correlated with time (r = 0.682) in group C. The correlations and linear increase in the above subpopulation were disrupted in the remaining groups. In group E3, a statistically significant (p < 0.05) decrease in CD4⁺8⁺ counts was observed in week 5, which could point to a transient depletion of regulatory mechanisms of immune responses. The noted results also suggest that in mixed mycotoxicosis, ZEN and DON exerted stronger immunomodulatory effects.

  13. Delayed effects of single neonatal subcutaneous exposure of low-dose 17α-ethynylestradiol on reproductive function in female rats.

    PubMed

    Shiorta, Mariko; Kawashima, Jun; Nakamura, Tomohiro; Ogawa, Yuko; Kamiie, Junichi; Yasuno, Kyohei; Shirota, Kinji; Yoshida, Midori

    2012-01-01

    Delayed effects of exposure to small amounts of estrogenic compounds during the critical period of brain sexual differentiation were investigated by subcutaneous treatment of female Sprague-Dawley rats with 0 (vehicle control), 0.08, 0.4, or 2 µg/kg of 17α-ethynylestradiol (EE) on postnatal day (PND) 1. The treatment did not affect growth and development of the treated animals, and the timings of vaginal opening were similar between the EE-treated and control groups. The animals were periodically examined for the estrous cycle from postnatal week (PNW) 8-9 to PNW 32-33. Patterns of the estrous cycle were similar among the groups until PNW 17. None of the control animals showed persistent estrus until PNW 33. The animals treated with 0.4 µg/kg or more EE showed persistent estrus from PNW 20. The alteration was reflected in the number of days judged as proestrus or estrus, and was found to gradually increase in the EE-treated groups. At necropsy on PNW 32-33, ovulation was not confirmed in most EE-treated animals, even on the day of estrus. In addition, sporadic milk accumulations were observed in the mammary gland of the EE-treated animals. Histological evaluation revealed cystic follicle formation in the EE-treated ovaries and also revealed hyperplasia of mammary glands. Furthermore, ovaries from the animals showing persistent estrus lacked corpus luteum, indicating long-term anovulation. These results clearly show that single exposure to EE during the critical period of brain sexual differentiation can exert effects on reproductive functions at a later period in rats.

  14. The long-term effects of exposure to low doses of lead in childhood. An 11-year follow-up report

    SciTech Connect

    Needleman, H.L.; Schell, A.; Bellinger, D.; Leviton, A.; Allred, E.N. )

    1990-01-11

    To determine whether the effects of low-level lead exposure persist, we reexamined 132 of 270 young adults who had initially been studied as primary school-children in 1975 through 1978. In the earlier study, neurobehavioral functioning was found to be inversely related to dentin lead levels. As compared with those we restudied, the other 138 subjects had had somewhat higher lead levels on earlier analysis, as well as significantly lower IQ scores and poorer teachers' ratings of classroom behavior. When the 132 subjects were reexamined in 1988, impairment in neurobehavioral function was still found to be related to the lead content of teeth shed at the ages of six and seven. The young people with dentin lead levels greater than 20 ppm had a markedly higher risk of dropping out of high school (adjusted odds ratio, 7.4; 95 percent confidence interval, 1.4 to 40.7) and of having a reading disability (odds ratio, 5.8; 95 percent confidence interval, 1.7 to 19.7) as compared with those with dentin lead levels less than 10 ppm. Higher lead levels in childhood were also significantly associated with lower class standing in high school, increased absenteeism, lower vocabulary and grammatical-reasoning scores, poorer hand-eye coordination, longer reaction times, and slower finger tapping. No significant associations were found with the results of 10 other tests of neurobehavioral functioning. Lead levels were inversely related to self-reports of minor delinquent activity. We conclude that exposure to lead in childhood is associated with deficits in central nervous system functioning that persist into young adulthood.

  15. Changes in quality of life and sexual health are associated with low-dose peginterferon therapy and disease progression in patients with chronic hepatitis C

    PubMed Central

    Snow, Kristin K.; Bonkovsky, Herbert L.; Fontana, Robert J.; Kim, Hae-Young; Sterling, Richard K.; Di Bisceglie, Adrian M.; Morgan, Timothy R.; Dienstag, Jules L.; Ghany, Marc G.

    2010-01-01

    Background/Aim We assessed the effects of long-term peginterferon therapy and disease progression on health-related quality of life (HRQOL), symptoms, and sexual health in patients with chronic hepatitis C (CHC) and advanced fibrosis or cirrhosis. Methods 517 HALT-C Trial patients received peginterferon alfa-2a (90 μg/week); 532 received no additional treatment for 3.5 years. Patients were followed for outcomes of death, hepatocellular carcinoma and hepatic decompensation. Sexual health, SF-36 scores, and symptoms were serially assessed by repeated measures analyses of covariance. Results Patients with cirrhosis (n=427) reported lower general well-being and more fatigue (p<0.001) than patients with fibrosis (n=622). Physical scores declined significantly over time, independent of treatment, and patients with cirrhosis reported lower scores. Vitality scores were lower in those with cirrhosis, and treated patients experienced a greater decline over time than untreated patients; HRQOL rebounded after treatment ended. Patients with a clinical outcome had significantly greater declines in all SF-36 and symptom scores. Among men, sexual health scores were significantly worse in treated patients and in those with a clinical outcome. Conclusions Clinical progression of CHC and maintenance peginterferon therapy led to worsening of symptoms, HRQOL, and, in men, sexual health in a large patient cohort followed over 4 years. PMID:20070284

  16. Low-dose neutron dose response of zebrafish embryos obtained from the Neutron exposure Accelerator System for Biological Effect Experiments (NASBEE) facility

    NASA Astrophysics Data System (ADS)

    Ng, C. Y. P.; Kong, E. Y.; Konishi, T.; Kobayashi, A.; Suya, N.; Cheng, S. H.; Yu, K. N.

    2015-09-01

    The dose response of embryos of the zebrafish, Danio rerio, irradiated at 5 h post fertilization (hpf) by 2-MeV neutrons with ≤100 mGy was determined. The neutron irradiations were made at the Neutron exposure Accelerator System for Biological Effect Experiments (NASBEE) facility in the National Institute of Radiological Sciences (NIRS), Chiba, Japan. A total of 10 neutron doses ranging from 0.6 to 100 mGy were employed (with a gamma-ray contribution of 14% to the total dose), and the biological effects were studied through quantification of apoptosis at 25 hpf. The responses for neutron doses of 10, 20, 25, and 50 mGy approximately fitted on a straight line, while those for neutron doses of 0.6, 1 and 2.5 mGy exhibited neutron hormetic effects. As such, hormetic responses were generically developed by different kinds of ionizing radiations with different linear energy transfer (LET) values. The responses for neutron doses of 70 and 100 mGy were significantly below the lower 95% confidence band of the best-fit line, which strongly suggested the presence of gamma-ray hormesis.

  17. Greenland sledge dogs (Canis familiaris) develop liver lesions when exposed to a chronic and dietary low dose of an environmental organohalogen cocktail.

    PubMed

    Sonne, Christian; Leifsson, Pall S; Dietz, Rune; Kirkegaard, Maja; Jensen, Asger L; Shahmiri, Soheila; Letcher, Robert J

    2008-01-01

    We assessed the relationship between exposure to organohalogen polluted minke whale (Balaenoptera acutorostrata) blubber and liver morphology and function in a generational controlled study of 28 Greenland sledge dogs (Canis familiaris). The prevalence of portal fibrosis, mild bile duct hyperplasia, and vascular leukocyte infiltrations was significantly higher in the exposed group (all Chi-square: p<0.05). In case of granulomas, the frequency was significantly highest in the bitches (P generation) while the prevalence of portal fibrosis was highest in the F generation (pups) (both Chi-square: p<0.05). No significant difference between exposed and controls was found for bile acid, ALAT, and ALKP, while ASAT and LDH were significantly highest in the control group (both ANOVA: p<0.05). We therefore suggest that a daily intake of 50-200g environmentally organohalogen polluted minke whale blubber can cause liver lesions in Greenland sledge dogs. It is reasonable to infer that other apex predators such as polar bears (Ursus maritimus) and humans may suffer from similar impacts.

  18. Perinatal Exposure to Low-Dose Bisphenol-A (BPA) Disrupts the Structural and Functional Development of the Hypothalamic Feeding Circuitry.

    PubMed

    MacKay, Harry; Patterson, Zachary R; Abizaid, Alfonso

    2017-02-07

    Bisphenol-A (BPA) is a component of polycarbonate and other plastics to which humans are regularly exposed at low levels. BPA is characterized as an endocrine disruptor due to observations of its estrogenic activity in various experimental models. We have previously shown evidence of disrupted hypothalamic feeding circuitry and leptin sensitivity in adult BPA-exposed animals subject to a high-fat diet, but because these animals were already exhibiting a diet-induced obese phenotype, we could not rule out the possibility that these observations were simply consequences of the obesity, not a pre-existing phenotype produced by BPA exposure. Here we study leptin sensitivity and hypothalamic structure in young BPA-exposed animals prior to the onset of a body weight or metabolic phenotype. Pregnant and lactating CD-1 mice were exposed to either BPA or diethylstilbestrol (DES) at low, environmentally relevant doses via their diet. Studies of leptin function and neurobiology were conducted on offspring at a number of timepoints. Young adult offspring from this experiment were resistant to leptin-induced suppression of food intake, body weight loss, and hypothalamic POMC upregulation. Both male and female BPA-exposed mice showed a reduced density of Pro-Opiomelanocortin (POMC) projections into the paraventricular hypothalamus (PVN). BPA-and DES-exposed pups had respectively delayed and blunted postnatal leptin surges, and POMC projections into the PVN were rescued in female BPA-exposed animals given daily injections of supplemental leptin. Our findings suggest that BPA, a putative obesogen, may exert its effects through developmental programming of the hypothalamic melanocortin circuitry, permanently altering the neurobiology of metabolic homeostasis.

  19. Risk of Cataract after Exposure to Low Doses of Ionizing Radiation: A 20-Year Prospective Cohort Study among US Radiologic Technologists

    PubMed Central

    Bekiroglu, Nural; Hauptmann, Michael; Alexander, Bruce H.; Freedman, D. Michal; Doody, Michele Morin; Cheung, Li C.; Simon, Steven L.; Weinstock, Robert M.; Bouville, André; Sigurdson, Alice J.

    2008-01-01

    The study aim was to determine the risk of cataract among radiologic technologists with respect to occupational and nonoccupational exposures to ionizing radiation and to personal characteristics. A prospective cohort of 35,705 cataract-free US radiologic technologists aged 24–44 years was followed for nearly 20 years (1983–2004) by using two follow-up questionnaires. During the study period, 2,382 cataracts and 647 cataract extractions were reported. Cigarette smoking for ≥5 pack-years; body mass index of ≥25 kg/m2; and history of diabetes, hypertension, hypercholesterolemia, or arthritis at baseline were significantly (p ≤ 0.05) associated with increased risk of cataract. In multivariate models, self-report of ≥3 x-rays to the face/neck was associated with a hazard ratio of cataract of 1.25 (95% confidence interval: 1.06, 1.47). For workers in the highest category (mean, 60 mGy) versus lowest category (mean, 5 mGy) of occupational dose to the lens of the eye, the adjusted hazard ratio of cataract was 1.18 (95% confidence interval: 0.99, 1.40). Findings challenge the National Council on Radiation Protection and International Commission on Radiological Protection assumptions that the lowest cumulative ionizing radiation dose to the lens of the eye that can produce a progressive cataract is approximately 2 Gy, and they support the hypothesis that the lowest cataractogenic dose in humans is substantially less than previously thought. PMID:18664497

  20. Urinary Metabolites of the Dietary Carcinogen PhIP are Predictive of Colon DNA Adducts After a Low Dose Exposure in Humans

    SciTech Connect

    Malfatti, M; Dingley, K; Nowell, S; Ubick, E; Mulakken, N; Nelson, D; Lang, N; Felton, J; Turteltaub, K

    2006-04-28

    Epidemiologic evidence indicates that exposure to heterocyclic amines (HAs) in the diet is an important risk factor for the development of colon cancer. Well-done cooked meats contain significant levels of HAs which have been shown to cause cancer in laboratory animals. To better understand the mechanisms of HA bioactivation in humans, the most mass abundant HA, 2-amino-l-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), was used to assess the relationship between PhIP metabolism and DNA adduct formation. Ten human volunteers were administered a dietary relevant dose of [{sup 14}C]PhIP 48-72 h prior to surgery to remove colon tumors. Urine was collected for 24 h after dosing for metabolite analysis, and DNA was extracted from colon tissue and analyzed by accelerator mass spectrometry for DNA adducts. All ten subjects were phenotyped for CYP1A2, NAT2, and SULT1A1 enzyme activity. Twelve PhIP metabolites were detected in the urine samples. The most abundant metabolite in all volunteers was N-hydroxy-PhIP-N{sup 2}-glucuronide. Metabolite levels varied significantly between the volunteers. Interindividual differences in colon DNA adducts levels were observed between each individual. The data showed that individuals with a rapid CYP1A2 phenotype and high levels of urinary N-hydroxy-PhIP-N{sup 2}-glucuronide, had the lowest level of colon PhIP-DNA adducts. This suggests that glucuronidation plays a significant role in detoxifying N-hydroxy-PhIP. The levels of urinary N-hydroxy-PhIP-N{sup 2}-glucuronide were negatively correlated to colon DNA adduct levels. Although it is difficult to make definite conclusions from a small data set, the results from this pilot study have encouraged further investigations using a much larger study group.

  1. Lipid peroxides and glutathione status in human progenitor mononuclear (U937) cells following exposure to low doses of nickel and copper.

    PubMed

    Boadi, William Y; Harris, Shalandus; Anderson, Justin B; Adunyah, Samuel E

    2013-04-01

    Effects of Cu(2+), Ni(2+) or Cu(2+) + Ni(2+) on lipid peroxide and glutathione (GSH) levels in U937 cells were investigated. Cells were treated with 0, 5, 10, and 20 µM of Cu(2+) and/or Ni(2+) and H(2)O(2) (0.01 mM) and incubated for 24 hours at 37°C. Lipid peroxides were measured by the thiobarbituric acid assay (TBA). GSH intracellular levels were assayed by the GSH assay kit from EMD/Calbiochem (San Diego, California, USA). Cu(2+) or Ni(2+) significantly (P < 0.01) increased lipid peroxides in a dose-dependent manner, compared to controls. The effect was more pronounced for Cu(2+), compared to the Ni(2+)-treated samples. Cu(2+) + Ni(2+) increased lipid peroxides in a significant (P < 0.001), dose-dependent manner, compared to Cu(2+) or Ni(2+) alone (i.e., ratio of 2.5:1-fold for combined versus single treatments, respectively). Cu(2+) or Ni(2+) significantly decreased GSH levels in U937 cells, with the effect being pronounced for Cu(2+). Cu(2+) + Ni(2+) metal ions significantly (P < 0.001) depleted cells of GSH in a dose-dependent manner. Ethylene diamine tetraacetic acid (EDTA) at 50 or 100 µM moderately reduced the Cu(2+)- or Ni(2+)-induced effects on GSH levels. Interestingly, GSH levels generally decreased to half (except for the combined metal dose of 20 µM at 100 µM EDTA) of its level at the highest metal concentration tested for both the single or combined treatments. In conclusion, multiple exposures of cells to metal ions may be lethal to cells, compared to their single treatments.

  2. Effects of chronic cerebral hypoperfusion and low-dose progesterone treatment on apoptotic processes, expression and subcellular localization of key elements within Akt and Erk signaling pathways in rat hippocampus.

    PubMed

    Stanojlović, M; Guševac, I; Grković, I; Zlatković, J; Mitrović, N; Zarić, M; Horvat, A; Drakulić, D

    2015-12-17

    The present study attempted to investigate how chronic cerebral hypoperfusion (CCH) and repeated low-dose progesterone (P) treatment affect gene and protein expression, subcellular distribution of key apoptotic elements within protein kinase B (Akt) and extracellular signal-regulated kinases (Erk) signal transduction pathways, as well as neurodegenerative processes and behavior. The results revealed the absence of Erk activation in CCH in cytosolic and synaptosomal fractions, indicating a lower threshold of Akt activation in brain ischemia, while P increased their levels above control values. CCH induced an increase in caspase 3 (Casp 3) and poly (ADP-ribose) polymerase (PARP) gene and protein expression. However, P restored expression of examined molecules in all observed fractions, except for the levels of Casp 3 in synapses which highlighted its possible non-apoptotic or even protective function. Our study showed the absence of nuclear factor kappa-light-chain-enhancer of activated b cells (NF-κB) response to this type of ischemic condition and its strong activation under the influence of P. Further, the initial increase in the number of apoptotic cells and amount of DNA fragmentation induced by CCH was significantly reduced by P. Finally, P reversed the CCH-induced reduction in locomotor activity, while promoting a substantial decrease in anxiety-related behavior. Our findings support the concept that repeated low-dose post-ischemic P treatment reduces CCH-induced neurodegeneration in the hippocampus. Neuroprotection is initiated through the activation of investigated kinases and regulation of their downstream molecules in subcellular specific manner, indicating that this treatment may be a promising therapy for alleviation of CCH-induced pathologies.

  3. Safety assessment of chronic oral exposure to iron oxide nanoparticles

    NASA Astrophysics Data System (ADS)

    Chamorro, Susana; Gutiérrez, Lucía; Vaquero, María Pilar; Verdoy, Dolores; Salas, Gorka; Luengo, Yurena; Brenes, Agustín; José Teran, Francisco

    2015-05-01

    Iron oxide nanoparticles with engineered physical and biochemical properties are finding a rapidly increasing number of biomedical applications. However, a wide variety of safety concerns, especially those related to oral exposure, still need to be addressed for iron oxide nanoparticles in order to reach clinical practice. Here, we report on the effects of chronic oral exposure to low doses of γ-Fe2O3 nanoparticles in growing chickens. Animal observation, weight, and diet intake reveal no adverse signs, symptoms, or mortality. No nanoparticle accumulation was observed in liver, spleen, and duodenum, with feces as the main excretion route. Liver iron level and duodenal villi morphology reflect the bioavailability of the iron released from the partial transformation of γ-Fe2O3 nanoparticles in the acid gastric environment. Duodenal gene expression studies related to the absorption of iron from γ-Fe2O3 nanoparticles indicate the enhancement of a ferric over ferrous pathway supporting the role of mucins. Our findings reveal that oral administration of iron oxide nanoparticles is a safe route for drug delivery at low nanoparticle doses.

  4. Chronic exposures and male fertility: the impacts of environment, diet, and drug use on spermatogenesis.

    PubMed

    Gabrielsen, J S; Tanrikut, C

    2016-07-01

    Several recent studies have suggested that sperm concentrations and semen quality have been decreasing over the past several decades in many areas of the world. The etiology of these decreases is currently unknown. Acute events can have significant impacts on spermatogenesis and are often readily identified during the male fertility evaluation. The majority of male factor infertility, however, is idiopathic. Chronic, low-dose exposures to chemicals and nutrients are more difficult to identify, but are extremely prevalent. These exposures have been shown to have dramatic effects on both individual and community health and interest in the cumulative and synergistic impacts of such agents on spermatogenesis has been increasing. While our understanding of these potential hazards is evolving, it is clear that they may significantly influence male reproductive potential. This review explores the literature related to effects of chronic exposures from drug use, dietary intake, and the environment on spermatogenesis in humans and animals.

  5. Investigation of the effects of subchronic low dose oral exposure to bisphenol A (BPA) and ethinyl estradiol (EE) on estrogen receptor expression in the juvenile and adult female rat hypothalamus.

    PubMed

    Rebuli, Meghan E; Cao, Jinyan; Sluzas, Emily; Delclos, K Barry; Camacho, Luísa; Lewis, Sherry M; Vanlandingham, Michelle M; Patisaul, Heather B

    2014-07-01

    Concerns have been raised regarding the long-term impacts of early life exposure to the ubiquitous environmental contaminant bisphenol A (BPA) on brain organization. Because BPA has been reported to affect estrogen signaling, and steroid hormones play a critical role in brain sexual differentiation, there is also concern that BPA exposure could alter neural sex differences. Here, we examine the impact of subchronic exposure from gestation to adulthood to oral doses of BPA below the current no-observed-adverse-effect level (NOAEL) of 5 mg/kg body weight (bw)/day on estrogen receptor (ESR) expression in sexually dimorphic brain regions of prepubertal and adult female rats. The dams were gavaged daily with vehicle (0.3% carboxymethylcellulose), 2.5, 25, 260, or 2700 μg BPA/kg bw/day, or 0.5 or 5.0 μg ethinyl estradiol (EE)/kg bw/day from gestational day 6 until labor began. Offspring were then gavaged directly from the day after birth until the day before scheduled sacrifice on postnatal days 21 or 90. Using in situ hybridization, one or more BPA doses produced significant decreases in Esr1 expression in the juvenile female rat anteroventral periventricular nucleus (AVPV) of the hypothalamus and significant decreases in Esr2 expression in the adult female rat AVPV and medial preoptic area (MPOA), relative to vehicle controls. BPA did not simply reproduce EE effects, indicating that BPA is not acting solely as an estrogen mimic. The possible consequences of long-term changes in hypothalamic ESR expression resulting from subchronic low dose BPA exposure on neuroendocrine effects are discussed and being addressed in ongoing, related work.

  6. Investigation of the Effects of Subchronic Low Dose Oral Exposure to Bisphenol A (BPA) and Ethinyl Estradiol (EE) on Estrogen Receptor Expression in the Juvenile and Adult Female Rat Hypothalamus

    PubMed Central

    Rebuli, Meghan E.; Cao, Jinyan; Sluzas, Emily; Delclos, K. Barry; Camacho, Luísa; Lewis, Sherry M.; Vanlandingham, Michelle M.; Patisaul, Heather B.

    2014-01-01

    Concerns have been raised regarding the long-term impacts of early life exposure to the ubiquitous environmental contaminant bisphenol A (BPA) on brain organization. Because BPA has been reported to affect estrogen signaling, and steroid hormones play a critical role in brain sexual differentiation, there is also concern that BPA exposure could alter neural sex differences. Here, we examine the impact of subchronic exposure from gestation to adulthood to oral doses of BPA below the current no-observed-adverse-effect level (NOAEL) of 5 mg/kg body weight (bw)/day on estrogen receptor (ESR) expression in sexually dimorphic brain regions of prepubertal and adult female rats. The dams were gavaged daily with vehicle (0.3% carboxymethylcellulose), 2.5, 25, 260, or 2700 μg BPA/kg bw/day, or 0.5 or 5.0 μg ethinyl estradiol (EE)/kg bw/day from gestational day 6 until labor began. Offspring were then gavaged directly from the day after birth until the day before scheduled sacrifice on postnatal days 21 or 90. Using in situ hybridization, one or more BPA doses produced significant decreases in Esr1 expression in the juvenile female rat anteroventral periventricular nucleus (AVPV) of the hypothalamus and significant decreases in Esr2 expression in the adult female rat AVPV and medial preoptic area (MPOA), relative to vehicle controls. BPA did not simply reproduce EE effects, indicating that BPA is not acting solely as an estrogen mimic. The possible consequences of long-term changes in hypothalamic ESR expression resulting from subchronic low dose BPA exposure on neuroendocrine effects are discussed and being addressed in ongoing, related work. PMID:24752507

  7. Health Effects of Chronic Arsenic Exposure

    PubMed Central

    Hong, Young-Seoub; Song, Ki-Hoon; Chung, Jin-Yong

    2014-01-01

    Arsenic is a unique element with distinct physical characteristics and toxicity whose importance in public health is well recognized. The toxicity of arsenic varies across its different forms. While the carcinogenicity of arsenic has been confirmed, the mechanisms behind the diseases occurring after acute or chronic exposure to arsenic are not well understood. Inorganic arsenic has been confirmed as a human carcinogen that can induce skin, lung, and bladder cancer. There are also reports of its significant association to liver, prostate, and bladder cancer. Recent studies have also suggested a relationship with diabetes, neurological effects, cardiac disorders, and reproductive organs, but further studies are required to confirm these associations. The majority of research to date has examined cancer incidence after a high exposure to high concentrations of arsenic. However, numerous studies have reported various health effects caused by chronic exposure to low concentrations of arsenic. An assessment of the health effects to arsenic exposure has never been performed in the South Korean population; thus, objective estimates of exposure levels are needed. Data should be collected on the biological exposure level for the total arsenic concentration, and individual arsenic concentration by species. In South Korea, we believe that biological exposure assessment should be the first step, followed by regular health effect assessments. PMID:25284195

  8. Chronic respiratory effects of indoor formaldehyde exposure

    SciTech Connect

    Krzyzanowski, M.; Quackenboss, J.J.; Lebowitz, M.D.

    1990-01-01

    The relation of chronic respiratory symptoms and pulmonary function to formaldehyde (HCHO) in homes was studied in a sample of 298 children (6-15 years of age) and 613 adults. HCHO measurements were made with passive samplers two one-week periods. Data on chronic cough and phlegm, wheeze, attacks of breathlessness, and doctor diagnoses of chronic bronchitis and asthma were collected with self-completed questionnaires. Peak expiratory flow rates (PEFR) were obtained during the evenings and mornings for up to 14 consecutive days for each individual. Significantly greater prevalence rates of asthma and chronic bronchitis were found in children from houses with HCHO levels 60-120 ppb than in those less exposed, especially in children also exposed to environmental tobacco smoke. In children, levels of PEFR linearly decreased with HCHO exposure, with estimated decrease due to 60 ppb of HCHO equivalent to 22% of PEFR level in nonexposed children.

  9. Hydrocarbon exposure and chronic renal disease.

    PubMed

    Asal, N R; Cleveland, H L; Kaufman, C; Nsa, W; Nelson, D I; Nelson, R Y; Lee, E T; Kingsley, B

    1996-01-01

    The study objective was to investigate further the potential role of long-term exposure to hydrocarbons (HCs) in the development of idiopathic chronic glomerulopathy (ICG) using a more refined measurement of HC exposure. A total of 321 pairs of cases and controls, matched by age, gender, and geographical area, were assembled. A detailed questionnaire was blindly administered to cases and controls to collect information on occupational and medical history and sociodemographic data. By integrating quantified measurements of HC exposure from a variety of sources with each subject's occupational history, a lifetime HC exposure score could be estimated and expressed in parts per million (ppm). Cases had an hydrocarbon exposure mean score of 165 ppm (median 48 ppm) as compared to 162 ppm (median 43 ppm) for controls (P = 0.757). When using hydrocarbon exposure as a dichotomous variable with a cutoff point at 100 ppm, cases had a higher proportion of exposed than controls, but the difference was not statistically significant at the 0.05 level, even after controlling for possible confounders through logistic regression. Subgroup analyses showed mixed results. In most subgroups differences between cases and controls tended to become significant when hydrocarbon was used as a dichotomous variable. Results from this study do not sufficiently support the hypothesized association of HC exposure and ICG in general. Subgroup analyses need further investigations. Efforts to generate accurate estimates of lifetime HC exposure should be emphasized for future investigations.

  10. Exposure of preimplantation embryos to low-dose bisphenol A impairs testes development and suppresses histone acetylation of StAR promoter to reduce production of testosterone in mice.

    PubMed

    Hong, Juan; Chen, Fang; Wang, Xiaoli; Bai, Yinyang; Zhou, Rong; Li, Yingchun; Chen, Ling

    2016-05-15

    Previous studies have shown that bisphenol A (BPA) is a potential endocrine disruptor and testicular toxicant. The present study focused on exploring the impact of exposure to low dose of BPA on male reproductive development during the early embryo stage and the underlying mechanisms. BPA (20 μg/kg/day) was orally administered to female mice on days 1-5 of gestation. The male offspring were euthanized at PND10, 20, 24, 35 or PND50. We found that the mice exposed to BPA before implantation (BPA-mice) displayed retardation of testicular development with reduction of testosterone level. The diameter and epithelium height of seminiferous tubules were reduced in BPA-mice at PND35. The numbers of spermatogenic cells at different stages were significantly reduced in BPA-mice at PND50. BPA-mice showed a persistent reduction in serum and testicular testosterone levels starting from PND24, whereas GnRH mRNA was significantly increased at PND35 and PND50. The expressions of testicular StAR and P450scc in BPA-mice also decreased relative to those of the controls at PND35 and PND50. Further analysis found that the levels of histone H3 and H3K14 acetylation (Ac-H3 and H3K14ac) in the promoter of StAR were decreased relative to those of control mice, whereas the level of Ac-H3 in the promoter of P450scc was not significantly different between the groups. These results provide evidence that exposure to BPA in preimplantation embryo retards the development of testes by reducing histone acetylation of the StAR promoter to disrupt the testicular testosterone synthesis.

  11. Low Dose Ionizing Radiation Modulates Immune Function

    SciTech Connect

    Nelson, Gregory A.

    2016-01-12

    In order to examine the effects of low dose ionizing radiation on the immune system we chose to examine an amplified adaptive cellular immunity response. This response is Type IV delayed-type hypersensitivity also called contact hypersensitivity. The agent fluorescein isothiocyanate (FITC) is a low molecular weight, lipophilic, reactive, fluorescent molecule that can be applied to the skin where it (hapten) reacts with proteins (carriers) to become a complete antigen. Exposure to FITC leads to sensitization which is easily measured as a hypersensitivity inflammatory reaction following a subsequent exposure to the ear. Ear swelling, eosinophil infiltration, immunoglobulin E production and cytokine secretion patterns characteristic of a “Th2 polarized” immune response are the components of the reaction. The reaction requires successful implementation of antigen processing and presentation by antigen presenting Langerhans cells, communication with naïve T lymphocytes in draining lymph nodes, expansion of activated T cell clones, migration of activated T cells to the circulation, and recruitment of memory T cells, macrophages and eosinophils to the site of the secondary challenge. Using this model our approach was to quantify system function rather than relying only on indirect biomarkers of cell. We measured the FITC-induced hypersensitivity reaction over a range of doses from 2 cGy to 2 Gy. Irradiations were performed during key events or prior to key events to deplete critical cell populations. In addition to quantifying the final inflammatory response, we assessed cell populations in peripheral blood and spleen, cytokine signatures, IgE levels and expression of genes associated with key processes in sensitization and elicitation/recall. We hypothesized that ionizing radiation would produce a biphasic effect on immune system function resulting in an enhancement at low doses and a depression at higher doses and suggested that this transition would occur in the

  12. Low-dose radiation epidemiology studies: status and issues.

    PubMed

    Shore, Roy E

    2009-11-01

    Although the Japanese atomic bomb study and radiotherapy studies have clearly documented cancer risks from high-dose radiation exposures, radiation risk assessment groups have long recognized that protracted or low exposures to low-linear energy transfer radiations are key radiation protection concerns because these are far more common than high-exposure scenarios. Epidemiologic studies of human populations with low-dose or low dose-rate exposures are one approach to addressing those concerns. A number of large studies of radiation workers (Chernobyl clean-up workers, U.S. and Chinese radiological technologists, and the 15-country worker study) or of persons exposed to environmental radiation at moderate to low levels (residents near Techa River, Semipalatinsk, Chernobyl, or nuclear facilities) have been conducted. A variety of studies of medical radiation exposures (multiple-fluoroscopy, diagnostic (131)I, scatter radiation doses from radiotherapy, etc.) also are of interest. Key results from these studies are summarized and compared with risk estimates from the Japanese atomic bomb study. Ideally, one would like the low-dose and low dose-rate studies to guide radiation risk estimation regarding the shape of the dose-response curve, DDREF (dose and dose-rate effectiveness factor), and risk at low doses. However, the degree to which low-dose studies can do so is subject to various limitations, especially those pertaining to dosimetric uncertainties and limited statistical power. The identification of individuals who are particularly susceptible to radiation cancer induction also is of high interest in terms of occupational and medical radiation protection. Several examples of studies of radiation-related cancer susceptibility are discussed, but none thus far have clearly identified radiation-susceptible genotypes.

  13. Low-dose IL-2 selectively activates subsets of CD4+ Tregs and NK cells

    PubMed Central

    Hirakawa, Masahiro; Matos, Tiago; Liu, Hongye; Koreth, John; Kim, Haesook T.; Paul, Nicole E.; Murase, Kazuyuki; Whangbo, Jennifer; Alho, Ana C.; Nikiforow, Sarah; Cutler, Corey; Ho, Vincent T.; Armand, Philippe; Alyea, Edwin P.; Antin, Joseph H.; Blazar, Bruce R.; Lacerda, Joao F.; Soiffer, Robert J.

    2016-01-01

    CD4+ regulatory T cells (CD4Tregs) play a critical role in the maintenance of immune tolerance and prevention of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. IL-2 supports the proliferation and survival of CD4Tregs and previous studies have demonstrated that IL-2 induces selective expansion of CD4Tregs and improves clinical manifestations of chronic GVHD. However, mechanisms for selective activation of CD4Tregs and the effects of low-dose IL-2 on other immune cells are not well understood. Using mass cytometry, we demonstrate that low concentrations of IL-2 selectively induce STAT5 phosphorylation in Helios+ CD4Tregs and CD56brightCD16– NK cells in vitro. Preferential activation and expansion of Helios+ CD4Tregs and CD56brightCD16– NK cells was also demonstrated in patients with chronic GVHD receiving low-dose IL-2. With prolonged IL-2 treatment for 48 weeks, phenotypic changes were also observed in Helios– CD4Tregs. The effects of low-dose IL-2 therapy on conventional CD4+ T cells and CD8+ T cells were limited to increased expression of PD-1 on effector memory T cells. These studies reveal the selective effects of low-dose IL-2 therapy on Helios+ CD4Tregs and CD56bright NK cells that constitutively express high-affinity IL-2 receptors as well as the indirect effects of prolonged exposure to low concentrations of IL-2 in vivo. PMID:27812545

  14. Low-Dose Radiotherapy in Indolent Lymphoma

    SciTech Connect

    Rossier, Christine; Schick, Ulrike; Miralbell, Raymond; Mirimanoff, Rene O.; Weber, Damien C.; Ozsahin, Mahmut

    2011-11-01

    Purpose: To assess the response rate, duration of response, and overall survival after low-dose involved-field radiotherapy in patients with recurrent low-grade lymphoma or chronic lymphocytic leukemia (CLL). Methods and Materials: Forty-three (24 women, 19 men) consecutive patients with indolent lymphoma or CLL were treated with a total dose of 4 Gy (2 x 2 Gy) using 6- 18-MV photons. The median age was 73 years (range, 39-88). Radiotherapy was given either after (n = 32; 75%) or before (n = 11; 25%) chemotherapy. The median time from diagnosis was 48 months (range, 1-249). The median follow-up period was 20 months (range, 1-56). Results: The overall response rate was 90%. Twelve patients (28%) had a complete response, 15 (35%) had a partial response, 11 (26%) had stable disease, and 5 (11%) had progressive disease. The median overall survival for patients with a positive response (complete response/partial response/stable disease) was 41 months; for patients with progressive disease it was 6 months (p = 0.001). The median time to in-field progression was 21 months (range, 0-24), and the median time to out-field progression was 8 months (range, 0-40). The 3-year in-field control was 92% in patients with complete response (median was not reached). The median time to in-field progression was 9 months (range, 0.5-24) in patients with partial response and 6 months (range, 0.6-6) in those with stable disease (p < 0.05). Younger age, positive response to radiotherapy, and no previous chemotherapy were the best factors influencing the outcome. Conclusions: Low-dose involved-field radiotherapy is an effective treatment in the management of patients with recurrent low-grade lymphoma or CLL.

  15. Low dose neutron late effects: Cataractogenesis

    SciTech Connect

    Worgul, B.V.

    1991-12-01

    The work is formulated to resolve the uncertainty regarding the relative biological effectiveness (RBE) of low dose neutron radiation. The study exploits the fact that cataractogenesis is sensitive to the inverse dose-rate effect as has been observed with heavy ions and was an endpoint considered in the follow-up of the A-bomb survivors. The neutron radiations were initiated at the Radiological Research Accelerator facility (RARAF) of the Nevis Laboratory of Columbia University. Four week old ({plus minus} 1 day) rats were divided into eight dose groups each receiving single or fractionated total doses of 0.2, 1.0, 5.0 and 25.0 cGy of monoenergetic 435 KeV neutrons. Special restraining jigs insured that the eye, at the midpoint of the lens, received the appropriate energy and dose with a relative error of {plus minus}5%. The fractionation regimen consisted of four exposures, each administered at three hour ({plus minus}) intervals. The neutron irradiated groups are being compared to rats irradiated with 250kVp X-rays in doses ranging from 0.5 to 7 Gy. The animals are being examined on a biweekly basis utilizing conventional slit-lamp biomicroscopy and the Scheimpflug Slit Lamp Imaging System (Zeiss). The follows-ups, entering their second year, will continue throughout the life-span of the animals. This is essential inasmuch as given the extremely low doses which are being utilized clinically detectable opacities were not anticipated until a significant fraction of the life span has lapsed. Current data support this contention. At this juncture cataracts in the irradiated groups are beginning to exceed control levels.

  16. Chronic respiratory effects of indoor formaldehyde exposure

    SciTech Connect

    Krzyzanowski, M.; Quackenboss, J.J.; Lebowitz, M.D. )

    1990-08-01

    The relation of chronic respiratory symptoms and pulmonary function to formaldehyde (HCHO) in homes was studied in a sample of 298 children (6-15 years of age) and 613 adults. HCHO measurements were made with passive samplers during two 1-week periods. Data on chronic cough and phlegm, wheeze, attacks of breathlessness, and doctor diagnoses of chronic bronchitis and asthma were collected with self-completed questionnaires. Peak expiratory flow rates (PEFR) were obtained during the evenings and mornings for up to 14 consecutive days for each individual. Significantly greater prevalence rates of asthma and chronic bronchitis were found in children from houses with HCHO levels 60-120 ppb than in those less exposed, especially in children also exposed to environmental tobacco smoke. In children, levels of PEFR decreased linearly with HCHO exposure, with the estimated decrease due to 60 ppb of HCHO equivalent to 22% of PEFR level in nonexposed children. The effects in asthmatic children exposed to HCHO below 50 ppb were greater than in healthy ones. The effects in adults were less evident: decrements in PEFR due to HCHO over 40 ppb were seen only in the morning, and mainly in smokers.

  17. Retrospective dosimetry related to chronic environmental exposure

    NASA Technical Reports Server (NTRS)

    Degteva, M. O.; Kozheurov, V. P.; Tolstykh, E. I.; Neta, R. (Principal Investigator)

    1998-01-01

    Radioactive contamination of the environment occurred in the early fifties as a result of the releases from the Mayak plutonium production complex (Southern Urals, Russia). The releases of liquid wastes into the Techa river resulted in chronic exposure of 30,000 residents of the riverside communities. Since 1951 90Sr body burdens have been measured for over half of this cohort. This paper presents the analysis of data on 90Sr in humans and describes the reconstruction of internal doses for these people.

  18. [Mechanism of cytogenetic adaptive response induced by low dose radiation].

    PubMed

    Cai, L; Liu, S

    1990-11-01

    Cytogenetic observation on human lymphocytes indicated that pre-exposure of 10, 50 and 75 mGy X-rays could induced the adaptive response. Experimental results with different temperature treatment showed that the adaptive response induced by low dose radiation could be enhanced by 41 degrees C and 43 degrees C, but inhibited by 4 degrees C in addition the treatment by 41 degrees C for one hour could also cause the adaptive response as did low dose radiation. Results showed that adaptive response induced by low dose radiation (10 or 50 mGy X-rays) could be eliminated by the protein synthesis inhibitor, implying that the adaptive response is related with the metabolism of cells, especially with the production of certain protective proteins.

  19. Early chronic lead exposure reduces exploratory activity in young C57BL/6J mice.

    PubMed

    Flores-Montoya, Mayra Gisel; Sobin, Christina

    2015-07-01

    Research has suggested that chronic low-level lead exposure diminishes neurocognitive function in children. Tests that are sensitive to behavioral effects at lowest levels of lead exposure are needed for the development of animal models. In this study we investigated the effects of chronic low-level lead exposure on exploratory activity (unbaited nose poke task), exploratory ambulation (open field task) and motor coordination (Rotarod task) in pre-adolescent mice. C57BL/6J pups were exposed to 0 ppm (controls), 30 ppm (low-dose) or 230 ppm (high-dose) lead acetate via dams' drinking water administered from birth to postnatal day 28, to achieve a range of blood lead levels (BLLs) from not detectable to 14.84 µg dl(-1) ). At postnatal day 28, mice completed behavioral testing and were killed (n = 61). BLLs were determined by inductively coupled plasma mass spectrometry. The effects of lead exposure on behavior were tested using generalized linear mixed model analyses with BLL, sex and the interaction as fixed effects, and litter as the random effect. BLL predicted decreased exploratory activity and no threshold of effect was apparent. As BLL increased, nose pokes decreased. The C57BL/6J mouse is a useful model for examining effects of early chronic low-level lead exposure on behavior. In the C57BL/6J mouse, the unbaited nose poke task is sensitive to the effects of early chronic low-level lead exposure. This is the first animal study to show behavioral effects in pre-adolescent lead-exposed mice with BLL below 5 µg dl(-1).

  20. Low dose naltrexone: side effects and efficacy in gastrointestinal disorders.

    PubMed

    Ploesser, Jennifer; Weinstock, Leonard B; Thomas, Erin

    2010-01-01

    Use of low dose naltrexone has been advocated for a variety of medical problems. Only a few articles published in peer review journals have documented side effects of low dose naltrexone. The purpose of this study was to determine the frequency of adverse effects of low dose naltrexone in patients who have been treated for a variety of gastrointestinal disorders. The secondary purpose was to determine global efficacy in a retrospective survey. Patients (206) form a single gastroenterologist's clinical practice who had been prescribed naltrexone were mailed a survey to evaluate the side effects and efficacy of naltrexone. Patients had either irritable bowel syndrome without evidence for small intestinal bacterial overgrowth, chronic idiopathic constipation, or inflammatory bowel disease. Patients with diarrhea were given 2.5 mg daily, constipation 2.5 mg twice daily, and inflammatory bowel disease 4.5 mg daily. In the patients who returned the survey, 47/121 (38.8%) had no side effects. Of the 74/121 (61.2%) patients who had side effects, 58 had one or more neurological complaints, and 32 had one or more gastrointestinal side effects. In the patients with side effects, 24/74 (32.4%) had short lived symptoms. Low dose naltrexone was terminated owing to side effects in 20/74 patients (27.0%). In 13 patients with idiopathic irritable bowel syndrome, 2 were markedly worse. In 85 patients with irritable bowel syndrome-small intestinal bacterial overgrowth, 15 were markedly improved, 32 were moderately worse, and 1 was markedly worse. In 12 patients with chronic constipation, 7 were markedly improved, 1 was moderately improved, 1 was mildly improved, and 4 were unchanged. Low dose naltrexone frequently has side effects but in most is tolerable. It appears to be helpful for a member of patients with gastrointestinal disorders.

  1. Mechanisms of Low Dose Radio-Suppression of Genomic Instability

    SciTech Connect

    Engelward, Bevin P

    2009-09-16

    The major goal of this project is to contribute toward the elucidation of the impact of long term low dose radiation on genomic stability. We have created and characterized novel technologies for delivering long term low dose radiation to animals, and we have studied genomic stability by applying cutting edge molecular analysis technologies. Remarkably, we have found that a dose rate that is 300X higher than background radiation does not lead to any detectable genomic damage, nor is there any significant change in gene expression for genes pertinent to the DNA damage response. These results point to the critical importance of dose rate, rather than just total dose, when evaluating public health risks and when creating regulatory guidelines. In addition to these studies, we have also further developed a mouse model for quantifying cells that have undergone a large scale DNA sequence rearrangement via homologous recombination, and we have applied these mice in studies of both low dose radiation and space radiation. In addition to more traditional approaches for assessing genomic stability, we have also explored radiation and possible beneficial effects (adaptive response), long term effects (persistent effects) and effects on communication among cells (bystander effects), both in vitro and in vivo. In terms of the adaptive response, we have not observed any significant induction of an adaptive response following long term low dose radiation in vivo, delivered at 300X background. In terms of persistent and bystander effects, we have revealed evidence of a bystander effect in vivo and with researchers at and demonstrated for the first time the molecular mechanism by which cells “remember” radiation exposure. Understanding the underlying molecular mechanisms by which radiation can induce genomic instability is fundamental to our ability to assess the biological impact of low dose radiation. Finally, in a parallel set of studies we have explored the effects of heavy

  2. Influence of low-dose and low-dose-rate ionizing radiation on mutation induction in human cells

    NASA Astrophysics Data System (ADS)

    Yatagai, F.; Umebayashi, Y.; Suzuki, M.; Abe, T.; Suzuki, H.; Shimazu, T.; Ishioka, N.; Iwaki, M.; Honma, M.

    This is a review paper to introduce our recent studies on the genetic effects of low-dose and low-dose-rate ionizing radiation (IR). Human lymphoblastoid TK6 cells were exposed to γ-rays at a dose-rate of 1.2 mGy/h (total 30 mGy). The frequency of early mutations (EMs) in the thymidine kinase ( TK) gene locus was determined to be 1.7 × 10 -6, or 1.9-fold higher than the level seen in unirradated controls [Umebayashi, Y., Honma, M., Suzuki, M., Suzuki, H., Shimazu, T., Ishioka, N., Iwaki, M., Yatagai, F., Mutation induction in cultured human cells after low-dose and low-dose-rate γ-ray irradiation: detection by LOH analysis. J. Radiat. Res., 48, 7-11, 2007]. These mutants were then analyzed for loss of heterozygosity (LOH) events. Small interstitial-deletion events were restricted to the TK gene locus and were not observed in EMs in unirradated controls, but they comprised about half of the EMs (8/15) after IR exposure. Because of the low level of exposure to IR, this specific type of event cannot be considered to be the direct result of an IR-induced DNA double strand break (DSB). To better understand the effects of low-level IR exposure, the repair efficiency of site-specific chromosomal DSBs was also examined. The pre γ-irradiation under the same condition did not largely influence the efficiency of DSB repair via end-joining, but enhanced such efficiency via homologous recombination to an about 40% higher level (unpublished data). All these results suggest that DNA repair and mutagenesis can be indirectly influenced by low-dose/dose-rate IR.

  3. Acceleration of atherogenesis in ApoE−/− mice exposed to acute or low-dose-rate ionizing radiation

    PubMed Central

    Mancuso, Mariateresa; Pasquali, Emanuela; Braga-Tanaka, Ignacia; Tanaka, Satoshi; Pannicelli, Alessandro; Giardullo, Paola; Pazzaglia, Simonetta; Tapio, Soile; Atkinson, Michael J.; Saran, Anna

    2015-01-01

    There is epidemiological evidence for increased non-cancer mortality, primarily due to circulatory diseases after radiation exposure above 0.5 Sv. We evaluated the effects of chronic low-dose rate versus acute exposures in a murine model of spontaneous atherogenesis. Female ApoE−/− mice (60 days) were chronically irradiated for 300 days with gamma rays at two different dose rates (1 mGy/day; 20 mGy/day), with total accumulated doses of 0.3 or 6 Gy. For comparison, age-matched ApoE−/− females were acutely exposed to the same doses and sacrificed 300 days post-irradiation. Mice acutely exposed to 0.3 or 6 Gy showed increased atherogenesis compared to age-matched controls, and this effect was persistent. When the same doses were delivered at low dose rate over 300 days, we again observed a significant impact on global development of atherosclerosis, although at 0.3 Gy effects were limited to the descending thoracic aorta. Our data suggest that a moderate dose of 0.3 Gy can have persistent detrimental effects on the cardiovascular system, and that a high dose of 6 Gy poses high risks at both high and low dose rates. Our results were clearly nonlinear with dose, suggesting that lower doses may be more damaging than predicted by a linear dose response. PMID:26359350

  4. Effect of low-dose ionizing radiation on luminous marine bacteria: radiation hormesis and toxicity.

    PubMed

    Kudryasheva, N S; Rozhko, T V

    2015-04-01

    The paper summarizes studies of effects of alpha- and beta-emitting radionuclides (americium-241, uranium-235+238, and tritium) on marine microorganisms under conditions of chronic low-dose irradiation in aqueous media. Luminous marine bacteria were chosen as an example of these microorganisms; bioluminescent intensity was used as a tested physiological parameter. Non-linear dose-effect dependence was demonstrated. Three successive stages in the bioluminescent response to americium-241 and tritium were found: 1--absence of effects (stress recognition), 2--activation (adaptive response), and 3--inhibition (suppression of physiological function, i.e. radiation toxicity). The effects were attributed to radiation hormesis phenomenon. Biological role of reactive oxygen species, secondary products of the radioactive decay, is discussed. The study suggests an approach to evaluation of non-toxic and toxic stages under conditions of chronic radioactive exposure.

  5. Effect of chronic exposure to zinc in young spats of the Pacific oyster (Crassostrea gigas).

    PubMed

    Devos, Alexandre; Voiseux, Claire; Caplat, Christelle; Fievet, Bruno

    2012-12-01

    The marine coastal environment is exposed to a mixture of environmental pollutants of anthropogenic origin, resulting in chronic low concentrations of contaminants. As a consequence, most coastal marine species are exposed to low doses of such pollutants during their entire life. Many marine species live for years in their natural environment, whereas they do not under laboratory exposure conditions. Using early stages of development in laboratory work allows animals to be chronically exposed from an early age over a reasonable experiment period. In the present study, the authors investigated the effect of chronic exposure to zinc in spats of the Pacific oyster (Crassostrea gigas), from metamorphosis up to 10 weeks. The authors investigated integrated biological endpoints that would account for the apparent general health of the animals as well as molecular markers showing more subtle effects that could potentially go unnoticed at a biologically integrated level. The authors measured in parallel both growth and the transcriptional level of target stress genes. Growth was monitored by image analysis of large samples to avoid high variability and ensure statistical robustness. A dose-response relationship was derived from growth data, yielding a median effective concentration (EC50) of 7.55 µM. Stress genes selected on the basis of available RNA sequences in C. gigas included genes involved in chaperone proteins, oxidative stress, detoxification, and cell cycle regulation. Out of nine stress target genes, only metallothionein displayed overexpression in response to high levels of zinc.

  6. Subclinical decelerations during developing hypotension in preterm fetal sheep after acute on chronic lipopolysaccharide exposure

    PubMed Central

    Lear, Christopher A.; Davidson, Joanne O.; Galinsky, Robert; Yuill, Caroline A.; Wassink, Guido; Booth, Lindsea C.; Drury, Paul P.; Bennet, Laura; Gunn, Alistair J.

    2015-01-01

    Subclinical (shallow) heart rate decelerations occur during neonatal sepsis, but there is limited information on their relationship with hypotension or whether they occur before birth. We examined whether subclinical decelerations, a fall in fetal heart rate (FHR) that remained above 100 bpm, were associated with hypotension in preterm fetal sheep exposed to lipopolysaccharide (LPS). Chronically-instrumented fetal sheep at 0.7 gestation received continuous low-dose LPS infusions (n = 15, 100 ng/kg over 24 h, followed by 250 ng/kg/24 h for 96 h) or saline (n = 8). Boluses of 1 μg LPS or saline were given at 48 and 72 h. FHR variability (FHRV) was calculated, and sample asymmetry was used to assess the severity and frequency of decelerations. Low-dose LPS infusion did not affect FHR. After the first LPS bolus, 7 fetuses remained normotensive, while 8 developed hypotension (a fall in mean arterial blood pressure of ≥5 mmHg). Developing hypotension was associated with subclinical decelerations, with a corresponding increase in sample asymmetry and FHRV (p < 0.05). The second LPS bolus was associated with similar but attenuated changes in FHR and blood pressure (p < 0.05). In conclusion, subclinical decelerations are not consistently seen during prenatal exposure to LPS, but may be a useful marker of developing inflammation-related hypotension before birth. PMID:26537688

  7. Animal Studies of Residual Hematopoietic and Immune System Injury from Low Dose/Low Dose Rate Radiation and Heavy Metals.

    DTIC Science & Technology

    1998-09-01

    accidents and industrial accidents (e.g., Chernobyl ) who receive high doses of radiation over a relatively short period of time, there are thousands of...several years after exposure may have been terminated. Examples of such groups include those affected by the fallout near Chernobyl , those living near...cohorts (e.g., Chernobyl victims) particular damage from low dose irradiation, especially membrane damage and mismatched DNA repair. Dosimetric Problems

  8. Chromosome Damage Caused by Accidental Chronic Whole-Body Gamma Radiation Exposure in Thailand

    PubMed Central

    Dolling, J.; Lavoie, J.; Mitchel, R. E. J.; Boreham, D. R.

    2015-01-01

    In February 2000, a radiation incident involving a medical 60Co source occurred in a metal scrapyard in Thailand. Several individuals were suspected to have received chronic or fractionated exposures ranging from a few mGy to a several Gy. Using fluorescence in situ hybridization to paint chromosomes, we determined the frequencies of chromosome aberrations in peripheral blood lymphocytes of 13 people who entered the scrapyard, 3 people who involved in recovering the source, and 9 nearby residents. Aberration frequencies greater than controls were observed in 13 of the donors at 3 months postexposure. The predominant form of aberration observed was simple, complete, symmetrical translocations. An approximate 50% decrease in these aberrations and in total color junctions was observed in 7 donors resampled at 16 months postexposure. Although high, acute exposures are known to have detrimental effects, the biological consequences of chronic, low dose-rate radiation exposures are unclear. Thirteen of the donors had elevated aberration frequencies, and 6 also had symptoms of acute radiation syndrome. If there are any long-term health consequences of this incident, it will most likely occur among this group of individuals. The consequences for the remaining donors, who presumably received lower total doses delivered at lower dose rates, are less clear. PMID:26740811

  9. Low Dose Naltrexone in the Treatment of Fibromyalgia.

    PubMed

    Metyas, Samy K; Yeter, Karen; Solyman, John; Arkfeld, Daniel

    2017-03-21

    Fibromyalgia is a chronic pain disorder characterized by diffuse musculoskeletal pain, fatigue, sleep disturbance and cognitive impairment. A significant number of fibromyalgia patients do not respond adequately to the current drugs (pregabalin, milnacipran, duloxetine) approved for fibromyalgia treatment by the Food and Drug Administration (FDA). Thus, there is still a need for adjunctive therapies. Naltrexone is an opioid receptor antagonist used to treat alcohol and opioid dependence. It is hypothesized that low dose naltrexone causes transient blockade of opioid receptors centrally resulting in a rebound of endorphin function which may attenuate pain in fibromyalgia. Treatment with low dose naltrexone may be an effective, highly tolerable and inexpensive treatment for fibromyalgia. Further controlled trials are needed.

  10. Multi-Level Effects of Low Dose Rate Ionizing Radiation on Southern Toad, Anaxyrus [Bufo] terrestris

    PubMed Central

    Stark, Karolina; Scott, David E.; Tsyusko, Olga; Coughlin, Daniel P.; Hinton, Thomas G.

    2015-01-01

    Despite their potential vulnerability to contaminants from exposure at multiple life stages, amphibians are one of the least studied groups of vertebrates in ecotoxicology, and research on radiation effects in amphibians is scarce. We used multiple endpoints to assess the radiosensitivity of the southern toad (Anaxyrus [Bufo] terrestris) during its pre-terrestrial stages of development –embryonic, larval, and metamorphic. Toads were exposed, from several hours after oviposition through metamorphosis (up to 77 days later), to four low dose rates of 137Cs at 0.13, 2.4, 21, and 222 mGy d-1, resulting in total doses up to 15.8 Gy. Radiation treatments did not affect hatching success of embryos, larval survival, or the length of the larval period. The individual family variation in hatching success of embryos was larger than the radiation response. In contrast, newly metamorphosed individuals from the higher dose-rate treatments had higher mass and mass/length body indices, a measure which may relate to higher post-metamorphic survival. The increased mass and index at higher dose rates may indicate that the chronic, low dose rate radiation exposures triggered secondary responses. Additionally, the increases in growth were linked to a decrease in DNA damage (as measured by the Comet Assay) in red blood cells at a dose rate of 21 mGy d-1 and a total dose of 1.1 Gy. In conclusion, the complex effects of low dose rates of ionizing radiation may trigger growth and cellular repair mechanisms in amphibian larvae. PMID:25927361

  11. Multi-Level Effects of Low Dose Rate Ionizing Radiation on Southern Toad, Anaxyrus [Bufo] terrestris.

    PubMed

    Stark, Karolina; Scott, David E; Tsyusko, Olga; Coughlin, Daniel P; Hinton, Thomas G

    2015-01-01

    Despite their potential vulnerability to contaminants from exposure at multiple life stages, amphibians are one of the least studied groups of vertebrates in ecotoxicology, and research on radiation effects in amphibians is scarce. We used multiple endpoints to assess the radiosensitivity of the southern toad (Anaxyrus [Bufo] terrestris) during its pre-terrestrial stages of development -embryonic, larval, and metamorphic. Toads were exposed, from several hours after oviposition through metamorphosis (up to 77 days later), to four low dose rates of 137Cs at 0.13, 2.4, 21, and 222 mGy d-1, resulting in total doses up to 15.8 Gy. Radiation treatments did not affect hatching success of embryos, larval survival, or the length of the larval period. The individual family variation in hatching success of embryos was larger than the radiation response. In contrast, newly metamorphosed individuals from the higher dose-rate treatments had higher mass and mass/length body indices, a measure which may relate to higher post-metamorphic survival. The increased mass and index at higher dose rates may indicate that the chronic, low dose rate radiation exposures triggered secondary responses. Additionally, the increases in growth were linked to a decrease in DNA damage (as measured by the Comet Assay) in red blood cells at a dose rate of 21 mGy d-1 and a total dose of 1.1 Gy. In conclusion, the complex effects of low dose rates of ionizing radiation may trigger growth and cellular repair mechanisms in amphibian larvae.

  12. Multi-level effects of low dose rate ionizing radiation on southern toad, Anaxyrus [Bufo] terrestris

    DOE PAGES

    Stark, Karolina; Scott, David E.; Tsyusko, Olga; ...

    2015-04-30

    Despite their potential vulnerability to contaminants from exposure at multiple life stages, amphibians are one of the least studied groups of vertebrates in ecotoxicology, and research on radiation effects in amphibians is scarce. We used multiple endpoints to assess the radiosensitivity of the southern toad (Anaxyrus [Bufo] terrestris) during its pre-terrestrial stages of development –embryonic, larval, and metamorphic. Toads were exposed, from several hours after oviposition through metamorphosis (up to 77 days later), to four low dose rates of ¹³⁷Cs at 0.13, 2.4, 21, and 222 mGy d⁻¹, resulting in total doses up to 15.8 Gy. Radiation treatments did notmore » affect hatching success of embryos, larval survival, or the length of the larval period. The individual family variation in hatching success of embryos was larger than the radiation response. In contrast, newly metamorphosed individuals from the higher dose-rate treatments had higher mass and mass/length body indices, a measure which may relate to higher post-metamorphic survival. The increased mass and index at higher dose rates may indicate that the chronic, low dose rate radiation exposures triggered secondary responses. Additionally, the increases in growth were linked to a decrease in DNA damage (as measured by the Comet Assay) in red blood cells at a dose rate of 21mGy d⁻¹ and a total dose of 1.1 Gy. In conclusion, the complex effects of low dose rates of ionizing radiation may trigger growth and cellular repair mechanisms in amphibian larvae.« less

  13. Rapid biosynthesis of silver nanoparticles using Crotalaria verrucosa leaves against the dengue vector Aedes aegypti: what happens around? An analysis of dragonfly predatory behaviour after exposure at ultra-low doses.

    PubMed

    Murugan, Kadarkarai; Sanoopa, C P; Madhiyazhagan, Pari; Dinesh, Devakumar; Subramaniam, Jayapal; Panneerselvam, Chellasamy; Roni, Mathath; Suresh, Udaiyan; Nicoletti, Marcello; Alarfaj, Abdullah A; Munusamy, Murugan A; Higuchi, Akon; Kumar, Suresh; Perumalsamy, Haribalan; Ahn, Young-Joon; Benelli, Giovanni

    2016-01-01

    Aedes aegypti is a primary vector of dengue, a mosquito-borne viral disease infecting 50-100 million people every year. Here, we biosynthesised mosquitocidal silver nanoparticles (AgNP) using the aqueous leaf extract of Crotalaria verrucosa. The green synthesis of AgNP was studied by UV-vis spectroscopy, SEM, EDX and FTIR. C. verrucosa-synthesised AgNPs were toxic against A. aegypti larvae and pupae. LC50 of AgNP ranged from 3.496 ppm (I instar larvae) to 17.700 ppm (pupae). Furthermore, we evaluated the predatory efficiency of dragonfly nymphs, Brachydiplax sobrina, against II and III instar larvae of A. aegypti in an aquatic environment contaminated with ultra-low doses of AgNP. Under standard laboratory conditions, predation after 24 h was 87.5% (II) and 54.7% (III). In an AgNP-contaminated environment, predation was 91 and 75.5%, respectively. Overall, C. verrucosa-synthesised AgNP could be employed at ultra-low doses to reduce larval population of dengue vectors enhancing predation rates of dragonfly nymphs.

  14. Low-Dose Radioactive Iodine Destroys Thyroid Tissue Left after Surgery

    Cancer.gov

    A low dose of radioactive iodine given after surgery for thyroid cancer destroyed (ablated) residual thyroid tissue as effectively as a higher dose, with fewer side effects and less exposure to radiation, according to two randomized controlled trials.

  15. Low doses of neutrons induce changes in gene expression

    SciTech Connect

    Woloschak, G.E.; Chang-Liu, C.M. ); Panozzo, J.; Libertin, C.R. )

    1993-01-01

    Studies were designed to identify genes induced following low-dose neutron but not following [gamma]-ray exposure in fibroblasts. Our past work had shown differences in the expression of [beta]-protein kinase C and c-fos genes, both being induced following [gamma]-ray but not neutron exposure. We have identified two genes that are induced following neutron, but not [gamma]-ray, exposure: Rp-8 (a gene induced by apoptosis) and the long terminal repeat (LTR) of the human immunodeficiency (HIV). Rp-8 mRNA induction was demonstrated in Syrian hamster embryo fibroblasts and was found to be induced in cells exposed to neutrons administered at low (0.5 cGy/min) and at high dose rate (12 cGy/min). The induction of transcription from the LTR of HIV was demonstrated in HeLa cells bearing a transfected construct of the chloramphenicol acetyl transferase (CAT) gene driven by the HIV-LTR promoter. Measures of CAT activity and CAT transcripts following irradiation demonstrated an unresponsiveness to [gamma] rays over a broad range of doses. Twofold induction of the HIV-LTR was detected following neutron exposure (48 cGy) administered at low (0.5 cGy/min) but not high (12 cGy/min) dose rates. Ultraviolet-mediated HIV-LTR induction was inhibited by low-dose-rate neutron exposure.

  16. Low doses of neutrons induce changes in gene expression

    SciTech Connect

    Woloschak, G.E.; Chang-Liu, C.M.; Panozzo, J.; Libertin, C.R.

    1993-06-01

    Studies were designed to identify genes induced following low-dose neutron but not following {gamma}-ray exposure in fibroblasts. Our past work had shown differences in the expression of {beta}-protein kinase C and c-fos genes, both being induced following {gamma}-ray but not neutron exposure. We have identified two genes that are induced following neutron, but not {gamma}-ray, exposure: Rp-8 (a gene induced by apoptosis) and the long terminal repeat (LTR) of the human immunodeficiency (HIV). Rp-8 mRNA induction was demonstrated in Syrian hamster embryo fibroblasts and was found to be induced in cells exposed to neutrons administered at low (0.5 cGy/min) and at high dose rate (12 cGy/min). The induction of transcription from the LTR of HIV was demonstrated in HeLa cells bearing a transfected construct of the chloramphenicol acetyl transferase (CAT) gene driven by the HIV-LTR promoter. Measures of CAT activity and CAT transcripts following irradiation demonstrated an unresponsiveness to {gamma} rays over a broad range of doses. Twofold induction of the HIV-LTR was detected following neutron exposure (48 cGy) administered at low (0.5 cGy/min) but not high (12 cGy/min) dose rates. Ultraviolet-mediated HIV-LTR induction was inhibited by low-dose-rate neutron exposure.

  17. Biological-Based Modeling of Low Dose Radiation Risks

    SciTech Connect

    Scott, Bobby R., Ph.D.

    2006-11-08

    The objective of this project was to refine a biological-based model (called NEOTRANS2) for low-dose, radiation-induced stochastic effects taking into consideration newly available data, including data on bystander effects (deleterious and protective). The initial refinement led to our NEOTRANS3 model which has undergone further refinement (e.g., to allow for differential DNA repair/apoptosis over different dose regions). The model has been successfully used to explain nonlinear dose-response curves for low-linear-energy-transfer (LET) radiation-induced mutations (in vivo) and neoplastic transformation (in vitro). Relative risk dose-response functions developed for neoplastic transformation have been adapted for application to cancer relative risk evaluation for irradiated humans. Our low-dose research along with that conducted by others collectively demonstrate the following regarding induced protection associated with exposure to low doses of low-LET radiation: (1) protects against cell killing by high-LET alpha particles; (2) protects against spontaneous chromosomal damage; (3) protects against spontaneous mutations and neoplastic transformations; (4) suppresses mutations induced by a large radiation dose even when the low dose is given after the large dose; (5) suppresses spontaneous and alpha-radiation-induced cancers; (6) suppresses metastasis of existing cancer; (7) extends tumor latent period; (8) protects against diseases other than cancer; and (9) extends life expectancy. These forms of radiation-induced protection are called adapted protection as they relate to induced adaptive response. Thus, low doses and dose rates of low-LET radiation generally protect rather than harm us. These findings invalidate the linear not threshold (LNT) hypothesis which is based on the premise that any amount of radiation is harmful irrespective of its type. The hypothesis also implicates a linear dose-response curve for cancer induction that has a positive slope and no

  18. MELODI: the 'Multidisciplinary European Low-Dose Initiative'.

    PubMed

    Belli, M; Salomaa, S; Ottolenghi, A

    2011-02-01

    The importance of research to reduce uncertainties in risk assessment of low and protracted exposures is now recognised globally. In Europe a new initiative, called 'Multidisciplinary European LOw Dose Initiative' (MELODI), has been proposed by a 'European High Level and Expert Group on low-dose risk research' (www.hleg.de), aimed at integrating national and EC (Euratom) efforts. Five national organisations: BfS (DE), CEA (FR), IRSN (FR), ISS (IT) and STUK (FI), with the support of the EC, have initiated the creation of MELODI by signing a letter of intent. In the forthcoming years, MELODI will integrate in a step-by-step approach EU institutions with significant programmes in the field and will be open to other scientific organisations and stakeholders. A key role of MELODI is to develop and maintain over time a strategic research agenda (SRA) and a road map of scientific priorities within a multidisciplinary approach, and to transfer the results for the radiation protection system. Under the coordination of STUK a network has been proposed in the 2009 Euratom Programme, called DoReMi (Low-Dose Research towards Mutidisciplinary Integration), which can help the integration process within the MELODI platform. DoReMi and the First MELODI Open Workshop, organised by BfS in September 2009, are now important inputs for the European SRA.

  19. Low dose naltrexone therapy in multiple sclerosis.

    PubMed

    Agrawal, Y P

    2005-01-01

    The use of low doses of naltrexone for the treatment of multiple sclerosis (MS) enjoys a worldwide following amongst MS patients. There is overwhelming anecdotal evidence, that in low doses naltrexone not only prevents relapses in MS but also reduces the progression of the disease. It is proposed that naltrexone acts by reducing apoptosis of oligodendrocytes. It does this by reducing inducible nitric oxide synthase activity. This results in a decrease in the formation of peroxynitrites, which in turn prevent the inhibition of the glutamate transporters. Thus, the excitatory neurotoxicity of glutamate on neuronal cells and oligodendrocytes via activation of the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid class of glutamate receptor is prevented. It is crucial that the medical community respond to patient needs and investigate this drug in a clinical trial.

  20. Gamma radiation at a human relevant low dose rate is genotoxic in mice

    PubMed Central

    Graupner, Anne; Eide, Dag M.; Instanes, Christine; Andersen, Jill M.; Brede, Dag A.; Dertinger, Stephen D.; Lind, Ole C.; Brandt-Kjelsen, Anicke; Bjerke, Hans; Salbu, Brit; Oughton, Deborah; Brunborg, Gunnar; Olsen, Ann K.

    2016-01-01

    Even today, 70 years after Hiroshima and accidents like in Chernobyl and Fukushima, we still have limited knowledge about the health effects of low dose rate (LDR) radiation. Despite their human relevance after occupational and accidental exposure, only few animal studies on the genotoxic effects of chronic LDR radiation have been performed. Selenium (Se) is involved in oxidative stress defence, protecting DNA and other biomolecules from reactive oxygen species (ROS). It is hypothesised that Se deficiency, as it occurs in several parts of the world, may aggravate harmful effects of ROS-inducing stressors such as ionising radiation. We performed a study in the newly established LDR-facility Figaro on the combined effects of Se deprivation and LDR γ exposure in DNA repair knockout mice (Ogg1−/−) and control animals (Ogg1+/−). Genotoxic effects were seen after continuous radiation (1.4 mGy/h) for 45 days. Chromosomal damage (micronucleus), phenotypic mutations (Pig-a gene mutation of RBCCD24−) and DNA lesions (single strand breaks/alkali labile sites) were significantly increased in blood cells of irradiated animals, covering three types of genotoxic activity. This study demonstrates that chronic LDR γ radiation is genotoxic in an exposure scenario realistic for humans, supporting the hypothesis that even LDR γ radiation may induce cancer. PMID:27596356

  1. Gamma radiation at a human relevant low dose rate is genotoxic in mice

    NASA Astrophysics Data System (ADS)

    Graupner, Anne; Eide, Dag M.; Instanes, Christine; Andersen, Jill M.; Brede, Dag A.; Dertinger, Stephen D.; Lind, Ole C.; Brandt-Kjelsen, Anicke; Bjerke, Hans; Salbu, Brit; Oughton, Deborah; Brunborg, Gunnar; Olsen, Ann K.

    2016-09-01

    Even today, 70 years after Hiroshima and accidents like in Chernobyl and Fukushima, we still have limited knowledge about the health effects of low dose rate (LDR) radiation. Despite their human relevance after occupational and accidental exposure, only few animal studies on the genotoxic effects of chronic LDR radiation have been performed. Selenium (Se) is involved in oxidative stress defence, protecting DNA and other biomolecules from reactive oxygen species (ROS). It is hypothesised that Se deficiency, as it occurs in several parts of the world, may aggravate harmful effects of ROS-inducing stressors such as ionising radiation. We performed a study in the newly established LDR-facility Figaro on the combined effects of Se deprivation and LDR γ exposure in DNA repair knockout mice (Ogg1‑/‑) and control animals (Ogg1+/‑). Genotoxic effects were seen after continuous radiation (1.4 mGy/h) for 45 days. Chromosomal damage (micronucleus), phenotypic mutations (Pig-a gene mutation of RBCCD24‑) and DNA lesions (single strand breaks/alkali labile sites) were significantly increased in blood cells of irradiated animals, covering three types of genotoxic activity. This study demonstrates that chronic LDR γ radiation is genotoxic in an exposure scenario realistic for humans, supporting the hypothesis that even LDR γ radiation may induce cancer.

  2. Low dose aprotinin and low dose tranexamic acid in elective cardiac surgery with cardiopulmonary bypass.

    PubMed

    Waldow, Thomas; Krutzsch, Diana; Wils, Michael; Plötze, Katrin; Matschke, Klaus

    2009-01-01

    The antifibrinolytic agents aprotinin and tranexamic acid have both been proven to be efficient in reducing postoperative blood loss and transfusion requirements in patients in cardiac surgery. In light of recent safety issues regarding aprotinin, this single-centre study compared efficacy and safety of low dose aprotinin (2 million KIU, pump-prime volume only) and low dose tranexamic acid (1 g, pump-prime volume) in 708 consecutive patients from two prospective registers undergoing elective cardiac procedures with cardiopulmonary bypass (CPB). Incidences of postoperative complications showed no significant differences between groups. Postoperative blood loss and transfusion requirements were significantly lower in aprotinin compared to tranexamic acid patients. Overall, both antifibrinolytic low dose regimens are safe components of perioperative patient management in elective cardiac surgery with CPB. Cardiac procedures requiring longer CPB times might benefit from the administration of low dose aprotinin.

  3. Mitochondrial-Derived Oxidants and Cellular Responses to Low Dose/Low LET Ionizing Radiation

    SciTech Connect

    Spitz, Douglas R.

    2009-11-09

    Exposure to ionizing radiation results in the immediate formation of free radicals and other reactive oxygen species (ROS). It has been assumed that the subsequent injury processes leading to genomic instability and carcinogenesis following radiation, derive from the initial oxidative damage caused by these free radicals and ROS. It is now becoming increasingly obvious that metabolic oxidation/reduction (redox) reactions can be altered by irradiation leading to persistent increases in steady-state levels of intracellular free radicals and ROS that contribute to the long term biological effects of radiation exposure by causing chronic oxidative stress. The objective during the last period of support (DE-FG02-05ER64050; 5/15/05-12/31/09) was to determine the involvement of mitochondrial genetic defects in metabolic oxidative stress and the biological effects of low dose/low LET radiation. Aim 1 was to determine if cells with mutations in succinate dehydrogenase (SDH) subunits C and D (SDHC and SDHD in mitochondrial complex II) demonstrated increases in steady-state levels of reactive oxygen species (ROS; O2•- and H2O2) as well as demonstrating increased sensitivity to low dose/low LET radiation (10 cGy) in cultured mammalian cells. Aim #2 was to determine if mitochondrially-derived ROS contributed to increased sensitivity to low dose/low LET radiation in mammalian cells containing mutations in SDH subunits. Aim #3 was to determine if a causal relationship existed between increases in mitochondrial ROS production, alterations in electron transport chain proteins, and genomic instability in the progeny of irradiated cells. Evidence gathered in the 2005-2009 period of support demonstrated that mutations in genes coding for mitochondrial electron transport chain proteins (ETC); either Succinate Dehydrogenase (SDH) subunit C (SDHC) or subunit D (SDHD); caused increased ROS production, increased genomic instability, and increased sensitivity to low dose/low LET radiation

  4. Chronic lead exposure reduces junctional resistance at an electrical synapse.

    PubMed

    Audesirk, G; Audesirk, T

    1984-01-01

    Both acute and chronic lead exposure have been found to inhibit transmission at chemical synapses, possibly by interfering with inward calcium current. We have found that chronic lead exposure slightly reduces input resistance and greatly reduces the junctional resistance between two strongly electrically coupled neurons in the pond snail Lymnaea stagnalis. The net effect is to increase the strength of electrical coupling. A reduction in gap junctional resistance would also be expected to increase the flow of small molecules between cells. However, Lucifer Yellow injections did not reveal dye-coupling between the cells. Lead exposure also increases the capacitance of the neurons.

  5. Oxytrex: an oxycodone and ultra-low-dose naltrexone formulation.

    PubMed

    Webster, Lynn R

    2007-08-01

    Oxytrex (Pain Therapeutics, Inc.) is an oral opioid that combines a therapeutic amount of oxycodone with an ultra-low dose of the antagonist naltrexone. Animal data indicate that this combination minimizes the development of physical dependence and analgesic tolerance while prolonging analgesia. Oxytrex is in late-stage clinical development by Pain Therapeutics for the treatment of moderate-to-severe chronic pain. To evaluate the safety and efficacy of the oxycodone/naltrexone combination, three clinical studies have been conducted, one in healthy volunteers and the other two in patients with chronic pain. The putative mechanism of ultra-low-dose naltrexone is to prevent an alteration in G-protein coupling by opioid receptors that is associated with opioid tolerance and dependence. Opioid agonists are initially inhibitory but become excitatory through constant opioid receptor activity. The agonist/antagonist combination of Oxytrex may reduce the conversion from an inhibitory to an excitatory receptor, thereby decreasing the development of tolerance and physical dependence.

  6. Improving abdomen tumor low-dose CT images using a fast dictionary learning based processing

    NASA Astrophysics Data System (ADS)

    Chen, Yang; Yin, Xindao; Shi, Luyao; Shu, Huazhong; Luo, Limin; Coatrieux, Jean-Louis; Toumoulin, Christine

    2013-08-01

    In abdomen computed tomography (CT), repeated radiation exposures are often inevitable for cancer patients who receive surgery or radiotherapy guided by CT images. Low-dose scans should thus be considered in order to avoid the harm of accumulative x-ray radiation. This work is aimed at improving abdomen tumor CT images from low-dose scans by using a fast dictionary learning (DL) based processing. Stemming from sparse representation theory, the proposed patch-based DL approach allows effective suppression of both mottled noise and streak artifacts. The experiments carried out on clinical data show that the proposed method brings encouraging improvements in abdomen low-dose CT images with tumors.

  7. Noise reduction with low dose CT data based on a modified ROF model.

    PubMed

    Zhu, Yining; Zhao, Mengliu; Zhao, Yunsong; Li, Hongwei; Zhang, Peng

    2012-07-30

    In order to reduce the radiation exposure caused by Computed Tomography (CT) scanning, low dose CT has gained much interest in research as well as in industry. One fundamental difficulty for low dose CT lies in its heavy noise pollution in the raw data which leads to quality deterioration for reconstructed images. In this paper, we propose a modified ROF model to denoise low dose CT measurement data in light of Poisson noise model. Experimental results indicate that the reconstructed CT images based on measurement data processed by our model are in better quality, compared to the original ROF model or bilateral filtering.

  8. Experimental study of relationship between biological hazards of low-dose radiofrequency exposure and energy flow density in Spirostomum ambiguum infusoria exposed at a mobile connection frequency (1 GHz).

    PubMed

    Sarapultseva, E I; Igolkina, J V

    2011-08-01

    Radiofrequency exposure at the mobile connection frequency (1 GHz) at different energy flow densities, 5 μW/cm(2)(2-fold below the maximum permissible level) and 50 μW/cm(2)(5-fold surpassing this level), caused a reduction of motor activity in unicellular hydrobionts Spirostomum ambiguum Ehrbg infusoria. In all cases, the effect was similar by the intensity and developed in a jump-wise manner after exposure of a certain duration, after which did not increase with prolongation of the exposure. The duration of radiofrequency exposure safe for the object varied significantly: 8-9 h and 10 min at 5 and 50 μW, respectively. These innovation data on harmful biological effects of very low radiofrequency exposure (5 μW/cm(2)), the threshold form of biological reaction, presence of "safe" periods of exposure, and the data demonstrating a clear-cut relationship between these periods and energy flow density are interesting from theoretical viewpoint and in connection with the problem of evaluating permissible levels of radiofrequency exposure of biological objects.

  9. TELOMERASE AND CHRONIC ARSENIC EXPOSURE IN HUMANS

    EPA Science Inventory

    Arsenic exposure has been associated with increased risk of skin, lung and bladder cancer in humans. The mechanisms of carcinogenesis are not well understood. Telomerase, a ribonucleoprotein containing human telomerase reverse transcriptase (hTERT), can extend telomeres of eukary...

  10. Effects of chronic caffeine pre-exposure on conditioned and unconditioned psychomotor activity induced by nicotine and amphetamine in rats.

    PubMed

    Palmatier, M I; Fung, E Y K; Bevins, R A

    2003-05-01

    Three experiments examined the effects of chronic pre-exposure to caffeine on the subsequent conditioned and unconditioned locomotor activating effects of nicotine or amphetamine in rats. Rats were given daily intraperitoneal injections of caffeine anhydrous (0, 10 or 30 mg/kg base) for 30 days. Conditioning (environment-drug pairings) began after the last day of caffeine pre-exposure. Pre-exposure to 30 mg/kg of caffeine enhanced the acute and chronic locomotor effects of amphetamine (0.5 mg/kg). A similar enhancement of activity was not seen with the high (0.421 mg/kg base) or low dose (0.175 mg/kg) of nicotine. In a drug-free test, the distinct environment paired with amphetamine and the high dose of nicotine evoked increases in activity relative to controls. Caffeine pre-exposure did not affect expression of this conditioned hyperactivity. These effects of caffeine pre-exposure on amphetamine-induced activity could not be attributed to non-specific effects of caffeine.

  11. Ultra-low dose naltrexone potentiates the anticonvulsant effect of low dose morphine on clonic seizures.

    PubMed

    Honar, H; Riazi, K; Homayoun, H; Sadeghipour, H; Rashidi, N; Ebrahimkhani, M R; Mirazi, N; Dehpour, A R

    2004-01-01

    Significant potentiation of analgesic effects of opioids can be achieved through selective blockade of their stimulatory effects on intracellular signaling pathways by ultra-low doses of opioid receptor antagonists. However, the generality and specificity of this interaction is not well understood. The bimodal modulation of pentylenetetrazole-induced seizure threshold by opioids provide a model to assess the potential usefulness of this approach in seizure disorders and to examine the differential mechanisms involved in opioid anti- (morphine at 0.5-3 mg/kg) versus pro-convulsant (20-100 mg/kg) effects. Systemic administration of ultra-low doses of naltrexone (100 fg/kg-10 ng/kg) significantly potentiated the anticonvulsant effect of morphine at 0.5 mg/kg while higher degrees of opioid receptor antagonism blocked this effect. Moreover, inhibition of opioid-induced excitatory signaling by naltrexone (1 ng/kg) unmasked a strong anticonvulsant effect for very low doses of morphine (1 ng/kg-100 microg/kg), suggesting that a presumed inhibitory component of opioid receptor signaling can exert strong seizure-protective effects even at very low levels of opioid receptor activation. However, ultra-low dose naltrexone could not increase the maximal anticonvulsant effect of morphine (1-3 mg/kg), possibly due to a ceiling effect. The proconvulsant effects of morphine on seizure threshold were minimally altered by ultra-low doses of naltrexone while being completely blocked by a higher dose (1 mg/kg) of the antagonist. The present data suggest that ultra-low doses of opioid receptor antagonists may provide a potent strategy to modulate seizure susceptibility, especially in conjunction with very low doses of opioids.

  12. Regulation of adenosine transport by acute and chronic ethanol exposure

    SciTech Connect

    Nagy, L.E.; Casso, D.; Diamond, I.; Gordon, A.S. )

    1989-02-09

    Chronic exposure to ethanol results in a desensitization of adenosine receptor-stimulated cAMP production. Since adenosine is released by cells and is known to desensitize its own as well as other receptors, it may be involved in ethanol-induced desensitization of adenosine receptor function. Therefore, we have examine the acute and chronic effects of ethanol on the transport of adenosine via the nucleoside transport. Acute exposure to ethanol caused an inhibition of adenosine uptake in S49 lymphoma cells. This decrease in uptake resulted in accumulation of extracellular adenosine after ethanol exposure. The effect of ethanol was specific to nucleoside transport. Uptake of uridine, also transported by the nucleoside transporter, was inhibited by ethanol to the same degree as adenosine uptake, while neither isoleucine nor deoxyglucose uptake was altered by ethanol treatment. Inhibition of adenosine uptake by ethanol was non-competitive and dependent on the concentration of ethanol. After chronic exposure to ethanol, cells became tolerant to the acute effects of ethanol. There was no longer an acute inhibition of adenosine uptake, nor was these accumulation of extracellular adenosine. Chronic ethanol exposure also resulted in a decrease in the absolute rate of adenosine uptake. Binding studies using a high affinity lignad for the nucleoside transporter, nitrobenzylthioinosine (NBMPR), indicate that this decreased uptake was due to a decrease in the maximal number of binding sites. These ethanol-induced changes in adenosine transport may be important for the acute and chronic effects of ethanol.

  13. Exposure-response relationships between occupational exposures and chronic respiratory illness: a community-based study.

    PubMed

    Xu, X; Christiani, D C; Dockery, D W; Wang, L

    1992-08-01

    Data from a random sample of 3,606 adults 40 to 69 yr of age residing in Beijing, China, were analyzed to investigate the association of reported occupational exposures to dusts and gases/fumes with the prevalence of chronic respiratory symptoms and level of pulmonary function. The prevalence of occupational dust exposure was 32%, and gas or fume exposure, 19%. After we adjusted for age, sex, area of residence, smoking status, coal stove heating, and education, an increased prevalence of chronic phlegm and breathlessness was significantly related to both types of exposures. Chronic cough was significantly related only to dust exposure, and persistent wheeze only to fume exposure. The global estimates of the relative odds of the four symptoms were 1.30 (95% CI [confidence interval] 1.09 to 1.48) and 1.27 (95% CI 1.09 to 1.48), respectively, for dusts and for gases/fumes. These two occupational exposures are associated with chronic respiratory symptoms independent of smoking, gender, and each other. There was an increasing prevalence of each symptom with increasing dust and fume exposure, represented by the index of cumulative exposure duration and exposure intensity. Linear trends for increased prevalence of chronic bronchitis and breathlessness were significant for both exposures, while the linear trend for wheeze was only significant for gases/fumes. Among subjects who did not report using coal stove heating, dust exposure was a significant predictor for FEV1, FEV1/FVC, FEF25-75, and peak expiratory flow rate (PEFR). There was also a significant decrease for FEV1 and FVC with increase of gas/fume exposure levels. Both current and former smokers appeared to be more susceptible to the effect of dusts than the never smokers.(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Low-Dose Radiation and Genotoxic Chemicals Can Protect Against Stochastic Biological Effects

    PubMed Central

    Scott, Bobby R.; Walker, Dale M.; Walker, Vernon E.

    2004-01-01

    A protective apoptosis-mediated (PAM) process that is turned on in mammalian cells by low-dose photon (X and γ) radiation and appears to also be turned on by the genotoxic chemical ethylene oxide is discussed. Because of the PAM process, exposure to low-dose photon radiation (and possibly also some genotoxic chemicals) can lead to a reduction in the risk of stochastic effects such as problematic mutations, neoplastic transformation (an early step in cancer occurrence), and cancer. These findings indicate a need to revise the current low-dose risk assessment paradigm for which risk of cancer is presumed to increase linearly with dose (without a threshold) after exposure to any amount of a genotoxic agent such as ionizing radiation. These findings support a view seldom mentioned in the past, that cancer risk can actually decrease, rather than increase, after exposure to low doses of photon radiation and possibly some other genotoxic agents. The PAM process (a form of natural protection) may contribute substantially to cancer prevention in humans and other mammals. However, new research is needed to improve our understanding of the process. The new research could unlock novel strategies for optimizing cancer prevention and novel protocols for low-dose therapy for cancer. With low-dose cancer therapy, normal tissue could be spared from severe damage while possibly eliminating the cancer. PMID:19330143

  15. Psychologic sequelae of chronic toxic waste exposure

    SciTech Connect

    Foulks, E.; McLellen, T. )

    1992-02-01

    Exposure to toxic industrial substances has been a topic of increasing concern to environmentalists, government agencies, industrial engineers, and medical specialists. Our study focuses on the psychologic symptom responses of a community to perceived long-term exposure to toxic waste products. We compared their symptom clusters, as shown by their responses to questions on the Hopkins Symptom Checklist-90 Item (SCL-90) and the Social Adjustment Scale (SAS), with symptom levels of normal and depressed subjects. Issues of media coverage, litigation, and potential for compensation complicate the psychiatric epidemiology of the subject.

  16. Reductions in carotid chemoreceptor activity with low-dose dopamine improves baroreflex control of heart rate during hypoxia in humans.

    PubMed

    Mozer, Michael T; Holbein, Walter W; Joyner, Michael J; Curry, Timothy B; Limberg, Jacqueline K

    2016-07-01

    The purpose of the present investigation was to examine the contribution of the carotid body chemoreceptors to changes in baroreflex control of heart rate with exposure to hypoxia. We hypothesized spontaneous cardiac baroreflex sensitivity (scBRS) would be reduced with hypoxia and this effect would be blunted when carotid chemoreceptor activity was reduced with low-dose dopamine. Fifteen healthy adults (11 M/4 F) completed two visits randomized to intravenous dopamine or placebo (saline). On each visit, subjects were exposed to 5-min normoxia (~99% SpO2), followed by 5-min hypoxia (~84% SpO2). Blood pressure (intra-arterial catheter) and heart rate (ECG) were measured continuously and scBRS was assessed by spectrum and sequence methodologies. scBRS was reduced with hypoxia (P < 0.01). Using the spectrum analysis approach, the fall in scBRS with hypoxia was attenuated with infusion of low-dose dopamine (P < 0.01). The decrease in baroreflex sensitivity to rising pressures (scBRS "up-up") was also attenuated with low-dose dopamine (P < 0.05). However, dopamine did not attenuate the decrease in baroreflex sensitivity to falling pressures (scBRS "down-down"; P > 0.05). Present findings are consistent with a reduction in scBRS with systemic hypoxia. Furthermore, we show this effect is partially mediated by the carotid body chemoreceptors, given the fall in scBRS is attenuated when activity of the chemoreceptors is reduced with low-dose dopamine. However, the improvement in scBRS with dopamine appears to be specific to rising blood pressures. These results may have important implications for impairments in baroreflex function common in disease states of acute and/or chronic hypoxemia, as well as the experimental use of dopamine to assess such changes.

  17. The Effect of Chronic Ozone Exposure on the Activation of Endoplasmic Reticulum Stress and Apoptosis in Rat Hippocampus

    PubMed Central

    Rodríguez-Martínez, Erika; Nava-Ruiz, Concepcion; Escamilla-Chimal, Elsa; Borgonio-Perez, Gabino; Rivas-Arancibia, Selva

    2016-01-01

    The chronic exposure to low doses of ozone, like in environmental pollution, leads to a state of oxidative stress, which has been proposed to contribute to neurodegenerative disorders, including Alzheimer’s disease (AD). It induces an increase of calcium in the endoplasmic reticulum (ER), which produces ER stress. On the other hand, different studies show that, in diseases such as Alzheimer’s, there exist disturbances in protein folding where ER plays an important role. The objective of this study was to evaluate the state of chronic oxidative stress on ER stress and its relationship with apoptotic death in the hippocampus of rats exposed to low doses of ozone. We used 108 male Wistar rats randomly divided into five groups. The groups received one of the following treatments: (1) Control (air); (2) Ozone (O3) 7 days; (3) O3 15 days; (4) O3 30 days; (5) O3 60 days; and (6) O3 90 days. Two hours after each treatment, the animals were sacrificed and the hippocampus was extracted. Afterwards, the tissue was processed for western blot and immunohistochemistry using the following antibodies: ATF6, 78 kDa glucose-regulated protein (GRP78) and caspase 12. It was also subjected to terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and electronic microscopy. Our results show an increase in ATF6, GRP78 and caspase 12 as well as ER ultrastructural alterations and an increase of TUNEL positive cells after 60 and 90 days of exposure to ozone. With the obtained results, we can conclude that oxidative stress induced by chronic exposure to low doses of ozone leads to ER stress. ER stress activates ATF6 inducing the increase of GRP78 in the cytoplasm, which leads to the increase in the nuclear translocation of ATF6. Finally, the translocation creates a vicious cycle that, together with the activation of the cascade for apoptotic cell death, contributes to the maintenance of ER stress. These events potentially contribute in the neurodegeneration processes

  18. Surrogates of Protection in Repeated Low-Dose Challenge Experiments

    PubMed Central

    Long, Dustin M.; Hudgens, Michael G.; Wu, Chih-Da

    2015-01-01

    A critical step toward developing a successful vaccine to control the human immunodeficiency virus (HIV) pandemic entails evaluation of vaccine candidates in non-human primates (NHPs). Historically, these studies have usually entailed challenges (i.e., exposures) with very high doses of a simian version of HIV, resulting in infection of all NHPs in the experiment after a single challenge. More recently, researchers have begun to conduct repeated low-dose challenge (RLC) studies in NHPs that are believed to more closely mimic typical exposure in natural human transmission settings. One objective of RLC studies is to assess whether measured immune responses to vaccination can serve as surrogate endpoints for the primary endpoint of interest, namely infection. In this paper, different designs of RLC studies for assessing a binary surrogate of protection are considered. PMID:25628249

  19. Leukemia risk associated with chronic external exposure to ionizing radiation in a French cohort of nuclear workers.

    PubMed

    Metz-Flamant, C; Samson, E; Caër-Lorho, S; Acker, A; Laurier, D

    2012-11-01

    Leukemia is one of the earliest cancer effects observed after acute exposure to relatively high doses of ionizing radiation. Leukemia mortality after external exposure at low doses and low-dose rates has been investigated at the French Atomic Energy Commission (CEA) and Nuclear Fuel Company (AREVA NC) after an additional follow-up of 10 years. The cohort included radiation-monitored workers employed for at least one year during 1950-1994 at CEA or AREVA NC and followed during 1968-2004. Association between external exposure and leukemia mortality was estimated with excess relative risk (ERR) models and time-dependent modifying factors were investigated with time windows. The cohort included 36,769 workers, followed for an average of 28 years, among whom 73 leukemia deaths occurred. Among the workers with a positive recorded dose, the mean cumulative external dose was 21.7 mSv. Results under a 2-year lag assumption suggested that the risk of leukemia (except chronic lymphatic leukemia) increased significantly by 8% per 10 mSv. The magnitude of the association for myeloid leukemia was larger. The higher ERR/Sv for doses received 2-14 years earlier suggest that time since exposure modifies the effect. The ERR/Sv also appeared higher for doses received at exposure rates ≥20 mSv per year. These results are consistent with those found in other studies of nuclear workers. However, confidence intervals are still wide. Further analyses should be conducted in pooled cohorts of nuclear workers.

  20. Cellular response to low dose radiation: Role of phosphatidylinositol-3 kinase like kinases

    SciTech Connect

    Balajee, A.S.; Meador, J.A.; Su, Y.

    2011-03-24

    It is increasingly realized that human exposure either to an acute low dose or multiple chronic low doses of low LET radiation has the potential to cause different types of cancer. Therefore, the central theme of research for DOE and NASA is focused on understanding the molecular mechanisms and pathways responsible for the cellular response to low dose radiation which would not only improve the accuracy of estimating health risks but also help in the development of predictive assays for low dose radiation risks associated with tissue degeneration and cancer. The working hypothesis for this proposal is that the cellular mechanisms in terms of DNA damage signaling, repair and cell cycle checkpoint regulation are different for low and high doses of low LET radiation and that the mode of action of phosphatidylinositol-3 kinase like kinases (PIKK: ATM, ATR and DNA-PK) determines the dose dependent cellular responses. The hypothesis will be tested at two levels: (I) Evaluation of the role of ATM, ATR and DNA-PK in cellular response to low and high doses of low LET radiation in simple in vitro human cell systems and (II) Determination of radiation responses in complex cell microenvironments such as human EpiDerm tissue constructs. Cellular responses to low and high doses of low LET radiation will be assessed from the view points of DNA damage signaling, DNA double strand break repair and cell cycle checkpoint regulation by analyzing the activities (i.e. post-translational modifications and kinetics of protein-protein interactions) of the key target proteins for PI-3 kinase like kinases both at the intra-cellular and molecular levels. The proteins chosen for this proposal are placed under three categories: (I) sensors/initiators include ATM ser1981, ATR, 53BP1, gamma-H2AX, MDC1, MRE11, Rad50 and Nbs1; (II) signal transducers include Chk1, Chk2, FANCD2 and SMC1; and (III) effectors include p53, CDC25A and CDC25C. The primary goal of this proposal is to elucidate the

  1. Chronic Ambient Hydrogen Sulfide Exposure and Cognitive Function

    PubMed Central

    Reed, Bruce R.; Crane, Julian; Garrett, Nick; Woods, David L.; Bates, Michael N.

    2014-01-01

    Background Exposures to hydrogen sulfide gas (H2S) have been inconclusively linked to a variety of negative cognitive outcomes. We investigated possible effects on cognitive function in an urban population with chronic, low-level exposure to H2S. Methods Participants were 1,637 adults, aged 18-65 years from Rotorua city, New Zealand, exposed to ambient H2S from geothermal sources. Exposures at homes and workplaces were estimated from data collected by summer and winter H2S monitoring networks across Rotorua in 2010/11. Metrics for H2S exposure at the time of participation and for exposure over the last 30 years were calculated. H2S exposure was modeled both as continuous variables and as quartiles of exposure covering the range of 0 – 64 ppb (0-88 μg/m3). Outcomes were neuropsychological tests measuring visual and verbal episodic memory, attention, fine motor skills, psychomotor speed and mood. Associations between cognition and measures of H2S exposure were investigated with multiple regression, while covarying demographics and factors known to be associated with cognitive performance. Results The consistent finding was of no association between H2S exposure and cognition. Quartiles of H2S exposure had a small association with simple reaction time: higher exposures were associated with faster response times. Similarly, for digit symbol, higher H2S exposures tended to be marginally associated with better performance. Conclusion The results provide evidence that chronic H2S exposure, at the ambient levels found in and around Rotorua, is not associated with impairment of cognitive function. PMID:24548790

  2. Low-Dose Radiation Cataract and Genetic Determinants of Radiosensitivity

    SciTech Connect

    Kleiman, Norman Jay

    2013-11-30

    The lens of the eye is one of the most radiosensitive tissues in the body. Ocular ionizing radiation exposure results in characteristic, dose related, progressive lens changes leading to cataract formation. While initial, early stages of lens opacification may not cause visual disability, the severity of such changes progressively increases with dose until vision is impaired and cataract extraction surgery may be required. Because of the transparency of the eye, radiation induced lens changes can easily be followed non-invasively over time. Thus, the lens provides a unique model system in which to study the effects of low dose ionizing radiation exposure in a complex, highly organized tissue. Despite this observation, considerable uncertainties remain surrounding the relationship between dose and risk of developing radiation cataract. For example, a growing number of human epidemiological findings suggest significant risk among various groups of occupationally and accidentally exposed individuals and confidence intervals that include zero dose. Nevertheless, questions remain concerning the relationship between lens opacities, visual disability, clinical cataract, threshold dose and/or the role of genetics in determining radiosensitivity. Experimentally, the response of the rodent eye to radiation is quite similar to that in humans and thus animal studies are well suited to examine the relationship between radiation exposure, genetic determinants of radiosensitivity and cataractogenesis. The current work has expanded our knowledge of the low-dose effects of X-irradiation or high-LET heavy ion exposure on timing and progression of radiation cataract and has provided new information on the genetic, molecular, biochemical and cell biological features which contribute to this pathology. Furthermore, findings have indicated that single and/or multiple haploinsufficiency for various genes involved in DNA repair and cell cycle checkpoint control, such as Atm, Brca1 or Rad9

  3. Neurotoxicity From Chronic Exposure to Depleted Uranium

    DTIC Science & Technology

    2006-04-01

    these response magnitudes. This suggests that UO2 +2 does not possess Ca+2-mimetic properties, but it could also be explained if the...intrasynaptosomal UO2 +2 concentrations did not achieve sufficient levels during the acute exposure to manifest such an effect. The uranium species involved in the...effect on glutamate exocytosis is not known. Uranyl ion ( UO2 +2) – the most common form produced in the body from all forms of the metal – is

  4. Does area deprivation modify the association between exposure to a nitrate and low-dose atrazine metabolite mixture in drinking water and small for gestational age? A historic cohort study.

    PubMed

    Limousi, F; Albouy-Llaty, M; Carles, C; Dupuis, A; Rabouan, S; Migeot, V

    2014-04-01

    Birth weight may be influenced by environmental and socio-economic factors that could interact. The main objective of our research was to investigate whether area deprivation may modify the association between drinking water exposure to a mixture of atrazine metabolites and nitrates during the second trimester of pregnancy and prevalence of small for gestational age (SGA) neonates. We conducted a historic cohort study in Deux-Sèvres, France between 2005 and 2010, using birth records, population census and regularly performed drinking water withdrawals at community water systems. Exposure to an atrazine metabolite/nitrate mixture in drinking water was divided into six classes according to the presence or absence of atrazine metabolites and to the terciles of nitrate concentrations in each trimester of pregnancy. We used a logistic regression to model the association between SGA and mixture exposure at the second trimester while taking into account the area deprivation measured by the Townsend index as an effect modifier and controlling for the usual confounders. We included 10,784 woman-neonate couples. The risk of SGA when exposed to second tercile of nitrate without atrazine metabolites was significantly greater in women living in less deprived areas (OR = 2.99; 95 % CI (1.14, 7.89)), whereas it was not significant in moderately and more deprived areas. One of the arguments used to explain this result is the presence of competing risk factors in poorer districts.

  5. Re-exposure of mallards to selenium after chronic exposure

    USGS Publications Warehouse

    Heinz, G.H.

    1993-01-01

    Adult male mallards (Anas platyrhynchos) were fed a control diet or a diet containing 15 ppm selenium as seleno-D,L-methionine for 21 weeks. After this initial exposure, the mallards were fed untreated food for 12 weeks, then were re-exposed to selenium at 100 ppm for five weeks. During re-exposure to 100 ppm selenium, the birds that had previously been exposed to 15 ppm selenium and those that had not previously been exposed did not differ in percentage of mortality (14.7 and 14.3%), weight loss in survivors (39.3 and 41.20%), selenium concentrations in the livers of survivors (35 and 53 ppm, wet weight), or selenium concentrations in the livers of birds that died (35 and 40 ppm, respectively). When the data from the birds that had previously been exposed to 15 ppm selenium were combined with the data from the birds that had not previously been exposed, selenium concentrations in the livers of birds that had died on the 100-ppm selenium treatment (38 ppm) did not differ from the concentrations in the livers of birds that had survived (43 ppm).

  6. DETECTION OF LOW DOSE RADIATION INDUCED DNA DAMAGE USING TEMPERATURE DIFFERENTIAL FLUORESCENCE ASSAY

    EPA Science Inventory

    A rapid and sensitive fluorescence assay for radiation-induced DNA damage is reported. Changes in temperature-induced strand separation in both calf thymus DNA and plasmid DNA (puc 19 plasmid from Escherichia coli) were measured after exposure to low doses of radiation. Exposur...

  7. DETECTION OF LOW DOSE RADIATION INDUCED DNA DAMAGE USING TEMPERATURE DIFFERENNTIAL FLUORESENCE ASSAY

    EPA Science Inventory

    A rapid and sensitive fluorescence assay for radiation-induced DNA damage is reported. Changes in temperature-induced strand separation in both calf thymus DNA and plasmid DNA (puc 19 plasmid from Escherichia coli) were measured after exposure to low doses of radiation. Exposures...

  8. Chronic cadmium exposure: relation to male reproductive toxicity and subsequent fetal outcome

    SciTech Connect

    Zenick, H.; Hastings, L.; Goldsmith, M.; Niewenhuis, R.J.

    1982-03-01

    Acute injections of high doses of Cd induced marked testicular necrosis. However, the effects of low-dose, oral Cd exposure on a chronic basis are not well documented. The present investigation was designed to examine the effects of such exposure as reflected in parameters of spermatotoxicity and histology. Moreover, the impact on fetal outcome was measured by evaluating teratological and postnatal neurobehavior endpoints. Male Long-Evans hooded rats (100 d of age) were exposed to 0, 17.2, 34.4, or 68.8 ppm Cd for 70 d. During this period, the animals were maintained on a semipurified diet to control for the contribution of Zn and other trace elements. Near the end of exposure the males were mated to three female rats. One was sacrificed on d 21 of pregnancy for teratological assessment, including fetal weight, and determination of preimplantation and postimplantation loss. The other two dams were allowed to deliver, and their offspring were tested on tasks of exploratory behavior (d 21) and learning (d 90). Subsequently, the male parent was sacrified and a variety of measures recorded including weights of testes and caudae epididymides, sperm count and sperm morphology, and Cd content of liver and kidney. One of the testes was also evaluated histologically. No significant effects were observed on any of the parameters of reproductive toxicity or fetal outcome. These findings suggest that, at the doses employed in this study, Cd did not have signficant deleterious effects on the male reproductive system. Morever, the traditional view of Cd-related testicular insult, based on acute exposure, injection protocols, needs to be reevaluated in terms of environmental relevance.

  9. Effects of low doses of radiation.

    PubMed

    Fry, R J

    1996-06-01

    This is a brief review of what is known from experimental studies about the effects of low doses of radiation, and approaches that might improve risk estimates are discussed. The dose-response relationships for cancer induction by radiation vary markedly between tissues. The evidence suggests that 1) the induction of the initial events is dependent on the cell type because the size and/or the number of targets and how the cells handle the initial lesions differs between cell types; and 2) there are marked differences among tissues how initial lesions are expressed and proceed to overt cancer. The recent findings about adaptive responses are discussed in the context of what they contribute to our understanding about the response to irradiation. Lastly, the possibility of extending the approach of determining "The probability of causation," which Vic Bond played such an important role in establishing, is raised.

  10. Low-dose total-body γ irradiation modulates immune response to acute proton radiation.

    PubMed

    Luo-Owen, Xian; Pecaut, Michael J; Rizvi, Asma; Gridley, Daila S

    2012-03-01

    Health risks due to exposure to low-dose/low-dose-rate radiation alone or when combined with acute irradiation are not yet clearly defined. This study quantified the effects of protracted exposure to low-dose/low-dose-rate γ rays with and without acute exposure to protons on the response of immune and other cell populations. C57BL/6 mice were irradiated with ⁵⁷Co (0.05 Gy at 0.025 cGy/h); subsets were subsequently exposed to high-dose/high-dose-rate proton radiation (250 MeV; 2 or 3 Gy at 0.5 Gy/min). Analyses were performed at 4 and 17 days postexposure. Spleen and thymus masses relative to body mass were decreased on day 4 after proton irradiation with or without pre-exposure to γ rays; by day 17, however, the decrease was attenuated by the priming dose. Proton dose-dependent decreases, either with or without pre-exposure to γ rays, occurred in white blood cell, lymphocyte and granulocyte counts in blood but not in spleen. A similar pattern was found for lymphocyte subpopulations, including CD3+ T, CD19+ B, CD4+ T, CD8+ T and NK1.1+ natural killer (NK) cells. Spontaneous DNA synthesis by leukocytes after proton irradiation was high in blood on day 4 and high in spleen on day 17; priming with γ radiation attenuated the effect of 3 Gy in both body compartments. Some differences were also noted among groups in erythrocyte and thrombocyte characteristics. Analysis of splenocytes activated with anti-CD3/anti-CD28 antibodies showed changes in T-helper 1 (Th1) and Th2 cytokines. Overall, the data demonstrate that pre-exposure of an intact mammal to low-dose/low-dose-rate γ rays can attenuate the response to acute exposure to proton radiation with respect to at least some cell populations.

  11. Enhanced Low Dose Rate Sensitivity at Ultra-Low Dose Rates

    NASA Technical Reports Server (NTRS)

    Chen, Dakai; Pease, Ronald; Forney, James; Carts, Martin; Phan, Anthony; Cox, Stephen; Kruckmeyer, Kriby; Burns, Sam; Albarian, Rafi; Holcombe, Bruce; Little, Bradley; Salzman, James; Chaumont, Geraldine; Duperray, Herve; Ouellet, Al; Buchner, Stephen; LaBel, Kenneth

    2011-01-01

    We have presented results of ultra-low dose rate irradiations (< or = 10 mrad(Si)/s) for a variety of radiation hardened and commercial linear bipolar devices. We observed low dose rate enhancement factors exceeding 1.5 in several parts. The worst case of dose rate enhancement resulted in functional failures, which occurred after 10 and 60 krad(Si), for devices irradiated at 0.5 and 10 mrad(Si)/s, respectively. Devices fabricated with radiation hardened processes and designs also displayed dose rate enhancement at below 10 mrad(Si)/s. Furthermore, the data indicated that these devices have not reached the damage saturation point. Therefore the degradation will likely continue to increase with increasing total dose, and the low dose rate enhancement will further magnify. The cases presented here, in addition to previous examples, illustrate the significance and pervasiveness of low dose rate enhancement at dose rates lower than 10 mrad(Si). These results present further challenges for radiation hardness assurance of bipolar linear circuits, and raise the question of whether the current standard test dose rate is conservative enough to bound degradations due to ELDRS.

  12. Chronic boron exposure and human semen parameters.

    PubMed

    Robbins, Wendie A; Xun, Lin; Jia, Juan; Kennedy, Nola; Elashoff, David A; Ping, Liu

    2010-04-01

    Boron found as borates in soil, food, and water has important industrial and medical applications. A panel reviewing NTP reproductive toxicants identified boric acid as high priority for occupational studies to determine safe versus adverse reproductive effects. To address this, we collected boron exposure/dose measures in workplace inhalable dust, dietary food/fluids, blood, semen, and urine from boron workers and two comparison worker groups (n=192) over three months and determined correlations between boron and semen parameters (total sperm count, sperm concentration, motility, morphology, DNA breakage, apoptosis and aneuploidy). Blood boron averaged 499.2 ppb for boron workers, 96.1 and 47.9 ppb for workers from high and low environmental boron areas (p<0.0001). Boron concentrated in seminal fluid. No significant correlations were found between blood or urine boron and adverse semen parameters. Exposures did not reach those causing adverse effects published in animal toxicology work but exceeded those previously published for boron occupational groups.

  13. Low-dose aripiprazole for refractory burning mouth syndrome

    PubMed Central

    Umezaki, Yojiro; Takenoshita, Miho; Toyofuku, Akira

    2016-01-01

    We report a case of refractory burning mouth syndrome (BMS) ameliorated with low dose of aripiprazole. The patient was a 66-year-old female who had suffered from chronic burning pain in her tongue for 13 months. No abnormality associated with the burning sensation was detected in the laboratory tests and the oral findings. Considering the clinical feature and the history together, we diagnosed the burning sensation as BMS. The BMS pain was decreased by aripiprazole (powder) 1.0 mg/d, though no other antidepressants had satisfying pain relief. It could be supposed that the efficacy of aripiprazole is caused by dopamine stabilization in this case, and BMS might have a subtype that is reactive to aripiprazole. Further studies are needed to confirm the efficacy of aripiprazole for BMS. PMID:27279742

  14. Low-dose aripiprazole for refractory burning mouth syndrome.

    PubMed

    Umezaki, Yojiro; Takenoshita, Miho; Toyofuku, Akira

    2016-01-01

    We report a case of refractory burning mouth syndrome (BMS) ameliorated with low dose of aripiprazole. The patient was a 66-year-old female who had suffered from chronic burning pain in her tongue for 13 months. No abnormality associated with the burning sensation was detected in the laboratory tests and the oral findings. Considering the clinical feature and the history together, we diagnosed the burning sensation as BMS. The BMS pain was decreased by aripiprazole (powder) 1.0 mg/d, though no other antidepressants had satisfying pain relief. It could be supposed that the efficacy of aripiprazole is caused by dopamine stabilization in this case, and BMS might have a subtype that is reactive to aripiprazole. Further studies are needed to confirm the efficacy of aripiprazole for BMS.

  15. CHRONIC DEVELOPMENTAL LEAD EXPOSURE REDUCES NEUROGENESIS IN ADULT HIPPOCAMPUS.

    EPA Science Inventory

    CHRONIC DEVELOPMENTAL LEAD EXPOSURE REDUCES NEUROGENESIS IN ADULT HIPPOCAMPUS. ME Gilbert1, ME Kelly2, S. Salant3, T Shafer1, J Goodman3 1Neurotoxicology Div, US EPA, RTP, NC, 27711, 2Children's Hospital, Philadelphia, PA, 19104, 3Helen Hayes Hospital, Haverstraw, NY, 10993.
    ...

  16. Chronic dysphagia and trigeminal anesthesia after trichloroethylene exposure

    SciTech Connect

    Lawrence, W.H.; Partyka, E.K.

    1981-12-01

    A patient is described who inhaled trichloroethylene fumes while working in a closed underground pit. At the time of exposure he developed dysphagia, dysarthria and dyspnea. Assessment of his condition 11 years after the incident indicated major damage of cranial nerves, particularly the trigeminal, chronic involvement of the bulbar cranial nerves, and resultant esophageal and pharnygeal motility impairment. (JMT)

  17. Low-dose exposure to alkylphenols adversely affects the sexual development of Atlantic cod (Gadus morhua): acceleration of the onset of puberty and delayed seasonal gonad development in mature female cod.

    PubMed

    Meier, Sonnich; Morton, H Craig; Andersson, Eva; Geffen, Audrey J; Taranger, Geir Lasse; Larsen, Marita; Petersen, Marianne; Djurhuus, Rune; Klungsøyr, Jarle; Svardal, Asbjørn

    2011-09-01

    Produced water (PW), a by-product of the oil-production process, contains large amount of alkylphenols (APs) and other harmful oil compounds. In the last 20 years, there have been increasing concerns regarding the environmental impact of large increases in the amounts of PW released into the North Sea. We have previously shown that low levels of APs can induce disruption of the endocrine and reproductive systems of Atlantic cod (Gadus morhua). The aims of this follow-up study were to: (i) identify the lowest observable effect concentration of APs; (ii) study the effects of exposure to real PW, obtained from a North Sea oil-production platform; and (iii) study the biological mechanism of endocrine disruption in female cod. Fish were fed with feed paste containing several concentrations of four different APs (4-tert-butylphenol, 4-n-pentylphenol, 4-n-hexylphenol and 4-n-heptylphenol) or real PW for 20 weeks throughout the normal period of vitellogenesis in Atlantic cod from October to January. Male and female cod, exposed to AP and PW, were compared to unexposed fish and to fish fed paste containing 17β-oestradiol (E(2)). Approximately 60% of the females and 96% of the males in the unexposed groups were mature at the end of the experiment. Our results show that exposure to APs and E(2) have different effects depending on the developmental stage of the fish. We observed that juvenile females are advanced into puberty and maturation, while gonad development was delayed in both maturing females and males. The AP-exposed groups contained increased numbers of mature females, and significant differences between the untreated group and the AP-treated groups were seen down to a dose of 4 μg AP/kg body weight. In the high-dose AP and the E(2) exposed groups, all females matured and no juveniles were seen. These results suggest that AP-exposure can affect the timing of the onset of puberty in fish even at extremely low concentrations. Importantly, similar effects were not

  18. Effect of low dose exposure to the herbicide atrazine and its metabolite on cytochrome P450 aromatase and steroidogenic factor-1 mRNA levels in the brain of premetamorphic bullfrog tadpoles (Rana catesbeiana)

    PubMed Central

    Gunderson, Mark P.; Veldhoen, Nik; Skirrow, Rachel C.; Macnab, Magnus K.; Ding, Wei; van Aggelen, Graham; Helbing, Caren C.

    2011-01-01

    The transcriptional regulator steroidogenic factor 1 (SF-1) and the enzyme cytochrome P450 aromatase (CYP19) play a central role in modulation of a broad range of tissue-specific developmental processes associated with hormone homeostasis that includes differentiation of the central nervous system. SF-1 and CYP19 expression may be targeted by a variety of endocrine disruptive agents prevalent within the environment. In the present study, we cloned and characterized partial sequences for bullfrog (Rana catesbeiana) SF-1 and CYP19 and examined the effects of a 48 h exposure to 1 and 100 μg/L of the herbicide atrazine (ATZ) and its major metabolite desethylatrazine (DEA), as well as 5 ng/L of the estrogenic chemical, 17α-ethynylestradiol (EE2), and 673 ng/L of the thyroid hormone, 3,5, 3′-triiodothyronine (T3), on SF-1 and CYP19 mRNA abundance in the brains of premetamorphic bullfrog tadpoles. Quantitative RT-PCR analysis showed an increase in CYP19 mRNA following a 48 h exposure to EE2 but not T3 while no significant changes in SF-1 transcript levels occurred. We observed a strong positive correlation between CYP19 and SF-1 transcript abundance in the ATZ-exposed animals which was not evident with DEA- or hormone-exposed tadpoles. Our results are intriguing in light of reported behavioral changes in ATZ-exposed frogs and suggest that further research is warranted to examine the relationship and role of CYP19 and SF-1 in amphibian brain development. PMID:21371610

  19. Solid cancer mortality associated with chronic external radiation exposure at the French atomic energy commission and nuclear fuel company.

    PubMed

    Metz-Flamant, C; Samson, E; Caër-Lorho, S; Acker, A; Laurier, D

    2011-07-01

    Studies of nuclear workers make it possible to directly quantify the risks associated with ionizing radiation exposure at low doses and low dose rates. Studies of the CEA (Commissariat à l'Energie Atomique) and AREVA Nuclear Cycle (AREVA NC) cohort, currently the most informative such group in France, describe the long-term risk to nuclear workers associated with external exposure. Our aim is to assess the risk of mortality from solid cancers among CEA and AREVA NC nuclear workers and its association with external radiation exposure. Standardized mortality ratios (SMRs) were calculated and internal Poisson regressions were conducted, controlling for the main confounding factors [sex, attained age, calendar period, company and socioeconomic status (SES)]. During the period 1968-2004, there were 2,035 solid cancers among the 36,769 CEA-AREVA NC workers. Cumulative external radiation exposure was assessed for the period 1950-2004, and the mean cumulative dose was 12.1 mSv. Mortality rates for all causes and all solid cancers were both significantly lower in this cohort than in the general population. A significant excess of deaths from pleural cancer, not associated with cumulative external dose, was observed, probably due to past asbestos exposure. We observed a significant excess of melanoma, also unassociated with dose. Although cumulative external dose was not associated with mortality from all solid cancers, the central estimated excess relative risk (ERR) per Sv of 0.46 for solid cancer mortality was higher than the 0.26 calculated for male Hiroshima and Nagasaki A-bomb survivors 50 years or older and exposed at the age of 30 years or older. The modification of our results after stratification for SES demonstrates the importance of this characteristic in occupational studies, because it makes it possible to take class-based lifestyle differences into account, at least partly. These results show the great potential of a further joint international study of

  20. Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: dose-limiting myelosuppression without evidence of DNA hypomethylation.

    PubMed

    Blum, Kristie A; Liu, Zhongfa; Lucas, David M; Chen, Ping; Xie, Zhiliang; Baiocchi, Robert; Benson, Donald M; Devine, Steven M; Jones, Jeffrey; Andritsos, Leslie; Flynn, Joseph; Plass, Christoph; Marcucci, Guido; Chan, Kenneth K; Grever, Michael R; Byrd, John C

    2010-07-01

    Targeting aberrant DNA hypermethylation in chronic lymphocytic leukaemia (CLL) and non-Hodgkin lymphoma (NHL) with decitabine may reverse epigenetic silencing in B-cell malignancies. Twenty patients were enrolled in two phase I trials to determine the minimum effective pharmacological dose of decitabine in patients with relapsed/refractory CLL (n = 16) and NHL (n = 4). Patients received 1-3 cycles of decitabine. Dose-limiting toxicity (DLT) was observed in 2 of 4 CLL and 2 of 2 NHL patients receiving decitabine at 15 mg/m(2) per d days 1-10, consisting of grade 3-4 thrombocytopenia and hyperbilirubinaemia. Six patients with CLL received decitabine at 10 mg/m(2) per d days 1-10 without DLT; however, re-expression of methylated genes or changes in global DNA methylation were not observed. Therefore, a 5-day decitabine schedule was examined. With 15 mg/m(2) per d decitabine days 1-5, DLT occurred in 2 of 6 CLL and 2 of 2 NHL patients, consisting of grade 3-4 neutropenia, thrombocytopenia, and febrile neutropenia. Eight patients had stable disease. In 17 patients, there were no significant changes in genome-wide methylation or in target gene re-expression. In conclusion, dose-limiting myelosuppression and infectious complications prevented dose escalation of decitabine to levels associated with changes in global methylation or gene re-expression in CLL and NHL.

  1. Low-Dose Total Body Irradiation and Donor Peripheral Blood Stem Cell Transplant Followed by Donor Lymphocyte Infusion in Treating Patients With Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, or Multiple Myeloma

    ClinicalTrials.gov

    2016-10-24

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage II Multiple Myeloma; Stage III Multiple Myeloma; Testicular Lymphoma; Waldenström Macroglobulinemia

  2. Health Risks From Low Doses and Low Dose-Rates of Ionizing Radiation. Session 5: Future of Radiation Protection Regulations.

    PubMed

    Cool, Donald A

    2016-03-01

    The system of radiological protection is a prospective approach to protection of individuals in all exposure situations. It must be applied equitably across all age groups and all populations. This is a very different circumstance from dose assessment for a particular individual where the unique characteristics of the individual and the exposure can be taken into account. Notwithstanding the ongoing discussions on the possible shape of the dose response at low doses and dose rates, the prospective system of protection has therefore historically used a linear assumption as a pragmatic, prudent and protective approach. These radiation protection criteria are not intended to be a demarcation between "safe" and "unsafe" and are the product of a risk-informed judgement that includes inputs from science, ethics, and experience. There are significant implications for different dose response relationships. A linear model allows for equal treatment of an exposure, irrespective of the previously accumulated exposure. In contrast, other models would predict different implications. Great care is therefore needed in separating the thinking around risk assessment from risk management, and prospective protection for all age groups and genders from retrospective assessment for a particular individual. In the United States, the prospective regulatory structure functions effectively because of assumptions that facilitate independent treatment of different types of exposures, and which provide pragmatic and prudent protection. While the a linear assumption may, in fact, not be consistent with the biological reality, the implications of a different regulatory model must be considered carefully.

  3. Multi-level effects of low dose rate ionizing radiation on southern toad, Anaxyrus [Bufo] terrestris

    SciTech Connect

    Stark, Karolina; Scott, David E.; Tsyusko, Olga; Coughlin, Daniel P.; Hinton, Thomas G.; Amendola, Roberto

    2015-04-30

    Despite their potential vulnerability to contaminants from exposure at multiple life stages, amphibians are one of the least studied groups of vertebrates in ecotoxicology, and research on radiation effects in amphibians is scarce. We used multiple endpoints to assess the radiosensitivity of the southern toad (Anaxyrus [Bufo] terrestris) during its pre-terrestrial stages of development –embryonic, larval, and metamorphic. Toads were exposed, from several hours after oviposition through metamorphosis (up to 77 days later), to four low dose rates of ¹³⁷Cs at 0.13, 2.4, 21, and 222 mGy d⁻¹, resulting in total doses up to 15.8 Gy. Radiation treatments did not affect hatching success of embryos, larval survival, or the length of the larval period. The individual family variation in hatching success of embryos was larger than the radiation response. In contrast, newly metamorphosed individuals from the higher dose-rate treatments had higher mass and mass/length body indices, a measure which may relate to higher post-metamorphic survival. The increased mass and index at higher dose rates may indicate that the chronic, low dose rate radiation exposures triggered secondary responses. Additionally, the increases in growth were linked to a decrease in DNA damage (as measured by the Comet Assay) in red blood cells at a dose rate of 21mGy d⁻¹ and a total dose of 1.1 Gy. In conclusion, the complex effects of low dose rates of ionizing radiation may trigger growth and cellular repair mechanisms in amphibian larvae.

  4. Quantifying exploratory low dose compounds in humans with AMS.

    PubMed

    Dueker, Stephen R; Vuong, Le T; Lohstroh, Peter N; Giacomo, Jason A; Vogel, John S

    2011-06-19

    Accelerator Mass Spectrometry is an established technology whose essentiality extends beyond simply a better detector for radiolabeled molecules. Attomole sensitivity reduces radioisotope exposures in clinical subjects to the point that no population need be excluded from clinical study. Insights in human physiochemistry are enabled by the quantitative recovery of simplified AMS processes that provide biological concentrations of all labeled metabolites and total compound related material at non-saturating levels. In this paper, we review some of the exploratory applications of AMS (14)C in toxicological, nutritional, and pharmacological research. This body of research addresses the human physiochemistry of important compounds in their own right, but also serves as examples of the analytical methods and clinical practices that are available for studying low dose physiochemistry of candidate therapeutic compounds, helping to broaden the knowledge base of AMS application in pharmaceutical research.

  5. Dose-dependent acceleration in the delayed effects of neonatal oral exposure to low-dose 17α-ethynylestradiol on reproductive functions in female Sprague-Dawley rats.

    PubMed

    Shirota, Mariko; Kawashima, Jun; Nakamura, Tomohiro; Kamiie, Junichi; Shirota, Kinji; Yoshida, Midori

    2015-12-01

    Xenoestrogen exposure during the critical period of sexual differentiation of the brain causes delayed effects on female reproduction. We investigated the internal dose of orally administered ethynylestradiol (EE) during the critical period and its delayed effects by administering 0 (vehicle control), 0.4, or 2 μg/kg EE to female Sprague-Dawley rats for 5 days from postnatal day (PND) 1. Determination of serum EE level 24 hr after the initial dosing and 6 and 24 hr after the final dosing of 2 μg/kg indicated that the administered EE entered the circulation and cleared after every administration. Although the treatment did not affect physical development, including growth, eyelid opening, and vaginal opening, the estrous cycle was arrested from postnatal week (PNW) 12 even with 0.4 μg/kg EE, with an inverse correlation between doses and arresting ages. Although ovarian morphology at PNW 22-23 indicated that the treatment caused long-term anovulation and cystic follicle formation, the number of primordial follicles at PNW 22-23 was similar among the groups. Because this number was lower than that at PND 10 in all groups, primordial follicles may have been consumed under long-term anovulation. The treatment also caused other abnormalities, including mammary gland hyperplasia, increase in pituitary and liver weights, and decrease in the uterine weight. Because the highest circulating EE level in the 2 μg/kg-treated neonates is considered to be comparable to the physiological range of estradiol-17β, we concluded that a slight increase in the circulating estrogens during the neonatal period exerts irreversible delayed effects.

  6. Chronic exposure to volcanic environments and chronic bronchitis incidence in the Azores, Portugal.

    PubMed

    Amaral, André Filipe Santos; Rodrigues, Armindo Santos

    2007-03-01

    The village of Furnas, like other active volcanic areas in the world, exhibits high levels of hazardous gases. We aimed to investigate the existence of a possible association between chronic exposure to volcanic sulfur gases and chronic bronchitis. To investigate this, we used two populations, one exposed to active manifestations of volcanism (Furnas) and another from an area where no volcanic activity took place for over three million years (Santa Maria), both in the Azores. We used data on the incidence of chronic bronchitis among both populations (1991-2001), obtained from the records of each local health center, and population denominators from censuses carried out in 1991 and 2001, using five age-groups. We also estimated relative risks and mean annual age-standardized rates of chronic bronchitis incidence. Incidence rates were extremely higher in the volcanically active area for both sexes, and especially in the youngest groups. Accordingly, the risk of chronic bronchitis for the people living in the volcanically active area was extremely higher (males RR=3.99; females RR=10.74) when compared to those living in the volcanically inactive area. Comparison of chronic bronchitis incidence rates between both populations suggests an association between this disease and the chronic exposure to the volcanically active environment, with all its hazardous gases like hydrogen sulfide and sulfur dioxide. These findings may help health officials to better advice people inhabiting volcanic areas, or others with high levels of sulfur gases, on how to prevent and minimize the risks of chronic bronchitis.

  7. Cardiovascular risks associated with low dose ionizing particle radiation.

    PubMed

    Yan, Xinhua; Sasi, Sharath P; Gee, Hannah; Lee, JuYong; Yang, Yongyao; Mehrzad, Raman; Onufrak, Jillian; Song, Jin; Enderling, Heiko; Agarwal, Akhil; Rahimi, Layla; Morgan, James; Wilson, Paul F; Carrozza, Joseph; Walsh, Kenneth; Kishore, Raj; Goukassian, David A

    2014-01-01

    Previous epidemiologic data demonstrate that cardiovascular (CV) morbidity and mortality may occur decades after ionizing radiation exposure. With increased use of proton and carbon ion radiotherapy and concerns about space radiation exposures to astronauts on future long-duration exploration-type missions, the long-term effects and risks of low-dose charged particle irradiation on the CV system must be better appreciated. Here we report on the long-term effects of whole-body proton ((1)H; 0.5 Gy, 1 GeV) and iron ion ((56)Fe; 0.15 Gy, 1GeV/nucleon) irradiation with and without an acute myocardial ischemia (AMI) event in mice. We show that cardiac function of proton-irradiated mice initially improves at 1 month but declines by 10 months post-irradiation. In AMI-induced mice, prior proton irradiation improved cardiac function restoration and enhanced cardiac remodeling. This was associated with increased pro-survival gene expression in cardiac tissues. In contrast, cardiac function was significantly declined in (56)Fe ion-irradiated mice at 1 and 3 months but recovered at 10 months. In addition, (56)Fe ion-irradiation led to poorer cardiac function and more adverse remodeling in AMI-induced mice, and was associated with decreased angiogenesis and pro-survival factors in cardiac tissues at any time point examined up to 10 months. This is the first study reporting CV effects following low dose proton and iron ion irradiation during normal aging and post-AMI. Understanding the biological effects of charged particle radiation qualities on the CV system is necessary both for the mitigation of space exploration CV risks and for understanding of long-term CV effects following charged particle radiotherapy.

  8. Cardiovascular Risks Associated with Low Dose Ionizing Particle Radiation

    DOE PAGES

    Yan, Xinhua; Sasi, Sharath P.; Gee, Hannah; ...

    2014-10-22

    Previous epidemiologic data demonstrate that cardiovascular (CV) morbidity and mortality may occur decades after ionizing radiation exposure. With increased use of proton and carbon ion radiotherapy and concerns about space radiation exposures to astronauts on future long-duration exploration-type missions, the long-term effects and risks of low-dose charged particle irradiation on the CV system must be better appreciated. Here we report on the long-term effects of whole-body proton (1H; 0.5 Gy, 1 GeV) and iron ion (56Fe; 0.15 Gy, 1GeV/nucleon) irradiation with and without an acute myocardial ischemia (AMI) event in mice. We show that cardiac function of proton-irradiated mice initiallymore » improves at 1 month but declines by 10 months post-irradiation. In AMI-induced mice, prior proton irradiation improved cardiac function restoration and enhanced cardiac remodeling. This was associated with increased pro-survival gene expression in cardiac tissues. In contrast, cardiac function was significantly declined in 56Fe ion-irradiated mice at 1 and 3 months but recovered at 10 months. In addition, 56Fe ion-irradiation led to poorer cardiac function and more adverse remodeling in AMI-induced mice, and was associated with decreased angiogenesis and pro-survival factors in cardiac tissues at any time point examined up to 10 months. This is the first study reporting CV effects following low dose proton and iron ion irradiation during normal aging and post-AMI. Finally, understanding the biological effects of charged particle radiation qualities on the CV system is necessary both for the mitigation of space exploration CV risks and for understanding of long-term CV effects following charged particle radiotherapy.« less

  9. Cardiovascular Risks Associated with Low Dose Ionizing Particle Radiation

    SciTech Connect

    Yan, Xinhua; Sasi, Sharath P.; Gee, Hannah; Lee, JuYong; Yang, Yongyao; Mehrzad, Raman; Onufrak, Jillian; Song, Jin; Enderling, Heiko; Agarwal, Akhil; Rahimi, Layla; Morgan, James; Wilson, Paul F.; Carrozza, Joseph; Walsh, Kenneth; Kishore, Raj; Goukassian, David A.

    2014-10-22

    Previous epidemiologic data demonstrate that cardiovascular (CV) morbidity and mortality may occur decades after ionizing radiation exposure. With increased use of proton and carbon ion radiotherapy and concerns about space radiation exposures to astronauts on future long-duration exploration-type missions, the long-term effects and risks of low-dose charged particle irradiation on the CV system must be better appreciated. Here we report on the long-term effects of whole-body proton (1H; 0.5 Gy, 1 GeV) and iron ion (56Fe; 0.15 Gy, 1GeV/nucleon) irradiation with and without an acute myocardial ischemia (AMI) event in mice. We show that cardiac function of proton-irradiated mice initially improves at 1 month but declines by 10 months post-irradiation. In AMI-induced mice, prior proton irradiation improved cardiac function restoration and enhanced cardiac remodeling. This was associated with increased pro-survival gene expression in cardiac tissues. In contrast, cardiac function was significantly declined in 56Fe ion-irradiated mice at 1 and 3 months but recovered at 10 months. In addition, 56Fe ion-irradiation led to poorer cardiac function and more adverse remodeling in AMI-induced mice, and was associated with decreased angiogenesis and pro-survival factors in cardiac tissues at any time point examined up to 10 months. This is the first study reporting CV effects following low dose proton and iron ion irradiation during normal aging and post-AMI. Finally, understanding the biological effects of charged particle radiation qualities on the CV system is necessary both for the mitigation of space exploration CV risks and for understanding of long-term CV effects following charged particle radiotherapy.

  10. Cardiovascular Risks Associated with Low Dose Ionizing Particle Radiation

    PubMed Central

    Yan, Xinhua; Sasi, Sharath P.; Gee, Hannah; Lee, JuYong; Yang, Yongyao; Mehrzad, Raman; Onufrak, Jillian; Song, Jin; Enderling, Heiko; Agarwal, Akhil; Rahimi, Layla; Morgan, James; Wilson, Paul F.; Carrozza, Joseph; Walsh, Kenneth; Kishore, Raj; Goukassian, David A.

    2014-01-01

    Previous epidemiologic data demonstrate that cardiovascular (CV) morbidity and mortality may occur decades after ionizing radiation exposure. With increased use of proton and carbon ion radiotherapy and concerns about space radiation exposures to astronauts on future long-duration exploration-type missions, the long-term effects and risks of low-dose charged particle irradiation on the CV system must be better appreciated. Here we report on the long-term effects of whole-body proton (1H; 0.5 Gy, 1 GeV) and iron ion (56Fe; 0.15 Gy, 1GeV/nucleon) irradiation with and without an acute myocardial ischemia (AMI) event in mice. We show that cardiac function of proton-irradiated mice initially improves at 1 month but declines by 10 months post-irradiation. In AMI-induced mice, prior proton irradiation improved cardiac function restoration and enhanced cardiac remodeling. This was associated with increased pro-survival gene expression in cardiac tissues. In contrast, cardiac function was significantly declined in 56Fe ion-irradiated mice at 1 and 3 months but recovered at 10 months. In addition, 56Fe ion-irradiation led to poorer cardiac function and more adverse remodeling in AMI-induced mice, and was associated with decreased angiogenesis and pro-survival factors in cardiac tissues at any time point examined up to 10 months. This is the first study reporting CV effects following low dose proton and iron ion irradiation during normal aging and post-AMI. Understanding the biological effects of charged particle radiation qualities on the CV system is necessary both for the mitigation of space exploration CV risks and for understanding of long-term CV effects following charged particle radiotherapy. PMID:25337914

  11. Methamphetamine exposure and chronic illness in police officers

    PubMed Central

    Ross, Gerald H; Sternquist, Marie C

    2012-01-01

    Background: The medical literature reports health hazards for law enforcement personnel from repeated exposure to methamphetamine and related chemical compounds. Most effects appear transitory, but some Utah police officers with employment-related methamphetamine exposures developed chronic symptoms, some leading to disability. This report is of an uncontrolled retrospective medical chart evaluation of symptomatic officers treated with a sauna detoxification protocol designed to reduce the chronic symptoms and improve the quality of life. Methods: Sixty-nine officers consecutively entering the Utah Meth Cops Project were assessed before and after a treatment program involving gradual exercise, comprehensive nutritional support and physical sauna therapy. Evaluations included pre- and post-treatment scores of the Research and Development Corporation (RAND) 36-item Short Form Health Survey (SF-36) in comparison with RAND population norms, pre- and post-treatment symptom score intensities, neurotoxicity scores, Mini-Mental Status Examination, presenting symptom frequencies and a structured evaluation of treatment program safety. Results: Statistically significant health improvements were seen in the SF-36 evaluations, symptom scores and neurotoxicity scores. The detoxification protocol was well tolerated, with a 92.8% completion rate. Conclusions: This investigation strongly suggests that utilizing sauna and nutritional therapy may alleviate chronic symptoms appearing after chemical exposures associated with methamphetamine-related law enforcement activities. This report also has relevance to addressing the apparent ill effects of other complex chemical exposures. In view of the positive clinical outcomes in this group, broader investigation of this sauna-based treatment regimen appears warranted. PMID:22089658

  12. Cytogenetic Low-Dose Hyperradiosensitivity Is Observed in Human Peripheral Blood Lymphocytes

    SciTech Connect

    Seth, Isheeta; Joiner, Michael C.; Tucker, James D.

    2015-01-01

    Purpose: The shape of the ionizing radiation response curve at very low doses has been the subject of considerable debate. Linear-no-threshold (LNT) models are widely used to estimate risks associated with low-dose exposures. However, the low-dose hyperradiosensitivity (HRS) phenomenon, in which cells are especially sensitive at low doses but then show increased radioresistance at higher doses, provides evidence of nonlinearity in the low-dose region. HRS is more prominent in the G2 phase of the cell cycle than in the G0/G1 or S phases. Here we provide the first cytogenetic mechanistic evidence of low-dose HRS in human peripheral blood lymphocytes using structural chromosomal aberrations. Methods and Materials: Human peripheral blood lymphocytes from 2 normal healthy female donors were acutely exposed to cobalt 60 γ rays in either G0 or G2 using closely spaced doses ranging from 0 to 1.5 Gy. Structural chromosomal aberrations were enumerated, and the slopes of the regression lines at low doses (0-0.4 Gy) were compared with doses of 0.5 Gy and above. Results: HRS was clearly evident in both donors for cells irradiated in G2. No HRS was observed in cells irradiated in G0. The radiation effect per unit dose was 2.5- to 3.5-fold higher for doses ≤0.4 Gy than for doses >0.5 Gy. Conclusions: These data provide the first cytogenetic evidence for the existence of HRS in human cells irradiated in G2 and suggest that LNT models may not always be optimal for making radiation risk assessments at low doses.

  13. A review of some epidemiological studies on cancer risk from low-dose radiation or other carcinogenic agents.

    PubMed

    Ogata, Hiromitsu

    2011-07-01

    It is extremely difficult to assess cancer risks accurately due to health effects of low-dose radiation exposure or other carcinogens based on epidemiological studies. For the detection of minute increases of the risk at low-level exposure, most of epidemiological studies lack statistical power, and they involve various complicated confounding factors. This paper reports on a literature survey of epidemiological studies published since 2000 on cancer risks associated with low-dose radiation and other carcinogens to gather major epidemiological data. Integrated risk indices were derived from those data by using, where possible, statistical models. Regarding risk assessment of low-dose radiation exposure, it is important to lower the degree of uncertainty arising from risk estimation. Risk assessment of low-dose radiation exposure could be scientific evidence when uncertainty is considered in comparing carcinogenic risks of radiation with those of other carcinogens.

  14. The Contribution of Tissue Level Organization to Genomic Stability Following Low Dose/Low Dose Rate Gamma and Proton Irradiation

    SciTech Connect

    Cheryl G. Burrell, Ph.D.

    2012-05-14

    The formation of functional tissue units is necessary in maintaining homeostasis within living systems, with individual cells contributing to these functional units through their three-dimensional organization with integrin and adhesion proteins to form a complex extra-cellular matrix (ECM). This is of particular importance in those tissues susceptible to radiation-induced tumor formation, such as epithelial glands. The assembly of epithelial cells of the thyroid is critical to their normal receipt of, and response to, incoming signals. Traditional tissue culture and live animals present significant challenges to radiation exposure and continuous sampling, however, the production of bioreactor-engineered tissues aims to bridge this gap by improve capabilities in continuous sampling from the same functional tissue, thereby increasing the ability to extrapolate changes induced by radiation to animals and humans in vivo. Our study proposes that the level of tissue organization will affect the induction and persistence of low dose radiation-induced genomic instability. Rat thyroid cells, grown in vitro as 3D tissue analogs in bioreactors and as 2D flask grown cultures were exposed to acute low dose (1, 5, 10 and 200 cGy) gamma rays. To assess immediate (6 hours) and delayed (up to 30 days) responses post-irradiation, various biological endpoints were studied including cytogenetic analyses, apoptosis analysis and cell viability/cytotoxicity analyses. Data assessing caspase 3/7 activity levels show that, this activity varies with time post radiation and that, overall, 3D cultures display more genomic instability (as shown by the lower levels of apoptosis over time) when compared to the 2D cultures. Variation in cell viability levels were only observed at the intermediate and late time points post radiation. Extensive analysis of chromosomal aberrations will give further insight on the whether the level of tissue organization influences genomic instability patterns after

  15. An evaluation of human ADME and mass balance studies using regular or low doses of radiocarbon.

    PubMed

    Roffel, A F; van Marle, S P; van Lier, J J; Hartstra, J; van Hoogdalem, E-J

    2016-12-01

    There has been increased interest in conducting human absorption, distribution, metabolism, and excretion (ADME) studies with low doses (up to 0.1 MBq) as opposed to regular doses (1.85-3.7 MBq) of radiocarbon ((14) C). This is due to the fact that low-dose human ADME studies may be conducted without dosimetry calculations and will lead to lower human radiation exposure. Here, we sought to compare the outcomes of low-dose versus regular-dose human ADME studies in healthy volunteers. Forty oral human ADME studies conducted at PRA were surveyed, among which 12 were low-dose studies. The fraction of drug material absorbed was 67% ± 7% in the regular-dose studies (data for 13 studies) versus 39% ± 16% in the low-dose studies (data for 5 studies). The average total recovery of (14) C in excreta was 93% ± 5% for regular-dose studies, and 21 of 28 such studies showed recoveries more than 90%. For low-dose studies, average total recovery was 89% ± 9%, and 6 of 12 studies showed recoveries more than 90%. Metabolite profiling was successful in all cases reported (13 regular-dose studies and 5 low-dose studies). There was no obvious relationship between the total recoveries of (14) C in excreta and the proportion of (14) C excreted in feces, or between the total recoveries and the plasma elimination half-lives for parent or total (14) C, neither in the low-dose nor the regular-dose studies. A significant correlation was found between the fraction absorbed and the recovery in feces in the low-dose but not in the regular-dose studies, and no correlation was found between the fractions absorbed and the total recoveries in both types of studies. Low-dose studies were more often conducted on drugs that had a plasma elimination half-life of parent drug more than 100 hours (5 of 12 studies) than regular-dose studies (1 of 26 studies). We conclude that both low-dose as well as regular-dose human ADME studies provide adequate data to support decision making for further

  16. Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses

    PubMed Central

    Colborn, Theo; Hayes, Tyrone B.; Heindel, Jerrold J.; Jacobs, David R.; Lee, Duk-Hee; Shioda, Toshi; Soto, Ana M.; vom Saal, Frederick S.; Welshons, Wade V.; Zoeller, R. Thomas

    2012-01-01

    For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from the cell culture, animal, and epidemiology literature. We illustrate that nonmonotonic responses and low-dose effects are remarkably common in studies of natural hormones and EDCs. Whether low doses of EDCs influence certain human disorders is no longer conjecture, because epidemiological studies show that environmental exposures to EDCs are associated with human diseases and disabilities. We conclude that when nonmonotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses. Thus, fundamental changes in chemical testing and safety determination are needed to protect human health. PMID:22419778

  17. Does chronic exposure to mobile phones affect cognition?

    PubMed Central

    Mohan, Mamta; Khaliq, Farah; Panwar, Aprajita; Vaney, Neelam

    2016-01-01

    Summary Mobile phones form an integral part of our modern lifestyle. Following the drastic rise in mobile phone use in recent years, it has become important to study its potential public health impact. Amongst the various mobile phone health hazards, the most alarming is the possible effect on the brain. The aim of the present study was to explore whether chronic exposure to mobile phones affects cognition. Ninety subjects aged 17–25 years with normal hearing were recruited for the study and divided into three groups according to their duration of mobile phone use. No significant differences in N100, P200, N200, P300 latencies or N2-P300 amplitude were observed. Our results suggest that chronic mobile phone exposure does not have detrimental effects on cognition. PMID:27027894

  18. Does chronic exposure to mobile phones affect cognition?

    PubMed

    Mohan, Mamta; Khaliq, Farah; Panwar, Aprajita; Vaney, Neelam

    2016-01-01

    Mobile phones form an integral part of our modern lifestyle. Following the drastic rise in mobile phone use in recent years, it has become important to study its potential public health impact. Amongst the various mobile phone health hazards, the most alarming is the possible effect on the brain. The aim of the present study was to explore whether chronic exposure to mobile phones affects cognition. Ninety subjects aged 17-25 years with normal hearing were recruited for the study and divided into three groups according to their duration of mobile phone use. No significant differences in N100, P200, N200, P300 latencies or N2-P300 amplitude were observed. Our results suggest that chronic mobile phone exposure does not have detrimental effects on cognition.

  19. Neuroimmune Effects of Inhaling Low Dose Sarin

    DTIC Science & Technology

    2008-02-01

    system Because two of the Japanese sarin terrorism survivors succumbed to Legionella infection nearly two years after the sarin exposure (Kamimura...lung organism, Legionella . However, our results indicated that both adaptive (antibody and T cell receptor-mediated responses) as well inflammatory...H. Niino, K. Saitoh, and A. Saitoh. 1998. Legionella pneumonia caused by aspiration of hot spring water after sarin exposure. Nihon. Kokyuki. Gakkai

  20. Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells

    PubMed Central

    Stueckle, Todd A.; Lu, Yongju; Davis, Mary E.; Wang, Liying; Jiang, Bing-Hua; Holaskova, Ida; Schafer, Rosana; Barnett, John B.; Rojanasakul, Yon

    2012-01-01

    Chronic arsenic exposure remains a human health risk; however a clear mode of action to understand gene signaling-driven arsenic carcinogenesis is currently lacking. This study chronically exposed human lung epithelial BEAS-2B cells to low-dose arsenic trioxide to elucidate cancer promoting gene signaling networks associated with arsenic-transformed (B-As) cells. Following a six month exposure, exposed cells were assessed for enhanced cell proliferation, colony formation, invasion ability and in vivo tumor formation compared to control cell lines. Collected mRNA was subjected to whole genome expression microarray profiling followed by in silico Ingenuity Pathway Analysis (IPA) to identify lung carcinogenesis modes of action. B-As cells displayed significant increases in proliferation, colony formation and invasion ability compared to BEAS-2B cells. B-As injections into nude mice resulted in development of primary and secondary metastatic tumors. Arsenic exposure resulted in widespread up-regulation of genes associated with mitochondrial metabolism and increased reactive oxygen species protection suggesting mitochondrial dysfunction. Carcinogenic initiation via reactive oxygen species and epigenetic mechanisms was further supported by altered DNA repair, histone, and ROS-sensitive signaling. NF-κB, MAPK and NCOR1 signaling disrupted PPARα/δ-mediated lipid homeostasis. A ‘pro-cancer’ gene signaling network identified increased survival, proliferation, inflammation, metabolism, anti-apoptosis and mobility signaling. IPA-ranked signaling networks identified altered p21, EF1α, Akt, MAPK, and NF-κB signaling networks promoting genetic disorder, altered cell cycle, cancer and changes in nucleic acid and energy metabolism. In conclusion, transformed B-As cells with their whole genome expression profile provide an in vitro arsenic model for future lung cancer signaling research and data for chronic arsenic exposure risk assessment. PMID:22521957

  1. Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells.

    PubMed

    Stueckle, Todd A; Lu, Yongju; Davis, Mary E; Wang, Liying; Jiang, Bing-Hua; Holaskova, Ida; Schafer, Rosana; Barnett, John B; Rojanasakul, Yon

    2012-06-01

    Chronic arsenic exposure remains a human health risk; however a clear mode of action to understand gene signaling-driven arsenic carcinogenesis is currently lacking. This study chronically exposed human lung epithelial BEAS-2B cells to low-dose arsenic trioxide to elucidate cancer promoting gene signaling networks associated with arsenic-transformed (B-As) cells. Following a 6month exposure, exposed cells were assessed for enhanced cell proliferation, colony formation, invasion ability and in vivo tumor formation compared to control cell lines. Collected mRNA was subjected to whole genome expression microarray profiling followed by in silico Ingenuity Pathway Analysis (IPA) to identify lung carcinogenesis modes of action. B-As cells displayed significant increases in proliferation, colony formation and invasion ability compared to BEAS-2B cells. B-As injections into nude mice resulted in development of primary and secondary metastatic tumors. Arsenic exposure resulted in widespread up-regulation of genes associated with mitochondrial metabolism and increased reactive oxygen species protection suggesting mitochondrial dysfunction. Carcinogenic initiation via reactive oxygen species and epigenetic mechanisms was further supported by altered DNA repair, histone, and ROS-sensitive signaling. NF-κB, MAPK and NCOR1 signaling disrupted PPARα/δ-mediated lipid homeostasis. A 'pro-cancer' gene signaling network identified increased survival, proliferation, inflammation, metabolism, anti-apoptosis and mobility signaling. IPA-ranked signaling networks identified altered p21, EF1α, Akt, MAPK, and NF-κB signaling networks promoting genetic disorder, altered cell cycle, cancer and changes in nucleic acid and energy metabolism. In conclusion, transformed B-As cells with their whole genome expression profile provide an in vitro arsenic model for future lung cancer signaling research and data for chronic arsenic exposure risk assessment.

  2. Low-dose effects of hormones and endocrine disruptors.

    PubMed

    Vandenberg, Laura N

    2014-01-01

    Endogenous hormones have effects on tissue morphology, cell physiology, and behaviors at low doses. In fact, hormones are known to circulate in the part-per-trillion and part-per-billion concentrations, making them highly effective and potent signaling molecules. Many endocrine-disrupting chemicals (EDCs) mimic hormones, yet there is strong debate over whether these chemicals can also have effects at low doses. In the 1990s, scientists proposed the "low-dose hypothesis," which postulated that EDCs affect humans and animals at environmentally relevant doses. This chapter focuses on data that support and refute the low-dose hypothesis. A case study examining the highly controversial example of bisphenol A and its low-dose effects on the prostate is examined through the lens of endocrinology. Finally, the chapter concludes with a discussion of factors that can influence the ability of a study to detect and interpret low-dose effects appropriately.

  3. Cancer risk at low doses of ionizing radiation: artificial neural networks inference from atomic bomb survivors.

    PubMed

    Sasaki, Masao S; Tachibana, Akira; Takeda, Shunichi

    2014-05-01

    Cancer risk at low doses of ionizing radiation remains poorly defined because of ambiguity in the quantitative link to doses below 0.2 Sv in atomic bomb survivors in Hiroshima and Nagasaki arising from limitations in the statistical power and information available on overall radiation dose. To deal with these difficulties, a novel nonparametric statistics based on the 'integrate-and-fire' algorithm of artificial neural networks was developed and tested in cancer databases established by the Radiation Effects Research Foundation. The analysis revealed unique features at low doses that could not be accounted for by nominal exposure dose, including (i) the presence of a threshold that varied with organ, gender and age at exposure, and (ii) a small but significant bumping increase in cancer risk at low doses in Nagasaki that probably reflects internal exposure to (239)Pu. The threshold was distinct from the canonical definition of zero effect in that it was manifested as negative excess relative risk, or suppression of background cancer rates. Such a unique tissue response at low doses of radiation exposure has been implicated in the context of the molecular basis of radiation-environment interplay in favor of recently emerging experimental evidence on DNA double-strand break repair pathway choice and its epigenetic memory by histone marking.

  4. Cancer risk at low doses of ionizing radiation: artificial neural networks inference from atomic bomb survivors

    PubMed Central

    Sasaki, Masao S.; Tachibana, Akira; Takeda, Shunichi

    2014-01-01

    Cancer risk at low doses of ionizing radiation remains poorly defined because of ambiguity in the quantitative link to doses below 0.2 Sv in atomic bomb survivors in Hiroshima and Nagasaki arising from limitations in the statistical power and information available on overall radiation dose. To deal with these difficulties, a novel nonparametric statistics based on the ‘integrate-and-fire’ algorithm of artificial neural networks was developed and tested in cancer databases established by the Radiation Effects Research Foundation. The analysis revealed unique features at low doses that could not be accounted for by nominal exposure dose, including (i) the presence of a threshold that varied with organ, gender and age at exposure, and (ii) a small but significant bumping increase in cancer risk at low doses in Nagasaki that probably reflects internal exposure to 239Pu. The threshold was distinct from the canonical definition of zero effect in that it was manifested as negative excess relative risk, or suppression of background cancer rates. Such a unique tissue response at low doses of radiation exposure has been implicated in the context of the molecular basis of radiation–environment interplay in favor of recently emerging experimental evidence on DNA double-strand break repair pathway choice and its epigenetic memory by histone marking. PMID:24366315

  5. Biochemical Markers for Exposure to Low Doses of Organophosphorus Insecticides

    DTIC Science & Technology

    2005-08-01

    dose of diazepam or ibuprofen. Or conver- Hui, D. M., and Minami, M. (2000). Monitoring of fluorine in urine samples ofpatients involved in the Tokyo...O’Hair, The role of nucleophile- electrophile interactions in 710 653 require further studies. the unimolecular and bimolecular gas-phase ion chemistry...consistent used in these studies. with P-F coupling. The doublet is the result of fluorine splitting Rate Constant for Inhibition of Human BChE by FP

  6. The Effects of Repeated Low-Dose Sarin Exposure

    DTIC Science & Technology

    2006-01-01

    subcutaneous. "" Research was conducted in compliance with the Animal Welfare Act and other Federal statutes and regulations relating to animals and...placing the animal on its back and recording the time it took for the was used to separate ACh and choline. A " biosensor " was created by coating a guinea...nerve agent sarin. Animals were injected once a day, 5 days per week (Monday-Friday), for 2 weeks with fractions (0.3x, 0.4x, 0.5x, or 0.6x) of the

  7. Low dose exposure of diethylnitrosamine affects mice liver thymidine kinase.

    PubMed

    Pariat, T; Sharan, R N

    1995-11-17

    Swiss albino mice exposed to 5 and 10 mg diethylnitrosamine kg-1 body weight by intravenous route up to four weeks showed cyto- and genotoxic effects. Distortion of cell and nucleus shapes and extensive necrosis were observed. Thymidine kinase activity in the liver declined in diethylnitrosamine dose and duration dependent manners. The adult-form of thymidine kinase isozyme declined continuously during this period. Simultaneously, two isozymic forms of thymidine kinase, with small anodic migrations in an electrophoretic field, were gradually induced. Significance of theses changes in diethylnitrosamine induced precarcinogenic toxicity has been discussed.

  8. Chronic obstructive pulmonary disease and occupational exposure to silica.

    PubMed

    Rushton, Lesley

    2007-01-01

    Prolonged exposure to high levels of silica has long been known to cause silicosis This paper evaluates the evidence for an increased risk of chronic obstructive pulmonary disease (COPD) in occupations and industries in which exposure to crystalline silica is the primary exposure, with a focus on the magnitude of risks and levels of exposure causing disabling health effects. The literature suggests consistently elevated risks of developing COPD associated with silica exposure in several occupations, including the construction industry; tunneling; cement industry; brick manufacturing; pottery and ceramic work; silica sand, granite and diatomaceous earth industries; gold mining; and iron and steel founding, with risk estimates being high in some, even after taking into account the effect of confounders like smoking. Average dust levels vary from about 0.5 mg.m3 to over 10 mg.m3 and average silica levels from 0.04 to over 5 mg.m3, often well above occupational standards. Factors influencing the variation from industry to industry in risks associated with exposure to silica-containing dusts include (a) the presence of other minerals in the dust, particularly when associated with clay minerals; (b) the size of the particles and percentage of quartz; (c) the physicochemical characteristics, such as whether the dust is freshly fractured. Longitudinal studies suggest that loss of lung function occurs with exposure to silica dust at concentrations of between 0.1 and 0.2 mg.m3, and that the effect of cumulative silica dust exposure on airflow obstruction is independent of silicosis. Nevertheless, a disabling loss of lung function in the absence of silicosis would not occur until between 30 and 40 years exposure.

  9. Chronic exposure to ELF fields may induce depression

    SciTech Connect

    Wilson, B.W.

    1988-01-01

    Exposure to extremely-low-frequency (ELF) electric or magnetic fields has been postulated as a potentially contributing factor in depression. Epidemiologic studies have yielded positive correlations between magnetic- and/or electric-field strengths in local environments and the incidence of depression-related suicide. Chronic exposure to ELF electric or magnetic fields can disrupt normal circadian rhythms in rat pineal serotonin-N-acetyltransferase activity as well as in serotonin and melatonin concentrations. Such disruptions in the circadian rhythmicity of pineal melatonin secretion have been associated with certain depressive disorders in human beings. In the rat, ELF fields may interfere with tonic aspects of neuronal input to the pineal gland, giving rise to what may be termed functional pinealectomy. If long-term exposure to ELF fields causes pineal dysfunction in human beings as it does in the rat, such dysfunction may contribute to the onset of depression or may exacerbate existing depressive disorders. 85 references.

  10. Low dose radiation-induced endothelial cell retraction.

    PubMed

    Kantak, S S; Diglio, C A; Onoda, J M

    1993-09-01

    We characterized in vitro the effects of gamma-radiation (12.5-100 cGy) on pulmonary microvascular endothelial cell (PMEC) morphology and F-actin organization. Cellular retraction was documented by phase-contrast microscopy and the organization of actin microfilaments was determined by immunofluorescence. Characterization included radiation dose effects, their temporal duration and reversibility of the effects. A dose-dependent relationship between the level of exposure (12.5-100 cGy) and the rate and extent of endothelial retraction was observed. Moreover, analysis of radiation-induced depolymerization of F-actin microfilament stress fibres correlated positively with the changes in PMEC morphology. The depolymerization of the stress fibre bundles was dependent on radiation dose and time. Cells recovered from exposure to reform contact inhibited monolayers > or = 24 h post-irradiation. Concomitantly, the depolymerized microfilaments reorganized to their preirradiated state as microfilament stress fibres arrayed parallel to the boundaries of adjacent contact-inhibited cells. The data presented here are representative of a series of studies designed to characterize low-dose radiation effects on pulmonary microvascular endothelium. Our data suggest that post-irradiation lung injuries (e.g. oedema) may be induced with only a single fraction of therapeutic radiation, and thus microscopic oedema may initiate prior to the lethal effects of radiation on the microvascular endothelium, and much earlier than would be suggested by the time course for clinically-detectable oedema.

  11. Metabolic consequences of chronic intermittent mild stress exposure.

    PubMed

    Thompson, Abigail K; Fourman, Sarah; Packard, Amy E B; Egan, Ann E; Ryan, Karen K; Ulrich-Lai, Yvonne M

    2015-10-15

    Chronic stress in humans has divergent effects on food intake, with some individuals reporting increased vs. decreased food intake during stress. This divergence may depend in part on stress intensity, with higher-intensity stressors preferentially promoting anorexia. Consistent with this idea, rodents given a high-intensity chronic variable stress paradigm have robustly decreased food intake and body weight gain. However, the metabolic effects of a less intense chronic stress paradigm are not clear. Thus in the present study, adult male rats were given chronic intermittent mild stress (CIMS) exposure (3 cycles, in which each cycle consists of once daily mild stress for 5 days/week for 2 weeks, followed by 2 weeks of no stress) vs. non-stress controls, combined with ongoing access to a palatable diet (PD; choice of chow, high-fat diet, 30% sucrose drink, and water) vs. control diet (chow and water). As expected, access to PD increased caloric intake, body weight gain, and adiposity, and impaired glucose tolerance. CIMS decreased body weight gain only during the first cycle of stress and did not affect body weight gain thereafter, regardless of diet. Moreover, CIMS did not alter total food intake, adiposity or glucose tolerance regardless of diet. Lastly, CIMS transiently increased high-fat diet preference in PD-fed rats during the first stress cycle. Collectively, these results suggest that CIMS has relatively modest metabolic effects that occur primarily during initial stress exposure. These results support the hypothesis that the metabolic consequences of chronic stress vary with stress intensity and/or frequency.

  12. Low-dose-rate, low-dose irradiation delays neurodegeneration in a model of retinitis pigmentosa.

    PubMed

    Otani, Atsushi; Kojima, Hiroshi; Guo, Congrong; Oishi, Akio; Yoshimura, Nagahisa

    2012-01-01

    The existence of radiation hormesis is controversial. Several stimulatory effects of low-dose (LD) radiation have been reported to date; however, the effects on neural tissue or neurodegeneration remain unknown. Here, we show that LD radiation has a neuroprotective effect in mouse models of retinitis pigmentosa, a hereditary, progressive neurodegenerative disease that leads to blindness. Various LD radiation doses were administered to the eyes in a retinal degeneration mouse model, and their pathological and physiological effects were analyzed. LD gamma radiation in a low-dose-rate (LDR) condition rescues photoreceptor cell apoptosis both morphologically and functionally. The greatest effect was observed in a condition using 650 mGy irradiation and a 26 mGy/minute dose rate. Multiple rounds of irradiation strengthened this neuroprotective effect. A characteristic up-regulation (563%) of antioxidative gene peroxiredoxin-2 (Prdx2) in the LDR-LD-irradiated retina was observed compared to the sham-treated control retina. Silencing the Prdx2 using small-interfering RNA administration reduced the LDR-LD rescue effect on the photoreceptors. Our results demonstrate for the first time that LDR-LD irradiation has a biological effect in neural cells of living animals. The results support that radiation exhibits hormesis, and this effect may be applied as a novel therapeutic concept for retinitis pigmentosa and for other progressive neurodegenerative diseases regardless of the mechanism of degeneration involved.

  13. Vulnerability of the neural circuitry underlying sexual behavior to chronic adult exposure to oral bisphenol a in male mice.

    PubMed

    Picot, Marie; Naulé, Lydie; Marie-Luce, Clarisse; Martini, Mariangela; Raskin, Kalina; Grange-Messent, Valérie; Franceschini, Isabelle; Keller, Matthieu; Mhaouty-Kodja, Sakina

    2014-02-01

    There are human reproduction concerns associated with extensive use of bisphenol A (BPA)-containing plastic and, in particular, the leaching of BPA into food and beverages. In this context, it remains unclear whether and how exposure to BPA interferes with the developmental organization and adult activation of male sexual behavior by testosterone. We evaluated the developmental and adult exposure to oral BPA at doses equivalent to the no-observed-adverse-effect-level (5 mg/kg body weight per day) and tolerable daily intake (TDI) (50 μg/kg body weight per day) on mouse sexual behavior and the potential mechanisms underlying BPA effects. Adult exposure to BPA reduced sexual motivation and performance at TDI dose only. Exposed males took longer to initiate mating and reach ejaculation despite normal olfactory chemoinvestigation. This deficiency was not restored by sexual experience and was associated with unchanged circulating levels of testosterone. By contrast, developmental exposure to BPA at TDI or no-observed-adverse-effect-level dose did not reduce sexual behavior or alter the neuroanatomical organization of the preoptic area. Disrupting the neural androgen receptor resulted in behavioral and neuroanatomical effects similar to those induced by adult exposure to TDI dose. Moreover, adult exposure of mutant males to BPA at TDI dose did not trigger additional alteration of sexual behavior, suggesting that BPA and neural androgen receptor mutation share a common mechanism of action. This shows, for the first time, that the neural circuitry underlying male sexual behavior is vulnerable to chronic adult exposure to low dose of BPA and suggests that BPA could act in vivo as an antiandrogenic compound.

  14. Low doses of ionizing radiation to mammalian cells may rather control than cause DNA damage

    SciTech Connect

    Feinendegen, L.E.; Bond, V.P.; Sondhaus, C.A.; Altman, K.I.

    1998-12-31

    This report examines the origin of tissue effects that may follow from different cellular responses to low-dose irradiation, using published data. Two principal categories of cellular responses are considered. One response category relates to the probability of radiation-induced DNA damage. The other category consists of low-dose induced metabolic changes that induce mechanisms of DNA damage mitigation, which do not operate at high levels of exposure. Modeled in this way, tissue is treated as a complex adaptive system. The interaction of the various cellular responses results in a net tissue dose-effect relation that is likely to deviate from linearity in the low-dose region. This suggests that the LNT hypothesis should be reexamined. This paper aims at demonstrating tissue effects as an expression of cellular responses, both damaging and defensive, in relation to the energy deposited in cell mass, by use of microdosimetric concepts.

  15. Chronic exposure to environmental levels of tribromophenol impairs zebrafish reproduction

    SciTech Connect

    Deng Jun; Liu Chunsheng; Yu Liqin; Zhou Bingsheng

    2010-02-15

    Tribromophenol (2,4,6-TBP) is ubiquitously found in aquatic environments and biota. In this study, we exposed zebrafish embryos (F{sub 0}; 2'''' days post-fertilization, dpf) to environmental concentration (0.3 mug/L) and a higher concentration (3.0 mug/L) of TBP and assessed the impact of chronic exposure (120 dpf) on reproduction. TBP exposure did not cause a significant increase in the malformation and reduction in the survival in the F{sub 0}-generation fish. After TBP exposure, the plasma testosterone and estradiol levels significantly increased in males and decreased in females. The transcription of steroidogenic genes (3beta-HSD, 17beta-HSD, CYP17, CYP19A, CYP19B) was significantly upregulated in the brain and testes in males and downregulated in the brain and ovary in females. TBP exposure significantly downregulated and upregulated the expression of VTG in the liver of female and male fish, respectively. Meanwhile, TBP exposure altered the sex ratio toward a male-dominant state. The F{sub 1}-generation larvae exhibited increased malformation, reduced survival, and retarded growth, suggesting that TBP in the aquatic environment has significant adverse effects on fish population.

  16. Estimation of Chronic Personal Exposure to Airborne Polycyclic Aromatic Hydrocarbons

    PubMed Central

    Choi, Hyunok; Zdeb, Michael; Perera, Frederica; Spengler, John

    2015-01-01

    Background Polycyclic aromatic hydrocarbons (PAH) exposure from solid fuel burning represents an important public health issue for the majority of the global population. Yet, understanding of individual-level exposures remains limited. Objectives To develop regionally adaptable chronic personal exposure model to pro-carcinogenic PAH (c-PAH) for the population in Kraków, Poland. Methods We checked the assumption of spatial uniformity in eight c-PAH using the coefficients of divergence (COD), a marker of absolute concentration differences. Upon successful validation, we developed personal exposure models for eight pro-carcinogenic PAH by integrating individual-level data with area-level meteorological or pollutant data. We checked the resulting model for accuracy and precision against home outdoor monitoring data. Results During winter, COD of 0.1 for Kraków suggest overall spatial uniformity in the ambient concentration of the eight c-PAH. The three models that we developed were associated with index of agreement approximately equal to 0.9, root mean square error < 2.6 ng/m3, and 90th percentile of absolute difference ≤ 4 ng/m3 for the predicted and the observed concentrations for eight pro-carcinogenic PAH. Conclusions Inexpensive and logistically feasible information could be used to estimate chronic personal exposure to PAH profiles, in lieu of costly and labor-intensive personal air monitoring at wide scale. At the same time, thorough validation through direct personal monitoring and assumption checking are critical for successful model development. PMID:25965038

  17. Low doses of ochratoxin A induce micronucleus formation and delay DNA repair in human lymphocytes.

    PubMed

    González-Arias, Cyndia A; Benitez-Trinidad, Alma B; Sordo, Monserrat; Robledo-Marenco, Lourdes; Medina-Díaz, Irma M; Barrón-Vivanco, Briscia S; Marín, Sonia; Sanchis, Vicente; Ramos, Antonio J; Rojas-García, Aurora E

    2014-12-01

    The contamination of food commodities by fungal toxins has attracted great interest because many of these mycotoxins are responsible for different diseases, including cancer and other chronic illnesses. Ochratoxin A (OTA) is a mycotoxin naturally present in food, and long-term exposure to food contaminated with low levels of OTA has been associated with renal cancer. In the present study, the cytotoxicity, cytostaticity, and genotoxicity of OTA (0.075-15 µM) in human lymphocytes were evaluated. A comet assay, a modified comet assay (DNA repair assay), which uses N-hydroxyurea (NHU) to detect non-repaired lesions produced by OTA, and a cytokinesis-blocked micronucleus assay were used. Treatments with OTA were not cytotoxic, but OTA caused a cytostatic effect in human lymphocytes at a concentration of 15 µM. OTA (0.075-5 µM) produced a slight increase in the percentage of DNA in the comets and a delay in the DNA repair capacity of the lymphocytes. Micronucleus (MN) induction was observed at OTA concentrations of 1.5 and 5 µM. Our results indicate that OTA induces DNA stable damage at low doses that are neither cytotoxic nor cytostatic, and OTA delays the DNA repair kinetics. These findings indicate that OTA affects two pivotal events in the carcinogenesis pathway.

  18. What can be learned from epidemiologic studies of persons exposed to low doses of radiation?

    SciTech Connect

    Gilbert, E.S.

    1993-04-01

    The main objective of radiation risk assessment is to determine the risk of various adverse health effects associated with exposure to low doses and low dose rates. Extrapolation of risks from studies of persons exposed at high doses (generally exceeding 1 Sv) and dose rates has been the primary approach used to achieve this objective. The study of Japanese atomic bomb survivors in Hiroshima and Nagasaki has played an especially important role in risk assessment efforts. A direct assessment of the dose-response function based on studies of persons exposed at low doses and dose rates is obviously desirable. This paper focuses on the potential of both current and future nuclear workers studies for investigating the dose-response functions at low doses, and also discusses analyses making use of the low dose portion of the atomic bomb survivor data. Difficulties in using these data are the statistical imprecision of estimated dose-response parameters, and potential bias resulting from confounding factors and from uncertainties in dose estimates.

  19. Acute marihuana (THC) exposure produces a "transient" topographic quantitative EEG profile identical to the "persistent" profile seen in chronic heavy users.

    PubMed

    Struve, Frederick A; Manno, Barbara R; Kemp, Philip; Patrick, Gloria; Manno, Joseph E

    2003-04-01

    In two published pilot studies and a controlled replication using screened normals, chronic marihuana (THC) use was associated with a unique topographic quantitative EEG profile, consisting of significant elevations of Absolute and Relative Power and Coherence of alpha activity over the bilateral frontal cortex as well as a significant decrease in alpha frequency. This report attempts to establish the causal influence of THC in the above findings by the transient production of this exact quantitative EEG profile in subjects who did not display it at the beginning. Using paced smoking of marihuana with high and low dose THC content and placebo marihuana in a counterbalanced design under double blind conditions, all four of the topographic features of chronic THC exposure were produced as transient effects by THC but not by placebo.

  20. [Indications for low-dose CT in the emergency setting].

    PubMed

    Poletti, Pierre-Alexandre; Andereggen, Elisabeth; Rutschmann, Olivier; de Perrot, Thomas; Caviezel, Alessandro; Platon, Alexandra

    2009-08-19

    CT delivers a large dose of radiation, especially in abdominal imaging. Recently, a low-dose abdominal CT protocol (low-dose CT) has been set-up in our institution. "Low-dose CT" is almost equivalent to a single standard abdominal radiograph in term of dose of radiation (about one sixth of those delivered by a standard CT). "Low-dose CT" is now used routinely in our emergency service in two main indications: patients with a suspicion of renal colic and those with right lower quadrant pain. It is obtained without intravenous contrast media. Oral contrast is given to patients with suspicion of appendicitis. "Low-dose CT" is used in the frame of well defined clinical algorithms, and does only replace standard CT when it can reach a comparable diagnostic quality.

  1. Low-Dose Cadmium Causes Metabolic and Genetic Dysregulation Associated With Fatty Liver Disease in Mice

    PubMed Central

    Go, Young-Mi; Sutliff, Roy L.; Chandler, Joshua D.; Khalidur, Rahman; Kang, Bum-Yong; Anania, Frank A.; Orr, Michael; Hao, Li; Fowler, Bruce A.; Jones, Dean P.

    2015-01-01

    Cadmium (Cd) is present in food at low levels and accumulates in humans throughout life because it is not effectively excreted. Cd from smoking or occupational exposure shows adverse effects on health, but the mechanistic effect of Cd at low dietary intake levels is poorly studied. Epidemiology studies found that nonalcoholic fatty liver disease (NAFLD), common in U.S. adults, is associated with Cd burden. In cell studies, we found that environmental low-dose Cd oxidized proteins and stimulated inflammatory signaling. However, little is known about low-dose Cd effects on liver function and associated metabolic pathways in vivo. We investigated effects of low-level Cd exposure on liver gene transcripts, metabolites, and associated metabolic pathways and function after challenging mice with Cd (10 mg/l) by drinking water. Results showed liver Cd in treated mice was similar to adult humans without occupational or smoking exposures and 10-fold higher than control mouse values. Pathway analysis of significantly altered liver genes and metabolites mapped to functional pathways of lipid metabolism, cell death and mitochondrial oxidative phosphorylation. These are well-recognized pathways associated with NAFLD. Cd–treated mice had higher liver enzymes in plasma and a trend toward fat accumulation in liver. To verify low-dose Cd-induced stimulation of cell death pathways, phosphorylation of c-Jun N-terminal kinase (JNK) was examined in cultured hepatic cells. Consistent with mouse liver data, low-dose Cd stimulated JNK activation. Together, the results show that low-dose Cd exposure causes liver function changes consistent with a role in NAFLD and possibly also nonalcoholic steatohepatitis. PMID:26187450

  2. Inconsistencies and open questions regarding low-dose health effects of ionizing radiation.

    PubMed Central

    Nussbaum, R H; Köhnlein, W

    1994-01-01

    The effects on human health of exposures to ionizing radiation at low doses have long been the subject of dispute. In this paper we focus on open questions regarding the health effects of low-dose exposures that require further investigations. Seemingly contradictory findings of radiation health effects have been reported for the same exposed populations, or inconsistent estimates of radiation risks were found when different populations and exposure conditions were compared. Such discrepancies may be indicative of differences in sensitivities among the applied methods of epidemiological analysis or indicative of significant discrepancies in health consequences after comparable total exposures of different populations under varying conditions. We focus first on inconsistencies and contradictions in presentations of the state of knowledge by different authoritative experts. We then review studies that found positive associations between exposure and risks in dose ranges where traditional notions (generalized primarily from high-dose studies of A-bomb survivors or exposed animals) would have predicted negligible effects. One persistent notion in many reviews of low-dose effects is the hypothesis of reduced biological effectiveness of fractionated low-dose exposures, compared to that of the same acute dose. This assumption is not supported by data on human populations. From studies of populations that live in contaminated areas, more and more evidence is accumulating on unusual rates of various diseases other than radiation-induced malignancies, health effects that are suspected to be associated with relatively low levels of internal exposures originating from radioactive fallout. Such effects include congenital defects, neonatal mortality, stillbirths, and possibly genetically transmitted disease. A range of open questions challenges scientists to test imaginative hypotheses about induction of disease by radiation with novel research strategies. Images Figure 1. PMID

  3. A chronic eosinophilic pneumonia case with long exposure to isocyanates.

    PubMed

    Yalcin, Funda; Sak, Zafer Hasan Ali; Boyaci, Nurefsan; Gencer, Mehmet

    2014-10-01

    Chronic eosinophilic pneumonia (CEP) is a disease with unknown etiology, characterized by peripheral blood eosinophilia and abnormal eosinophil accumulation in the lungs. A 43-year-old male with 30 years history of exposure to isocyanates was admitted with the complaint of sputum, cough, progressive dyspnoea, and weight loss. Physical examination revealed bilaterally decreased breath sounds and extensive rales. On laboratory analysis; leukocytosis (12.3 10(3)/proportional variant L), hypereosinophilia (30%), elevated CRP and RF (1000 IU/ml), and IgE levels (1160 IU/ml) in the serum were observed. Chest radiograph and computed tomography on admission showed reticulonodular pattern at both lung fields. Pulmonary function tests assumed a restrictive pattern and a low diffusing capacity. Bronchoalveolar lavage revealed a marked eosinophilia (50%). Transbronchial lung biopsy indicated eosinophilic pneumonia. In this case we aimed to describe a rare case of CEP probably caused by exposure to isocyanate.

  4. Chronic ethanol exposure during development: disturbances of breathing and adaptation.

    PubMed

    Dubois, C J; Kervern, M; Naassila, M; Pierrefiche, O

    2013-11-01

    The effects of prenatal exposure to some drugs of abuse, such as nicotine, on breathing function have been clearly established. However, the case of alcohol (ethanol), the most widely consume drug of abuse, remains unknown. Prenatal ethanol consumption in humans may lead to fetal alcohol syndrome and although the effect of chronic prenatal ethanol exposure (CPEE) on cognitive function is frequently studied, nothing is known about CPEE's effects on breathing as compared with other drugs of abuse. The role of nicotine for example, in human neonatal pathology, such as sudden infant death syndrome, is acknowledged today, whereas the full scope of CPEE's role is only recently emerging. Here, we review preclinical investigations on the effects of CPEE on breathing in different animal models, including possible mechanisms of adaptation to CPEE. These recent preclinical studies shed new light on a widely used drug of abuse and should facilitate the understanding of the danger posed by alcohol consumption during pregnancy.

  5. Chronic Ethanol Exposure: Pathogenesis of Pulmonary Disease and Dysfunction

    PubMed Central

    Traphagen, Nicole; Tian, Zhi; Allen-Gipson, Diane

    2015-01-01

    Ethanol (EtOH) is the world’s most commonly used drug, and has been widely recognized as a risk factor for developing lung disorders. Chronic EtOH exposure affects all of the organ systems in the body and increases the risk of developing pulmonary diseases such as acute lung injury and pneumonia, while exacerbating the symptoms and resulting in increased mortality in many other lung disorders. EtOH and its metabolites inhibit the immune response of alveolar macrophages (AMs), increase airway leakage, produce damaging reactive oxygen species (ROS), and disrupt the balance of antioxidants/oxidants within the lungs. In this article, we review the role of EtOH exposure in the pathogenesis and progression of pulmonary disease. PMID:26492278

  6. Responses of Hyalella azteca to acute and chronic microplastic exposures.

    PubMed

    Au, Sarah Y; Bruce, Terri F; Bridges, William C; Klaine, Stephen J

    2015-11-01

    Limited information is available on the presence of microplastics in freshwater systems, and even less is known about the toxicological implications of the exposure of aquatic organisms to plastic particles. The present study was conducted to evaluate the effects of microplastic ingestion on the freshwater amphipod, Hyalella azteca. Hyalella azteca was exposed to fluorescent polyethylene microplastic particles and polypropylene microplastic fibers in individual 250-mL chambers to determine 10-d mortality. In acute bioassays, polypropylene microplastic fibers were significantly more toxic than polyethylene microplastic particles; 10-d lethal concentration 50% values for polyethylene microplastic particles and polypropylene microplastic fibers were 4.64 × 10(4) microplastics/mL and 71.43 microplastics/mL, respectively. A 42-d chronic bioassay using polyethylene microplastic particles was conducted to quantify effects on reproduction, growth, and egestion. Chronic exposure to polyethylene microplastic particles significantly decreased growth and reproduction at the low and intermediate exposure concentrations. During acute exposures to polyethylene microplastic particles, the egestion times did not significantly differ from the egestion of normal food materials in the control; egestion times for polypropylene microplastic fibers were significantly slower than the egestion of food materials in the control. Amphipods exposed to polypropylene microplastic fibers also had significantly less growth. The greater toxicity of microplastic fibers than microplastic particles corresponded with longer residence times for the fibers in the gut. The difference in residence time might have affected the ability to process food, resulting in an energetic effect reflected in sublethal endpoints.

  7. Impacts of chronic sublethal exposure to clothianidin on winter honeybees.

    PubMed

    Alkassab, Abdulrahim T; Kirchner, Wolfgang H

    2016-07-01

    A wide application of systemic pesticides and detection of their residues in bee-collected pollen and nectar at sublethal concentrations led to the emergence of concerns about bees' chronic exposure and possible sublethal effects on insect pollinators. Therefore, special attention was given to reducing unintentional intoxications under field conditions. The sensitivity of winter bees throughout their long lifespan to residual exposure of pesticides is not well known, since most previous studies only looked at the effects on summer bees. Here, we performed various laboratory bioassays to assess the effects of clothianidin on the survival and behavior of winter bees. Oral lethal and sublethal doses were administered throughout 12-day. The obtained LD50 values at 48, 72, 96 h and 10 days were 26.9, 18.0, 15.1 and 9.5 ng/bee, respectively. Concentrations <20 µg/kg were found to be sublethal. Oral exposure to sublethal doses was carried out for 12-day and, the behavioral functions were tested on the respective 13th day. Although slight reductions in the responses at the concentrations 10 and 15 µg/kg were observed, all tested sublethal concentrations had showed non-significant effects on the sucrose responsiveness, habitation of the proboscis extension reflex and olfactory learning performance. Nevertheless, chronic exposure to 15 µg/kg affected the specificity of the early long-term memory (24 h). Since the tested concentrations were in the range of field-relevant concentrations, our results strongly suggest that related-effects on winter and summer bees' sensitivity should also be studied under realistic conditions.

  8. Chronic bronchiolitis in nonhuman primates after prolonged ozone exposure

    SciTech Connect

    Eustis, S.L.; Schwartz, L.W.; Kosch, P.C.; Dungworth, D.L.

    1981-01-01

    Bonnet monkeys (Macaca radiata) were exposed to 0.0, 0.5, or 0.8 ppm ozone for 7, 28, or 90 consecutive days, 8 hours per day. The pulmonary response was evaluated by means of pulmonary function testing, light microscopy, scanning electron microscopy, transmission microscopy, autoradiography, and morphometry. Pulmonary function values obtained before exposure did not statistically differ from values obtained after exposure. A general trend of increased quasistatic compliance of the lung was observed in both groups of exposed monkeys. Morphologic changes were principally characterized as low-grade chronic respiratory bronchiolitis. Tritiated thymidine labeling and counts of respiratory bronchiolar epithelium demonstrated up to a 37-fold increase in labeling index at 7 days but only a sevenfold increase at 90 days. Differential cell counts demonstrated an increase in the proportion of cuboidal bronchiolar cells constituting the respiratory bronchiolar epithelium. In control monkeys, 60% of the epithelial cells were cuboidal bronchiolar cells. At 90 days of exposure, more than 90% of the respiratory bronchiolar cells were cuboidal in appearance. The cuboidal bronchiolar cell in control monkeys does not appear secretory, but membrane-bound electron-dense secretory granules are present in this cell type from exposed monkeys. Epithelial hyperplasia (increased number of cells per millimeter of airway length) persisted through 90 days of exposure at a level slightly above that present at 7 days.

  9. Increased interleukin-1β levels following low dose MDMA induces tolerance against the 5-HT neurotoxicity produced by challenge MDMA

    PubMed Central

    2011-01-01

    Background Preconditioning is a phenomenon by which tolerance develops to injury by previous exposure to a stressor of mild severity. Previous studies have shown that single or repeated low dose MDMA can attenuate 5-HT transporter loss produced by a subsequent neurotoxic dose of the drug. We have explored the mechanism of delayed preconditioning by low dose MDMA. Methods Male Dark Agouti rats were given low dose MDMA (3 mg/kg, i.p.) 96 h before receiving neurotoxic MDMA (12.5 mg/kg, i.p.). IL-1β and IL1ra levels and 5-HT transporter density in frontal cortex were quantified at 1 h, 3 h or 7 days. IL-1β, IL-1ra and IL-1RI were determined between 3 h and 96 h after low dose MDMA. sIL-1RI combined with low dose MDMA or IL-1β were given 96 h before neurotoxic MDMA and toxicity assessed 7 days later. Results Pretreatment with low dose MDMA attenuated both the 5-HT transporter loss and elevated IL-1β levels induced by neurotoxic MDMA while producing an increase in IL-1ra levels. Low dose MDMA produced an increase in IL-1β at 3 h and in IL-1ra at 96 h. sIL-1RI expression was also increased after low dose MDMA. Coadministration of sIL-1RI (3 μg, i.c.v.) prevented the protection against neurotoxic MDMA provided by low dose MDMA. Furthermore, IL-1β (2.5 pg, intracortical) given 96 h before neurotoxic MDMA protected against the 5-HT neurotoxicity produced by the drug, thus mimicking preconditioning. Conclusions These results suggest that IL-1β plays an important role in the development of delayed preconditioning by low dose MDMA. PMID:22114930

  10. Characterization of the role of Fhit in maintenance of genomic integrity following low dose radiation, in vivo and in vitro

    SciTech Connect

    Wang, Ya

    2010-05-14

    The major goal of this study is to determine the effects of the Fhit pathway on low dose (< 0.1 Gy) ionizing radiation (IR)-induced genetic instability. Reduction of Fhit protein expression is observed in most solid tumors particularly in those tumors resulting from exposure to environmental carcinogens. Therefore, characterization of the role of the Fhit-dependent pathway in preventing low dose IR-induced genetic instability will provide useful parameters for evaluating the low dose IR-induced risk of mutagenesis and carcinogenesis. We pursued 3 specific aims to study our hypothesis that the Fhit-dependent pathways maintain genomic integrity through adjusting checkpoint response and repair genes expression following low dose IR. Aim 1: Determine whether Fhit interaction with RPA is necessary for Fhit to affect the cellular response to low dose IR. We combined the approaches of in vitro (GST pull-down and site-directed mutagenesis) and in vivo (observing the co-localization and immunoprecipitation of Fhit and RPA in Fhit knock out mouse cells transfected with mutant Fhit which has lost ability to interact with RPA in vitro). Aim 2: Determine the role of genes whose expression is affected by Fhit in low dose irradiated cells. We analyzed the distinct signature of gene expression in low dose irradiated Fhit-/- cells compared with Fhit+/+ cells by combining microarray, gene transfection and siRNA approaches. Aim 3: Determine the role of Fhit in genetic susceptibility to low dose IR in vivo. We compared the gene mutation frequency and the fragile site stability in the cells isolated from the Fhit+/+ and Fhit-/- mice at 1.5 years following low dose IR. These results determine the role of the Fhit-dependent pathway in maintaining genomic integrity in vitro and in vivo, which provide a basis for choosing surrogate markers in the Fhit-dependent pathway to evaluate low dose IR-induced risk of mutagenesis and carcinogenesis.

  11. Characterization of the role of Fhit in maintenance of genomic integrity following low dose radiation, in vivo and in vitro

    SciTech Connect

    Ya Wang

    2010-05-31

    The major goal of this study is to determine the effects of the Fhit pathway on low dose ({le} 0.1 Gy) ionizing radiation (IR)-induced genetic instability. Reduction of Fhit protein expression is observed in most solid tumors particularly in those tumors resulting from exposure to environmental carcinogens. Therefore, characterization of the role of the Fhit-dependent pathway in preventing low dose IR-induced genetic instability will provide useful parameters for evaluating the low dose IR-induced risk of mutagenesis and carcinogenesis. We pursued 3 specific aims to study our hypothesis that the Fhit-dependent pathways maintain genomic integrity through adjusting checkpoint response and repair genes expression following low dose IR. Aim 1: Determine whether Fhit interaction with RPA is necessary for Fhit to affect the cellular response to low dose IR. We combined the approaches of in vitro (GST pull-down and site-directed mutagenesis) and in vivo (observing the co-localization and immunoprecipitation of Fhit and RPA in Fhit knock out mouse cells transfected with mutant Fhit which has lost ability to interact with RPA in vitro). Aim 2: Determine the role of genes whose expression is affected by Fhit in low dose irradiated cells. We analyzed the distinct signature of gene expression in low dose irradiated Fhit-/- cells compared with Fhit+/+ cells by combining microarray, gene transfection and siRNA approaches. Aim 3: Determine the role of Fhit in genetic susceptibility to low dose IR in vivo. We compared the gene mutation frequency and the fragile site stability in the cells isolated from the Fhit+/+ and Fhit-/- mice at 1.5 years following low dose IR. These results determine the role of the Fhit-dependent pathway in maintaining genomic integrity in vitro and in vivo, which provide a basis for choosing surrogate markers in the Fhit-dependent pathway to evaluate low dose IR-induced risk of mutagenesis and carcinogenesis.

  12. Chronic plus binge ethanol exposure causes more severe pancreatic injury and inflammation.

    PubMed

    Ren, Zhenhua; Yang, Fanmuyi; Wang, Xin; Wang, Yongchao; Xu, Mei; Frank, Jacqueline A; Ke, Zun-Ji; Zhang, Zhuo; Shi, Xianglin; Luo, Jia

    2016-10-01

    Alcohol abuse increases the risk for pancreatitis. The pattern of alcohol drinking may impact its effect. We tested a hypothesis that chronic ethanol consumption in combination with binge exposure imposes more severe damage to the pancreas. C57BL/6 mice were divided into four groups: control, chronic ethanol exposure, binge ethanol exposure and chronic plus binge ethanol exposure. For the control group, mice were fed with a liquid diet for two weeks. For the chronic ethanol exposure group, mice were fed with a liquid diet containing 5% ethanol for two weeks. In the binge ethanol exposure group, mice were treated with ethanol by gavage (5g/kg, 25% ethanol w/v) daily for 3days. For the chronic plus binge exposure group, mice were fed with a liquid diet containing 5% ethanol for two weeks and exposed to ethanol by gavage during the last 3days. Chronic and binge exposure alone caused minimal pancreatic injury. However, chronic plus binge ethanol exposure induced significant apoptotic cell death. Chronic plus binge ethanol exposure altered the levels of alpha-amylase, glucose and insulin. Chronic plus binge ethanol exposure caused pancreatic inflammation which was shown by the macrophages infiltration and the increase of cytokines and chemokines. Chronic plus binge ethanol exposure increased the expression of ADH1 and CYP2E1. It also induced endoplasmic reticulum stress which was demonstrated by the unfolded protein response. In addition, chronic plus binge ethanol exposure increased protein oxidation and lipid peroxidation, indicating oxidative stress. Therefore, chronic plus binge ethanol exposure is more detrimental to the pancreas.

  13. Standardization and optimization of CT protocols to achieve low dose.

    PubMed

    Trattner, Sigal; Pearson, Gregory D N; Chin, Cynthia; Cody, Dianna D; Gupta, Rajiv; Hess, Christopher P; Kalra, Mannudeep K; Kofler, James M; Krishnam, Mayil S; Einstein, Andrew J

    2014-03-01

    The increase in radiation exposure due to CT scans has been of growing concern in recent years. CT scanners differ in their capabilities, and various indications require unique protocols, but there remains room for standardization and optimization. In this paper, the authors summarize approaches to reduce dose, as discussed in lectures constituting the first session of the 2013 UCSF Virtual Symposium on Radiation Safety and Computed Tomography. The experience of scanning at low dose in different body regions, for both diagnostic and interventional CT procedures, is addressed. An essential primary step is justifying the medical need for each scan. General guiding principles for reducing dose include tailoring a scan to a patient, minimizing scan length, use of tube current modulation and minimizing tube current, minimizing tube potential, iterative reconstruction, and periodic review of CT studies. Organized efforts for standardization have been spearheaded by professional societies such as the American Association of Physicists in Medicine. Finally, all team members should demonstrate an awareness of the importance of minimizing dose.

  14. Personalized low dose CT via variable kVp

    NASA Astrophysics Data System (ADS)

    Wang, Hui; Jin, Yannan; Yao, Yangyang; Wu, Mingye; Yan, Ming; Tao, Kun; Yin, Zhye; De Man, Bruno

    2015-03-01

    Computerized Tomography (CT) is a powerful radiographic imaging technology but the health risk due to the exposure of x-ray radiation has drawn wide concern. In this study, we propose to use kVp modulation to reduce the radiation dose and achieve the personalized low dose CT. Two sets of simulation are performed to demonstrate the effectiveness of kVp modulation and the corresponding calibration. The first simulation used the helical body phantom (HBP) that is an elliptical water cylinder with high density bone inserts. The second simulation uses the NCAT phantom to emulate the practical use of kVp modulation approach with region of interest (ROI) selected in the cardiac region. The kVp modulation profile could be optimized view by view based on the knowledge of patient attenuation. A second order correction is applied to eliminate the beam hardening artifacts. To simplify the calibration process, we first generate the calibration vectors for a few representative spectra and then acquire other calibration vectors with interpolation. The simulation results demonstrate the beam hardening artifacts in the images with kVp modulation can be eliminated with proper beam hardening correction. The results also show that the simplification of calibration did not impair the image quality: the calibration with the simplified and the complete vectors both eliminate the artifacts effectively and the results are comparable. In summary, this study demonstrates the feasibility of kVp modulation and gives a practical way to calibrate the high order beam hardening artifacts.

  15. Is There a Safe Level of Exposure to a Carcinogen?

    ERIC Educational Resources Information Center

    Hrudey, Steve E.; Krewski, Daniel

    1995-01-01

    Presents an approach to estimating the "safe" levels of low-dose exposure to carcinogens that involves working upward from the smallest conceivable chronic dose instead of extrapolating downward from high exposures. Discusses expert and public opinion and other issues related to quantitative cancer risk assessment. (LZ)

  16. Radiation Hormesis: Historical Perspective and Implications for Low-Dose Cancer Risk Assessment

    PubMed Central

    Vaiserman, Alexander M.

    2010-01-01

    Current guidelines for limiting exposure of humans to ionizing radiation are based on the linear-no-threshold (LNT) hypothesis for radiation carcinogenesis under which cancer risk increases linearly as the radiation dose increases. With the LNT model even a very small dose could cause cancer and the model is used in establishing guidelines for limiting radiation exposure of humans. A slope change at low doses and dose rates is implemented using an empirical dose and dose rate effectiveness factor (DDREF). This imposes usually unacknowledged nonlinearity but not a threshold in the dose-response curve for cancer induction. In contrast, with the hormetic model, low doses of radiation reduce the cancer incidence while it is elevated after high doses. Based on a review of epidemiological and other data for exposure to low radiation doses and dose rates, it was found that the LNT model fails badly. Cancer risk after ordinarily encountered radiation exposure (medical X-rays, natural background radiation, etc.) is much lower than projections based on the LNT model and is often less than the risk for spontaneous cancer (a hormetic response). Understanding the mechanistic basis for hormetic responses will provide new insights about both risks and benefits from low-dose radiation exposure. PMID:20585444

  17. Low dose irradiation profoundly affects transcriptome and microRNAme in rat mammary gland tissues

    PubMed Central

    Luzhna, Lidia; Kovalchuk, Olga

    2014-01-01

    Ionizing radiation has been successfully used in medical tests and treatment therapies for a variety of medical conditions. However, patients and health-care workers are greatly concerned about overexposure to medical ionizing radiation and possible cancer induction due to frequent mammographies and/or CT scans. Diagnostic imaging involves the use of low doses of ionizing radiation, and its potential carcinogenic role creates a cancer risk concern for exposed individuals. In this study, the effects of X-ray exposure of different doses on the gene expression patterns and the micro-RNA expression patterns in normal breast tissue were investigated in rats. Our results revealed the activation of immune response pathways upon low dose of radiation exposure. These included natural killer mediated cytotoxicity pathways, antigen processing and presentation pathways, chemokine signaling pathways, and T- and B-cell receptor signaling pathways. Both high and low doses of radiation led to miRNA expression alterations. Increased expression of miR-34a may be linked to cell cycle arrest and apoptosis. Up-regulation of miR-34a was correlated with down-regulation of its target E2F3 and up-regulation of p53. This data suggests that ionizing radiation at specific high and low doses leads to cell cycle arrest and a possible initiation of apoptosis. PMID:25594002

  18. Mammalian Tissue Response to Low Dose Ionizing Radiation: The Role of Oxidative Metabolism and Intercellular Communication

    SciTech Connect

    Azzam, Edouard I

    2013-01-16

    The objective of the project was to elucidate the mechanisms underlying the biological effects of low dose/low dose rate ionizing radiation in organs/tissues of irradiated mice that differ in their susceptibility to ionizing radiation, and in human cells grown under conditions that mimic the natural in vivo environment. The focus was on the effects of sparsely ionizing cesium-137 gamma rays and the role of oxidative metabolism and intercellular communication in these effects. Four Specific Aims were proposed. The integrated outcome of the experiments performed to investigate these aims has been significant towards developing a scientific basis to more accurately estimate human health risks from exposures to low doses ionizing radiation. By understanding the biochemical and molecular changes induced by low dose radiation, several novel markers associated with mitochondrial functions were identified, which has opened new avenues to investigate metabolic processes that may be affected by such exposure. In particular, a sensitive biomarker that is differentially modulated by low and high dose gamma rays was discovered.

  19. Modeling Dose-response at Low Dose: A Systems Biology Approach for Ionization Radiation.

    PubMed

    Zhao, Yuchao; Ricci, Paolo F

    2010-03-18

    For ionization radiation (IR) induced cancer, a linear non-threshold (LNT) model at very low doses is the default used by a number of national and international organizations and in regulatory law. This default denies any positive benefit from any level of exposure. However, experimental observations and theoretical biology have found that both linear and J-shaped IR dose-response curves can exist at those very low doses. We develop low dose J-shaped dose-response, based on systems biology, and thus justify its use regarding exposure to IR. This approach incorporates detailed, molecular and cellular descriptions of biological/toxicological mechanisms to develop a dose-response model through a set of nonlinear, differential equations describing the signaling pathways and biochemical mechanisms of cell cycle checkpoint, apoptosis, and tumor incidence due to IR. This approach yields a J-shaped dose response curve while showing where LNT behaviors are likely to occur. The results confirm the hypothesis of the J-shaped dose response curve: the main reason is that, at low-doses of IR, cells stimulate protective systems through a longer cell arrest time per unit of IR dose. We suggest that the policy implications of this approach are an increasingly correct way to deal with precautionary measures in public health.

  20. The toxicity of continuous long-term low-dose formaldehyde inhalation in mice.

    PubMed

    Cheng, Jiaying; Zhang, Long; Tang, Yufu; Li, Zhenhai

    2016-12-01

    Although the toxicity of high-dose formaldehyde (FA) inhalation has been extensively analyzed in animals, the effect of continuous long-term exposure to low-dose FA has not been well documented. This study aims to evaluate the toxicity of continuous long-term low-dose FA inhalation in mice. Forty-eight Kunming male mice were equally randomized to three groups according to the dose of FA inhalation exposure: a control (0 mg/m(3)) group, a low-dose (0.08 mg/m(3)) group and a high-dose (0.8 mg/m(3)) group. The mice have been selected to expose to FA for different consecutive days at 24 h/day. The learning and memory functions, pathological changes in the lung and liver, and the percentage of CD4 (+) T and CD8 (+) T cells were observed and analyzed. It was found that continuous long-term inhalation of FA at relatively low doses could impair the learning and memory functions and induce pathological changes in the lung and liver, but did not seem to significantly affect the number of immune (CD4 (+) T and CD8 (+) T) cells.

  1. Chronic Exposure to Diquat Causes Reproductive Toxicity in Female Mice.

    PubMed

    Zhang, Jia-Qing; Gao, Bin-Wen; Wang, Jing; Wang, Xian-Wei; Ren, Qiao-Ling; Chen, Jun-Feng; Ma, Qiang; Xing, Bao-Song

    2016-01-01

    Diquat is a bipyridyl herbicide that has been widely used as a model chemical for in vivo studies of oxidative stress due to its generation of superoxide anions, and cytotoxic effects. There is little information regarding the toxic effects of diquat on the female reproductive system, particularly ovarian function. Thus, we investigated the reproductive toxic effects of diquat on female mice. Chronic exposure to diquat reduced ovary weights, induced ovarian oxidative stress, resulted in granulosa cell apoptosis, and disrupted oocyte developmental competence, as shown by reactive oxygen species (ROS) accumulation, decreased polar body extrusion rates and increased apoptosis-related genes expression. Additionally, after diquat treatment, the numbers of fetal mice and litter sizes were significantly reduced compared to those of control mice. Thus, our results indicated that chronic exposure to diquat induced reproductive toxicity in female mice by promoting the ROS production of gruanousa cells and ooctyes, impairing follicle development, inducing apoptosis, and reducing oocyte quality. In conclusion, our findings indicate that diquat can be used as a potent and efficient chemical for in vivo studies of female reproductive toxicity induced by oxidative stress. Moreover, the findings from this study will further enlarge imitative research investigating the effect of ovarian damage induced by oxidative stress on reproductive performance and possible mechanisms of action in large domestic animals.

  2. Risk of Low Dose/Low Dose Rate Ionizing Radiation to Humans Symposium Annual Meeting of the Environmental Mutagen Society: Agenda and Abstracts

    SciTech Connect

    Veigl, Martina L.; Morgan, William F.; Schwartz, Jeffrey L.

    2009-11-11

    The low dose symposium thoughtfully addressed controversy of risk from low dose radiation exposure, hormesis and radon therapy. The stem cell symposium cogently considered the role of DNA damage and repair in hematopoietic stem cells underlying aging and malignancy and provocatively presented evidence that stem cells may have distinct morphologies and replicative properties, as well as special roles in cancer initiation. In the epigenetics symposium, studies illustrated the long range interaction of epigenetic mechanisms, the roles of CTCF and BORIS in region/specific regulation of epigenetic processes, the impact of DNA damage on epigenetic processes as well as links between epigenetic mechanisms and early nutrition and bystander effects. This report shows the agenda and abstracts for this symposium.

  3. Quantitative Proteomic Profiling of Low Dose Ionizing Radiation Effects in a Human Skin Model

    SciTech Connect

    Hengel, Shawna; Aldrich, Joshua T.; Waters, Katrina M.; Pasa-Tolic, Ljiljana; Stenoien, David L.

    2014-07-29

    To assess molecular responses to low doses of radiation that may be encountered during medical diagnostic procedures, nuclear accidents, or terrorist acts, a quantitative global proteomic approach was used to identify protein alterations in a reconstituted human skin tissue treated with 10 cGy of ionizing radiation. Subcellular fractionation was employed to remove highly abundant structural proteins and provide insight on radiation induced alterations in protein abundance and localization. In addition, peptides were post-fractionated using high resolution 2-dimensional liquid chromatography to increase the dynamic range of detection of protein abundance and translocation changes. Quantitative data was obtained by labeling peptides with 8-plex isobaric iTRAQ tags. A total of 207 proteins were detected with statistically significant alterations in abundance and/or subcellular localization compared to sham irradiated tissues. Bioinformatics analysis of the data indicated that the top canonical pathways affected by low dose radiation are related to cellular metabolism. Among the proteins showing alterations in abundance, localization and proteolytic processing was the skin barrier protein filaggrin which is consistent with our previous observation that ionizing radiation alters profilaggrin processing with potential effects on skin barrier functions. In addition, a large number of proteases and protease regulators were affected by low dose radiation exposure indicating that altered proteolytic activity may be a hallmark of low dose radiation exposure. While several studies have demonstrated altered transcriptional regulation occurs following low dose radiation exposures, the data presented here indicates post-transcriptional regulation of protein abundance, localization, and proteolytic processing play an important role in regulating radiation responses in complex human tissues.

  4. Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells

    SciTech Connect

    Stueckle, Todd A.; Lu, Yongju; Davis, Mary E.; Wang, Liying; Jiang, Bing-Hua; Holaskova, Ida; Schafer, Rosana; Barnett, John B.; Rojanasakul, Yon

    2012-06-01

    Chronic arsenic exposure remains a human health risk; however a clear mode of action to understand gene signaling-driven arsenic carcinogenesis is currently lacking. This study chronically exposed human lung epithelial BEAS-2B cells to low-dose arsenic trioxide to elucidate cancer promoting gene signaling networks associated with arsenic-transformed (B-As) cells. Following a 6 month exposure, exposed cells were assessed for enhanced cell proliferation, colony formation, invasion ability and in vivo tumor formation compared to control cell lines. Collected mRNA was subjected to whole genome expression microarray profiling followed by in silico Ingenuity Pathway Analysis (IPA) to identify lung carcinogenesis modes of action. B-As cells displayed significant increases in proliferation, colony formation and invasion ability compared to BEAS-2B cells. B-As injections into nude mice resulted in development of primary and secondary metastatic tumors. Arsenic exposure resulted in widespread up-regulation of genes associated with mitochondrial metabolism and increased reactive oxygen species protection suggesting mitochondrial dysfunction. Carcinogenic initiation via reactive oxygen species and epigenetic mechanisms was further supported by altered DNA repair, histone, and ROS-sensitive signaling. NF-κB, MAPK and NCOR1 signaling disrupted PPARα/δ-mediated lipid homeostasis. A ‘pro-cancer’ gene signaling network identified increased survival, proliferation, inflammation, metabolism, anti-apoptosis and mobility signaling. IPA-ranked signaling networks identified altered p21, EF1α, Akt, MAPK, and NF-κB signaling networks promoting genetic disorder, altered cell cycle, cancer and changes in nucleic acid and energy metabolism. In conclusion, transformed B-As cells with their whole genome expression profile provide an in vitro arsenic model for future lung cancer signaling research and data for chronic arsenic exposure risk assessment. Highlights: ► Chronic As{sub 2}O

  5. Low dose neutron late effects: Cataractogenesis

    SciTech Connect

    Worgul, B.V.

    1991-04-01

    The work is formulated to resolve the uncertainty regarding the relative biological effectiveness. The endpoint which is being utilized is cataractogenesis. The advantages conferred by this system stems primarily from the non-invasive longitudinal analysis which it allows. It also exploits a well defined system and one which has demonstrated sensitivity to the inverse dose rate effect observed with heavy ions. Four week old rats were divided into 8 dose groups which received single or fractionated total doses of .2, 1.0, 5.0 and 25 cGy of monoenergetic 435 keV neutrons. Special restraining jigs were devised to insure that the eye at the midpoint of the lens received the appropriate energy and dose with a relative error of {plus minus} 5%. The fractionated regimen consisted of four exposures, each administered at 3 hour intervals. The reference radiations, 250 kVp X-rays, were administered in the same fashion but in doses ranging from .5 to 6.0 Gy. The animals are examined on a bi-weekly basis utilizing conventional slit-lamp biomicroscopy and the Scheimpflug Slit-lamp Imaging System. The follow-ups will continue throughout the lifespan of the animals. When opacification begins full documentation will involve the Zeiss imaging system and Oxford retroillumination photography. The processing routinely employs the Merriam/Focht scoring system for cross-referencing with previous cataract studies and establish cataractogenecity using a proven scoring method.

  6. Ultra low-dose CT attenuation correction in PET SPM

    NASA Astrophysics Data System (ADS)

    Wang, Shyh-Jen; Yang, Bang-Hung; Tsai, Chia-Jung; Yang, Ching-Ching; Lee, Jason J. S.; Wu, Tung-Hsin

    2010-07-01

    The use of CT images for attenuation correction (CTAC) allows significantly shorter scanning time and a high quality noise-free attenuation map compared with conventional germanium-68 transmission scan because at least 10 4 times greater of photon flux would be generated from a CT scan under standard operating condition. However, this CTAC technique would potentially introduce more radiation risk to the patients owing to the higher radiation exposure from CT scan. Statistic parameters mapping (SPM) is a prominent technique in nuclear medicine community for the analysis of brain imaging data. The purpose of this study is to assess the feasibility of low-dose CT (LDCT) and ultra low-dose CT (UDCT) in PET SPM applications. The study was divided into two parts. The first part was to evaluate of tracer uptake distribution pattern and quantity analysis by using the striatal phantom to initially assess the feasibility of AC for clinical purpose. The second part was to examine the group SPM analysis using the Hoffman brain phantom. The phantom study is to simulate the human brain and to reduce the experimental uncertainty of real subjects. The initial studies show that the results of PET SPM analysis have no significant differences between LDCT and UDCT comparing to the current used default CTAC. Moreover, the dose of the LDCT is lower than that of the default CT by a factor of 9, and UDCT can even yield a 42 times dose reduction. We have demonstrated the SPM results while using LDCT and UDCT for PET AC is comparable to those using default CT setting, suggesting their feasibility in PET SPM applications. In addition, the necessity of UDCT in PET SPM studies to avoid excess radiation dose is also evident since most of the subjects involved are non-cancer patients or children and some normal subjects are even served as a comparison group in the experiment. It is our belief that additional attempts to decrease the radiation dose would be valuable, especially for children and

  7. Low Dose Radiation Hypersensitivity is Caused by p53-dependent Apoptosis

    SciTech Connect

    Enns, L; Bogen, K; Wizniak, J; Murtha, A; Weinfeld, M

    2004-04-08

    Exposure to environmental radiation and the application of new clinical modalities, such as radioimmunotherapy, have heightened the need to understand cellular responses to low dose and low-dose rate ionizing radiation. Many tumor cell lines have been observed to exhibit a hypersensitivity to radiation doses below 50 cGy, which manifests as a significant deviation from the clonogenic survival response predicted by a linear-quadratic fit to higher doses. However, the underlying processes for this phenomenon remain unclear. Using a gel microdrop/flow cytometry assay to monitor single cell proliferation at early times post irradiation, we examined the response of human A549 lung carcinoma, T98G glioma and MCF7 breast carcinoma cell lines exposed to gamma radiation doses from 0 to 200 cGy delivered at 0.18 and 22 cGy/min. The A549 and T98G cells, but not MCF7 cells, showed the marked hypersensitivity at doses <50 cGy. To further characterize the low-dose hypersensitivity, we examined the influence of low-dose radiation on cell cycle status and apoptosis by assays for active caspase-3 and phosphatidylserine translocation (annexin-V binding). We observed that caspase-3 activation and annexin-V binding mirrored the proliferation curves for the cell lines. Furthermore, the low-dose hypersensitivity and annexin-V binding to irradiated A549 and T98G cells were eliminated by treating the cells with pifithrin, an inhibitor of p53. When p53-inactive cell lines (2800T skin fibroblasts and HCT116 colorectal carcinoma cells) were examined for similar patterns, we found that there was no HRS