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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. 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

  3. Effects of chronic low-dose cadmium exposure on selected biochemical and antioxidant parameters in rats.

    PubMed

    Lovásová, Eva; Rácz, Oliver; Cimboláková, Iveta; Nováková, Jaroslava; Dombrovský, Peter; Ništiar, František

    2013-01-01

    The effects of long-term (1 yr) exposure to low doses of cadmium (Cd) dissolved in drinking water on selected biochemical and antioxidant parameters were studied in Wistar rats. Rats were divided into four groups: male control group (C-m), female control group (C-f), male Cd-exposed group (Cd-m), and female Cd-exposed group (Cd-f). Cd groups were exposed to Cd dissolved in drinking water (cadmium dichloride 4.8 mg CdCl2/L, i.e., 2.5 mg Cd/L, 500-fold of maximal allowable concentration for potable water). The experiment was terminated on d 370. In all groups, biochemical parameters (total protein [TP], albumin, alanine aminotransferase, aspartate aminotransferase, glucose, cholesterol, triacylglycerols, urea, and creatinine) and antioxidant parameters (glutathione peroxidase, superoxide dismutase, and total antioxidant capacity) were measured in the blood. Total protein and albumin concentrations were decreased significantly in the Cd-m group. Other biochemical parameters did not change in Cd groups compared to control groups. Superoxide dismutase fell significantly in both male and female Cd-exposed groups. Activity of glutathione peroxidase was markedly lower in Cd-exposed groups. Total antioxidant capacity increased significantly in Cd-f group. These results suggest that chronic low-dose oral Cd exposure induces oxidative stress. PMID:24168039

  4. Injury to the blood-testis barrier after low-dose-rate chronic radiation exposure in mice.

    PubMed

    Son, Y; Heo, K; Bae, M J; Lee, C G; Cho, W S; Kim, S D; Yang, K; Shin, I S; Lee, M Y; Kim, J S

    2015-11-01

    Exposure to ionising radiation induces male infertility, accompanied by increasing permeability of the blood-testis barrier. However, the effect on male fertility by low-dose-rate chronic radiation has not been investigated. In this study, the effects of low-dose-rate chronic radiation on male mice were investigated by measuring the levels of tight-junction-associated proteins (ZO-1 and occludin-1), Niemann-Pick disease type 2 protein (NPC-2) and antisperm antibody (AsAb) in serum. BALB/c mice were exposed to low-dose-rate radiation (3.49 mGy h(-1)) for total exposures of 0.02 (6 h), 0.17 (2 d) and 1.7 Gy (21 d). Based on histological examination, the diameter and epithelial depth of seminiferous tubules were significantly decreased in 1.7-Gy-irradiated mice. Compared with those of the non-irradiated group, 1.7-Gy-irradiated mice showed significantly decreased ZO-1, occludin-1 and NPC-2 protein levels, accompanied with increased serum AsAb levels. These results suggest potential blood-testis barrier injury and immune infertility in male mice exposed to low-dose-rate chronic radiation.

  5. 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

  6. Morphological and functional deterioration of the rat thyroid following chronic exposure to low-dose PCB118.

    PubMed

    Tang, Jin-Mei; Li, Wen; Xie, Yu-Chun; Guo, Hong-Wei; Cheng, Pei; Chen, Huan-Huan; Zheng, Xu-Qin; Jiang, Lin; Cui, Dai; Liu, Yun; Ding, Guo-Xian; Duan, Yu

    2013-11-01

    Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that can severely disrupt the synthesis and secretion of endocrine hormones. To investigate the effects of 2,3',4,4',5-pentachlorobiphenyl (PCB118) on thyroid structure and function, 40 male Wistar rats were divided into 4 equal treatment groups and administered vehicle or one of three doses of PCB118. The experimental groups received intraperitoneal (i.p.) injection of 10, 100, or 1000μg/kg/day PCB118, 5 days per week for 13 weeks, whereas the control group was injected with corn oil (vehicle). Serum concentrations of free thyroxine (FT4), free triiodothyronine (FT3) and thyroid stimulating hormone (TSH) were measured by radioimmunoassays. Histopathological and ultrastructural changes in the thyroid were observed under light microscopy and transmission electron microscopy (TEM). The mRNA expression levels of the sodium-iodide symporter (NIS) and thyroglobulin (TG) were quantified by real-time PCR. Increasing doses of PCB118 resulted in progressively lower FT3, FT4 and TSH concentrations in serum. Injection of PCB118 at all doses led to histopathological deterioration of the thyroid characterized by follicular hyperplasia and expansion, shedding of epithelial cells and fibrinoid necrosis. Follicle cells exhibited swollen or vacuolated endoplasmic reticula, as revealed by TEM. Exposure to PCB118 also caused significant decreases in NIS and TG mRNA expression levels. Chronic exposure to low-dose PCB118 and other PCB congeners may be a significant risk factor for thyroid diseases. PMID:23557935

  7. 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

  8. 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.

  9. 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

    2015-01-01

    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. PMID:26168333

  10. 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. PMID:26046630

  11. 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

  12. 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

  13. 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. PMID:26825299

  14. 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

  15. Impact of chronic exposure to low doses of chlorpyrifos on the intestinal microbiota in the Simulator of the Human Intestinal Microbial Ecosystem (SHIME) and in the rat.

    PubMed

    Joly, Claire; Gay-Quéheillard, Jérôme; Léké, André; Chardon, Karen; Delanaud, Stéphane; Bach, Véronique; Khorsi-Cauet, Hafida

    2013-05-01

    The impact of the insecticide chlorpyrifos (CPF) on the mammalian digestive system has been poorly described. The present study aimed at evaluating the effect of chronic, low-dose exposure to CPF on the composition of the gut microbiota in a Simulator of the Human Intestinal Microbial Ecosystem: the SHIME and in rats. The SHIME comprises six reactor vessels (stomach to colon). The colonic segments were inoculated with feces from healthy humans. Then, the simulator was exposed to a daily dose of 1 mg of CPF for 30 days. The changes over time in the populations of bacteria were examined at different time points: prior to pesticide exposure (as a control) and after exposure. In parallel, pregnant rats were gavaged daily with 1 mg/kg of CPF (or vehicle) until the pups were weaned. Next, the rats were gavaged with same dose of CPF until 60 days of age (adulthood). Then, samples of different parts of the digestive tract were collected under sterile conditions for microbiological assessment. Chronic, low-dose exposure to CPF in the SHIME and in the rat was found to induce dysbiosis in the microbial community with, in particular, proliferation of subpopulations of some strains and a decrease in the numbers of others bacteria. In compliance with European guidelines, the use of the SHIME in vitro tool would help to (1) elucidate the final health effect of toxic agents and (2) minimize (though not fully replace) animal testing. Indeed, certain parameters would still have to be studied further in vivo. PMID:23135753

  16. 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. PMID:22641644

  17. 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. PMID:26113293

  18. 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.

  19. 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. PMID:27240828

  20. N-Acetyl cysteine does not prevent liver toxicity from chronic low-dose plus subacute high-dose paracetamol exposure in young or old mice.

    PubMed

    Kane, Alice Elizabeth; Huizer-Pajkos, Aniko; Mach, John; McKenzie, Catriona; Mitchell, Sarah Jayne; de Cabo, Rafael; Jones, Brett; Cogger, Victoria; Le Couteur, David G; Hilmer, Sarah Nicole

    2016-06-01

    Paracetamol is an analgesic commonly used by people of all ages, which is well documented to cause severe hepatotoxicity with acute overexposures. The risk of hepatotoxicity from nonacute paracetamol exposures is less extensively studied, and this is the exposure most common in older adults. Evidence on the effectiveness of N-acetyl cysteine (NAC) for nonacute paracetamol exposures, in any age group, is lacking. This study aimed to examine the effect of long-term exposure to therapeutic doses of paracetamol and subacute paracetamol overexposure, in young and old mice, and to investigate whether NAC was effective at preventing paracetamol hepatotoxicity induced by these exposures. Young and old male C57BL/6 mice were fed a paracetamol-containing (1.33 g/kg food) or control diet for 6 weeks. Mice were then dosed orally eight times over 3 days with additional paracetamol (250 mg/kg) or saline, followed by either one or two doses of oral NAC (1200 mg/kg) or saline. Chronic low-dose paracetamol exposure did not cause hepatotoxicity in young or old mice, measured by serum alanine aminotransferase (ALT) elevation, and confirmed by histology and a DNA fragmentation assay. Subacute paracetamol exposure caused significant hepatotoxicity in young and old mice, measured by biochemistry (ALT) and histology. Neither a single nor double dose of NAC protected against this toxicity from subacute paracetamol in young or old mice. This finding has important clinical implications for treating toxicity due to different paracetamol exposure types in patients of all ages, and implies a need to develop new treatments for subacute paracetamol toxicity. PMID:26821200

  1. Chronic exposure of mice to environmentally relevant, low doses of cadmium leads to early renal damage, not predicted by blood or urine cadmium levels.

    PubMed

    Thijssen, Sandy; Maringwa, John; Faes, Christel; Lambrichts, Ivo; Van Kerkhove, Emmy

    2007-01-01

    Mice were exposed to cadmium (Cd) concentrations ranging from 0 to 100mg CdCl(2)/l in the drinking water for 1, 4, 8, 16 and 23 weeks. Urine samples were taken regularly, Cd content was determined in blood, liver, kidney and urine and histological analyses of the kidney were performed. Kidney cortex Cd content increased linearly with time and dose, while blood levels reached a plateau at 8 weeks and liver at 16 weeks in mice exposed to 100mg CdCl(2)/l after which both started to decrease. Urinary Cd levels were not correlated with the kidney Cd content. A multivariate regression model taking into account the actual Cd intake, calculated from the volume of water taken in by each animal and the exposure concentration, confirmed that blood is an indicator of acute exposure, while kidney Cd content is a reliable indicator of chronic exposure. The urinary protein content was significantly increased from 16 weeks on in mice exposed to 100mg CdCl(2)/l (p<0.05), while other signs of proximal tubular damage (glucosuria, enzymuria) were not detected. Histologically more vacuoles and lysosomes were present in the proximal tubule cells with increasing time and dose. The results indicate that chronic exposure to low doses of Cd induced functional and histological signs of early damage at concentrations in or below the ones generally accepted as safe. Our study does not corroborate the statement that urine Cd levels are a reliable indicator of total Cd body burden, at least when the body burden is low.

  2. 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.

  3. Array-CGH analyses of murine malignant lymphomas: genomic clues to understanding the effects of chronic exposure to low-dose-rate gamma rays on lymphomagenesis.

    PubMed

    Takabatake, Takashi; Fujikawa, Katsuyoshi; Tanaka, Satoshi; Hirouchi, Tokuhisa; Nakamura, Masako; Nakamura, Shingo; Braga-Tanaka, Ignacia; Ichinohe, Kazuaki; Saitou, Mikio; Kakinuma, Shizuko; Nishimura, Mayumi; Shimada, Yoshiya; Oghiso, Yoichi; Tanaka, Kimio

    2006-07-01

    We previously reported that mice chronically irradiated with low-dose-rate gamma rays had significantly shorter mean life spans than nonirradiated controls. This life shortening appeared to be due primarily to earlier death due to malignant lymphomas in the irradiated groups (Tanaka et al., Radiat. Res. 160, 376-379, 2003). To elucidate the molecular pathogenesis of murine lymphomas after low-dose-rate irradiation, chromosomal aberrations in 82 malignant lymphomas from mice irradiated at a dose rate of 21 mGy/day and from nonirradiated mice were compared precisely by microarray-based comparative genomic hybridization (array-CGH) analysis. The array carried 667 BAC clones densely selected for the genomic regions not only of lymphoma-related loci but also of surface antigen receptors, enabling immunogenotyping. Frequent detection of the apparent loss of the Igh region on chromosome 12 suggested that most lymphomas in both groups were of B-cell origin. Array-CGH profiles showed a frequent gain of whole chromosome 15 in lymphomas predominantly from the irradiated group. The profiles also demonstrated copy-number imbalances of partial chromosomal regions. Partial gains on chromosomes 12, 14 and X were found in tumors from nonirradiated mice, whereas losses on chromosomes 4 and 14 were significantly associated with the irradiated group. These findings suggest that lymphomagenesis under the effects of continuous low-dose-rate irradiation is accelerated by a mechanism different from spontaneous lymphomagenesis that is characterized by the unique spectrum of chromosomal aberrations. PMID:16808621

  4. 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

  5. Effects of chronic dietary exposure to a low-dose of Malathion, Aroclor-1254 and 3-methylcholanthrene on three biomarkers in male mice.

    PubMed

    Hackenberger, B K; Jarić, Davorka; Hackenberger, Dubravka; Stepić, Sandra

    2010-12-01

    The aim of this research was to examine the applicability of some chronic toxicological tests in the determination of exposure to xenobiotics present in concentrations below No Observed Adverse Effect Level (NOAEL) and below the detection limit of analytical instruments. In the present experiment tested chemicals (Malathion, Aroclor-1254 and 3-methylcholanthrene (3-MC)) were mixed with wheat grains and given to male mice as feed over a period of 12 months. 7-ethoxyresorufin-O-deethylase (EROD) activity with the 3-MC and Aroclor-1254 treatments reached the peak at 9th month of exposure (26.7 and 42.4 pmol⁻¹ mg(prot)-⁻¹, respectively), while malathion did not have significant influence. Glutathione (GSH) level depletion was highest after three months of exposure. Unexpectedly, acetylcholinesterase (AChE) activity increased after treatment with malathion, an organophosphorous insecticide. In conclusion, low-level concentrations chronically administered exert certain effects on the levels of selected enzymes, e.g. biomarkers.

  6. 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.

  7. Effects of chronic exposure to estradiol on ovarian cyclicity in C57BL/6J mice: potentiation at low doses and only partial suppression at high doses.

    PubMed

    Jesionowska, H; Karelus, K; Nelson, J F

    1990-08-01

    Long-term exposure to ovarian hormones contributes to age-related changes in estrous cyclicity in rodents. Estrogens are implicated in this process, but the concentration of estrogen required to exert these effects is not well established. Also, although estrogens are presumed to alter vaginal cyclicity by affecting the hypothalamic-pituitary axis, they may also impair the ability of the vaginal epithelium to cornify. To address these issues, young and middle-aged ovariectomized (ovx) C57BL/6J mice were exposed for 7-10 wk to plasma levels of estradiol (E2) at one of three ranges (30-40, 50-80, or 120-160 pg/ml). Ovaries from young mice were then transplanted under the renal capsule, and vaginal cyclicity was monitored for 4 mo. Mice exposed to the lowest level of E2 not only failed to stop cycling, but had a higher monthly frequency of estrous cycles than did controls (nearly 1 extra cycle/mo). Mice exposed to the intermediate level of E2 showed no impairment in cyclicity. Although mice exposed to the highest concentrations of E2 showed no vaginal cyclicity, they continued to ovulate as evidenced by fresh, albeit reduced, numbers of corpora lutea. These results indicate that, in ovx mice, (1) chronic exposure to relatively low concentrations of E2 potentiates cyclicity, (2) very high levels of E2 are required to induce acyclicity, and (3) this acyclicity reflects vaginal as well as neuroendocrine alterations. The results also indicate that vaginal acylicity may be a poor indicator of ovulatory acyclicity in mice that have been chronically exposed to E2.

  8. 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. PMID:27156071

  9. 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.

  10. Neurological Toxicity of Individual and Mixtures of Low Dose Arsenic, Mono and Di (n-butyl) Phthalates on Sub-Chronic Exposure to Mice.

    PubMed

    Mao, Guanghua; Zhou, Zhaoxiang; Chen, Yao; Wang, Wei; Wu, Xueshan; Feng, Weiwei; Cobbina, Samuel Jerry; Huang, Jing; Zhang, Zhen; Xu, Hai; Yang, Liuqing; Wu, Xiangyang

    2016-03-01

    The objective of this study was to evaluate the toxicity of individual and mixtures of di(n-butyl) phthalates (DBP) and their active metabolite monobutyl phthalate (MBP) and arsenic (As) on spatial cognition associated with hippocampal apoptosis in mice. Mice were exposed, individually or in combination, to DBP (50 mg/kg body weight, intragastrically), MBP (50 mg/kg body weight, intragastrically), and As (10 mg/L, per os) for 8 weeks. The Morris water maze test showed that mice exposed to DBP/MBP combined with As exhibited longer escape latencies and the lower average number of crossing the platform. The As content in the hippocampus after As exposure increased as compared to those without As exposure. In mice exposed to DBP/MBP combined with As, pathological alterations and oxidative damage to the hippocampus were found. Expression of apoptosis-related protein: Bax and caspase-3 were significantly increased in the hippocampus, while there was no significant change in expression of Bcl-2. The results suggested that DBP and MBP combined with As can induce spatial cognitive deficits through altering the expression of apoptosis-related protein and As played a critical role in cognition impairments. And the joint exposure has antagonistic effect.

  11. 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

  12. 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

  13. Metabolomics identifies a biological response to chronic low-dose natural uranium contamination in urine samples.

    PubMed

    Grison, Stéphane; Favé, Gaëlle; Maillot, Matthieu; Manens, Line; Delissen, Olivia; Blanchardon, Eric; Banzet, Nathalie; Defoort, Catherine; Bott, Romain; Dublineau, Isabelle; Aigueperse, Jocelyne; Gourmelon, Patrick; Martin, Jean-Charles; Souidi, Maâmar

    2013-01-01

    Because uranium is a natural element present in the earth's crust, the population may be chronically exposed to low doses of it through drinking water. Additionally, the military and civil uses of uranium can also lead to environmental dispersion that can result in high or low doses of acute or chronic exposure. Recent experimental data suggest this might lead to relatively innocuous biological reactions. The aim of this study was to assess the biological changes in rats caused by ingestion of natural uranium in drinking water with a mean daily intake of 2.7 mg/kg for 9 months and to identify potential biomarkers related to such a contamination. Subsequently, we observed no pathology and standard clinical tests were unable to distinguish between treated and untreated animals. Conversely, LC-MS metabolomics identified urine as an appropriate biofluid for discriminating the experimental groups. Of the 1,376 features detected in urine, the most discriminant were metabolites involved in tryptophan, nicotinate, and nicotinamide metabolic pathways. In particular, N-methylnicotinamide, which was found at a level seven times higher in untreated than in contaminated rats, had the greatest discriminating power. These novel results establish a proof of principle for using metabolomics to address chronic low-dose uranium contamination. They open interesting perspectives for understanding the underlying biological mechanisms and designing a diagnostic test of exposure.

  14. [Relationship to Carcinogenesis of Repetitive Low-Dose Radiation Exposure].

    PubMed

    Ootsuyama, Akira

    2016-06-01

    We studied the carcinogenic effects caused by repetitive irradiation at a low dose, which has received attention in recent years, and examined the experimental methods used to evaluate radiation-induced carcinogenesis. For this experiment, we selected a mouse with as few autochthonous cancers as possible. Skin cancer was selected as the target for analysis, because it is a rare cancer in mice. Beta-rays were selected as the radiation source. The advantage of using beta-rays is weaker penetration power into tissues, thus protecting organs, such as the digestive and hematogenous organs. The benefit of our experimental method is that only skin cancer requires monitoring, and it is possible to perform long-term experiments. The back skin of mice was exposed repetitively to beta-rays three times a week until the occurrence of cancer or death, and the dose per exposure ranged from 0.5 to 11.8 Gy. With the high-dose range (2.5-11.8 Gy), the latency period and carcinogenic rate were almost the same in each experimental group. When the dose was reduced to 1-1.5 Gy, the latency period increased, but the carcinogenic rate remained. When the dose was further reduced to 0.5 Gy, skin cancer never happened, even though we continued irradiation until death of the last mouse in this group. The lifespan of 0.5 Gy group mice was the same as that of the controls. We showed that the 0.5 Gy dose did not cause cancer, even in mice exposed repetitively throughout their life span, and thus refer to 0.5 Gy as the threshold-like dose. PMID:27302731

  15. [Relationship to Carcinogenesis of Repetitive Low-Dose Radiation Exposure].

    PubMed

    Ootsuyama, Akira

    2016-06-01

    We studied the carcinogenic effects caused by repetitive irradiation at a low dose, which has received attention in recent years, and examined the experimental methods used to evaluate radiation-induced carcinogenesis. For this experiment, we selected a mouse with as few autochthonous cancers as possible. Skin cancer was selected as the target for analysis, because it is a rare cancer in mice. Beta-rays were selected as the radiation source. The advantage of using beta-rays is weaker penetration power into tissues, thus protecting organs, such as the digestive and hematogenous organs. The benefit of our experimental method is that only skin cancer requires monitoring, and it is possible to perform long-term experiments. The back skin of mice was exposed repetitively to beta-rays three times a week until the occurrence of cancer or death, and the dose per exposure ranged from 0.5 to 11.8 Gy. With the high-dose range (2.5-11.8 Gy), the latency period and carcinogenic rate were almost the same in each experimental group. When the dose was reduced to 1-1.5 Gy, the latency period increased, but the carcinogenic rate remained. When the dose was further reduced to 0.5 Gy, skin cancer never happened, even though we continued irradiation until death of the last mouse in this group. The lifespan of 0.5 Gy group mice was the same as that of the controls. We showed that the 0.5 Gy dose did not cause cancer, even in mice exposed repetitively throughout their life span, and thus refer to 0.5 Gy as the threshold-like dose.

  16. 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

  17. 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

  18. Non linear processes modulated by low doses of radiation exposure

    NASA Astrophysics Data System (ADS)

    Mariotti, Luca; Ottolenghi, Andrea; Alloni, Daniele; Babini, Gabriele; Morini, Jacopo; Baiocco, Giorgio

    The perturbation induced by radiation impinging on biological targets can stimulate the activation of several different pathways, spanning from the DNA damage processing to intra/extra -cellular signalling. In the mechanistic investigation of radiobiological damage this complex “system” response (e.g. omics, signalling networks, micro-environmental modifications, etc.) has to be taken into account, shifting from a focus on the DNA molecule solely to a systemic/collective view. An additional complication comes from the finding that the individual response of each of the involved processes is often not linear as a function of the dose. In this context, a systems biology approach to investigate the effects of low dose irradiations on intra/extra-cellular signalling will be presented, where low doses of radiation act as a mild perturbation of a robustly interconnected network. Results obtained through a multi-level investigation of both DNA damage repair processes (e.g. gamma-H2AX response) and of the activation kinetics for intra/extra cellular signalling pathways (e.g. NFkB activation) show that the overall cell response is dominated by non-linear processes - such as negative feedbacks - leading to possible non equilibrium steady states and to a poor signal-to-noise ratio. Together with experimental data of radiation perturbed pathways, different modelling approaches will be also discussed.

  19. The effects of chronic low-dose capsaicin treatment on substance P levels.

    PubMed

    Erin, Nuray; Zik, Berrin; Sarigül, Münevver; Tütüncü, Serife

    2009-02-25

    Capsaicin, the pungent ingredient of red pepper, is consumed in varying amounts by many ethnic groups. It serves both therapeutically and as a specific tool to investigate sensory neurons. Although effects of high capsaicin doses are well-established, systemic effects of chronic low-dose capsaicin exposure are unknown. Sprague-Dawley rats (21-day old) were injected with capsaicin (0.5 mg/kg, ip) for 6 and 19 days. Changes in Substance P (SP) levels of lung and skin were measured. Two-step sequential acetic acid extraction was used to estimate neuronal and non-neuronal SP. Six-day, but not 19-day capsaicin treatment decreased SP levels in first as well as second extractions of both tissues. Because the cumulative dose used here was much lower than the neurotoxic doses of capsaicin, initial decrease of SP levels must be due to continuous release of SP from nerve endings as well as non-neuronal tissues. The fact that SP levels returned to control values at the end of 19-day treatment demonstrates that reactive increases in SP synthesis occurred. These findings suggest that systemic exposure to low-dose capsaicin enhances sensory nerve function and also increases SP in non-neuronal tissues. In addition, significantly decreased SP levels of both tissues were observed in 40-day, compared to 27-day old rats.

  20. [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.

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

    PubMed Central

    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. PMID:27403445

  2. Effect of low-dose cadmium exposure on DNA methylation in the endangered European eel.

    PubMed

    Pierron, Fabien; Baillon, Lucie; Sow, Mohamedou; Gotreau, Salomé; Gonzalez, Patrice

    2014-01-01

    There is increasing evidence that epigenetics can play a key role in the etiology of diseases engendered by chronic pollutant exposure. Although epigenetics has received significant attention in the field of biomedicine during the last years, epigenetics research is surprisingly very limited in ecotoxicology. The aim of the present study was to investigate the possible effects of low-dose cadmium exposure on the DNA methylation profile in a critically endangered fish species, the European eel. Eels were exposed to environmentally realistic concentrations of cadmium (0.4 and 4 μg·L(-1)) during 45 days. The global CpG methylation status of eel liver was determined by means of a homemade ELISA assay. We then used a methylation-sensitive arbitrarily primed PCR method to identify genes that are differentially methylated between control and Cd-exposed eels. Our results show that cadmium exposure is associated with DNA hypermethylation and with a decrease in total RNA synthesis. Among hypermethylated sequences identified, several fragments presented high homologies with genes encoding for proteins involved in intracellular trafficking, lipid biosynthesis, and phosphatidic acid signaling pathway. In addition, few fragments presented high homologies with retrotransposon-like sequences. Our study illustrates how DNA methylation can be involved in the chronic stress response to Cd in fish. PMID:24328039

  3. Low-dose exposure to inorganic mercury accelerates disease and mortality in acquired murine lupus.

    PubMed

    Via, Charles S; Nguyen, Phuong; Niculescu, Florin; Papadimitriou, John; Hoover, Dennis; Silbergeld, Ellen K

    2003-08-01

    Inorganic mercury (iHg) is known to induce autoimmune disease in susceptible rodent strains. Additionally, in inbred strains of mice prone to autoimmune disease, iHg can accelerate and exacerbate disease manifestations. Despite these well-known links between iHg and autoimmunity in animal models, no association between iHg alone and autoimmune disease in humans has been documented. However, it is possible that low-level iHg exposure can interact with disease triggers to enhance disease expression or susceptibility. To address whether exposure to iHg can alter the course of subsequent acquired autoimmune disease, we used a murine model of acquired autoimmunity, lupus-like chronic graft-versus-host disease (GVHD), in which autoimmunity is induced using normal, nonautoimmune prone donor and F1 recipient mice resistant to Hg-induced autoimmunity. Our results indicate that a 2-week exposure to low-dose iHg (20 or 200 micro g/kg every other day) to donor and host mice ending 1 week before GVHD induction can significantly worsen parameters of disease severity, resulting in premature mortality. iHg pretreatment clearly worsened chronic lupus-like disease, rather than GVHD worsening iHg immunotoxicity. These results are consistent with the hypothesis that low-level, nontoxic iHg preexposure may interact with other risk factors, genetic or acquired, to promote subsequent autoimmune disease development.

  4. Changes in thyroid status of rats after prolonged exposure to low dose dichlorodiphenyltrichloroethane.

    PubMed

    Yaglova, N V; Yaglov, V V

    2014-04-01

    The effect of low dose dichlorodiphenyltrichloroethane (DDT), omnipresent ecotoxicant and endocrine disruptor, on the functioning of the endocrine system is an urgent problem. We studied the effect of low dose DDT on thyroid status in rats. Rats receiving DDT in a dose of 1.890±0.086 μg/kg for 6 weeks showed increased concentrations of thyroid hormones, particularly triiodothyronine, and reduced level of thyrotropin. Longer exposure reduced the production of thyroid hormones. The dynamics of thyroid status parameters during DDT treatment in a low dose was similar to changes observed during the development of hypothyroidism induced by iodine deficiency. PMID:24824690

  5. Radon Exposure and the Definition of Low Doses-The Problem of Spatial Dose Distribution.

    PubMed

    Madas, Balázs G

    2016-07-01

    Investigating the health effects of low doses of ionizing radiation is considered to be one of the most important fields in radiological protection research. Although the definition of low dose given by a dose range seems to be clear, it leaves some open questions. For example, the time frame and the target volume in which absorbed dose is measured have to be defined. While dose rate is considered in the current system of radiological protection, the same cancer risk is associated with all exposures, resulting in a given amount of energy absorbed by a single target cell or distributed among all the target cells of a given organ. However, the biological effects and so the health consequences of these extreme exposure scenarios are unlikely to be the same. Due to the heterogeneous deposition of radon progeny within the lungs, heterogeneous radiation exposure becomes a practical issue in radiological protection. While the macroscopic dose is still within the low dose range, local tissue doses on the order of Grays can be reached in the most exposed parts of the bronchial airways. It can be concluded that progress in low dose research needs not only low dose but also high dose experiments where small parts of a biological sample receive doses on the order of Grays, while the average dose over the whole sample remains low. A narrow interpretation of low dose research might exclude investigations with high relevance to radiological protection. Therefore, studies important to radiological protection should be performed in the frame of low dose research even if the applied doses do not fit in the dose range used for the definition of low doses. PMID:27218294

  6. Radon Exposure and the Definition of Low Doses-The Problem of Spatial Dose Distribution.

    PubMed

    Madas, Balázs G

    2016-07-01

    Investigating the health effects of low doses of ionizing radiation is considered to be one of the most important fields in radiological protection research. Although the definition of low dose given by a dose range seems to be clear, it leaves some open questions. For example, the time frame and the target volume in which absorbed dose is measured have to be defined. While dose rate is considered in the current system of radiological protection, the same cancer risk is associated with all exposures, resulting in a given amount of energy absorbed by a single target cell or distributed among all the target cells of a given organ. However, the biological effects and so the health consequences of these extreme exposure scenarios are unlikely to be the same. Due to the heterogeneous deposition of radon progeny within the lungs, heterogeneous radiation exposure becomes a practical issue in radiological protection. While the macroscopic dose is still within the low dose range, local tissue doses on the order of Grays can be reached in the most exposed parts of the bronchial airways. It can be concluded that progress in low dose research needs not only low dose but also high dose experiments where small parts of a biological sample receive doses on the order of Grays, while the average dose over the whole sample remains low. A narrow interpretation of low dose research might exclude investigations with high relevance to radiological protection. Therefore, studies important to radiological protection should be performed in the frame of low dose research even if the applied doses do not fit in the dose range used for the definition of low doses.

  7. Oral and Conjunctival Exposure of Nonhuman Primates to Low Doses of Ebola Makona Virus

    PubMed Central

    Mire, Chad E.; Geisbert, Joan B.; Agans, Krystle N.; Deer, Daniel J.; Fenton, Karla A.; Geisbert, Thomas W.

    2016-01-01

    Nonhuman primate (NHP) models of Ebola virus (EBOV) infection primarily use parenteral or aerosol routes of exposure. Uniform lethality can be achieved in these models at low doses of EBOV (≤100 plaque-forming units [PFU]). Here, we exposed NHPs to low doses of EBOV (Makona strain) by the oral or conjunctival routes. Surprisingly, animals exposed to 10 PFU by either route showed no signs of disease. Exposure to 100 PFU resulted in illness and/or lethal infection. These results suggest that these more natural routes require higher doses of EBOV to produce disease or that there may be differences between Makona and historical strains. PMID:27284090

  8. 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.

  9. 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

  10. 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...

  11. Low Dose Prenatal Alcohol Exposure Does Not Impair Spatial Learning and Memory in Two Tests in Adult and Aged Rats

    PubMed Central

    Cullen, Carlie L.; Burne, Thomas H. J.; Lavidis, Nickolas A.; Moritz, Karen M.

    2014-01-01

    Consumption of alcohol during pregnancy can have detrimental impacts on the developing hippocampus, which can lead to deficits in learning and memory function. Although high levels of alcohol exposure can lead to severe deficits, there is a lack of research examining the effects of low levels of exposure. This study used a rat model to determine if prenatal exposure to chronic low dose ethanol would result in deficits in learning and memory performance and if this was associated with morphological changes within the hippocampus. Sprague Dawley rats were fed a liquid diet containing 6% (vol/vol) ethanol (EtOH) or an isocaloric control diet throughout gestation. Male and Female offspring underwent behavioural testing at 8 (Adult) or 15 months (Aged) of age. Brains from these animals were collected for stereological analysis of pyramidal neuron number and dendritic morphology within the CA1 and CA3 regions of the dorsal hippocampus. Prenatal ethanol exposed animals did not differ in spatial learning or memory performance in the Morris water maze or Y maze tasks compared to Control offspring. There was no effect of prenatal ethanol exposure on pyramidal cell number or density within the dorsal hippocampus. Overall, this study indicates that chronic low dose prenatal ethanol exposure in this model does not have long term detrimental effects on pyramidal cells within the dorsal hippocampus or impair spatial learning and memory performance. PMID:24978807

  12. 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

  13. 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.

  14. Perinatal exposure to low-dose methoxychlor impairs testicular development in C57BL/6 mice.

    PubMed

    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.

  15. 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

  16. Inherited effects of low-dose exposure to methylmercury in neural stem cells.

    PubMed

    Bose, Raj; Onishchenko, Natalia; Edoff, Karin; Janson Lang, Ann Marie; Ceccatelli, Sandra

    2012-12-01

    Methylmercury (MeHg) is an environmental contaminant with recognized neurotoxic effects, particularly to the developing nervous system. In the present study, we show that nanomolar concentrations of MeHg can induce long-lasting effects in neural stem cells (NSCs). We investigated short-term direct and long-term inherited effects of exposure to MeHg (2.5 or 5.0 nM) using primary cultures of rat embryonic cortical NSCs. We found that MeHg had no adverse effect on cell viability but reduced NSC proliferation and altered the expression of cell cycle regulators (p16 and p21) and senescence-associated markers. In addition, we demonstrated a decrease in global DNA methylation in the exposed cells, indicating that epigenetic changes may be involved in the mechanisms underlying the MeHg-induced effects. These changes were observed in cells directly exposed to MeHg (parent cells) and in their daughter cells cultured under MeHg-free conditions. In agreement with our in vitro data, a trend was found for decreased cell proliferation in the subgranular zone in the hippocampi of adult mice exposed to low doses of MeHg during the perinatal period. Interestingly, this impaired proliferation had a measurable impact on the total number of neurons in the hippocampal dentate gyrus. Importantly, this effect could be reversed by chronic antidepressant treatment. Our study provides novel evidence for programming effects induced by MeHg in NSCs and supports the idea that developmental exposure to low levels of MeHg may result in long-term consequences predisposing to neurodevelopmental disorders and/or neurodegeneration.

  17. 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.

  18. Radiation-Induced Bystander Effects: Evidence for an Adaptive Response to Low Dose Exposures?

    PubMed Central

    Mothersill, Carmel; Seymour, Colin

    2006-01-01

    This paper reviews our current knowledge of the mechanisms underlying the induction of bystander effects by low dose, low-LET ionizing radiation and discusses how they may be related to observed adaptive responses or other protective effects of low dose exposures. Bystander effects appear to be the result of a generalized stress response in tissues or cells. The signals may be produced by all exposed cells, but the response appears to require a quorum in order to be expressed. The major response involving low LET radiation exposure discussed in the existing literature is a death response. This has many characteristics of apoptosis but is p53 independent. While a death response might appear to be adverse, the position is argued in this paper that it is in fact protective and removes damaged cells from the population. Since many cell populations carry damaged cells without being exposed to radiation, so called “background damage”, it is possible that low doses exposures cause removal of cells damaged by agents other than the test dose of radiation. This mechanism would lead to the production of “U-shaped” dose response curves. In this scenario, the level of “adaptive” or beneficial response will be related to the background damage carried by the cell population. This model may be important when attempting to predict the consequences of mixed exposures involving radiation and other environmental stressors. PMID:18648593

  19. 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

  20. Low-dose ethanol consumption allows strength recovery in chronic alcoholic myopathy.

    PubMed

    Fernández-Solà, J; Nicolás, J M; Sacanella, E; Robert, J; Cofan, M; Estruch, R; Urbano-Márquez, A

    2000-01-01

    Chronic skeletal myopathy may affect one third of chronic alcohol misusers. It is generally accepted that abstinence allows partial recovery, and that continued high-dose ethanol consumption progressively deteriorates muscle function. However, the effect of low-dose ethanol consumption in alcoholic myopathy has not been studied. We studied 58 chronic alcoholic male patients with biopsy-proven chronic alcoholic myopathy over 5 years. We evaluated ethanol intake, biochemical and nutritional parameters, and assessed muscle strength. Eighteen patients who remained abstinent showed marked improvement in muscle strength. As expected, the 19 patients who persisted in high-dose ethanol consumption further diminished in their muscle strength. In the 11 patients who maintained low-dose (

  1. In utero exposure to low dose arsenic via drinking water impairs early life lung mechanics in mice

    PubMed Central

    2013-01-01

    Background Exposure to arsenic via drinking water is a significant environmental issue affecting millions of people around the world. Exposure to arsenic during foetal development has been shown to impair somatic growth and increase the risk of developing chronic respiratory diseases. The aim of this study was to determine if in utero exposure to low dose arsenic via drinking water is capable of altering lung growth and postnatal lung mechanics. Methods Pregnant C57BL/6 mice were given drinking water containing 0, 10 (current World Health Organisation (WHO) maximum contaminant level) or 100μg/L arsenic from gestational day 8 to birth. Birth outcomes and somatic growth were monitored. Plethysmography and the forced oscillation technique were used to collect measurements of lung volume, lung mechanics, pressure-volume curves and the volume dependence of lung mechanics in male and female offspring at two, four, six and eight weeks of age. Results In utero exposure to low dose arsenic via drinking water resulted in low birth weight and impaired parenchymal lung mechanics during infancy. Male offspring were more susceptible to the effects of arsenic on growth and lung mechanics than females. All alterations to lung mechanics following in utero arsenic exposure were recovered by adulthood. Conclusions Exposure to arsenic at the current WHO maximum contaminant level in utero impaired somatic growth and the development of the lungs resulting in alterations to lung mechanics during infancy. Deficits in growth and lung development in early life may contribute to the increased susceptibility of developing chronic respiratory disease in arsenic exposed human populations. PMID:23419080

  2. Mitochondrial hormesis links low-dose arsenite exposure to lifespan extension

    PubMed Central

    Schmeisser, Sebastian; Schmeisser, Kathrin; Weimer, Sandra; Groth, Marco; Priebe, Steffen; Fazius, Eugen; Kuhlow, Doreen; Pick, Denis; Einax, Jürgen W; Guthke, Reinhard; Platzer, Matthias; Zarse, Kim; Ristow, Michael

    2013-01-01

    Arsenite is one of the most toxic chemical substances known and is assumed to exert detrimental effects on viability even at lowest concentrations. By contrast and unlike higher concentrations, we here find that exposure to low-dose arsenite promotes growth of cultured mammalian cells. In the nematode C. elegans, low-dose arsenite promotes resistance against thermal and chemical stressors and extends lifespan of this metazoan, whereas higher concentrations reduce longevity. While arsenite causes a transient increase in reactive oxygen species (ROS) levels in C. elegans, co-exposure to ROS scavengers prevents the lifespan-extending capabilities of arsenite, indicating that transiently increased ROS levels act as transducers of arsenite effects on lifespan, a process known as mitohormesis. This requires two transcription factors, namely DAF-16 and SKN-1, which employ the metallothionein MTL-2 as well as the mitochondrial transporter TIN-9.1 to extend lifespan. Taken together, low-dose arsenite extends lifespan, providing evidence for nonlinear dose-response characteristics of toxin-mediated stress resistance and longevity in a multicellular organism. PMID:23534459

  3. In silico modeling of spore inhalation reveals fungal persistence following low dose exposure

    PubMed Central

    Tanaka, Reiko J.; Boon, Neville J.; Vrcelj, Katarina; Nguyen, Anita; Vinci, Carmelina; Armstrong-James, Darius; Bignell, Elaine

    2015-01-01

    The human lung is constantly exposed to spores of the environmental mould Aspergillus fumigatus, a major opportunistic pathogen. The spectrum of resultant disease is the outcome of complex host-pathogen interactions, an integrated, quantitative understanding of which lies beyond the ethical and technical reach permitted by animal studies. Here we construct a mathematical model of spore inhalation and clearance by concerted actions of macrophages and neutrophils, and use it to derive a mechanistic understanding of pathogen clearance by the healthy, immunocompetent host. In particular, we investigated the impact of inoculum size upon outcomes of single-dose fungal exposure by simulated titrations of inoculation dose, from 106 to 102 spores. Simulated low-dose (102) spore exposure, an everyday occurrence for humans, revealed a counter-intuitive prediction of fungal persistence (>3 days). The model predictions were reflected in the short-term dynamics of experimental murine exposure to fungal spores, thereby highlighting the potential of mathematical modelling for studying relevant behaviours in experimental models of fungal disease. Our model suggests that infectious outcomes can be highly dependent upon short-term dynamics of fungal exposure, which may govern occurrence of cyclic or persistent subclinical fungal colonisation of the lung following low dose spore inhalation in non-neutropenic hosts. PMID:26364644

  4. 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.

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

    PubMed

    Camarata, Andrew S; Switchenko, Jeffrey M; Demidenko, Eugene; Flood, Ann B; Swartz, Harold M; Ali, Arif N

    2016-04-01

    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 the 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

  6. Consequences of low dose ionizing radiation exposure on the hippocampal microenvironment.

    PubMed

    Acharya, Munjal M; Patel, Neal H; Craver, Brianna M; Tran, Katherine K; Giedzinski, Erich; Tseng, Bertrand P; Parihar, Vipan K; Limoli, Charles L

    2015-01-01

    The response of the brain to irradiation is complex, involving a multitude of stress inducible pathways that regulate neurotransmission within a dynamic microenvironment. While significant past work has detailed the consequences of CNS radiotherapy following relatively high doses (≥ 45 Gy), few studies have been conducted at much lower doses (≤ 2 Gy), where the response of the CNS (like many other tissues) may differ substantially from that expected from linear extrapolations of high dose data. Low dose exposure could elicit radioadaptive modulation of critical CNS processes such as neurogenesis, that provide cellular input into hippocampal circuits known to impact learning and memory. Here we show that mice deficient for chemokine signaling through genetic disruption of the CCR2 receptor exhibit a neuroprotective phenotype. Compared to wild type (WT) animals, CCR2 deficiency spared reductions in hippocampal neural progenitor cell survival and stabilized neurogenesis following exposure to low dose irradiation. While radiation-induced changes in microglia levels were not found in WT or CCR2 deficient animals, the number of Iba1+ cells did differ between each genotype at the higher dosing paradigms, suggesting that blockade of this signaling axis could moderate the neuroinflammatory response. Interestingly, changes in proinflammatory gene expression were limited in WT animals, while irradiation caused significant elevations in these markers that were attenuated significantly after radioadaptive dosing paradigms in CCR2 deficient mice. These data point to the importance of chemokine signaling under low dose paradigms, findings of potential significance to those exposed to ionizing radiation under a variety of occupational and/or medical scenarios.

  7. Lifetime exposure to low doses of lead in rats: effect on selected parameters of carbohydrate metabolism.

    PubMed

    Nováková, Jaroslava; Lukačínová, Agnesa; Lovásová, Eva; Cimboláková, Iveta; Rácz, Oliver; Ništiar, František

    2015-05-01

    The aim of the study was to assess the effects of exposure to low doses of lead dissolved in drinking water (average daily dose of 2.2 mg kg(-1) day(-1)) on selected carbohydrate metabolism parameters in 20 wistar rats. Animals were divided into two groups - control (C) (group drinking clear water) and experimental group (Pb; group exposed to low doses of lead acetate in a concentration of 100 μmol l(-1) of drinking water). In this study, we studied the biochemical parameters (glucose, haemoglobin (Hb), glycated haemoglobin (HbA1c), lactate dehydrogenase (LDH) and amylase (AMS)) in rat blood. Glucose and Hb concentration and AMS activity decreased, LDH activity increased but HbA1c concentration levels did not change in rats exposed to lead. Our results well documented that lifetime exposure to lead affected carbohydrate metabolism of rats. Some parameters like concentration of Hb as well as activities of AMS and LDH are useful markers of intoxication of rats with lead. For the evaluation of results (e.g. AMS), not only the data at the end of the experiment should be taken into account but also the entire duration of trials (i.e. more time steps) that makes results more objective should be considered.

  8. 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

  9. 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. PMID:26106144

  10. [Radiation situation prognosis for deep space: reactions of water and living systems to chronic low-dose ionizing irradiation].

    PubMed

    Ushakov, I B; Tsetlin, V V; Moisa, S S

    2013-01-01

    The authors review the findings of researches into the effects of low-dose ionizing irradiation on diverse biological objects (embryonic Japanese quails, Aspergillus niger, Spirostomum ambiguum Ehrbg., mesenchymal stem cells from mouse marrow, dry higher plants seeds, blood lymphocytes from pilots and cosmonauts). Model experiments with chronic exposure to ionizing radiation doses comparable with the measurements inside orbital vehicles and estimations for trips through the interplanetary space resulted in morphological disorders (embryonic Japanese quails, Aspergillus niger), radiation hormesis (Aspergillus niger, MSCs from mouse marrow), increase in the seed germination rate, inhibition of Spirostomum spontaneous activity, DNA damages, chromosomal aberrations, and increase of the blood lymphocytes reactivity to additional radiation loading. These facts give grounds to assume that the crucial factor in the radiation outcomes is changes in liquid medium. In other words, during extended orbiting within the magnetosphere region and interplanetary missions ionizing radiation affects primarily liquids of organism and, secondarily, its morphofunctional structures. PMID:23700619

  11. [Radiation situation prognosis for deep space: reactions of water and living systems to chronic low-dose ionizing irradiation].

    PubMed

    Ushakov, I B; Tsetlin, V V; Moisa, S S

    2013-01-01

    The authors review the findings of researches into the effects of low-dose ionizing irradiation on diverse biological objects (embryonic Japanese quails, Aspergillus niger, Spirostomum ambiguum Ehrbg., mesenchymal stem cells from mouse marrow, dry higher plants seeds, blood lymphocytes from pilots and cosmonauts). Model experiments with chronic exposure to ionizing radiation doses comparable with the measurements inside orbital vehicles and estimations for trips through the interplanetary space resulted in morphological disorders (embryonic Japanese quails, Aspergillus niger), radiation hormesis (Aspergillus niger, MSCs from mouse marrow), increase in the seed germination rate, inhibition of Spirostomum spontaneous activity, DNA damages, chromosomal aberrations, and increase of the blood lymphocytes reactivity to additional radiation loading. These facts give grounds to assume that the crucial factor in the radiation outcomes is changes in liquid medium. In other words, during extended orbiting within the magnetosphere region and interplanetary missions ionizing radiation affects primarily liquids of organism and, secondarily, its morphofunctional structures.

  12. 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.

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

    SciTech Connect

    Hunt, W.A.; Joseph, J.A.; Rabin, B.M.

    1989-01-01

    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.

  14. Prenatal exposure to low doses of atrazine affects mating behaviors in male guppies.

    PubMed

    Shenoy, Kausalya

    2014-07-01

    Performing appropriate mating behaviors is crucial to male reproductive success, especially in species where mating is predominantly via female mate choice. Mating behaviors are hormonally regulated and may be sexually selected traits: courtship displays are selected via mate choice, while forced copulations and aggressive behaviors are selected for via intrasexual competition. Endocrine disrupting compounds interfere with proper hormonal functioning in exposed animals. Exposures during developmentally crucial life stages can have irreversible effects lasting through adulthood. I tested the effects of prenatal exposure to environmentally relevant doses of a commonly used herbicide, atrazine (1 and 13.5μg/L) on mating behaviors in male guppies. Guppies were used as a model organism to test the effects of atrazine exposure on wildlife reproductive health. Adult female guppies were mated and exposed to the treatments throughout the gestation period, and offspring born to them were raised without further treatment. At adulthood, the males were tested for the effects of prenatal exposure on their mating behaviors such as courtship displays, gonopodium swings, forced copulatory attempts, and competitive and aggressive behaviors towards rivals who were not exposed to atrazine. I also tested female preference for treated males compared to control males. Atrazine-exposed males were less likely to perform the mating behaviors, and performed them less frequently, than control males. Atrazine exposure also made males less aggressive towards rivals. Females preferred untreated males over atrazine-treated males. In all cases, a non-monotonic pattern was seen, highlighting the significance of low-dose exposures.

  15. Effects of Low-Dose Diethylstilbestrol Exposure on DNA Methylation in Mouse Spermatocytes

    PubMed Central

    Yin, Li; Zheng, Li-juan; Jiang, Xiao; Liu, Wen-bin; Han, Fei; Cao, Jia; Liu, Jin-yi

    2015-01-01

    Evidence from previous studies suggests that the male reproductive system can be disrupted by fetal or neonatal exposure to diethylstilbestrol (DES). However, the molecular basis for this effect remains unclear. To evaluate the effects of DES on mouse spermatocytes and to explore its potential mechanism of action, the levels of DNA methyltransferases (DNMTs) and DNA methylation induced by DES were detected. The results showed that low doses of DES inhibited cell proliferation and cell cycle progression and induced apoptosis in GC-2 cells, an immortalized mouse pachytene spermatocyte-derived cell line, which reproduces primary cells responses to E2. Furthermore, global DNA methylation levels were increased and the expression levels of DNMTs were altered in DES-treated GC-2 cells. A total of 141 differentially methylated DNA sites were detected by microarray analysis. Rxra, an important component of the retinoic acid signaling pathway, and mybph, a RhoA pathway-related protein, were found to be hypermethylated, and Prkcd, an apoptosis-related protein, was hypomethylated. These results showed that low-dose DES was toxic to spermatocytes and that DNMT expression and DNA methylation were altered in DES-exposed cells. Taken together, these data demonstrate that DNA methylation likely plays an important role in mediating DES-induced spermatocyte toxicity in vitro. PMID:26588706

  16. 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

  17. 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

  18. Investigations of putative reproductive toxicity of low-dose exposures to flutamide in Wistar rats.

    PubMed

    Fussell, Karma C; Schneider, Steffen; Buesen, Roland; Groeters, Sibylle; Strauss, Volker; Melching-Kollmuss, Stephanie; van Ravenzwaay, Bennard

    2015-12-01

    The current investigation examines whether the model anti-androgenic substance flutamide is capable of disrupting endocrine homeostasis at very low doses. The data generated clarify whether a non-monotonic dose-response relationship exists to enhance the current debate about the regulation of endocrine disruptors. Moreover, it is part of a series of investigations assessing the dose-response relationship of single and combined administration of anti-androgenic substances. A pre-postnatal in vivo study design was chosen, which was compliant with regulatory testing protocols. The test design was improved by additional endpoints addressing hormone levels, morphology, and histopathological examinations. Doses were chosen to represent a clear effect level (2.5 mg/kg bw/d), a low endocrine effect level (LOAEL, 0.25 mg/kg bw/d), a NOAEL for endocrine effects (0.025 mg/kg bw/d), a further dose at 0.0025 mg/kg bw/d flutamide, as well as an "ADI" (0.00025 mg/kg bw/d or 100-fold below the NOAEL) for the detection of a possible non-monotonic dose-response curve. Anti-androgenic changes were observable at LOAEL and the clear effect dose level but not at lower exposures. Nipple retention appeared to be the most sensitive measure of anti-androgenic effects, followed by age at sexual maturation, anogenital distance/anogenital index and male sex organ weights, as well as gross and histopathological findings. The results of all five doses indicate the absence of evidence for effects at very low dose levels. A non-monotonic dose-response relationship was not evident for the anti-androgenic drug flutamide. PMID:26525394

  19. Investigations of putative reproductive toxicity of low-dose exposures to flutamide in Wistar rats.

    PubMed

    Fussell, Karma C; Schneider, Steffen; Buesen, Roland; Groeters, Sibylle; Strauss, Volker; Melching-Kollmuss, Stephanie; van Ravenzwaay, Bennard

    2015-12-01

    The current investigation examines whether the model anti-androgenic substance flutamide is capable of disrupting endocrine homeostasis at very low doses. The data generated clarify whether a non-monotonic dose-response relationship exists to enhance the current debate about the regulation of endocrine disruptors. Moreover, it is part of a series of investigations assessing the dose-response relationship of single and combined administration of anti-androgenic substances. A pre-postnatal in vivo study design was chosen, which was compliant with regulatory testing protocols. The test design was improved by additional endpoints addressing hormone levels, morphology, and histopathological examinations. Doses were chosen to represent a clear effect level (2.5 mg/kg bw/d), a low endocrine effect level (LOAEL, 0.25 mg/kg bw/d), a NOAEL for endocrine effects (0.025 mg/kg bw/d), a further dose at 0.0025 mg/kg bw/d flutamide, as well as an "ADI" (0.00025 mg/kg bw/d or 100-fold below the NOAEL) for the detection of a possible non-monotonic dose-response curve. Anti-androgenic changes were observable at LOAEL and the clear effect dose level but not at lower exposures. Nipple retention appeared to be the most sensitive measure of anti-androgenic effects, followed by age at sexual maturation, anogenital distance/anogenital index and male sex organ weights, as well as gross and histopathological findings. The results of all five doses indicate the absence of evidence for effects at very low dose levels. A non-monotonic dose-response relationship was not evident for the anti-androgenic drug flutamide.

  20. Exposure to low doses of endosulfan and chlorpyrifos modifies endogenous antioxidants in tissues of rats.

    PubMed

    Bebe, Frederick N; Panemangalore, Myna

    2003-05-01

    Two experiments were conducted in male SD rats (225-250 g) to determine changes in the activities of endogenous antioxidants superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and concentrations of glutathione (GSH) in tissues after exposure to low doses of endosulfan and chlorpyrifos using a whole body exposure technique. In both experiments, 6 rats/group were exposed 3 hr/day, 5 days/week for 30 days to: 0 (control), 5, 10, 20, 40 and 60% of LD50 of either pesticide in 50% ethanol; actual concentrations were: endosulfan = 0, 0.5, 1.0, 2.0, 4.0, 6.0 mg/250 g body weight; chlorpyrifos = 0, 1.9, 3.8, 7.6, 15.2, and 22.8 mg/250 g body weight. Endosulfan decreased erythrocyte SOD by 21% in all groups and chlorpyrifos increased SOD by 18% in groups 40 and 60. Liver SOD was 12%-20% lower after endosulfan exposure; lung SOD was altered: endosulfan decreased activity by 21% and 51% and chlorpyrifos by 58 and 75% in the 40 and 60 groups, respectively (P < or = 0.05). Both pesticides increased plasma GPX activity at lower levels and reduced it by 26% and 19% in groups 40 and 60, respectively (P < or = 0.05). Liver GPX increased in the 60 group and lung GPX declined between 20% and 38% after endosulfan exposure. GSH in the liver and lung: endosulfan reduced GSH by about 30% at lower levels and increased by 41% or 70% at higher levels; chlorpyrifos decreased GSH by 28-40% in 20 and 60 groups, respectively (P < or = 0.05). Exposure to low, increasing levels of endosulfan and chlorpyrifos can differentially modify endogenous antioxidants SOD, GPX and GSH, which may lead to the development of oxidative stress in some tissues.

  1. Perinatal exposure to low doses of tributyltin chloride reduces sperm count and quality in mice.

    PubMed

    Si, Jiliang; Li, Peng; Xin, Quanbing; Li, Xuewen; An, Lihong; Li, Jie

    2015-01-01

    Exposure to endocrine disruptors (EDs) during early development might lead to adverse health outcomes later in life. Tributyltin (TBT), a proven ED, is widely used in consumer goods and industrial products. Herein we demonstrate the effects of low doses of tributyltin chloride (TBTCl) on reproduction of male KM mice. Pregnant mice were administered by gavage with 0, 1, 10, or 100 μg TBTCl/kg body weight/day from day 6 of pregnancy through the period of lactation. TBTCl dramatically decreased sperm counts and motility on postnatal days (PNDs) 49 and 152. Meanwhile, a significant increase in sperm abnormality was observed in exposed mice on PND 49, but comparable to that in the control on PND 152. The histopathological analysis of testes of treated animals showed a dose-dependent increase in sloughing of germ cells in seminiferous tubules. Mice treated with 10 μg TBTCl/kg exhibited decreased intratesticular 17β-estradiol (E2) levels on PND 49, and then followed by an obvious recovery on PND 152. While, no significant differences in serum E2, testosterone (T) levels and intratesticular T levels were detectable between control and TBTCl-exposed offspring at the sacrifice. These results suggest that perinatal TBTCl exposure is implicated in causing long lasting alterations in male reproductive system and these changes may persist far into adulthood.

  2. 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.

  3. 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

  4. 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

  5. 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...

  6. Murine neocortical histogenesis is perturbed by prenatal exposure to low doses of Bisphenol A.

    PubMed

    Nakamura, Keiko; Itoh, Kyoko; Yaoi, Takeshi; Fujiwara, Yasuhiro; Sugimoto, Tohru; Fushiki, Shinji

    2006-11-01

    Bisphenol A (BPA) has been shown to disrupt thyroid hormone function. We therefore studied whether prenatal exposure to low-doses of BPA affects the morphology and the expression of some genes related to brain development in the murine fetal neocortex. Pregnant mice were injected subcutaneously with 20 microg/kg of BPA daily from embryonic day 0 (E0). Control animals received vehicle alone. For evaluating cell proliferation, neuronal differentiation and migration, bromodeoxyuridine (BrdU) was injected intraperitoneally into pregnant mice with various regimens and the brains were processed for immunohistochemistry. The total RNA was extracted from the embryonic telencephalon at various embryonic stages. The BrdU-labeled cells examined 1 hour after BrdU injection showed no differences between the BPA-treated and control groups (n = 10, each), which indicated that the proliferation of precursor cells was not affected. The BrdU-labeled cells, analysed 2 days after BrdU injection, were decreased in the ventricular zone of BPA-treated mice at E14.5 and E16.5, whereas they were increased in the cortical plate at E14.5 as compared with those in control mice (n = 10, each). Furthermore, the expression of Math3, Ngn2, Hes1, LICAM, and THRalpha was significantly upregulated at E14.5 in the BPA-treated group. These results suggested that BPA might disrupt normal neocortical development by accelerating neuronal differentiation/migration. PMID:16902998

  7. 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.

  8. 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.

  9. 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. PMID:25611260

  10. 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

  11. Low dose alpha interferon therapy can be effective in chronic active hepatitis C. Results of a multicentre, randomised trial.

    PubMed Central

    Sánchez-Tapias, J M; Forns, X; Ampurdanés, S; Titó, L; Planas, R; Viver, J M; Acero, D; Torres, M; Mas, P; Morillas, R; Forné, M; Espinós, J; Llovet, J M; Costa, J; Olmedo, E; López-Labrador, F X; Jiménez de Anta, M T; Rodés, J

    1996-01-01

    BACKGROUND--There is some controversy concerning the efficacy of low dose alpha interferon therapy in chronic hepatitis C. AIMS--To evaluate the effectiveness of treatment with low doses of alpha interferon in chronic hepatitis C. PATIENTS--One hundred and forty one patients with anti-HCV positive chronic active hepatitis C from six hospitals were enrolled in the study. METHODS--Patients were randomised to treatment with 5 MU (group A) or 1.5 MU (group B) injections. The dose was reduced in responders from group A or increased in non-responders from group B to maintain treatment with the minimal effective dose. Patients were treated for 48 weeks and followed up for 24 additional weeks with no treatment. Normalisation of alanine aminotransferase (ALT) was used to evaluate response. RESULTS--A sustained response was seen in eight patients from group A (12%) and in 15 (21%) from group B. This difference was not statistically significant. Increasing the dose of interferon led to sustained response in only five of 58 patients (9%) from group B who did not respond to 1.5 MU injections. In contrast, 15 of 21 patients (71%) in whom ALT remained normal with 1.5 MU injections developed a sustained response. By multivariate analysis sustained response seemed associated with young age and was more frequent in patients with genotype 3 HCV infection. Sustained response was preceded by a rapid normalisation of ALT and was inversely related to the amount of alpha interferon necessary to maintain ALT at low values during treatment. CONCLUSIONS--Some patients with chronic hepatitis C are very sensitive to alpha interferon and can be successfully treated with low doses. Treatment with higher doses may be effective in a minority of patients who do not respond to low doses. PMID:8707096

  12. 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.

  13. 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.

  14. 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.

  15. Characterization of potential endocrine-related health effects at low-dose levels of exposure to PCBs.

    PubMed Central

    Brouwer, A; Longnecker, M P; Birnbaum, L S; Cogliano, J; Kostyniak, P; Moore, J; Schantz, S; Winneke, G

    1999-01-01

    This article addresses issues related to the characterization of endocrine-related health effects resulting from low-level exposures to polychlorinated biphenyls (PCBs). It is not intended to be a comprehensive review of the literature but reflects workshop discussions. "The Characterizing the Effects of Endocrine Disruptors on Human Health at Environmental Exposure Levels," workshop provided a forum to discuss the methods and data needed to improve risk assessments of endocrine disruptors. This article contains an overview of endocrine-related (estrogen and thyroid system) interactions and other low-dose effects of PCBs. The data set on endocrine effects includes results obtained from mechanistic methods/ and models (receptor based, metabolism based, and transport protein based), as well as from (italic)in vivo(/italic) models, including studies with experimental animals and wildlife species. Other low-dose effects induced by PCBs, such as neurodevelopmental and reproductive effects and endocrine-sensitive tumors, have been evaluated with respect to a possible causative linkage with PCB-induced alterations in endocrine systems. In addition, studies of low-dose exposure and effects in human populations are presented and critically evaluated. A list of conclusions and recommendations is included. PMID:10421775

  16. 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

  17. 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.

  18. 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. PMID:26106142

  19. 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.

  20. 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

  1. 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.

  2. 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

  3. 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. PMID:26687398

  4. 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.

  5. 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...

  6. 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.

  7. 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

  8. Low-dose laser acupuncture for non-specific chronic low back pain: a double-blind randomised controlled trial

    PubMed Central

    Glazov, Gregory; Yelland, Michael; Emery, Jon

    2014-01-01

    Objective To determine if infrared laser acupuncture (LA) may have a specific effect in reducing pain and disability in treatment of chronic low back pain (LBP). Methods This was a double-blind sham laser controlled trial performed in general practices in Perth, Western Australia. The participants were 144 adults with chronic non-specific LBP. They were randomised to receive eight once-weekly treatments. Laser machines (20 mW, 840 nm diode, power density 0.1 W/cm2) stimulated points in three treatment groups: sham (0 joules/point), low dose (0.2 J/point) and high dose (0.8 joules/point). Participants were followed-up at 1 and 6 weeks, and 6 and 12 months post treatment. Primary outcomes were pain (Numerical Pain Rating Scale (NPRS)) and disability (Oswestry Disability Inventory (ODI)) at 6 weeks post treatment. Secondary outcomes included numerical rating scale for limitation of activity, global assessment of improvement, analgesic usage and adverse effects after treatment. Results The analysis showed no difference between sham and the laser groups at 6 weeks for pain or disability. There was a significant reduction in mean pain and disability in all groups at 6 weeks (p<0.005); NPRS: sham (−1.5 (95% CI −2.1 to −0.8)), low dose (−1.3 (−2.0 to −0.8)), high dose (−1.1 (−1.7 to −0.5)). ODI: sham (−4.0 (−7.1 to −1.0)), low dose (−4.1, (−6.7 to −1.5)), high dose (−2.6 (−5.7 to 0.5)). All secondary outcomes also showed clinical improvement over time but with no differences between groups. Conclusions LA using energy density range (0–4 J/cm2) for the treatment of chronic non-specific LBP resulted in clinical improvement unrelated to laser stimulation. Trial registration http://www.anzctr.org.au ACTRN12610000043033. PMID:24280948

  9. 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. PMID:25560395

  10. Behavioral effects in mice of postnatal exposure to low-doses of 137-cesium and bisphenol A.

    PubMed

    Heredia, Luis; Bellés, Montserrat; LLovet, Maria Isabel; Domingo, Jose L; Linares, Victoria

    2016-01-18

    Bisphenol A (BPA) is the most important plasticizer used in many household products such as polycarbonate plastics or epoxy resins. Public and scientific concerns exist regarding the possibility that the neonatal exposure to BPA may contribute to neurobehavioral disorders. On the other hand, there is little information on the effects of low doses of ionizing radiation during critical phases of postnatal brain development, as well as the combination of radiation and environmental chemicals. In this study, C57BL/6J mice were exposed to low doses of internal radiation ((137)Cs), and/or BPA on postnatal day 10 (PND10). At the age of two months, animals were submitted to several tests to assess anxiety, activity, learning, and memory. Results showed that exposure to (137)Cs, alone or in combination with BPA, increased the anxiety-like of the animals without changing the activity levels. Animals exposed to (137)Cs showed impaired learning, and spatial memory, an impairment that was not observed in the groups co-exposed to BPA.

  11. Behavioral effects in mice of postnatal exposure to low-doses of 137-cesium and bisphenol A.

    PubMed

    Heredia, Luis; Bellés, Montserrat; LLovet, Maria Isabel; Domingo, Jose L; Linares, Victoria

    2016-01-18

    Bisphenol A (BPA) is the most important plasticizer used in many household products such as polycarbonate plastics or epoxy resins. Public and scientific concerns exist regarding the possibility that the neonatal exposure to BPA may contribute to neurobehavioral disorders. On the other hand, there is little information on the effects of low doses of ionizing radiation during critical phases of postnatal brain development, as well as the combination of radiation and environmental chemicals. In this study, C57BL/6J mice were exposed to low doses of internal radiation ((137)Cs), and/or BPA on postnatal day 10 (PND10). At the age of two months, animals were submitted to several tests to assess anxiety, activity, learning, and memory. Results showed that exposure to (137)Cs, alone or in combination with BPA, increased the anxiety-like of the animals without changing the activity levels. Animals exposed to (137)Cs showed impaired learning, and spatial memory, an impairment that was not observed in the groups co-exposed to BPA. PMID:26719215

  12. 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

  13. 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. PMID:26829110

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

    PubMed

    Houten, Sander M; 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

  15. 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

  16. [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. PMID:25552505

  17. [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.

  18. Effects of low-dose cadmium exposure during gestation and lactation on development and reproduction in rats.

    PubMed

    Luo, Xue; Li, Lianbing; Ma, Mingfu; Li, Renyan

    2015-07-01

    Cadmium (Cd) is an important toxic chemical due to its increasing levels in the environment and its resulting accumulation in humans and animals. The present study was performed to evaluate the long-term effects of low doses of Cd administered in offspring by oral route to rats during pregnancy and lactation. There were no adverse effects on the physical and sexual development in the pups, except to delay the development of offspring. The relative weights of livers and kidneys in the adult female offspring were significantly decreased after exposure to 10 ppm Cd. These results indicated that there were adverse effects on growth and development from exposure to 5 or 10 ppm Cd in utero and during lactation. The results also showed differential gender sensitivity effects on the organ weights.

  19. 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.

  20. Exposure to Low Dose of Cinnabar (a Naturally Occurring Mercuric Sulfide (HgS)) Caused Neurotoxicological Effects in Offspring Mice

    PubMed Central

    Huang, Chun-Fa; Hsu, Chuan-Jen; Liu, Shing-Hwa; Lin-Shiau, Shoei-Yn

    2012-01-01

    Cinnabar, a naturally occurring mercuric sulfide (HgS), has long been used in Chinese mineral medicine for more than 2000 years. Although mercury is well-known for its toxicity, whether cinnabar induces neurotoxicity, especially in infants and children, is unknown. The purpose of this study was to explore the neurotoxic effects of low-dose of cinnabar (10 mg/kg/day) on developing mice. The results revealed neurobehavioral defects in F1-C-Cin group, which were associated with Hg accumulation, increased NOx levels in whole blood, and Na+/K+-ATPase activities in brain tissues. F1- and F2-Cin-V groups were found to increase brain Hg contents and prominent neurobehavioral defects compared with F1-C-V group, suggesting that the fetal brain was more susceptible to irreversible effects for cinnabar-induced damage. Moreover, F1- and F2-Cin-Cin groups had severely neurobehavioral dysfunctions, closely correlated with the further alteration of NOx levels and Na+/K+-ATPase activities than F1- and F2-C-Cin groups. Effects in F2-Cin-Cin group were more significant than those in F1-Cin-Cin group. In conclusion, this study demonstrates that exposure to low-dose of cinnabar during the perinatal and developmental stages results in irreversible and severe injuries of the neurotoxicity in offspring, and NOx and Na+/K+-ATPase activities may exist potential and useful biomarkers for neurotoxicity-induced by low-doses of mercuric compounds. PMID:22888198

  1. Sustained improvement of motor function in hemiparkinsonian rats chronically treated with low doses of caffeine or trihexyphenidyl.

    PubMed

    Bata-García, José L; Villanueva-Toledo, Jairo; Gutiérrez-Ospina, Gabriel; Alvarez-Cervera, Fernando J; Heredia-López, Francisco J; Góngora-Alfaro, José L

    2007-01-01

    The effects of chronic oral treatment with low doses of caffeine (1-3 mg/kg) and trihexyphenidyl (0.1-0.2 mg/kg) were tested on hemiparkinsonian rats, which received the following treatments in a counterbalanced order: vehicle, caffeine, trihexyphenidyl, and caffeine plus trihexyphenidyl. Three preclinical models were used: the stepping test, the cylinder test, and the staircase test. Compared to pre-lesion values, the forepaw contralateral to the dopamine-denervated side showed impaired stepping, fewer wall contacts in the cylinder test, and fewer pellets retrieved in the staircase test. In the stepping test both doses of caffeine produced a complete recovery of motor function (100%), whereas the effect of trihexyphenidyl was less intense (77-80%). In this same test the maximal effect of drugs did not develop tolerance during 2-3 weeks, and was completely reversible after drug cessation. In the cylinder test only the wall contacts performed simultaneously with both forepaws were significantly increased by caffeine (3 mg/kg) and trihexyphenidyl (0.2 mg/kg), and this effect was also reversible. In the staircase test none of the treatments improved food pellet retrieval with the contralateral forepaw. Altogether, these results show that chronic treatment with caffeine, at doses similar to daily human consumption, produces a sustained improvement in the use of the contralateral forelimb in unilaterally 6-hydroxydopamine denervated rats, without the development of tolerance. Although the combined administration of caffeine plus trihexyphenidyl showed no synergism in these models, the results suggest that low doses of caffeine (1-3 mg/kg/day) could be of therapeutic value for the reversal of motor symptoms in parkinsonian patients.

  2. New challenges in risk assessment of chemicals when simulating real exposure scenarios; simultaneous multi-chemicals' low dose exposure.

    PubMed

    Tsatsakis, Aristidis M; Docea, Anca Oana; Tsitsimpikou, Christina

    2016-10-01

    The general population experiences uncontrolled multi-chemicals exposure from many different sources at doses around or well below regulatory limits. Therefore, traditional chronic toxicity evaluations for a single chemical could possibly miss to identify adequately all the risks. For this an experimental methodology that has the ambition to provide at one strike multi-answers to multi-questions is hereby proposed: a long-term toxicity study of non-commercial chemical mixtures, consisting of common everyday life chemicals (pesticides, food additives, life-style products components) at low and realistic dose levels around the regulatory limits and with the simultaneous investigation of several key endpoints, like genotoxicity, endocrine disruption, target organ toxicity including the heart and systemic mechanistic pathways, like oxidative stress.

  3. New challenges in risk assessment of chemicals when simulating real exposure scenarios; simultaneous multi-chemicals' low dose exposure.

    PubMed

    Tsatsakis, Aristidis M; Docea, Anca Oana; Tsitsimpikou, Christina

    2016-10-01

    The general population experiences uncontrolled multi-chemicals exposure from many different sources at doses around or well below regulatory limits. Therefore, traditional chronic toxicity evaluations for a single chemical could possibly miss to identify adequately all the risks. For this an experimental methodology that has the ambition to provide at one strike multi-answers to multi-questions is hereby proposed: a long-term toxicity study of non-commercial chemical mixtures, consisting of common everyday life chemicals (pesticides, food additives, life-style products components) at low and realistic dose levels around the regulatory limits and with the simultaneous investigation of several key endpoints, like genotoxicity, endocrine disruption, target organ toxicity including the heart and systemic mechanistic pathways, like oxidative stress. PMID:27515866

  4. Assessment of the Technologies for Molecular Biodosimetry for Human Low-Dose Radiation Exposure Symposium

    SciTech Connect

    Matthew A. Coleman Ph.D.; Narayani Ramakrishnan, Ph.D.; Sally A. Amundson; James D. Tucker, Ph.D.; Stephen D. Dertinger, Ph.D.; Natalia I. Ossetrova, Ph.D.; Tao Chen

    2009-11-16

    Exposure to ionizing radiation produces few immediate outwardly-visible clinical signs, yet, depending on dose, can severely damage vital physiological functions within days to weeks and produce long-lasting health consequences among survivors. In the event of a radiological accident, the rapid evaluation of the individual absorbed dose is paramount to discriminate the worried but unharmed from those individuals who must receive medical attention. Physical, clinical and biological dosimetry are usually combined for the best dose assessment. However, because of the practical limits of physical and clinical dosimetry, many attempts have been made to develop a dosimetry system based on changes in biological parameters, including techniques for hematology, biochemistry, immunology, cytogenetics, etc. Lymphocyte counts and chromosome aberrations analyses are among the methods that have been routinely used for estimating radiation dose. However, these assays require several days to a week to be completed and therefore cannot be used to obtain a fast estimate of the dose during the first few days after exposure when the information would be most critical for identifying victims of radiation accidents who could benefit the most by medical intervention. The steadily increasing sophistication in our understanding of the early biochemical responses of irradiated cells and tissues provides the opportunity for developing mechanism-based biosignatures of exposure. Compelling breakthroughs have been made in the technologies for genome-scale analysis of cellular transcriptional and proteomic profiles. There have also been major strides in the mechanistic understanding of the early events in DNA damage and radiation damage products, as well as in the cellular pathways that lead to radiation injury. New research with genomic- and proteomic-wide tools is showing that within minutes to hours after exposure to ionizing radiation protein machines are modified and activated, and large

  5. 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.

  6. 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.

  7. 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.

  8. [Complex pathogenetic treatment schemes of vascular dyscirculatory disorders in the remote period after exposure to low dose radiation].

    PubMed

    Holodova, N B; Zhavoronkova, L A; Ryzhov, B N

    2013-01-01

    Complex studies including modern methods of investigation of structures and functions of nervous system: electroencephalograsphy (EEG), coherent analysis, neuropsychological study and methods of neuroimaging were performed in 517 participants in liquidation of consequences of the accident (LCA) at the Chernobyl NPP in 1986-1987. Dyscirculatory metabolic encephalopathy was revealed to be the main pathology with the etiological mechanism based on dyscirculatorhypoxic and metabolic disorders. Complexity of the revealed symptoms testified to an early organism aging in remote periods after exposure to low dose radiation. Pathogenetic schemes were developed for treatment of dyscirculatory encephalopathy in liquidators, which include drugs improving blood supply, antiaggregants, antioxidants and metabolites of the brains in various combinations. Taking into consideration that early appearance of vascular dyscirculatory disorders observed in liquidators is the sign of early aging of the organism, geroprotectors were added to treatment schemes.

  9. Adverse effects on sexual development in rat offspring after low dose exposure to a mixture of endocrine disrupting pesticides.

    PubMed

    Hass, Ulla; Boberg, Julie; Christiansen, Sofie; Jacobsen, Pernille Rosenskjold; Vinggaard, Anne Marie; Taxvig, Camilla; Poulsen, Mette Erecius; Herrmann, Susan Strange; Jensen, Bodil Hamborg; Petersen, Annette; Clemmensen, Line Harder; Axelstad, Marta

    2012-09-01

    The present study investigated whether a mixture of low doses of five environmentally relevant endocrine disrupting pesticides, epoxiconazole, mancozeb, prochloraz, tebuconazole and procymidone, would cause adverse developmental toxicity effects in rats. In rat dams, a significant increase in gestation length was seen, while in male offspring increased nipple retention and increased incidence and severity of genital malformations were observed. Severe mixture effects on gestation length, nipple retention and genital malformations were seen at dose levels where the individual pesticides caused no or smaller effects when given alone. Generally, the mixture effect predictions based on dose-additivity were in good agreement with the observed effects. The results indicate that there is a need for modification of risk assessment procedures for pesticides, in order to take account of the mixture effects and cumulative intake, because of the potentially serious impact of mixed exposure on development and reproduction in humans. PMID:22659286

  10. Negative Effects of Low Dose Atrazine Exposure on the Development of Effective Immunity to FV3 in Xenopus laevis

    PubMed Central

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

    2014-01-01

    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 ecotoxiciology 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. PMID:24984115

  11. 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.

  12. Maternal exposure to low doses of delta9-tetrahydrocannabinol facilitates morphine-induced place conditioning in adult male offspring.

    PubMed

    Rubio, P; Rodríguez de Fonseca, F; Martín-Calderón, J L; Del Arco, I; Bartolomé, S; Villanúa, M A; Navarro, M

    1998-11-01

    The possible existence of an increased susceptibility to the reinforcing properties of morphine was analyzed in male and female rats born from mothers exposed to delta9-tetrahydrocannabinol (THC, 1, 5, or 20 mg/kg) during gestation and lactation. Maternal exposure to low doses of THC (1 and 5 mg/kg), relevant for human consumption, resulted in an increased response to the reinforcing effects of a moderate dose of morphine (350 microg/kg), as measured in the place-preference conditioning paradigm (CPP) in the adult male offspring. These animals also displayed an enhanced exploratory behavior in the defensive withdrawal test. However, only females born from mothers exposed to THC 1 mg/kg exhibited a small increment in the place conditioning induced by morphine. The possible implication of the hypothalamo-pituitary-adrenal axis (HPA) was analyzed by monitoring plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone in basal and moderate-stress conditions (after the end of the CPP test). Female offspring perinatally exposed to THC (1 or 5 mg/kg) displayed high basal levels of corticosterone and a blunted adrenal response to the HPA-activating effects of the CPP test. However, male offspring born from mothers exposed to THC (1 or 5 mg/kg) displayed the opposite pattern: normal to low basal levels of corticosterone, and a sharp adrenal response to the CPP challenge. The present study reveals that maternal exposure to low doses of THC results in an increased sensitivity to the reinforcing effects of morphine in the adult male offspring, and in sexually dimorphic behavioral and endocrine alterations in the adaptative responses to stressors such as novelty or place-preference testing. These results support the growing evidence of the importance of monitoring the long-term consequences of maternal consumption of cannabis derivatives.

  13. Maternal exposure to low doses of delta9-tetrahydrocannabinol facilitates morphine-induced place conditioning in adult male offspring.

    PubMed

    Rubio, P; Rodríguez de Fonseca, F; Martín-Calderón, J L; Del Arco, I; Bartolomé, S; Villanúa, M A; Navarro, M

    1998-11-01

    The possible existence of an increased susceptibility to the reinforcing properties of morphine was analyzed in male and female rats born from mothers exposed to delta9-tetrahydrocannabinol (THC, 1, 5, or 20 mg/kg) during gestation and lactation. Maternal exposure to low doses of THC (1 and 5 mg/kg), relevant for human consumption, resulted in an increased response to the reinforcing effects of a moderate dose of morphine (350 microg/kg), as measured in the place-preference conditioning paradigm (CPP) in the adult male offspring. These animals also displayed an enhanced exploratory behavior in the defensive withdrawal test. However, only females born from mothers exposed to THC 1 mg/kg exhibited a small increment in the place conditioning induced by morphine. The possible implication of the hypothalamo-pituitary-adrenal axis (HPA) was analyzed by monitoring plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone in basal and moderate-stress conditions (after the end of the CPP test). Female offspring perinatally exposed to THC (1 or 5 mg/kg) displayed high basal levels of corticosterone and a blunted adrenal response to the HPA-activating effects of the CPP test. However, male offspring born from mothers exposed to THC (1 or 5 mg/kg) displayed the opposite pattern: normal to low basal levels of corticosterone, and a sharp adrenal response to the CPP challenge. The present study reveals that maternal exposure to low doses of THC results in an increased sensitivity to the reinforcing effects of morphine in the adult male offspring, and in sexually dimorphic behavioral and endocrine alterations in the adaptative responses to stressors such as novelty or place-preference testing. These results support the growing evidence of the importance of monitoring the long-term consequences of maternal consumption of cannabis derivatives. PMID:9768557

  14. Exposure of cats to low doses of FeLV: seroconversion as the sole parameter of infection.

    PubMed

    Major, Andrea; Cattori, Valentino; Boenzli, Eva; Riond, Barbara; Ossent, Peter; Meli, Marina Luisa; Hofmann-Lehmann, Regina; Lutz, Hans

    2010-01-01

    In felids, feline leukemia virus (FeLV) infection results in a variety of outcomes that range from abortive (virus readily eliminated and never detectable) to progressive infection (persistent viremia and viral shedding). Recently, a novel outcome was postulated for low FeLV infectious doses. Naïve cats exposed to faeces of persistently infected cats seroconverted, indicating infection, but remained negative for provirus and p27 antigen in blood. FeLV provirus was found in some tissues but not in the bone marrow, infection of which is usually considered a necessary stage for disease progression. To investigate the impact of low FeLV doses on young cats and to test the hypothesis that low dose exposure may lead to an unknown pathogenesis of infection without involvement of the bone marrow, 21 cats were infected oronasally with variable viral doses. Blood p27, proviral and viral loads were followed until week 20 post-infection. Tissue proviral loads were determined as well. The immune response was monitored by measuring FeLV whole virus and p45 antibodies; and feline oncornavirus-associated cell membrane antigen (FOCMA) assay. One cat showed regressive infection (transient antigenemia, persistent provirus-positivity, and seroconversion) with provirus only found in some organs at sacrifice. In 7 of the 20 remaining cats FOCMA assay positivity was the only sign of infection, while all other tests were negative. Overall, the results show that FeLV low dose exposure can result in seroconversion during a presumed abortive infection. Therefore, commonly used detection methods do not detect all FeLV-infected animals, possibly leading to an underestimation of the prevalence of infection.

  15. Exposure of cats to low doses of FeLV: seroconversion as the sole parameter of infection

    PubMed Central

    Major, Andrea; Cattori, Valentino; Boenzli, Eva; Riond, Barbara; Ossent, Peter; Meli, Marina Luisa; Hofmann-Lehmann, Regina; Lutz, Hans

    2009-01-01

    In felids, feline leukemia virus (FeLV) infection results in a variety of outcomes that range from abortive (virus readily eliminated and never detectable) to progressive infection (persistent viremia and viral shedding). Recently, a novel outcome was postulated for low FeLV infectious doses. Naïve cats exposed to faeces of persistently infected cats seroconverted, indicating infection, but remained negative for provirus and p27 antigen in blood. FeLV provirus was found in some tissues but not in the bone marrow, infection of which is usually considered a necessary stage for disease progression. To investigate the impact of low FeLV doses on young cats and to test the hypothesis that low dose exposure may lead to an unknown pathogenesis of infection without involvement of the bone marrow, 21 cats were infected oronasally with variable viral doses. Blood p27, proviral and viral loads were followed until week 20 post-infection. Tissue proviral loads were determined as well. The immune response was monitored by measuring FeLV whole virus and p45 antibodies; and feline oncornavirus-associated cell membrane antigen (FOCMA) assay. One cat showed regressive infection (transient antigenemia, persistent provirus-positivity, and seroconversion) with provirus only found in some organs at sacrifice. In 7 of the 20 remaining cats FOCMA assay positivity was the only sign of infection, while all other tests were negative. Overall, the results show that FeLV low dose exposure can result in seroconversion during a presumed abortive infection. Therefore, commonly used detection methods do not detect all FeLV-infected animals, possibly leading to an underestimation of the prevalence of infection. PMID:19861115

  16. Perturbation of Defense Pathways by Low-Dose Arsenic Exposure in Zebrafish Embryos

    PubMed Central

    Mattingly, Carolyn J.; Hampton, Thomas H.; Brothers, Kimberly M.; Griffin, Nina E.; Planchart, Antonio

    2009-01-01

    Background Exposure to arsenic is a critical risk factor in the complex interplay among genetics, the environment, and human disease. Despite the potential for in utero exposure, the mechanism of arsenic action on vertebrate development and disease is unknown. Objectives The objective of this study was to identify genes and gene networks perturbed by arsenic during development in order to enhance understanding of the molecular mechanisms of arsenic action. Methods We exposed zebrafish embryos at 0.25–1.25 hr postfertilization to 10 or 100 ppb arsenic for 24 or 48 hr. We then used total RNA to interrogate genome microarrays and to test levels of gene expression changes by quantitative real-time polymerase chain reaction (QPCR). Computational analysis was used to identify gene expression networks perturbed by arsenic during vertebrate development. Results We identified a set of 99 genes that responded to low levels of arsenic. Nineteen of these genes were predicted to function in a common regulatory network that was significantly associated with immune response and cancer (p < 10−41). Arsenic-mediated expression changes were validated by QPCR. Conclusions In this study we demonstrated that arsenic significantly down-regulates expression levels of multiple genes potentially critical for regulating the establishment of an immune response. The data also provide molecular evidence consistent with phenotypic observations reported in other model systems. Additional mechanistic studies will help explain molecular events regulating early stages of the immune system and long-term consequences of arsenic-mediated perturbation of this system during development. PMID:19590694

  17. Effect of chronic low dose natural radiation in human peripheral blood mononuclear cells: Evaluation of DNA damage and repair using the alkaline comet assay.

    PubMed

    Kumar, P R Vivek; Seshadri, M; Jaikrishan, G; Das, Birajalaxmi

    2015-05-01

    This study investigates whether peripheral blood mononuclear cells (PBMCs) from inhabitants of Kerala in southwest India, exposed to chronic low dose natural radiation in vivo (>1 mSv year(-1)), respond with a radioadaptive response to a challenging dose of gamma radiation. Toward this goal, PBMCs isolated from 77 subjects from high-level natural radiation areas (HLNRA) and 37 subjects from a nearby normal level natural radiation area (NLNRA) were challenged with 2 Gy and 4 Gy gamma radiation. Subjects from HLNRA were classified based on the mean annual effective dose received, into low dose group (LDG) and high dose group (HDG) with mean annual effective doses of 2.69 mSv (N=43, range 1.07 mSv year(-1) to 5.55 mSv year(-1)) and 9.62 mSv (N = 34, range 6.07 mSv year(-1) to 17.41 mSv year(-1)), respectively. DNA strand breaks and repair kinetics (at 7 min, 15 min and 30 min after 4 Gy) were evaluated using the alkaline single cell gel electrophoresis (comet) assay. Initial levels of DNA strand breaks observed after either a 2 Gy or a 4 Gy challenging dose were significantly lower in subjects of the HDG from HLNRA compared to subjects of NLNRA (2 Gy, P = 0.01; 4 Gy, P = 0.02) and LDG (2 Gy P = 0.01; 4 Gy, P=0.05). Subjects of HDG from HLNRA showed enhanced rejoining of DNA strand breaks (HDG/NLNRA, P = 0.06) during the early stage of repair (within 7 min). However at later times a similar rate of rejoining of strand breaks was observed across the groups (HDG, LDG and NLNRA). Preliminary results from our study suggest in vivo chronic low-level natural radiation provides an initial exposure that allows an adaptation to a subsequent higher radiation exposure, perhaps through improving DNA repair via an unknown mechanism. Therefore, further investigations would be necessary in this population to understand the biological and health effects of chronic low-level natural radiation exposures.

  18. Low-dose effect of developmental bisphenol A exposure on sperm count and behaviour in rats.

    PubMed

    Hass, U; Christiansen, S; Boberg, J; Rasmussen, M G; Mandrup, K; Axelstad, M

    2016-07-01

    Bisphenol A is widely used in food contact materials and other products and is detected in human urine and blood. Bisphenol A may affect reproductive and neurological development; however, opinion of the European Food Safety Authority (EFSA) on bisphenol A (EFSA J, 13, 2015 and 3978) concluded that none of the available studies were robust enough to provide a point of departure for setting a tolerable daily intake for bisphenol A. In the present study, pregnant Wistar rats (n = 17-21) were gavaged from gestation day 7 to pup day 22 with bisphenol A doses of 0, 25 μg, 250 μg, 5 mg or 50 mg/kg bw/day. In the offspring, growth, sexual maturation, weights and histopathology of reproductive organs, oestrus cyclicity and sperm counts were assessed. Neurobehavioural development was investigated using a behavioural testing battery including tests for motor activity, sweet preference, anxiety and spatial learning. Decreased sperm count was found at the lowest bisphenol A dose, that is 25 μg/kg/day, but not at the higher doses. Reproductive organ weight and histology were not affected and no behavioural effects were seen in male offspring. In the female offspring, exposure to 25 μg/kg bw/day bisphenol A dose resulted in increased body weight late in life and altered spatial learning in a Morris water maze, indicating masculinization of the brain. Decreased intake of sweetened water was seen in females from the highest bisphenol A dose group, also a possible sign of masculinization. The other investigated endpoints were not significantly affected. In conclusion, the present study using a robust experimental study design, has shown that developmental exposure to 25 μg/kg bw/day bisphenol A can cause adverse effects on fertility (decreased sperm count), neurodevelopment (masculinization of spatial learning in females) and lead to increased female body weight late in life. These results suggest that the new EFSA temporary tolerable daily intake of 4 μg/kg bw

  19. Physiological Responses in Chinese Rare Minnow Larvae Following Exposure to Low-Dose Tributyltin.

    PubMed

    Li, Ping; Li, Zhi-Hua

    2015-11-01

    In the present study, the antioxidant response and acetylcholinesterase (AChE) activity were measured in Chinese rare minnow larvae (Gobiocypris rarus) after exposure to tributyltin (TBT) (0, 100, 400 and 800 ngL(-1)) for 7 days, as well as the expression of a series of genes, including cr, aptase and prl genes involved in the ion-regulatory process and igfbp3 and gh related to growth rate. Results shows that oxidative stress was generated in fish exposed to TBT, as evidenced by elevated malondialdehyde levels and the inhibition of antioxidant parameters. The activity of acetylcholinesterase (AChE) was also inhibited in fish under higher TBT stress. Moreover, genes involved in ion regulation and growth were affected, based on the regulated transcription of the cr, atpase, gh, prl and igfbp3 genes in the treated groups. The observed effects of TBT upon antioxidant responses and altered expression of genes provides insight into the use of these molecular biomarkers in evaluating mechanisms of TBT toxicity in fish. PMID:26385694

  20. Adverse effects of exposure to low doses of chlorpyrifos in lactating rats.

    PubMed

    Mansour, Sameeh A; Mossa, Abdel-Tawab H

    2011-04-01

    This study was conducted to shed light on the effect of exposure of lactating rat to chlorpyrifos (CPF). CPF was orally administered to lactating rats at 0.01 mg kg(-1) b.wt. (acceptable daily intake, ADI), 1.00 mg kg(-1) b.wt. (no observed adverse effects level, NOAEL) and 1.35 mg kg(-1) b.wt. (1/100 LD( 50)) from postnatal day 1 (PN1) until day 20 (PN20) after delivery. Results indicated decreases in body weight and increases in relative liver and kidney weights of exposed dams. Significant damage to liver was observed via increased plasma levels of aminotransferases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) lactate dehydrogenase (LDH) and γ-glutamyle transferase (γ-GT) in a dose-dependent manner. At two high doses of CPF (1.00 and 1.35 mg kg(-1) b.wt.), the lactating mothers showed significant decrease in the activity of cholinesterase (ChE). Lipid peroxidation was significantly increased, while glutathione s-transferase (GST) and superoxide dismutase (SOD) were significantly decreased compared to control. At high dose of CPF (1.35 mg kg(-1) b.wt.), total protein and uric acid levels were significantly increased. CPF caused dose-related histopathological changes in liver and kidney of the CPF-treated dams.

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

    PubMed

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

    2015-02-01

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

    PubMed

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

    2015-02-01

    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.

  3. 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

  4. Genome-wide analysis of epigenomic alterations in fetal mouse forebrain after exposure to low doses of bisphenol A.

    PubMed

    Yaoi, Takeshi; Itoh, Kyoko; Nakamura, Keiko; Ogi, Hiroshi; Fujiwara, Yasuhiro; Fushiki, Shinji

    2008-11-21

    Bisphenol A (BPA) is one of endocrine disrupting chemicals, being distributed widely in the environment. We have been studying the low dose effects of BPA on murine forebrain development. Here, we have investigated the genome-wide effect of maternal exposure to BPA on the epigenome in mouse forebrain at E12.5 and at E14.5. We scanned CpG methylation status in 2500 NotI loci, representing 48 (de)methylated unique loci. Methylation status in most of them was primarily developmental stage-dependent. Each of almost all cloned NotI loci was located in a CpG island (CGI) adjacent to 5' end of the transcriptional unit. The mRNA expression of two functionally related genes changed with development as well as the exposure to BPA. In both genes, changes at the transcriptional level correlated well with the changes in NotI methylation status. Taken together, epigenetic alterations in promoter-associated CGIs after exposure to BPA may underlie some effects on brain development. PMID:18804091

  5. Long-term, low-dose lead exposure alters the gonadotropin-releasing hormone system in the male rat.

    PubMed Central

    Sokol, Rebecca Z; Wang, Saixi; Wan, Yu-Jui Y; Stanczyk, Frank Z; Gentzschein, Elisabet; Chapin, Robert E

    2002-01-01

    Lead is a male reproductive toxicant. Data suggest that rats dosed with relatively high levels of lead acetate for short periods of time induced changes in the hypothalamic gonadotropin-releasing hormone (GnRH) at the molecular level, but these changes were attenuated with increased concentration of exposure. The current study evaluated whether exposure to low levels of lead acetate over longer periods of time would produce a similar pattern of adaptation to toxicity at the molecular and biologic levels. Adult 100-day-old Sprague-Dawley male rats were dosed with 0, 0.025, 0.05, 0.1, and 0.3% lead acetate in water. Animals were killed after 1, 4, 8, and 16 weeks of treatment. Luteinzing hormone (LH) and GnRH levels were measured in serum, and lead levels were quantified in whole blood. Hypothalamic GnRH mRNA levels were also quantified. We found no significant differences in serum LH and GnRH among the groups of animals treated within each time period. A significant dose-related increase of GnRH mRNA concentrations with lead dosing occurred in animals treated for 1 week. Animals treated for more than 1 week also exhibited a significant increase in GnRH mRNA, but with an attenuation of the increase at the higher concentrations of lead with increased duration of exposure. We conclude that the signals within and between the hypothalamus and pituitary gland appear to be disrupted by long-term, low-dose lead exposure. PMID:12204820

  6. 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

  7. [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. PMID:26973191

  8. [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.

  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. 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. PMID:26934482

  11. 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

  12. 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

  13. Sex-specific effects of low-dose gestational estradiol-17β exposure on bone development in porcine offspring.

    PubMed

    Flöter, Veronika L; Galateanu, Gabriela; Fürst, Rainer W; Seidlová-Wuttke, Dana; Wuttke, Wolfgang; Möstl, Erich; Hildebrandt, Thomas B; Ulbrich, Susanne E

    2016-07-29

    Estrogens are important for the bone development and health. Exposure to endocrine disrupting chemicals during the early development has been shown to affect the bone phenotype later in life. Several studies have been performed in rodents, while in larger animals that are important to bridge the gap to humans there is a paucity of data. To this end, the pig as large animal model was used in the present study to assess the influence of gestational estradiol-17β (E2) exposure on the bone development of the prepubertal and adult offspring. Two low doses (0.05 and 10μg E2/kg body weight) referring to the 'acceptable daily intake' (ADI) and the 'no observed effect level' (NOEL) as stated for humans, and a high-dose (1000μg E2/kg body weight), respectively, were fed to the sows every day from insemination until delivery. In the male prepubertal offspring, the ADI dose group had a lower strength strain index (p=0.002) at the proximal tibia compared to controls, which was determined by peripheral quantitative computed tomography. Prepubertal females were not significantly affected. However, there was a higher cortical cross-sectional area (CSA) (p=0.03) and total CSA (p=0.02) at the femur midpoint in the adult female offspring of the NOEL dose group as measured by computed tomography. These effects were independent from plasma hormone concentrations (leptin, IGF1, estrogens), which remained unaltered. Overall, sex-specific effects on bone development and non-monotonic dose responses were observed. These results substantiate the high sensitivity of developing organisms to exogenous estrogens.

  14. 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.

  15. Disruption of thyroid hormone functions by low dose exposure of tributyltin: an in vitro and in vivo approach.

    PubMed

    Sharan, Shruti; Nikhil, Kumar; Roy, Partha

    2014-09-15

    Triorganotins, such as tributyltin chloride (TBTCl), are environmental contaminants that are commonly found in the antifouling paints used in ships and other vessels. The importance of TBTCl as an endocrine-disrupting chemical (EDC) in different animal models is well known; however, its adverse effects on the thyroid gland are less understood. Hence, in the present study, we aimed to evaluate the thyroid-disrupting effects of this chemical using both in vitro and in vivo approaches. We used HepG2 hepatocarcinoma cells for the in vitro studies, as they are a thyroid hormone receptor (TR)-positive and thyroid responsive cell line. For the in vivo studies, Swiss albino male mice were exposed to three doses of TBTCl (0.5, 5 and 50μg/kg/day) for 45days. TBTCl showed a hypo-thyroidal effect in vivo. Low-dose treatment of TBTCl exposure markedly decreased the serum thyroid hormone levels via the down-regulation of the thyroid peroxidase (TPO) and thyroglobulin (Tg) genes by 40% and 25%, respectively, while augmenting the thyroid stimulating hormone (TSH) levels. Thyroid-stimulating hormone receptor (TSHR) expression was up-regulated in the thyroid glands of treated mice by 6.6-fold relative to vehicle-treated mice (p<0.05). In the transient transactivation assays, TBTCl suppressed T3 mediated transcriptional activity in a dose-dependent manner. In addition, TBTCl was found to decrease the expression of TR. The present study thus indicates that low concentrations of TBTCl suppress TR transcription by disrupting the physiological concentrations of T3/T4, followed by the recruitment of NCoR to TR, providing a novel insight into the thyroid hormone-disrupting effects of this chemical.

  16. Disruption of thyroid hormone functions by low dose exposure of tributyltin: an in vitro and in vivo approach.

    PubMed

    Sharan, Shruti; Nikhil, Kumar; Roy, Partha

    2014-09-15

    Triorganotins, such as tributyltin chloride (TBTCl), are environmental contaminants that are commonly found in the antifouling paints used in ships and other vessels. The importance of TBTCl as an endocrine-disrupting chemical (EDC) in different animal models is well known; however, its adverse effects on the thyroid gland are less understood. Hence, in the present study, we aimed to evaluate the thyroid-disrupting effects of this chemical using both in vitro and in vivo approaches. We used HepG2 hepatocarcinoma cells for the in vitro studies, as they are a thyroid hormone receptor (TR)-positive and thyroid responsive cell line. For the in vivo studies, Swiss albino male mice were exposed to three doses of TBTCl (0.5, 5 and 50μg/kg/day) for 45days. TBTCl showed a hypo-thyroidal effect in vivo. Low-dose treatment of TBTCl exposure markedly decreased the serum thyroid hormone levels via the down-regulation of the thyroid peroxidase (TPO) and thyroglobulin (Tg) genes by 40% and 25%, respectively, while augmenting the thyroid stimulating hormone (TSH) levels. Thyroid-stimulating hormone receptor (TSHR) expression was up-regulated in the thyroid glands of treated mice by 6.6-fold relative to vehicle-treated mice (p<0.05). In the transient transactivation assays, TBTCl suppressed T3 mediated transcriptional activity in a dose-dependent manner. In addition, TBTCl was found to decrease the expression of TR. The present study thus indicates that low concentrations of TBTCl suppress TR transcription by disrupting the physiological concentrations of T3/T4, followed by the recruitment of NCoR to TR, providing a novel insight into the thyroid hormone-disrupting effects of this chemical. PMID:25101840

  17. 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).

  18. 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

  19. The acceleration of amygdala kindling epileptogenesis by chronic low-dose corticosterone involves both mineralocorticoid and glucocorticoid receptors.

    PubMed

    Kumar, Gaurav; Couper, Abbie; O'Brien, Terence J; Salzberg, Michael R; Jones, Nigel C; Rees, Sandra M; Morris, Margaret J

    2007-08-01

    We have previously demonstrated that low-dose corticosterone (CS) administration, used as a model of the effect of chronic stress, accelerates epileptogenesis in the electrical amygdala kindling rat model of temporal lobe epilepsy (TLE). This current study examined the relative contributions to this effect of mineralocorticoid (MR) and glucocorticoid (GR) subtypes of glucocorticoid receptors. Female non-epileptic wistar rats 10-13 weeks of age were implanted with a bipolar electrode into the left amygdala. Five treatment groups were subjected to rapid amygdala kindling: water-control (n=9), CS treated (6 mg/100 ml added to drinking water; n=9), CS+spironolactone (MR antagonist, 50 mg/kg sc; n=9), CS+mifepristone (GR antagonist, 25 mg/kg sc; n=9), and CS+both antagonists (n=7). Rats were injected with vehicle or the relevant antagonist twice daily for the entire kindling period. Experimental groups differed significantly in the number of stimulations required to reach the 'fully kindled state' (Racine, 1972) ANOVA, F(4,38)=2.73, p=0.04). Amygdala kindling was accelerated in the CS-treated group compared with water controls (mean stimulations for full kindling: 45.2 vs. 86.5, p<0.01). This acceleration was inhibited by both the MR and GR antagonist treatments (mean stimulations: 69.6 and 70.4, p=0.04 and 0.04 vs. CS group, respectively), with the kindling rates in these groups not significantly different from water-treated subjects (p=0.26 and 0.29, respectively). The kindling rates in the MR and GR antagonist treatment groups did not significantly differ from each other (p=0.93), nor from the combined treatment group (mean stimulations: 62.8, p=0.59 and 0.54, respectively). This study demonstrates that activation of both high-affinity (MR) and low-affinity (GR) glucocorticoid receptors are involved in mediating CS-induced acceleration of amygdala kindling epileptogenesis.

  20. Perinatal exposure to low-dose methylmercury induces dysfunction of motor coordination with decreases in synaptophysin expression in the cerebellar granule cells of rats.

    PubMed

    Fujimura, Masatake; Cheng, Jinping; Zhao, Wenchang

    2012-06-29

    Methylmercury (MeHg) is an environmental pollutant that is toxic to the developing central nervous system (CNS) in children, even at low exposure levels. Perinatal exposure to MeHg is known to induce neurological symptoms with neuropathological changes in the CNS. However, the relationship between the neurological symptoms and neuropathological changes induced in offspring as a result of exposure to low-dose MeHg is not well defined. In the present study, neurobehavioral analyses revealed that exposure to a low level of MeHg (5 ppm in drinking water) during developmental caused a significant deficit in the motor coordination of rats in the rotating rod test. In contrast, general neuropathological findings, including neuronal cell death and the subsequent nerve inflammation, were not observed in the region of the cerebellum responsible for regulating motor coordination. Surprisingly, the expression of synaptophysin (SPP), a marker protein for synaptic formation, significantly decreased in cerebellar granule cells. These results showed that perinatal exposure to low-dose MeHg causes neurobehavioral impairment without general neuropathological changes in rats. We demonstrated for the first time that exposure to low-dose MeHg during development induces the dysfunction of motor coordination due to changes of synaptic homeostasis in cerebellar granule cells.

  1. 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.

  2. Low-dose rotenone exposure induces early senescence leading to late apoptotic signaling cascade in human trabecular meshwork (HTM) cell line: An in vitro glaucoma model.

    PubMed

    Maurya, Nancy; Agarwal, Nupur Rani; Ghosh, Ilora

    2016-01-01

    This study aimed to determine whether the prolonged exposure of the human trabecular meshwork (HTM) cell line to a low dose (1 nM) of rotenone could simulate a glaucomatous-like condition and serve as a cellular model for its etiological analysis. Under 1-nM rotenone exposure for 24-72 h, HTM cells showed a decrease in cell viability as assessed by an MTT assay and showed mitochondrial dysfunction as assessed by measuring H2 DCFDA fluorescence; a decrease in ATP level was also observed. Flow cytometric analysis showed an increase in cellular size and granularity. Elevated AF showed initial senescence. LF staining with SBB and its spectrofluorometric quantification confirmed growth arrest. An accumulation of cytoplasmic myocilin, IL-6, and MMP-9 at 72 h of exposure supported glaucomatous induction. TEM revealed morphological changes in mitochondria and nuclei of treated cells. Signaling cascades were assessed by immunoblotting and immunocytochemical analysis. This study showed a shift in status of the cells from initial senescence to induction of apoptosis in the HTM cell line due to continuous low-dose exposure to rotenone; however, at 72 h, both senescence and apoptotic features are apparent in these cells. This is the first report that reveals the potential of a prolonged low-dose exposure of rotenone to simulate senescence in the HTM cell line to cause a glaucomatous condition.

  3. Radiation-induced bystander effects in the Atlantic salmon (salmo salar L.) following mixed exposure to copper and aluminum combined with low-dose gamma radiation.

    PubMed

    Mothersill, Carmel; Smith, Richard W; Heier, Lene Sørlie; Teien, Hans-Christian; Lind, Ole Christian; Land, Ole Christian; Seymour, Colin B; Oughton, Deborah; Salbu, Brit

    2014-03-01

    Very little is known about the combined effects of low doses of heavy metals and radiation. However, such "multiple stressor" exposure is the reality in the environment. In the work reported in this paper, fish were exposed to cobalt 60 gamma irradiation with or without copper or aluminum in the water. Doses of radiation ranged from 4 to 75 mGy delivered over 48 or 6 h. Copper doses ranged from 10 to 80 μg/L for the same time period. The aluminum dose was 250 μg/L. Gills and skin were removed from the fish after exposure and explanted in tissue culture flasks for investigation of bystander effects of the exposures using a stress signal reporter assay, which has been demonstrated to be a sensitive indicator of homeostatic perturbations in cells. The results show complex synergistic interactions of radiation and copper. Gills on the whole produce more toxic bystander signals than skin, but the additivity scores show highly variable results which depend on dose and time of exposure. The impacts of low doses of copper and low doses of radiation are greater than additive, medium levels of copper alone have a similar level of effect of bystander signal toxicity to the low dose. The addition of radiation stress, however, produces clear protective effects in the reporters treated with skin-derived medium. Gill-derived medium from the same fish did not show protective effects. Radiation exposure in the presence of 80 μg/L led to highly variable results, which due to animal variation were not significantly different from the effect of copper alone. The results are stressor type, stressor concentration and time dependent. Clearly co-exposure to radiation and heavy metals does not always lead to simple additive effects.

  4. 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

  5. Sex-Specific Enhanced Behavioral Toxicity Induced by Maternal Exposure to a Mixture of Low Dose Endocrine-Disrupting Chemicals

    PubMed Central

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

    2014-01-01

    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 – 0.1 mg/kg), Bisphenol-A (BPA - 50μg/kg), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD – 0.25μg/kg) alone or combined in a mixture (MIX), from gestational day 7 until weaning. EDC-treated males maintained significantly higher horizontal activity levels across 3 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 more fully investigate

  6. Administration of low dose estrogen attenuates persistent inflammation, promotes angiogenesis, and improves locomotor function following chronic spinal cord injury in rats.

    PubMed

    Samantaray, Supriti; Das, Arabinda; Matzelle, Denise C; Yu, Shan P; Wei, Ling; Varma, Abhay; Ray, Swapan K; Banik, Naren L

    2016-05-01

    Spinal cord injury (SCI) causes loss of neurological function and, depending upon the severity of injury, may lead to paralysis. Currently, no FDA-approved pharmacotherapy is available for SCI. High-dose methylprednisolone is widely used, but this treatment is controversial. We have previously shown that low doses of estrogen reduces inflammation, attenuates cell death, and protects axon and myelin in SCI rats, but its effectiveness in recovery of function is not known. Therefore, the goal of this study was to investigate whether low doses of estrogen in post-SCI would reduce inflammation, protect cells and axons, and improve locomotor function during the chronic phase of injury. Injury (40 g.cm force) was induced at thoracic 10 in young adult male rats. Rats were treated with 10 or 100 μg 17β-estradiol (estrogen) for 7 days following SCI and compared with vehicle-treated injury and laminectomy (sham) controls. Histology (H&E staining), immunohistofluorescence, Doppler laser technique, and Western blotting were used to monitor tissue integrity, gliosis, blood flow, angiogenesis, the expression of angiogenic factors, axonal degeneration, and locomotor function (Basso, Beattie, and Bresnahan rating) following injury. To assess the progression of recovery, rats were sacrificed at 7, 14, or 42 days post injury. A reduction in glial reactivity, attenuation of axonal and myelin damage, protection of cells, increased expression of angiogenic factors and microvessel growth, and improved locomotor function were found following estrogen treatment compared with vehicle-treated SCI rats. These results suggest that treatment with a very low dose of estrogen has significant therapeutic implications for the improvement of locomotor function in chronic SCI. Experimental studies with low dose estrogen therapy in chronic spinal cord injury (SCI) demonstrated the potential for multi-active beneficial outcomes that could ameliorate the degenerative pathways in chronic SCI as

  7. Possibilities and limitations of fluorescence in situ hybridization technique in retrospective detection of low dose radiation exposure in post-chernobyl human cohorts.

    PubMed

    Maznyk, N A; Vinnikov, V A

    2005-01-01

    Cytogenetic analysis using the fluorescence in situ hybridisation (FISH) technique was performed late time after the Chernobyl accident in groups of liquidators, evacuees from 30 km exclusive zone, residents of radioactively contaminated areas and control donors age-matched to exposed persons. Stable and unstable chromosome type exchanges were recorded using a hybrid conventional-PAINT nomenclature. The mean yield of stable chromosome exchanges in liquidators did not correlate with registered radiation doses but had a clear negative dependence on the duration of liquidators' staying in Chernobyl zone, that was in a good agreement with early data based on conventional dicentrics plus rings analysis. The overspontaneous excess for stable chromosome exchange level appeared to be higher in evacuees 16-40 years old than that of senior persons, whereas no age-dependent difference occurred for initially induced dicentrics plus rings yields in this cohort. The stable chromosome exchange yield, as well as combined yield of dicentrics plus rings and potentially unstable incomplete translocations in residents of radioactively contaminated areas showed a reasonable positive correlation with levels of 137Cs contamination. The observed yields of stable chromosome exchanges in all three exposed groups appeared to be somewhat lower than those of expected from unstable exchange-based doses which were referred to an in vitro dose response of stable exchanges outcome in human lymphocytes. Thus, FISH analysis can be successfully applied for qualitative cytogenetic indication of past and chronic radiation exposure to low doses but further refinement of FISH-based system for quantitative dose assessment is still required. Some practical approaches of solving this task are discussed.

  8. 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.

  9. 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.

  10. 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.

  11. Risk Evaluation of Endocrine-Disrupting Chemicals: Effects of Developmental Exposure to Low Doses of Bisphenol A on Behavior and Physiology in Mice (Mus musculus).

    PubMed

    Gioiosa, Laura; Palanza, Paola; Parmigiani, Stefano; Vom Saal, Frederick S

    2015-01-01

    We review here our studies on early exposure to low doses of the estrogenic endocrine-disrupting chemical bisphenol A (BPA) on behavior and metabolism in CD-1 mice. Mice were exposed in utero from gestation day (GD) 11 to delivery (prenatal exposure) or via maternal milk from birth to postnatal day 7 (postnatal exposure) to 10 µg/kg body weight/d of BPA or no BPA (controls). Bisphenol A exposure resulted in long-term disruption of sexually dimorphic behaviors. Females exposed to BPA pre- and postnatally showed increased anxiety and behavioral profiles similar to control males. We also evaluated metabolic effects in prenatally exposed adult male offspring of dams fed (from GD 9 to 18) with BPA at doses ranging from 5 to 50 000 µg/kg/d. The males showed an age-related significant change in a number of metabolic indexes ranging from food intake to glucose regulation at BPA doses below the no observed adverse effect level (5000 µg/kg/d). Consistent with prior findings, low but not high BPA doses produced significant effects for many outcomes. These findings provide further evidence of the potential risks that developmental exposure to low doses of the endocrine disrupter BPA may pose to human health, with fetuses and infants being highly vulnerable. PMID:26740806

  12. 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. PMID:26970683

  13. 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

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

    PubMed

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

    2015-06-09

    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.

  15. Efficacy and tolerability of low-dose oral prolonged-release oxycodone/naloxone for chronic nononcological pain in older patients

    PubMed Central

    Guerriero, Fabio; Sgarlata, Carmelo; Marcassa, Claudio; Ricevuti, Giovanni; Rollone, Marco

    2015-01-01

    Purpose Chronic pain is highly prevalent in older adults. Increasing evidence indicates strong opioids as a valid option for chronic pain management in geriatrics. The aim of this study was to evaluate efficacy and safety of low-dose oral prolonged-release oxycodone–naloxone (OXN-PR) in patients aged ≥70 years. Methods This open-label prospective study assessed older patients naïve to strong opioids presenting with moderate-to-severe chronic pain. Patients were prescribed OXN-PR at an initial dose of 10/5 mg/day for 28 days. In case of insufficient analgesia, the initial daily dose could be increased gradually. The primary efficacy measure was change in pain intensity from baseline, assessed by a ten-point Numeric Rating Scale (NRS) at day 28 (T28). Changes in cognitive state, daily functioning, quality of life, constipation, and other adverse events were assessed. Results Of 53 patients enrolled (mean 81.7±6.2 years [range 70–92 years]), 52 (98.1%) completed the 28-day observation. At T28, the primary end point (≥30% reduction in mean pain from baseline in the absence of bowel function deterioration) was achieved in 38 patients (71.7%). OXN-PR significantly relieved pain (NRS score –3.26; P<0.0001), as well as daily need for rescue paracetamol (from 86.8% at baseline to 40.4% at T28; P<0.001), and reduced impact of pain on daily activities (Brief Pain Inventory Short Form from 6.2±1.5 to 3.4±2.1; P<0.0001). OXN-PR was also associated with significant improvement in daily functioning (Barthel Index from 53.3±14.1 to 61.3±14.3; P<0.01). No changes were observed in cognitive status and bowel function. OXN-PR was well tolerated; only one patient (1.9%) prematurely withdrew from treatment, due to drowsiness. Conclusion Findings from this open-label prospective study suggest that low-dose OXN-PR may be effective and well tolerated for treatment of moderate-to-severe chronic pain in older patients. Besides its effectiveness, these data indicate that low-dose

  16. 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.

  17. Calmodulin Mediates DNA Repair Pathways Involving H2AX in Response to Low-Dose Radiation Exposure of RAW 264.7 Macrophages

    SciTech Connect

    Smallwood, Heather S.; Lopez Ferrer, Daniel; Eberlein, P. Elis; Watson, David J.; Squier, Thomas C.

    2009-02-05

    Understanding the molecular mechanisms that modulate macrophage radioresistance is necessary for the development of effective radiation therapies, as tumor-associated macrophages promote both angiogenesis and matrix remodeling that, in turn, enhance metastasis. In this respect, we have identified a dose-dependent increase in the abundance of the calcium regulatory protein calmodulin (CaM) in RAW 264.7 macrophages upon irradiation. CaM overexpression results in increased macrophage survival following radiation exposure, acting to diminish the sensitivity to low-dose exposures. Increases in CaM abundance also result in an increase in the number of phosphorylated histone H2AX protein complexes associated with DNA repair following macrophage irradiation, with no change in the extent of double-stranded DNA damage. In comparison, when NFκB-dependent pathways are inhibited, through the expression of a dominant-negative IκB construct, there is no significant increase in phosphorylated H2AX upon irradiation. These results indicate that the molecular basis for the up-regulation of histone H2AX mediated DNA-repair pathways is not the result of nonspecific NFκB-dependent pathways or a specific threshold of DNA damage. Rather, increases in CaM abundance act to minimize the low-dose hypersensitivity to radiation to enhance macrophage radioresistance through processes that include the upregulation of DNA repair pathways involving histone protein H2AX phosphorylation.

  18. 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

  19. 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

  20. Low-Dose Tramadol and Non-Steroidal Anti-Inflammatory Drug Combination Therapy Prevents the Transition to Chronic Low Back Pain

    PubMed Central

    Orita, Sumihisa; Yamauchi, Kazuyo; Suzuki, Takane; Suzuki, Miyako; Sakuma, Yoshihiro; Kubota, Go; Oikawa, Yasuhiro; Sainoh, Takeshi; Sato, Jun; Fujimoto, Kazuki; Shiga, Yasuhiro; Abe, Koki; Kanamoto, Hirohito; Inoue, Masahiro; Kinoshita, Hideyuki; Takahashi, Kazuhisa; Ohtori, Seiji

    2016-01-01

    Study Design Retrospective study. Purpose To determine whether low-dose tramadol plus non-steroidal anti-inflammatory drug combination therapy could prevent the transition of acute low back pain to chronic low back pain. Overview of Literature Inadequately treated early low back pain transitions to chronic low back pain occur in approximately 30% of affected individuals. The administration of non-steroidal anti-inflammatory drugs is effective for treatment of low back pain in the early stages. However, the treatment of low back pain that is resistant to non-steroidal anti-inflammatory drugs is challenging. Methods Patients who presented with acute low back pain at our hospital were considered for inclusion in this study. After the diagnosis of acute low back pain, non-steroidal anti-inflammatory drug administration was started. Forty patients with a visual analog scale score of >5 for low back pain 1 month after treatment were finally enrolled. The first 20 patients were included in a non-steroidal anti-inflammatory drug group, and they continued non-steroidal anti-inflammatory drug therapy for 1 month. The next 20 patients were included in a combination group, and they received low-dose tramadol plus non-steroidal anti-inflammatory drug combination therapy for 1 month. The incidence of adverse events and the improvement in the visual analog scale score at 2 months after the start of treatment were analyzed. Results No adverse events were observed in the non-steroidal anti-inflammatory drug group. In the combination group, administration was discontinued in 2 patients (10%) due to adverse events immediately following the start of tramadol administration. At 2 months, the improvement in the visual analog scale score was greater in the combination group than in the non-steroidal anti-inflammatory drug group (p<0.001). Conclusions Low-dose tramadol plus non-steroidal anti-inflammatory drug combination therapy might decrease the incidence of adverse events and prevent

  1. 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.

  2. 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.

  3. Persistent developmental toxicity in rat offspring after low dose exposure to a mixture of endocrine disrupting pesticides.

    PubMed

    Jacobsen, Pernille Rosenskjold; Axelstad, Marta; Boberg, Julie; Isling, Louise Krag; Christiansen, Sofie; Mandrup, Karen Riiber; Berthelsen, Line Olrik; Vinggaard, Anne Marie; Hass, Ulla

    2012-09-01

    There is growing concern of permanent damage to the endocrine and nervous systems after developmental exposure to endocrine disrupting chemicals. In this study the permanent reproductive and neurobehavioral effects of combined exposure to five endocrine disrupting pesticides, epoxiconazole, mancozeb, prochloraz, tebuconazole and procymidone, were examined. Pregnant and lactating rat dams were dosed with a mixture of the five pesticides at three different doses, or with the individual pesticides at one of two doses. Adverse effects were observed in young and adult male offspring from the group exposed to the highest dose of the mixture. These included reduced prostate and epididymis weights, increased testes weights, altered prostate histopathology, increased density of mammary glands, reduced sperm counts, and decreased spatial learning. As no significant effects were seen following single compound exposure at the doses included in the highest mixture dose, these results indicate cumulative adverse effects of the pesticide mixture. PMID:22677472

  4. Prolonged exposure to low doses of ozone: short- and long-term changes in behavioral performance in mice.

    PubMed

    Sorace, A; de Acetis, L; Alleva, E; Santucci, D

    2001-02-01

    Two separate experiments were designed to assess the effects of ozone exposure on outbred CD-1 mice. In the first experiment, adult males were exposed continuously to O3 at 0, 0.3, or 0.6 ppm for 30 days and their behavior was assessed in a 5-min open-field test on exposure days 4 and 19 and on day 3 after the end of the exposure phase. In addition, mice performed a Morris water maze task from exposure day 24 to 28. In the second experiment, adult females were exposed from 30 days prior to the formation of breeding pairs until gestational day 17 to the same doses used in the first experiment. Litters were fostered at birth to untreated dams and neurobehavioral development of the offspring was investigated until adulthood. Specifically, somatic and sensorimotor development [postnatal day (PND) 2-20], homing performance (PND 12), motor activity (PND 21), passive avoidance (PND 22-23), water maze performances (PND 70-74), and response to a nociceptive stimulus (PND 100) were assessed. Results from both experiments confirm that exposure to O3 slightly but selectively affected neurobehavioral performance in rodents. Exposure to O3 did not grossly affect neurobehavioral development, whereas it consistently impaired reversal learning in the Morris water maze test in both prenatally and adult exposed mice. Moreover, longer latency to step-through in the first trial of the passive avoidance test and a decrease in wall rearing in the hot-plate test were recorded in O3 prenatally exposed mice. Except for the first open-field test, altered responses were observed only in animals exposed at the intermediate concentration of the gas. Adaptation and/or onset of compensatory mechanisms might be responsible for the lack of linear dose-response relationships.

  5. Absence of long-term behavioral effects after sub-chronic administration of low doses of methamidophos in male and female rats.

    PubMed

    Temerowski, M; van der Staay, F J

    2005-01-01

    Putative long-term learning and memory effects of low-dose exposure to the cholinesterase inhibitor organophosphate methamidophos (Tamaron) early in life were studied in two parallel studies in middle-aged rats. Methamidophos was administered via the drinking water to female and male Wistar rats using nominal concentrations of 0 (control), 0.5, 1.5 and 4.5 ppm active ingredient for 16 weeks. Animals were then maintained for a recovery period of about 14 months without treatment. They were tested in the standard and repeated acquisition version of the Morris water escape task in two series of tests starting 33 and 55 weeks after termination of the methamidophos treatment. Functional observations and motor activity measurements preceded each series of testing. Exposure to methamidophos was confirmed by measurement of brain cholinesterase (ChE-B) at the end of the 16 weeks of treatment in satellite animals. At 4.5 ppm a biologically relevant reduction in ChE-B activity was observed without clinical signs of intoxication (males: 66%, females: 64% of control activity). Mid- and low-dose exposure to methamidophos revealed ChE-B activity of 90% and 100% in males and 88% and 97% in females, respectively. General examinations of the animals during treatment revealed no clinical signs suggesting cholinergic stimulation. Functional observations and motor activity measurements exhibited no relevant differences between treatment groups and controls. Neither the performance in the standard Morris water escape task that predominantly measures spatial reference memory, nor in the repeated acquisition task in the Morris tank, which predominantly measures spatial working memory, was affected by treatment with methamidophos. A small number of statistically significant differences were noted in the mean performance level between treatment groups, or between treatment by sex groups in both versions of the Morris task. However, these findings appeared to be idiosyncratic for a

  6. Occupational exposure to low doses of ionizing radiation and cataract development: a systematic literature review and perspectives on future studies.

    PubMed

    Hammer, Gaël P; Scheidemann-Wesp, Ulrike; Samkange-Zeeb, Florence; Wicke, Henryk; Neriishi, Kazuo; Blettner, Maria

    2013-08-01

    Ionizing radiation is a well-known but little understood risk factor for lens opacities. Until recently, cataract development was considered to be a deterministic effect occurring at lens doses exceeding a threshold of 5-8 Gy. Substantial uncertainty about the level and the existence of a threshold subsists. The International Commission on Radiation Protection recently revised it to 0.5 Gy. Based on a systematic literature review of epidemiological studies on exposure to low levels of ionizing radiation and the occurrence of lens opacities, a list of criteria for new epidemiological studies was compiled, and a list of potential study populations was reviewed. Among 24 publications finally identified, six report analyses of acute exposures in atomic bomb survivors and Chernobyl liquidators, and the others report analyses of protracted exposures in occupationally, medically or accidentally exposed populations. Three studies investigated a dose threshold: in atomic bomb survivors, the best estimates were 1 Sv (95 % CI <0-0.8 Sv) regarding lensectomies; in survivors exposed as children, 0.6 Sv (90 % CI <0.0-1.2 Sv) for cortical cataract prevalence and 0.7 Sv (90 % CI 0.0-2.8 Sv) for posterior subcapsular cataract; and in Chernobyl liquidators, 0.34 Sv (95 % CI 0.19-0.68 Sv) for stage 1 cataract. Current studies are heterogeneous and inconclusive regarding the dose-response relationship. Protracted exposures and high lens doses occur in several occupational groups, for instance, in physicians performing fluoroscopy-guided interventional procedures, and in accidentally exposed populations. New studies with a good retrospective exposure assessment are feasible and should be initiated.

  7. Low dose monoethyl phthalate (MEP) exposure triggers proliferation by activating PDX-1 at 1.1B4 human pancreatic beta cells.

    PubMed

    Güven, Celal; Dal, Fulya; Aydoğan Ahbab, Müfide; Taskin, Eylem; Ahbab, Süleyman; Adin Çinar, Suzan; Sırma Ekmekçi, Sema; Güleç, Çağrı; Abacı, Neslihan; Akçakaya, Handan

    2016-07-01

    Phthalate plasticizers used in a wide range of common plastic products are released into the environment and may pose a risk of increased incidence of type 2 diabetes. In this work, we studied the effects of monoethyl phthalate (MEP), the metabolite of diethyl phthalate, exposure on 1.1B4 human pancreatic beta cells at low doses (1-1000 nM). We showed that MEP treatment induced proliferation in 1.1B4 cells. Also PCNA protein expression levels were increased related to proliferation induction. It has been noted that phthalates can exert estrogen mediated response by interacting with ER. In our study 24 h MEP treatment decreased ERα protein expression level conversely it increased the same protein expression level after 72 h treatment. Also MEP treatment decreased ERβ expression after 72 h at 1.1B4 cells. Our results further show that insulin content of 1.1B4 cells were increased with low dose MEP treatment. Along with our insulin content results, PDX- 1 expression levels were also increased at 1.1B4 cells with MEP treatment. These findings suggest that MEP acts as an estrogenic compound and PPARγ agonist at lower concentrations. Also it should be noted that PDX-1 may be a critical regulator of 1.1B4 cells treated with MEP.

  8. Multiple vaginal exposures to low doses of R5 simian-human immunodeficiency virus: strategy to study HIV preclinical interventions in nonhuman primates.

    PubMed

    Otten, Ron A; Adams, Debra R; Kim, Caryn N; Jackson, Eddie; Pullium, Jennifer K; Lee, Kemba; Grohskopf, Lisa A; Monsour, Michael; Butera, Sal; Folks, Thomas M

    2005-01-15

    A nonhuman-primate model of human immunodeficiency virus type 1 (HIV-1) infection that more closely emulates human heterosexual transmission by use of multiple exposures to low doses of virus is critical to better evaluate intervention strategies that include microbicides or vaccines. In this report, we describe such a system that uses female pig-tailed macaques exposed vaginally to a CCR5-using simian-human immunodeficiency virus (SHIV(SF162P3)) at weekly intervals. Results of dose-titration experiments indicated that 3 once-weekly exposures to 10 tissue culture infectious doses of SHIV(SF162P3) resulted in consistent transmission of virus and establishment of systemic infection. The efficacy of cellulose acetate phthalate (CAP) as a vaginal microbicide was evaluated by applying it to the vaginal vault of macaques (n = 4) 15 min before each weekly exposure to SHIV(SF162P3). One conclusion that can be drawn from the data derived from multiple exposures to virus is that CAP prevented infection in 12 of 13 possible chances for infection, over the course of 39 total exposures. Our findings provide a basis to refine monkey models for transmission of HIV-1, which may be relevant to preclinical evaluation for therapeutic interventions.

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

    PubMed

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

    2016-02-15

    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

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

    PubMed

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

    2016-02-15

    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.

  11. 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

    2015-12-01

    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.

  12. Induction of potent local cellular immunity with low dose X4 SHIV{sub SF33A} vaginal exposure

    SciTech Connect

    Tasca, Silvana; Tsai, Lily; Trunova, Nataliya; Gettie, Agegnehu; Saifuddin, Mohammed; Bohm, Rudolf; Chakrabarti, Lisa; Cheng-Mayer, Cecilia

    2007-10-10

    Intravaginal inoculation of rhesus macaques with varying doses of the CXCR4 (X4)-tropic SHIV{sub SF33A} isolate revealed a threshold inoculum for establishment of systemic virus infection and a dose dependency in overall viral burden and CD4+ T cell depletion. While exposure to inoculum size of 1000 or greater 50% tissue infectious dose (TCID{sub 50}) resulted in high viremia and precipitous CD4+ T cell loss, occult infection was observed in seven of eight macaques exposed to 500 TCID{sub 50} of the same virus. The latter was characterized by intermittent detection of low level virus with no evidence of seroconversion or CD4+ T cell decline, but with signs of an ongoing antiviral T cell immune response. Upon vaginal re-challenge with the same limiting dose 11-12 weeks after the first, classic pathogenic X4 SHIV{sub SF33A} infection was established in four of the seven previously exposed seronegative macaques, implying enhanced susceptibility to systemic infection with prior exposure. Pre-existing peripheral SIV gag-specific CD4+ T cells were more readily demonstrable in macaques that became systemically infected following re-exposure than those that were not. In contrast, early presence of circulating polyfunctional cytokine secreting CD8+ T cells or strong virus-specific proliferative responses in draining lymph nodes and in the gut associated lymphoid tissue (GALT) following the first exposure was associated with protection from systemic re-infection. These studies identify the gut and lymphoid tissues proximal to the genital tract as sites of robust CD8 T lymphocyte responses that contribute to containment of virus spread following vaginal transmission.

  13. Persistent Cognitive Alterations in Rats after Early Postnatal Exposure to Low Doses of the Organophosphate Pesticide, Diazinon

    PubMed Central

    Timofeeva, Olga A.; Roegge, Cindy S.; Seidler, Frederic J.; Slotkin, Theodore A.; Levin, Edward D.

    2008-01-01

    Background Developmental neurotoxicity of organophosphorous insecticides (OPs) involves multiple mechanisms in addition to cholinesterase inhibition. We have found persisting effects of developmental chlorpyrifos (CPF) and diazinon (DZN) on cholinergic and serotonergic neurotransmitter systems and gene expression as well as behavioral function. Both molecular/neurochemical and behavioral effects of developmental OP exposure have been seen at doses below those which cause appreciable cholinesterase inhibition. Objectives We sought to determine if developmental DZN exposure at doses which do not produce significant acetylcholinesterase inhibition cause cognitive deficits. Methods Rats were exposed to DZN on postnatal days 1-4 at doses (0.5 and 2 mg/kg/d) that span the threshold for cholinesterase inhibition. They were later examined with a cognitive battery tests similar to that used with CPF. Results In the T-maze DZN caused significant hyperactivity in the initial trials of the session, but not later. In a longer assessment of locomotor activity no DZN-induced changes were seen over a 1-hour session. Prepulse inhibition was reduced by DZN exposure selectively in males vs. females; DZN eliminated the sex difference present in controls. In the radial maze, the lower but not higher DZN dose significantly impaired spatial learning. This has previously been seen with CPF as well. The lower dose DZN group also showed significantly greater sensitivity to the memory-impairing effects of the anticholinergic drug scopolamine. Conclusions Neonatal DZN exposure below the threshold for appreciable cholinesterase inhibition caused neurocognitive deficits in adulthood. The addition of some inhibition of AChE with a higher dose reversed the cognitive impairment. This non-monotonic dose-effect function has also been seen with neurochemical effects. Some of the DZN effects on cognition resemble those seen earlier for CPF, some differ. Our data suggest that DZN and CPF affect

  14. γ-H2AX responds to DNA damage induced by long-term exposure to combined low-dose-rate neutron and γ-ray radiation.

    PubMed

    Zhang, Junlin; He, Ying; Shen, Xianrong; Jiang, Dingwen; Wang, Qingrong; Liu, Qiong; Fang, Wen

    2016-01-01

    Risk estimates for low-dose radiation (LDR) remain controversial. The possible involvement of DNA repair-related genes in long-term low-dose-rate neutron-gamma radiation exposure is poorly understood. In this study, 60 rats were divided into control groups and irradiated groups, which were exposed to low-dose-rate n-γ combined radiation (LDCR) for 15, 30, or 60 days. The effects of different cumulative radiation doses on peripheral blood cell (PBC), subsets of T cells of peripheral blood lymphocytes (PBL) and DNA damage repair were investigated. Real-time PCR and immunoblot analyses were used to detect expression of DNA DSB-repair-related genes involved in the NHEJ pathway, such as Ku70 and Ku80, in PBL. The mRNA level of H2AX and the expression level of γ-H2AX were detected by real-time PCR, immunoblot, and flow cytometry. White blood cells (WBC) and platelets (PLT) of all ionizing radiation (IR) groups decreased significantly, while no difference was seen between the 30 day and 60 day exposure groups. The numbers of CD3(+), CD4(+) T cells and CD4(+)/CD8(+) in the PBL of IR groups were lower than in the control group. In the 30 day and 60 day exposure groups, CD8(+) T cells decreased significantly. Real-time PCR and immunoblot results showed no significant difference in the mRNA and protein expression of Ku70 and Ku80 between the control groups and IR groups. However, the mRNA of H2AX increased significantly, and there was a positive correlation with dose. There was no difference in the protein expression of γ-H2AX between 30 day and 60 day groups, which may help to explain the damage to PBL. In conclusion, PBL damage increased with cumulative dose, suggesting that γ-H2AX, but neither Ku70 nor Ku80, plays an important role in PBL impairment induced by LDCR.

  15. Corticosterone-regulated actions in the rat brain are affected by perinatal exposure to low dose of bisphenol A.

    PubMed

    Poimenova, A; Markaki, E; Rahiotis, C; Kitraki, E

    2010-05-19

    The estrogen-mimicking endocrine disrupter bisphenol A (BPA) which is used in the manufacture of plastic and epoxy resins, is one of the world's most heavily produced synthetic chemicals. BPA is detected in animal tissues, and its bio-accumulation has shown to be higher in the fetus than the mother. Exposure to doses below the daily safe limit has been reported to affect the sexual differentiation of the brain and modify the behavior of the exposed rodent offspring. The aim of the present study was to investigate in the rat the possible organizational effects of low BPA exposure on glucocorticoid-regulated responses. Female breeders were exposed to 40 microg/kg b.w. BPA daily throughout pregnancy and lactation. Plasma corticosterone levels and the two types of hippocampal corticosteroid receptors (GR and MR) were determined in mid-adolescent offspring under basal conditions and following a Y-maze task. BPA treated females had higher corticosterone levels than control females and BPA males and lower GR levels than BPA males, under basal conditions. Following the mildly stressful experience of Y-maze, corticosterone levels were increased in BPA-treated animals of both sexes, compared to the controls. GR levels were also increased in BPA-treated females compared to males. No effect of BPA was observed on MR levels, whereas the Y-maze experience significantly decreased receptors' levels in both female groups. The animals' performance in the task was also evaluated. BPA exposure significantly impaired the spatial recognition memory in both sexes, and modified the behavioural coping in a sex-dependent manner. Female BPA-treated offspring exhibited increased "anxiety-like" behaviour and dramatic loss of exploration attitude during the task, in comparison to males. This study provides for the first time evidence that corticosterone and its actions in the brain are sensitive to the programming effects of BPA at a dose below the currently acceptable daily intake. PMID

  16. [Using atomic force microscopy to analyze morphological changes and mechanical properties caused by cellular exposure to low doses of pesticides].

    PubMed

    L'Abbate, N; Lasalvia, M; Perna, G; D'Antonio, P; Quartucci, G; Gallo, C; Capozzi, V

    2012-01-01

    A commercial pesticide is usually composed of active ingredients and formulants. Among the active ingredients, Deltamethrin is a pyrethroid chemical widely used for synthesizing pesticides products which are very effective in damaging the central nervous system of pests. In this work, we analyze, by means of atomic force microscopy (AFM), cellular morphological changes induced by exposure to a Deltamethrin-based commercial pesticide (Decaflow). AFM microscopy, in addition to the well-known characterization of the cellular topography, has the ability to monitor interesting biomechanical parameters of the surface as roughness and elastic modulus. In particular, we exposed normal human keratinocytes for 24 hours at different solutions of Decaflow, well below the threshold of cytotoxicity. The AFM images of exposed cells show alterations of surface cell shape. Moreover exposed cells are characterized by an increase of the value of membrane roughness. The mechanical properties of cells are also modified after Decaflow exposure, as confirmed by a decrease of the elasticity modulus with increasing the concentration of pesticide.

  17. 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.

  18. 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

  19. Behavior of Bragg gratings, written in germanosilicate fibers, against [gamma]-ray exposure at low dose rate

    SciTech Connect

    Niay, P.; Bernage, P.; Douay, M.; Fertein, E.; Lahoreau, F. . Lab. de Dynamique Moleculaire et Photonique); Bayon, J.F.; Georges, T.; Monerie, M. ); Ferdinand, P.; Rougeault, S.; Cetier, P. )

    1994-11-01

    Bragg gratings have been written within four germanosilicate fibers either by a pulsed or by a continuous-wave exposure of each fiber to a coherent UV two-beam interference pattern. These gratings have been exposed under steady state conditions to [gamma]-ray doses as high as 10[sup 4] Grays. The dose rates ranged between 10 Gy/h and 1.3 [times] 10[sup 2] Gy/h. The transmission spectra of the fibers have been recorded during and after the [sup 60]Co irradiation, near the grating Bragg wavelengths. Whereas the induced loss reached 600 dB/km near 1.3 [mu]m, no significant change in the spectral characteristics of the gratings could be detected within the experimental accuracy, enabling their future use in a nuclear environment.

  20. Repeated exposure of rhesus macaques to low doses of simian immunodeficiency virus (SIV) did not protect them against the consequences of a high-dose SIV challenge.

    PubMed

    Dittmer, U; Stahl-Hennig, C; Coulibaly, C; Nisslein, T; Lüke, W; Fuchs, D; Bodemer, W; Petry, H; Hunsmann, G

    1995-06-01

    As part of an in vivo titration study of the macaque simian immunodeficiency virus (SIVmac) strain 251/spl, macaques were inoculated intravenously with various dilutions of this infectious SIVmac. Seven animals received dilutions from 10(-3) to 10(-6) of SIVmac251/spl. Two monkeys infected with the 10(-3) dilution of SIVmac exhibited a productive infection as indicated by seroconversion, detection of genomic RNA and proviral DNA and positive virus isolation. These animals showed a cytotoxic T cell (CTL) response against different SIVmac proteins without any measurable T cell proliferation. The five macaques receiving higher virus dilutions did not seroconvert and were negative for both viral RNA and for infectious virus, although proviral DNA was detected in their peripheral blood mononuclear cells. In contrast to the animals receiving the 10(-3) virus dilution, these five silently infected monkeys developed an SIV-specific proliferative T cell response but SIV-specific CTL could not be observed. The SIV-specific T cell proliferation of the silently infected animals could be boosted by a second low-dose exposure with a 10(-4) or 10(-5) dilution of SIVmac251/spl. The virological status of the animals was not changed following this second virus inoculation. Four months later these macaques were challenged intravenously with 2 ml of a 10(-4) dilution of SIVmac251/32H containing 10 monkey ID50. After this challenge all SIV-pre-exposed animals and three naive controls became productively infected. In addition, all infected animals developed typical signs of an immunodeficiency within 6 months after infection. These observations indicate that macaques infected silently by a low-dose exposure to infectious virus generated a virus-specific cellular immune response. However, SIV-specific T cell proliferation alone could not protect the monkeys against an intravenous challenge with SIVmac and the subsequent development of AIDS-like symptoms.

  1. Dietary exposure to low doses of bisphenol A: effects on reproduction and development in two generations of C57BL/6J mice.

    PubMed

    Kobayashi, Kenichi; Ohtani, Katsumi; Kubota, Hisayo; Miyagawa, Muneyuki

    2010-09-01

    The present study was conducted to examine the effects of low-dose exposure to bisphenol A on reproduction and development in two generations of mice. Pregnant female C57BL/6J mice (F(0)) were fed a diet containing low doses of bisphenol A (0, 0.33, 3.3, or 33 ppm) from gestational day 6 through postnatal day 22, and the weanlings (F(1) and F(2)) from each F(0) and F(1) dam group, respectively, were also fed these same concentrations of bisphenol A ad libitum until sacrifice. There were no treatment-related changes in body weight, body weight gain, food consumption, gestation length, or the number of live births on postnatal day 1 in F(0) dams between the control group and bisphenol A groups. Sex ratio and viability were similar in all F(1) pups. No treatment-related changes were observed in body weight, food consumption, developmental parameters, anogenital distance, or weight of any of the organs (liver, kidney, heart, spleen, thymus, testis, ovary, or uterus) in F(1) and F(2) adults in either sex. The epididymis weight was slightly higher with 0.33 and 3.3 ppm in F(1) males, but this slight increase was neither dose dependent nor seen across generations. There were no treatment-related effects of bisphenol A on cauda epididymal sperm count or sperm motility in F(1) or F(2) males. These findings indicate that dietary exposure to bisphenol A between 0.33 and 33 ppm does not adversely affect reproduction or development as assessed in two generations of mice.

  2. Effect of low-dose diuretics on the level of serum cystatin C and prognosis in patients with asymptomatic chronic heart failure

    PubMed Central

    ZHANG, YUAN; LI, YANMING; CHENG, GUANCHANG

    2015-01-01

    The aim of the present study was to investigate the effect of low-dose diuretics on the serum cystatin C (CysC) and serum creatinine (Scr) levels, and on the prognosis in patients with asymptomatic chronic heart failure (HF). A total of 66 asymptomatic chronic HF patients were divided into the observation and control groups (n=33 in each group). Patients in the control group were treated with a routine treatment, while the patients in the observation group were treated with the diuretic hydrochlorothiazide along with the same routine treatment as the control group. The left ventricular ejection fraction (LVEF), serum CysC levels, Scr levels, heart function, prognosis, adverse reactions and complications of the patients in the two groups were compared prior to and following treatment. The LVEF increased in the two groups following treatment, while the levels of serum CysC and Scr decreased. The LVEF in the observation group increased following treatment for 1, 3 and 6 months compared with the LVEF values in the control group. In addition, the levels of serum CysC and Scr in the observation group were found to be lower compared with those in the control group (P<0.05). The incidence of adverse prognosis following treatment for 6 months in the observation group was lower compared with that in the control group (P<0.05). The proportion of HF patients with New York Heart Association (NYHA) class I and II increased following treatment for 6 months in the two groups (P<0.05). However, in the observation group, a higher number of patients exhibited class I and II disease after treatment for 6 months compared with the number in the control group (P<0.05). Furthermore, no statistically significant difference was observed between adverse reactions and complications in the two groups (P>0.05). In conclusion, low-dose diuretics may effectively improve the cardiac and renal functions and prognosis in asymptomatic chronic HF patients, without increasing the incidence of side

  3. 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

  4. 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.

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

    PubMed Central

    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. PMID:26222054

  6. The effects of early postnatal exposure to a low dose of decabromodiphenyl ether (BDE-209) on serum metabolites in male mice.

    PubMed

    Eguchi, Akifumi; Miyaso, Hidenobu; Mori, Chisato

    2016-01-01

    The toxicity of decabromodiphenyl ether (BDE-209) has been reported in several studies. However, there is not much known about the toxicological biomarkers that characterize BDE-209 exposure. In this study, we subcutaneously exposed mice to 0.025 mg/kg/day BDE-209 on postnatal days 1‑5 and sacrificed the animals at 12 weeks of age (day 84). Flow injection analysis and hydrophilic interaction chromatography-triple quadrupole mass spectrometry were used to determine the serum metabolomes of these mice in order to characterize the effects of BDE-209 exposure. Data analysis showed a good separation between control and exposed mice (R(2) = 0.953, Q(2) = 0.728, and ANOVA of the cross‑validated residuals (CV‑ANOVA): P‑value = 0.0317) and 54 metabolites were identified as altered in the exposed animals. These were selected using variable importance (VIP) and loadings scaled by a correlation coefficient criteria and orthogonal partial least squares discriminant analysis (OPLS‑DA). BDE‑209‑exposed mice showed lower levels of long-chain acylcarnitines and citrate cycle-related metabolites, and higher levels of some amino acids, long-chain phospholipids, and short-chain acylcarnitines. The disruption of fatty acid, carbohydrate, and amino acid metabolism observed in the serum metabolome might be related to the previously observed impaired spermatogenesis in mice with early postnatal exposure to a low dose of BDE-209. PMID:27665776

  7. 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

  8. 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.

  9. Effects of perinatal exposure to low-dose cadmium on thyroid hormone-related and sex hormone receptor gene expressions in brain of offspring.

    PubMed

    Ishitobi, Hiromi; Mori, Kohki; Yoshida, Katsumi; Watanabe, Chiho

    2007-07-01

    Perinatal cadmium (Cd) exposure has been shown to alter behaviors and reduce learning ability of offspring. A few studies have shown that Cd reduced serum thyroid hormones (THs), which are important for brain development during the perinatal period. Brain specific genes, neurogranin (RC3) and myelin basic protein (BMP), are known to be regulated by TH through TH receptors (TR). It has been suggested that RC3 may play roles in memory and learning. In addition, Cd has been suggested to have estrogen-like activity. To evaluate the effects of perinatal low-dose exposure to Cd on thyroid hormone-related gene (RC3, TR-beta1, MBP, RAR-beta) and sex hormone receptor gene (ER-alpha, ER-beta and PgR) expressions in the brain and on behaviors of offspring, mice were administered with 10ppm Cd (from gestational day 1 to postnatal day 10) and/or 0.025% methimazole (MMI; anti-thyroid drug) (from gestational day 12 to postnatal day 10) in drinking water. Also, 0.1% MMI was administered as a positive control (high MMI group). RC3 mRNA expression was reduced in the female brain of combined exposure and high MMI groups and was negatively correlated with the activity in the open-field. ER-alpha, ER-beta and PgR mRNA expressions were decreased in male and female Cd, and female Cd+MMI groups, respectively; among these changes the reduced expression of PgR was opposite to estrogenic action. These results suggested that perinatal exposure to Cd disrupted the gene expressions of sex hormone receptors, which could not be considered to be a result of estrogenic action. Our study indicates that alteration in the gene expressions of RC3 and sex hormone receptors in the brain induced by perinatal Cd and MMI exposure might be one mechanism of developmental toxicity of Cd. PMID:17408746

  10. Renal effects of chronic exposure to malathion in Octodon degus.

    PubMed

    Bosco, C; Rodrigo, R; Diaz, S; Borax, J

    1997-10-01

    We studied the effects of chronic exposure to malathion in the kidney of Octodon degus, a caviomorph whose habitat may be exposed to pesticides currently used in Chilean agriculture. A group of adult female animals received malathion (200 ppm) as sole drinking fluid for 90 days. Kidneys showed signs of histologic damage, marked by hyperplasia and hypertrophy of tubular cells. Exposed animals had unchanged glomerular filtration rates and renal handling of sodium and chloride, but a significant increase in fractional excretion of potassium resulted from this treatment. The activities of Na+/K(+)-ATPase and Mg(2+)-ATPase in renal cortex and outer medulla were not affected by malathion exposure. This study provides evidence of both morphologic and functional renal damage elicited by chronic exposure of O. degus to a low dose of malathion. Morphologic alterations in glomerulus were accompanied by either morphologic and functional impairments of the distal nephron.

  11. The effects of postnatal exposure to low-dose bisphenol-A on activity-dependent plasticity in the mouse sensory cortex.

    PubMed

    Kelly, Emily A; Opanashuk, Lisa A; Majewska, Ania K

    2014-01-01

    Bisphenol-A (BPA) is a monomer used in the production of polycarbonate plastics, epoxies and resins and is present in many common household objects ranging from water bottles, can linings, baby bottles, and dental resins. BPA exposure has been linked to numerous negative health effects throughout the body, although the mechanisms of BPA action on the developing brain are still poorly understood. In this study, we sought to investigate whether low dose BPA exposure during a developmental phase when brain connectivity is being organized can cause long-term deleterious effects on brain function and plasticity that outlast the BPA exposure. Lactating dams were orally exposed to 25 μg/kg/day of BPA (one half the U.S. Environmental Protection Agency's 50 μg/kg/day rodent dose reference) or vehicle alone from postnatal day (P)5 to P21. Pups exposed to BPA in their mother's milk exhibited deficits in activity-dependent plasticity in the visual cortex during the visual critical period (P28). To determine the possible mechanisms underlying BPA action, we used immunohistochemistry to examine histological markers known to impact cortical maturity and developmental plasticity and quantified cortical dendritic spine density, morphology, and dynamics. While we saw no changes in parvalbumin neuron density, myelin basic protein expression or microglial density in BPA-exposed animals, we observed increases in spine density on apical dendrites in cortical layer five neurons but no significant alterations in other morphological parameters. Taken together our results suggest that exposure to very low levels of BPA during a critical period of brain development can have profound consequences for the normal wiring of sensory circuits and their plasticity later in life. PMID:25374513

  12. The effects of postnatal exposure to low-dose bisphenol-A on activity-dependent plasticity in the mouse sensory cortex

    PubMed Central

    Kelly, Emily A.; Opanashuk, Lisa A.; Majewska, Ania K.

    2014-01-01

    Bisphenol-A (BPA) is a monomer used in the production of polycarbonate plastics, epoxies and resins and is present in many common household objects ranging from water bottles, can linings, baby bottles, and dental resins. BPA exposure has been linked to numerous negative health effects throughout the body, although the mechanisms of BPA action on the developing brain are still poorly understood. In this study, we sought to investigate whether low dose BPA exposure during a developmental phase when brain connectivity is being organized can cause long-term deleterious effects on brain function and plasticity that outlast the BPA exposure. Lactating dams were orally exposed to 25 μg/kg/day of BPA (one half the U.S. Environmental Protection Agency’s 50 μg/kg/day rodent dose reference) or vehicle alone from postnatal day (P)5 to P21. Pups exposed to BPA in their mother’s milk exhibited deficits in activity-dependent plasticity in the visual cortex during the visual critical period (P28). To determine the possible mechanisms underlying BPA action, we used immunohistochemistry to examine histological markers known to impact cortical maturity and developmental plasticity and quantified cortical dendritic spine density, morphology, and dynamics. While we saw no changes in parvalbumin neuron density, myelin basic protein expression or microglial density in BPA-exposed animals, we observed increases in spine density on apical dendrites in cortical layer five neurons but no significant alterations in other morphological parameters. Taken together our results suggest that exposure to very low levels of BPA during a critical period of brain development can have profound consequences for the normal wiring of sensory circuits and their plasticity later in life. PMID:25374513

  13. Stress and combined exposure to low doses of pyridostigmine bromide, DEET, and permethrin produce neurochemical and neuropathological alterations in cerebral cortex, hippocampus, and cerebellum.

    PubMed

    Abdel-Rahman, A; Abou-Donia, Suzanne; El-Masry, Eman; Shetty, Ashok; Abou-Donia, Mohamed

    2004-01-23

    Exposure to a combination of stress and low doses of the chemicals pyridostigmine bromide (PB), DEET, and permethrin in adult rats, a model of Gulf War exposure, produces blood-brain barrier (BBB) disruption and neuronal cell death in the cingulate cortex, dentate gyrus, thalamus, and hypothalamus. In this study, neuropathological alterations in other areas of the brain where no apparent BBB disruption was observed was studied following such exposure. Animals exposed to both stress and chemical exhibited decreased brain acetylcholinesterase (AChE) activity in the midbrain, brainstem, and cerebellum and decreased m2 muscarinic acetylcholine (ACh) receptor ligand binding in the midbrain and cerebellum. These alterations were associated with significant neuronal cell death, reduced microtubule-associated protein (MAP-2) expression, and increased glial fibrillary acidic protein (GFAP) expression in the cerebral cortex and the hippocampal subfields CA1 and CA3. In the cerebellum, the neurochemical alterations were associated with Purkinje cell loss and increased GFAP immunoreactivity in the white matter. However, animals subjected to either stress or chemicals alone did not show any of these changes in comparison to vehicle-treated controls. Collectively, these results suggest that prolonged exposure to a combination of stress and the chemicals PB, DEET, and permethrin can produce significant damage to the cerebral cortex, hippocampus, and cerebellum, even in the absence of apparent BBB damage. As these areas of the brain are respectively important for the maintenance of motor and sensory functions, learning and memory, and gait and coordination of movements, such alterations could lead to many physiological, pharmacological, and behavioral abnormalities, particularly motor deficits and learning and memory dysfunction. PMID:14675905

  14. 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.

  15. 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...

  16. Exposure to Low-Dose 56Fe-Ion Radiation Induces Long-Term Epigenetic Alterations in Mouse Bone Marrow Hematopoietic Progenitor and Stem Cells

    PubMed Central

    Chang, Jianhui; Feng, Wei; Wang, Yingying; Allen, Antiño R.; Turner, Jennifer; Stewart, Blair; Raber, Jacob; Zhou, Daohong

    2014-01-01

    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 56Fe 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 56Fe-ion irradiation on epigenetic alterations in bone marrow mononuclear cells (BM-MNCs) and hematopoietic progenitor and stem cells (HPSCs). Exposure to 56Fe 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 56Fe 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 56Fe-ion radiation. These findings suggest that epigenetic reprogramming is possibly involved in the

  17. 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. PMID:27148865

  18. 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...

  19. [Behavioral analysis of chronic exposure to diphenylarsinic and associated influence on central nervous systems].

    PubMed

    Miyagawa, Kazuya; Narita, Minoru; Miyatake, Mayumi; Kato, Koichi; Yamanaka, Kenzo; Suzuki, Tsutomu

    2007-11-01

    It has been clinically reported that chronic exposure to diphenylarsinic acid (DPAA) induced prominent cerebellar symptoms in apartment building residents in Kamisu, Japan. The aim of the present study was then to investigate the effect of chronic treatment with DPAA on the central motor impairment in mice. In the present study, we found that chronic in vivo exposure to a high dose of DPAA induced motor impairment in adult mice. This impairment was reversed by withdrawal following chronic DPAA treatment. The [35S]GTPgammaS binding assay showed the down-regulation of the dopamine receptor function in the striatum in adult mice treated with DPAA. We also found that neonatal exposure to a low dose of DPAA induced motor learning impairment in mice. Furthermore, treatment with an extremely low dose of DPAA caused the activation of caspase-3, the increase in glial fibrillary acidic protein-like immunoreactivity (IR) and the reduction in levels of myelin-associated glycoprotein-IR in mouse cerebellum neuron/glia co-cultures. In addition, we found that neonatal exposure to a low dose of DPAA induced anxiogenic behavior in a plus maze in mice. Taken together, these results suggest that chronic treatment with DPAA may induce motor impairment in adult mice. Moreover, neonatal exposure to DPAA leads to the irreversible motor impairment associated with abnormalities in the cerebellum.

  20. 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.

  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. Very Low Dose Fetal Exposure to Chernobyl Contamination Resulted in Increases in Infant Leukemia in Europe and Raises Questions about Current Radiation Risk Models

    PubMed Central

    Busby, Christopher C.

    2009-01-01

    Following contamination from the Chernobyl accident in April 1986 excess infant leukemia (0–1 y) was reported from five different countries, Scotland, Greece, Germany, Belarus and Wales and Scotland combined. The cumulative absorbed doses to the fetus, as conventionally assessed, varied from 0.02 mSv in the UK through 0.06 mSv in Germany, 0.2 mSv in Greece and 2 mSv in Belarus, where it was highest. Nevertheless, the effect was real and given the specificity of the cohort raised questions about the safety of applying the current radiation risk model of the International Commission on Radiological Protection (ICRP) to these internal exposures, a matter which was discussed in 2000 by Busby and Cato [7,8] and also in the reports of the UK Committee examining Radiation Risk from Internal Emitters. Data on infant leukemia in the United Kingdom, chosen on the basis of the cohorts defined by the study of Greece were supplied by the UK Childhood Cancer Research Group. This has enabled a study of leukemia in the combined infant population of 15,466,845 born in the UK, Greece, and Germany between 1980 and 1990. Results show a statistically significant excess risk RR = 1.43 (95% CI 1.13 < RR < 1.80 (2-tailed); p = 0.0025) in those born during the defined peak exposure period of 01/07/86 to 31/12/87 compared with those born between 01/01/80 and 31/12/85 and 01/01/88 and 31/12/90. The excess risks in individual countries do not increase monotonically with the conventionally calculated doses, the relation being biphasic, increasing sharply at low doses and falling at high doses. This result is discussed in relation to fetal/cell death at higher doses and also to induction of DNA repair. Since the cohort is chosen specifically on the basis of exposure to internal radionuclides, the result can be expressed as evidence for a significant error in the conventional modeling for such internal fetal exposures. PMID:20049249

  4. 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.

  5. Low-dose oral prolonged-release oxycodone/naloxone for chronic pain in elderly patients with cognitive impairment: an efficacy–tolerability pilot study

    PubMed Central

    Petrò, Emiliano; Ruffini, Elena; Cappuccio, Melania; Guerini, Valeria; Belotti, Gloria; Fascendini, Sara; Licini, Cristina; Marcassa, Claudio

    2016-01-01

    Objective This pilot study evaluated the efficacy and safety of prolonged-release oxycodone/naloxone (OXN-PR) in older subjects with chronic pain and mild-to-moderate cognitive impairment. Methods This was a prospective, observational, open-label study of 45-day duration. Patients with moderate-to-severe chronic pain and naïve to strong opioids were recruited from nursing homes and Alzheimer’s disease centers. OXN-PR was initiated at low doses (5 mg od or bid) and increased to a maximum of 20 mg bid. The primary efficacy endpoint was a pain intensity reduction of ≥30% from baseline (T0) to 15 days after OXN-PR initiation, as assessed by a numerical rating scale or the Pain Assessment in Advanced Dementia scale. Other assessments included the Barthel activities of daily living index, Neuropsychiatric Inventory, Bowel Function Index, and adverse events. Results The analysis included 53 patients (mean age, 83.0 years; mean Mini-Mental State Examination score, 18.6) with severe pain (median Numerical Rating Scale/Pain Assessment in Advanced Dementia 6) and substantial impairment in daily functioning (mean Barthel index, 32.2). The primary endpoint was achieved by 92.4% of patients. OXN-PR significantly reduced mean pain intensity from baseline to study end (numerical rating scale, 6.6±1.0 vs 2.3±1.1, P<0.0001; Pain Assessment in Advanced Dementia, 6.9±1.6 vs 0.9±0.8, P<0.0001). Substantial improvements from T0 to T45 in daily functioning (mean Barthel index, 32.2±16.8 vs 53.7±23.9, P<0.0001) and neuropsychiatric symptoms (mean Neuropsychiatric Inventory, 25.5±27.3 vs 8.8±9.0, P<0.0001) were also reported. OXN-PR was well tolerated and did not worsen bowel function. Conclusion In this pilot study, OXN-PR was effective in improving pain and other symptoms associated with dementia, with a favorable safety and tolerability profile. Large-scale trials in people with dementia are needed to improve clinical guidance for the assessment and treatment of pain in

  6. Pre-exposure with low-dose UVA suppresses lesion development and enhances Th1 response in BALB/c mice infected with Leishmania (Leishmania) amazonensis.

    PubMed

    Khaskhely, N M; Maruno, M; Takamiyagi, A; Uezato, H; Kasem, K M; Hosokawa, A; Kariya, K; Hashiguchi, Y; Landires, E A; Nonaka, S

    2001-07-01

    This study was conducted to determine whether exposing mice to ultraviolet (UV) radiation would alter the pathogenesis of infection with Leishmania (Leishmania) amazonensis (L. amazonensis) which causes progressive cutaneous disease in susceptible mouse strains. BALB/c mice were irradiated with 10 and 30 J/cm(2) UVA on shaved skin of the back from Dermaray (M-DMR-100) for 4 consecutive days before infection with Leishmania promastigotes. The course of disease was recorded by measuring the size of lesions at various times after infection. Mice groups irradiated with UVA 10 and 30 J/cm(2) showed significantly suppressed lesion development compared with the non-irradiated mice. Light and electron microscopy revealed a few parasites at the site of inoculation in UVA-irradiated subjects. Sandwich enzyme-linked-immunosorbent-assay (ELISA) examination of sera showed dose dependently upregulated interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-12, and downregulated interleukin (IL)-4 and interleukin (IL)-10 levels in UVA-irradiated as compared with the non-irradiated mice. Positive signals for IFN-gamma mRNA in irradiated mice were obtained by RT-PCR, while non-irradiated mice showed negative results. None of the examined samples showed signal for IL-4 mRNA. The present study disclosed that exposure of mice to different low-doses of UVA irradiation prior to infection may interfere with immunity to L. amazonensis in the murine model. This indicates that the cell-mediated response switch from Th2 to Th1 pattern suppressed the cutaneous lesions of L. amazonensis. PMID:11390207

  7. Effects of Acute Low-Dose Exposure to the Chlorinated Flame Retardant Dechlorane 602 and Th1 and Th2 Immune Responses in Adult Male Mice

    PubMed Central

    Feng, Yu; Tian, Jijing; Xie, Heidi Qunhui; She, Jianwen; Xu, Sherry Li; Xu, Tuan; Tian, Wenjing; Fu, Hualing; Li, Shuaizhang; Tao, Wuqun; Wang, Lingyun; Chen, Yangsheng; Zhang, Songyan; Zhang, Wanglong; Guo, Tai L.; Zhao, Bin

    2016-01-01

    , Zhang S, Zhang W, Guo TL, Zhao B. 2016. Effects of acute low-dose exposure to the chlorinated flame retardant dechlorane 602 and Th1 and Th2 immune responses in adult male mice. Environ Health Perspect 124:1406–1413; http://dx.doi.org/10.1289/ehp.1510314 PMID:27081854

  8. 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

  9. Oral (gavage), in utero and postnatal exposure of Sprague-Dawley rats to low doses of tributyltin chloride. Part 1: Toxicology, histopathology and clinical chemistry.

    PubMed

    Cooke, G M; Tryphonas, H; Pulido, O; Caldwell, D; Bondy, G S; Forsyth, D

    2004-02-01

    Tributyltin (TBT) is a biocide that contaminates foods, especially shellfish. TBT is an endocrine disrupter in several marine species and is neurotoxic and immunotoxic in mammals. We have examined the effects of exposure to low doses of tributyltin chloride (TBTC) from day 8 of gestation until adulthood. Pregnant rats were gavaged daily with 0, 0.025, 0.25 or 2.5 mg TBTC/kg body weight from day 8 of gestation until weaning. Stomach contents of suckling pups contained undetectable levels of TBT and dibutyltin (DBT) levels were detectable only in the highest TBTC dose used, indicating negligible lactational transfer to pups. Post weaning, pups were gavaged daily with the same dose of TBTC administered to their mothers and sacrificed on post-natal days (PND) 30 (males and females), 60 (females) and 90 (males). TBTC had no effects on dams' body weights, food consumption, litter size, sex ratio or survival of pups to weaning. However, all doses of TBTC significantly affected parameters of the growth profile of the pups (mean body weights, average slope, curvature) and the ratio of weekly food consumption to weekly body weight gain indicated enhanced food conversion to body mass in females but a decreased conversion in males. Liver, spleen and thymus weights were also affected by TBTC. In male pups dosed at 2.5 mg/kg/day, reduced serum thyroxine levels were evident, indicating that the thyroid is a target for TBTC toxicity. No histopathological lesions were seen in the liver but elevated serum alanine aminotransferase, gamma-glutamyl transferase and amylase indicated hepatotoxicity. Significant decreases in liver weights in female pups exposed to 0.025 mg/kg/day TBTC were observed at PND 60. Decreases in spleen and thymus weights also pointed towards toxic effects of TBTC on the immune system. The 0.025 mg/kg/day TBTC should have been a no affect dose and yet this dose caused significant effects on growth profiles, decreased liver weights and elevated serum GGT levels in

  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. 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

  12. 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.

  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. 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.

  15. Effects of Prenatal Exposure to a Low Dose Atrazine Metabolite Mixture on Pubertal Timing and Prostate Development of Male Long Evans Rats

    PubMed Central

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

    2010-01-01

    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. PMID:20727709

  16. 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.

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

    SciTech Connect

    Truta-Popa, Lucia-Adina; Hofmann, Werner; Fakir, Hatim; Cosma, Constantin

    2008-08-07

    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.

  18. 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.

  19. Chemoimmunotherapy for relapsed/refractory and progressive 17p13-deleted chronic lymphocytic leukemia (CLL) combining pentostatin, alemtuzumab, and low-dose rituximab is effective and tolerable and limits loss of CD20 expression by circulating CLL cells.

    PubMed

    Zent, Clive S; Taylor, Ronald P; Lindorfer, Margaret A; Beum, Paul V; LaPlant, Betsy; Wu, Wenting; Call, Timothy G; Bowen, Deborah A; Conte, Michael J; Frederick, Lori A; Link, Brian K; Blackwell, Sue E; Veeramani, Suresh; Baig, Nisar A; Viswanatha, David S; Weiner, George J; Witzig, Thomas E

    2014-07-01

    Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analog refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab-containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a Phase II trial testing the efficacy and tolerability of a short-duration regimen combining pentostatin, alemtuzumab, and low-dose high-frequency rituximab designed to decrease the risk of treatment-associated infections and to limit the loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n = 36) or previously untreated with 17p13 deletion (17p13-) (n = 3). Thirteen (33%) patients had both 17p13- and TP53 mutations predicted to be dysfunctional, and eight patients had purine analog refractory CLL without TP53 dysfunction. Twenty-six (67%) patients completed therapy, with only five (13%) patients having treatment-limiting toxicity and no treatment-related deaths. Twenty-two (56%) patients responded to treatment, with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression-free survival was 7.2 months, time to next treatment was 9.1 months, and overall survival was 34.1 months. The majority of deaths (82%) were caused by progressive disease, including transformed diffuse large B-cell lymphoma (n = 6). Correlative studies showed that low-dose rituximab activates complement and natural killer cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that pentostatin, alemtuzumab, and low-dose high-frequency rituximab is a tolerable and effective therapy for CLL and that low-dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression. PMID:24723493

  20. 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

  1. 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

  2. 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.’

  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. 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...

  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. Low-dose paroxetine exposure causes lifetime declines in male mouse body weight, reproduction and competitive ability as measured by the novel organismal performance assay

    PubMed Central

    Gaukler, Shannon M.; Ruff, James S.; Galland, Tessa; Kandaris, Kirstie A.; Underwood, Tristan K.; Liu, Nicole M.; Young, Elizabeth L.; Morrison, Linda C.; Yost, Garold S.; Potts, Wayne K.

    2014-01-01

    Paroxetine is a selective serotonin reuptake inhibitor (SSRI) that is currently available on the market and is suspected of causing congenital malformations in babies born to mothers who take the drug during the first trimester of pregnancy. We utilized organismal performance assays (OPAs), a novel toxicity assessment method, to assess the safety of paroxetine during pregnancy in a rodent model. OPAs utilize genetically diverse wild mice (Mus musculus) to evaluate competitive performance between experimental and control animals as they compete amongst each other for limited resources in semi-natural enclosures. Performance measures included reproductive success, male competitive ability and survivorship. Paroxetine-exposed males weighed 13% less, had 44% fewer offspring, dominated 53% fewer territories and experienced a 2.5-fold increased trend in mortality, when compared with controls. Paroxetine-exposed females had 65% fewer offspring early in the study, but rebounded at later time points. In cages, paroxetine-exposed breeders took 2.3 times longer to produce their first litter and pups of both sexes experienced reduced weight when compared with controls. Low-dose paroxetine-induced health declines detected in this study were undetected in preclinical trials with dose 2.5-8 times higher than human therapeutic doses. These data indicate that OPAs detect phenotypic adversity and provide unique information that could useful towards safety testing during pharmaceutical development. PMID:25446017

  7. 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.

  8. 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.

  9. 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...

  10. 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.

  11. 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

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

    PubMed

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

    2015-02-01

    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.

  13. Mycosis fungoides progression and chronic solvent exposure.

    PubMed

    Nikkels, Arjen F; Quatresooz, Pascale; Delvenne, Philippe; Balsat, Alain; Piérard, Gérald E

    2004-01-01

    The effect of repeated exposure to specific chemicals on the initiation or progression of mycosis fungoides (MF) remains unsettled. A patient with low-grade patch stage MF progressively developed MF plaques restricted to his arms, and a tumour on his right thigh. These areas were subject to repeated exposure to solvents. His thigh was indeed in close contact with his trousers pocket where he used to store a wiping rag drenched into white spirit and cellulosic thinner. Immunophenotyping these lesions revealed a dense LCA+, CD2+, CD3+, CD4+, CD5+, CD7+, CD45+, CD45RO+ T-cell infiltrate admixed with many factor XIIIa+ dendrocytes. T-cell receptor rearrangement analysis identified a monoclonal T-cell infiltrate. An internal work-up remained negative. Stopping further solvent exposure failed to improve his condition. Oral corticotherapy combined with low-dose interferon-alpha2a halted disease progression. This observation suggests that long-term solvent exposure may trigger MF and hasten its progression from the patch stage to the plaque and tumour stages.

  14. Mycosis fungoides progression and chronic solvent exposure.

    PubMed

    Nikkels, Arjen F; Quatresooz, Pascale; Delvenne, Philippe; Balsat, Alain; Piérard, Gérald E

    2004-01-01

    The effect of repeated exposure to specific chemicals on the initiation or progression of mycosis fungoides (MF) remains unsettled. A patient with low-grade patch stage MF progressively developed MF plaques restricted to his arms, and a tumour on his right thigh. These areas were subject to repeated exposure to solvents. His thigh was indeed in close contact with his trousers pocket where he used to store a wiping rag drenched into white spirit and cellulosic thinner. Immunophenotyping these lesions revealed a dense LCA+, CD2+, CD3+, CD4+, CD5+, CD7+, CD45+, CD45RO+ T-cell infiltrate admixed with many factor XIIIa+ dendrocytes. T-cell receptor rearrangement analysis identified a monoclonal T-cell infiltrate. An internal work-up remained negative. Stopping further solvent exposure failed to improve his condition. Oral corticotherapy combined with low-dose interferon-alpha2a halted disease progression. This observation suggests that long-term solvent exposure may trigger MF and hasten its progression from the patch stage to the plaque and tumour stages. PMID:15057012

  15. 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.

  16. 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

  17. Response of Biological Systems to Low Doses of Ionizing Radiation.

    PubMed

    Hei, Tom K

    2016-03-01

    Radiation is ubiquitous in the environment. Biological effects of exposure to low doses of ionizing radiation are subjected to several modulating factors. Two of these, bystander response and adaptive protections, are discussed briefly. PMID:26808883

  18. 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

  19. 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.

  20. Low-dose fludarabine with or without darbepoetin alfa in patients with chronic lymphocytic leukemia and comorbidity: primary results of the CLL9 trial of the German CLL Study Group.

    PubMed

    Goede, Valentin; Busch, Raymonde; Bahlo, Jasmin; Chataline, Viktoria; Kremers, Stephan; Müller, Lothar; Reschke, Daniel; Schlag, Rudolf; Schmidt, Burkhard; Vehling-Kaiser, Ursula; Wedding, Ulrich; Stilgenbauer, Stefan; Hallek, Michael

    2016-01-01

    This study was planned as a phase 3 trial to investigate low-dose fludarabine with or without darbepoetin alfa in older patients with previously untreated or treated chronic lymphocytic leukemia (CLL) and comorbidity. Due to slow recruitment, the study was terminated prematurely after accrual of 97 patients who, on average, were 74 years old and had a cumulative illness rating scale (CIRS) total score of 5. We report toxicity and efficacy of the study treatment. Grade 3-5 neutropenia and infection were observed in 25% and 10% of patients, respectively. Response was seen in 73% (5% complete remissions). Median event-free and overall survival was 12.2 and 44.8 months, respectively. No differences in outcome were found for patients treated with versus without darbepoetin alfa. In subjects with progressive/recurrent CLL during or after study treatment, overall survival was similar for patients receiving chemotherapy versus chemoimmunotherapy as salvage treatment. PMID:26293380

  1. 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...

  2. Long-term effects of fetal exposure to low doses of the xenoestrogen bisphenol-A in the female mouse genital tract.

    PubMed

    Markey, Caroline M; Wadia, Perinaaz R; Rubin, Beverly S; Sonnenschein, Carlos; Soto, Ana M

    2005-06-01

    Developmental exposure to estrogenic chemicals induces morphological, functional, and behavioral anomalies associated with reproduction. Humans are routinely exposed to bisphenol-A (BPA), an estrogenic compound that leaches from dental materials and plastic food and beverage containers. The aim of the present study was to determine the effects of in utero exposure to low, environmentally relevant doses of BPA on the development of female reproductive tissues in CD-1 mice. In previous publications, we have shown that this treatment alters the morphology of the mammary gland and affects estrous cyclicity. Here we report that in utero exposure to 25 and 250 ng BPA/ kg of body weight per day via osmotic pumps implanted into pregnant dams at Gestational Day 9 induces alterations in the genital tract of female offspring that are revealed during adulthood. They include decreased wet weight of the vagina, decreased volume of the endometrial lamina propria, increased incorporation of bromodeoxyuridine into the DNA of endometrial gland epithelial cells, and increased expression of estrogen receptor-alpha (ERalpha) and progesterone receptor in the luminal epithelium of the endometrium and subepithelial stroma. Because ERalpha is known to be expressed in these estrogen-target organs at the time of BPA exposure, it is plausible that BPA may directly affect the expression of ER-controlled genes involved in the morphogenesis of these organs. In addition, BPA-induced alterations that specifically affect hypothalamic-pituitary-gonadal axis function may further contribute to the anomalies observed at 3 mo of age, long after the cessation of BPA exposure.

  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. 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. 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.

  6. Detection of urinary stones at reduced radiation exposure: a phantom study comparing computed radiography and a low-dose digital radiography linear slit scanning system

    PubMed Central

    Szucs-Farkas, Zsolt; Chakraborty, D. P.; Thoeny, Harriet C.; Loupatatzis, Christos; Vock, Peter; Harald, Bonel

    2010-01-01

    Objective In this experimental study we assessed the diagnostic performance of linear slit scanning radiography (LSSR) compared to conventional computed radiography (CR) in the detection of urinary calculi in an anthropomorphic phantom imitating patients weighing approximately 58 to 88 kg. Conclusion Compared to computed radiography, LSSR is superior in the detection of urinary stones and may be used for pretreatment localization and follow-up at a lower patient exposure. PMID:19457787

  7. 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. PMID:26209558

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

    PubMed

    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

  9. Switching to low-dose oral prolonged-release oxycodone/naloxone from WHO-Step I drugs in elderly patients with chronic pain at high risk of early opioid discontinuation

    PubMed Central

    Lazzari, Marzia; Marcassa, Claudio; Natoli, Silvia; Carpenedo, Roberta; Caldarulo, Clarissa; Silvi, Maria B; Dauri, Mario

    2016-01-01

    Purpose Chronic pain has a high prevalence in the aging population. Strong opioids also should be considered in older people for the treatment of moderate to severe pain or for pain that impairs functioning and the quality of life. This study aimed to assess the efficacy and safety of the direct switch to low-dose strong opioids (World Health Organization-Step III drugs) in elderly, opioid-naive patients. Patients and methods This was a single-center, retrospective, observational study in opioid-naive patients aged ≥75 years, with moderate to severe chronic pain (>6-month duration) and constipation, who initiated treatment with prolonged-release oxycodone/naloxone (OXN-PR). Patients were re-evaluated after 15, 30, and 60 days (T60, final observation). Response to treatment was defined as an improvement in pain of ≥30% after 30 days of therapy without worsening of constipation. Results One-hundred and eighty-six patients (mean ± SD age 80.7±4.7 years; 64.5% women) with severe chronic pain (mean average pain intensity 7.1±1.0 on the 11-point numerical rating scale) and constipation (mean Bowel Function Index 64.1±24.4; 89.2% of patients on laxatives) were initiated treatment with OXN-PR (mean daily dose 11.3±3.5 mg). OXN-PR reduced pain intensity rapidly and was well tolerated; 63.4% of patients responded to treatment with OXN-PR. At T60 (mean daily OXN-PR dose, 21.5±9.7 mg), the pain intensity was reduced by 66.7%. In addition, bowel function improved (mean decrease of Bowel Function Index from baseline to T60, −28.2, P<0.0001) and the use of laxatives decreased. Already after 15 days and throughout treatment, ~70% of patients perceived their status as much/extremely improved. Only 1.6% of patients discontinued treatment due to adverse events. Conclusion Low-dose OXN-PR in elderly patients naive to opioids proved to be an effective option for the treatment of moderate to severe chronic pain. Large-scale trials are needed to improve clinical guidance in

  10. A New Era of Low-Dose Radiation Epidemiology.

    PubMed

    Kitahara, Cari M; Linet, Martha S; Rajaraman, Preetha; Ntowe, Estelle; Berrington de González, Amy

    2015-09-01

    The last decade has introduced a new era of epidemiologic studies of low-dose radiation facilitated by electronic record linkage and pooling of cohorts that allow for more direct and powerful assessments of cancer and other stochastic effects at doses below 100 mGy. Such studies have provided additional evidence regarding the risks of cancer, particularly leukemia, associated with lower-dose radiation exposures from medical, environmental, and occupational radiation sources, and have questioned the previous findings with regard to possible thresholds for cardiovascular disease and cataracts. Integrated analysis of next generation genomic and epigenetic sequencing of germline and somatic tissues could soon propel our understanding further regarding disease risk thresholds, radiosensitivity of population subgroups and individuals, and the mechanisms of radiation carcinogenesis. These advances in low-dose radiation epidemiology are critical to our understanding of chronic disease risks from the burgeoning use of newer and emerging medical imaging technologies, and the continued potential threat of nuclear power plant accidents or other radiological emergencies. PMID:26231501

  11. 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. PMID:26778786

  12. Effects of long-term maternal exposure to low doses of PCB126 and PCB153 on the reproductive system and related hormones of young male goats.

    PubMed

    Oskam, Irma C; Lyche, Jan L; Krogenaes, Anette; Thomassen, Ragnar; Skaare, Janneche U; Wiger, Richard; Dahl, Ellen; Sweeney, Torres; Stien, Audun; Ropstad, Erik

    2005-11-01

    In this study, female goats were orally exposed to PCB126 or PCB153, at 49 ng/kg body weight per day and 98 microg/kg body weight per day respectively, from gestational day 60 until delivery at approximately day 150. Exposure of the offspring continued via lactation until postnatal day 40. Reproductive toxicity in the male offspring was studied by the evaluation of conventional reproductive endpoints as well as flow cytometric analyses of spermatogenesis and sperm chromatin structure. PCB153-treated animals showed a significant smaller testis diameter in comparison to the control group. Neither of the treated groups showed differences for plasma FSH in comparison to controls. PCB153-treated animals differed significantly from the control group with respect to plasma LH and testosterone levels, whereas PCB126-treated animals only differed from the controls in plasma testosterone concentrations. Neither the PCB126 nor the PCB153 group differed from the controls with respect to the conventional sperm parameters or testis histology. A significant lower ratio of interstitium area to seminiferous tubules area and proportion of diploid testis cells were observed for the PCB153 group. Sperm from PCB153-treated animals showed a significantly higher percentage of sperm with damaged DNA. From the results of the present study it was concluded that PCB153 was able to induce alterations in reproductive endpoints related to the hypothalamic-pituitary-axis as well as to the testis. The effects observed in male kids after a long-term maternal exposure to PCB153 support the concept that exposure to endocrine-disrupting compounds during foetal development may lead to adverse reproductive effects in adult life.

  13. 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.

  14. 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. PMID:26894944

  15. Low dose exposure to sodium arsenite synergistically interacts with UV radiation to induce mutations and alter DNA repair in human cells.

    PubMed

    Danaee, Hadi; Nelson, Heather H; Liber, Howard; Little, John B; Kelsey, Karl T

    2004-03-01

    Inorganic arsenic is a known human carcinogen, yet its mechanism of action remains poorly understood. Epidemiological data suggest that arsenic exposure interacts with UV radiation exposure to increase the risk of skin cancer. Studies have suggested that arsenic is able to impair DNA repair enzymes and alter the repair of UV-induced DNA damage. Here we have tested the hypothesis that arsenite [As(III)] and UV interact synergistically to enhance mutagenesis. TK6 human lymphoblastoid cells that are functionally heterozygous at the thymidine kinase (TK) locus were pre-exposed to As(III) alone and in combination with UV. Our data suggest that As(III) is mutagenic only at high doses at the TK locus. As(III) enhanced UV mutagenesis in a more than additive fashion. To investigate the mechanism underlying this synergy we assessed the removal of UV-induced dimers in TK6 cells using the T4 endonuclease-incorporated Comet assay. Pre-treatment with As(III) specifically inhibited the repair of UV-induced pyrimidine dimer-related DNA damage. Taken together, these data suggest that pre-treatment of human cells with arsenic impairs the nucleotide excision repair pathway and leads to enhanced UV mutagenesis.

  16. 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 Central

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

    2015-01-01

    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. PMID:25805407

  17. 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.

  18. A phase II randomized trial comparing standard and low dose rituximab combined with alemtuzumab as initial treatment of progressive chronic lymphocytic leukemia in older patients: a trial of the ECOG-ACRIN cancer research group (E1908).

    PubMed

    Zent, Clive S; Victoria Wang, Xin; Ketterling, Rhett P; Hanson, Curtis A; Libby, Edward N; Barrientos, Jacqueline C; Call, Timothy G; Chang, Julie E; Liu, Jane J; Calvo, Alejandro R; Lazarus, Hillard M; Rowe, Jacob M; Luger, Selina M; Litzow, Mark R; Tallman, Martin S

    2016-03-01

    Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients requiring initial therapy are often older and frailer and unsuitable candidates for standard chemoimmunotherapy regimens. Shorter duration combination monoclonal antibody (mAb) therapy using alemtuzumab and rituximab has been shown to be effective and tolerable treatment for CLL. Standard dose anti-CD20 mAb therapy causes loss of CD20 expression by surviving CLL cells, which can be minimized by decreasing the mAb dose. We report a randomized phase II clinical trial enrolling older (≥ 65 years) patients (median age 76 years, n = 31) with treatment naïve progressive CLL. Patients received 8-12 weeks of standard subcutaneous alemtuzumab with either intravenous standard (375 mg/m(2) weekly)(n = 16) or low dose (20 mg/m(2) 3x week)(n = 15) rituximab. This study was closed before full accrual because the manufacturer withdrew alemtuzumab for treatment of CLL. The overall response rate was 90% with an 45% complete response rate, median progression-free survival of 17.9 months and no significant differences in outcome between the low and standard dose rituximab arms. The major toxicities were cytopenia and infection with one treatment fatality caused by progressive multifocal leukoencephalopathy but no other opportunistic infections. Combination mAb therapy was effective and tolerable treatment for older and frailer patients with progressive CLL, achieving a high rate of complete remissions. These data support the role of mAb in therapy for less fit CLL patients and the further study of low dose higher frequency anti-CD20 mAb therapy as a potentially more effective use of anti-CD20 mAb in the treatment of CLL.

  19. 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.

  20. 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

  1. 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.

  2. 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

  3. Sex differences in the adult HPA axis and affective behaviors are altered by perinatal exposure to a low dose of bisphenol A.

    PubMed

    Chen, Fang; Zhou, Libin; Bai, Yinyang; Zhou, Rong; Chen, Ling

    2014-07-01

    Bisphenol A (BPA), an estrogen-mimicking endocrine disrupter, when administered perinatally can affect affective behaviors in adult rodents, however the underlying mechanisms remain largely unclear. Postnatal day (PND) 80 vehicle-injected control female rats showed more obvious depression- and anxiety-like behaviors than males, indicative of sexually dimorphic affective behaviors. When female breeders were subcutaneously injected with BPA (2µg/kg) from gestation day 10 to lactation day 7, sex difference of affective behaviors was impaired in their offspring (PND80 BPA-rats), as results that female BPA-rats showed a visible "antianxiety-like" behavior, and male BPA-rats increased depression-like behavior compared to vehicle-injected controls. Notably, basal levels of serum corticosterone and adrenocorticotropin (ACTH), and corticotropin-releasing hormone mRNA were increased in male BPA-rats, but not in female BPA-rats, in comparison with vehicle-injected controls. Following mild-stressor the elevation of corticosterone or ACTH levels was higher in male BPA-rats, whereas it was lower in female BPA-rats than vehicle-injected controls. In comparison with vehicle-injected controls, the level of glucocorticoid receptor (GR) mRNA in hippocampus or hypothalamic paraventricular nucleus was increased in female BPA-rats, while decreased in male BPA-rats. In addition, the levels of hippocampal mineralocorticoid receptor (MR) mRNA, neuronal nitric oxide synthase (nNOS) and phospho-cAMP response element binding protein (p-CREB) were increased in female BPA-rats, but were decreased in male BPA-rats. Furthermore, the testosterone level was reduced in male BPA-rats. The results indicate that the perinatal exposure to BPA through altering the GR and MR expression disrupts the GR-mediated feedback of hypothalamic-pituitary-adrenal (HPA) axis and MR-induced nNOS-CREB signaling, which alters sex difference in affective behaviors. PMID:24857958

  4. 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.

  5. Olfactory recognition memory is disrupted in young mice with chronic low-level lead exposure.

    PubMed

    Flores-Montoya, Mayra Gisel; Alvarez, Juan Manuel; Sobin, Christina

    2015-07-01

    Chronic developmental lead exposure yielding very low blood lead burden is an unresolved child public health problem. Few studies have attempted to model neurobehavioral changes in young animals following very low level exposure, and studies are needed to identify tests that are sensitive to the neurobehavioral changes that may occur. Mechanisms of action are not yet known however results have suggested that hippocampus/dentate gyrus may be uniquely vulnerable to early chronic low-level lead exposure. This study examined the sensitivity of a novel odor recognition task to differences in pre-adolescent C57BL/6J mice chronically exposed from birth to PND 28, to 0 ppm (control), 30 ppm (low-dose), or 330 ppm (higher-dose) lead acetate (N=33). Blood lead levels (BLLs) determined by ICP-MS ranged from 0.02 to 20.31 μg/dL. Generalized linear mixed model analyses with litter as a random effect showed a significant interaction of BLL×sex. As BLLs increased olfactory recognition memory decreased in males. Among females, non-linear effects were observed at lower but not higher levels of lead exposure. The novel odor detection task is sensitive to effects associated with early chronic low-level lead exposure in young C57BL/6J mice.

  6. Olfactory recognition memory is disrupted in young mice with chronic low-level lead exposure

    PubMed Central

    Flores-Montoya, Mayra Gisel; Alvarez, Juan Manuel; Sobin, Christina

    2015-01-01

    Chronic developmental lead exposure yielding very low blood lead burden is an unresolved child public health problem. Few studies have attempted to model neurobehavioral changes in young animals following very low level exposure, and studies are needed to identify tests that are sensitive to the neurobehavioral changes that may occur. Mechanisms of action are not yet known however results have suggested that hippocampus/dentate gyrus may be uniquely vulnerable to early chronic low-level lead exposure. This study examined the sensitivity of a novel odor recognition task to differences in pre-adolescent C57BL/6J mice chronically exposed from birth to PND 28, to 0 ppm (control), 30 ppm (low-dose), or 330 ppm (higher-dose) lead acetate (N = 33). Blood lead levels (BLLs) determined by ICP-MS ranged from 0.02 to 20.31 µg/dL. Generalized linear mixed model analyses with litter as a random effect showed a significant interaction of BLL × sex. As BLLs increased olfactory recognition memory decreased in males. Among females, non-linear effects were observed at lower but not higher levels of lead exposure. The novel odor detection task is sensitive to effects associated with early chronic low-level lead exposure in young C57BL/6J mice. PMID:25936521

  7. 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.

  8. 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

  9. Effects of Low-Dose and Long-Term Treatment with Erythromycin on Interleukin-17 and Interleukin-23 in Peripheral Blood and Induced Sputum in Patients with Stable Chronic Obstructive Pulmonary Disease

    PubMed Central

    Tan, Caimei; Huang, Huijuan; Zhang, Jianquan; He, Zhiyi; Zhong, Xiaoning; Bai, Jing

    2016-01-01

    Objective. To study the effects of low-dose and long-term treatment with erythromycin on IL-17 and IL-23, in peripheral blood and induced sputum, in patients with stable chronic obstructive pulmonary disease (COPD). Methods. Patients were randomly divided into placebo-treated group, group A (12 months of additive treatment with erythromycin, N = 18), and group B (6 months of additive treatment with erythromycin followed by 6 months of follow-up, N = 18). Inflammatory cells in induced sputum, pulmonary function, and the 6-minute walk distance (6MWD) were analyzed. Concentrations of IL-17 and IL-23 in peripheral blood and sputum were measured using enzyme-linked immunosorbent assays. Results. After treatment, sputum and peripheral blood concentrations of IL-17 and IL-23 significantly decreased in groups A and B compared with placebo-treated group. There were no significant differences after erythromycin withdrawal at months 9 and 12 in group B compared with placebo-treated group. An increase in 6MWD was observed after treatment. Conclusions. Erythromycin was beneficial and reduced airway inflammation in COPD patients. Underlying mechanisms may involve inhibition of IL-17 and IL-23 mediated airway inflammation. COPD patients treated with erythromycin for 6 months experienced improved exercise capacity. Finally, treatment for 12 months may be more effective than treatment for 6 months. PMID:27127346

  10. [Risk of deterministic effects after exposure to low doses of ionizing radiation: retrospective study among health workers in view of a new publication of International Commission on Radiological Protection].

    PubMed

    Negrone, Mario; Di Lascio, Doriana

    2016-01-01

    The new recommended equivalent (publication n. 118 of International Commission on Radiological Protection) dose limit for occupational exposure of the lens of the eye is based on prevention of radiogenic cataracts, with the underlying assumption of a nominal threshold which has been adjusted from 2,5 Gy to 0.5 Gy for acute or protracted exposure. The study aim was to determine the prevalence of ocular lens opacity among healthcare workers (radiologic technologists, physicians, physician assistants) with respect to occupational exposures to ionizing radiations. Therefore, we conducted another retrospective study to explore the relationship between occupational exposure to radiation and opacity lens increase. Healthcare data (current occupational dosimetry, occupational history) are used to investigate risk of increase of opacity lens of eye. The sample of this study consisted of 148 health-workers (64 M and 84 W) aged from 28 to 66 years coming from different hospitals of the ASL of Potenza (clinic, hospital and institute with scientific feature). On the basis of the evaluation of the dosimetric history of the workers (global and effective dose) we agreed to ascribe the group of exposed subjects in cat A (equivalent dose > 2 mSV) and the group of non exposed subjects in cat B (workers with annual absorbed level of dose near 0 mSv). The analisys was conducted using SPSS 15.0 (Statistical Package for Social Science). A trend of increased ocular lens opacity was found with increasing number for workers in highest category of exposure (cat. A, Yates' chi-squared test = 13,7 p = 0,0002); variable significantly related to opacity lens results job: nurse (Χ(2)Y = 14,3 p = 0,0002) physician (Χ(2)Y = 2.2 p = 0,1360) and radiologic technologists (Χ(2)Y = 0,1 p = 0,6691). In conclusion our provides evidence that exposure to relatively low doses of ionizing radiation may be harmful to the lens of the eye and may increase a long-term risk of cataract formation; similary

  11. Low-Dose Risk, Decisions, and Risk Communication

    SciTech Connect

    Flynn, James; Slovic, Paul

    2001-06-01

    To conduct basic research on how people receive, evaluate, and form positions on scientific information and its relationship to low-dose radiation exposure. There are three major areas of study in our research program. First is the development of theories, frameworks and concepts essential to guiding data collection and analysis. The second area is a program of experimental studies on risk perception, evaluation of science information, and the structure of individual positions regarding low dose exposures. This involves the study of existing knowledge and the evaluation of science information presented within a variety of formats, as educational information, news media stories, and alternative communication methods (personal contact, small group interaction, email & internet, etc.). Third is the community-level studies to examine and record how the social conditions, under which science communications take place, influence the development of attitudes and opinions about: low- dose exposures, the available management options, control of radiation risks, and preferences for program and policy goals.

  12. Simulated Microgravity and Low-Dose/Low-Dose-Rate Radiation Induces Oxidative Damage in the Mouse Brain.

    PubMed

    Mao, Xiao Wen; Nishiyama, Nina C; Pecaut, Michael J; Campbell-Beachler, Mary; Gifford, Peter; Haynes, Kristine E; Becronis, Caroline; Gridley, Daila S

    2016-06-01

    Microgravity and radiation are stressors unique to the spaceflight environment that can have an impact on the central nervous system (CNS). These stressors could potentially lead to significant health risks to astronauts, both acutely during the course of a mission or chronically, leading to long-term, post-mission decrements in quality of life. The CNS is sensitive to oxidative injury due to high concentrations of oxidizable, unsaturated lipids and low levels of antioxidant defenses. The purpose of this study was to evaluate oxidative damage in the brain cortex and hippocampus in a ground-based model for spaceflight, which includes prolonged unloading and low-dose radiation. Whole-body low-dose/low-dose-rate (LDR) gamma radiation using (57)Co plates (0.04 Gy at 0.01 cGy/h) was delivered to 6 months old, mature, female C57BL/6 mice (n = 4-6/group) to simulate the radiation component. Anti-orthostatic tail suspension was used to model the unloading, fluid shift and physiological stress aspects of the microgravity component. Mice were hindlimb suspended and/or irradiated for 21 days. Brains were isolated 7 days or 9 months after irradiation and hindlimb unloading (HLU) for characterization of oxidative stress markers and microvessel changes. The level of 4-hydroxynonenal (4-HNE) protein, an oxidative specific marker for lipid peroxidation, was significantly elevated in the cortex and hippocampus after LDR + HLU compared to controls (P < 0.05). The combination group also had the highest level of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) expression compared to controls (P < 0.05). There was a significant decrease in superoxide dismutase (SOD) expression in the animals that received HLU only or combined LDR + HLU compared to control (P < 0.05). In addition, 9 months after LDR and HLU exposure, microvessel densities were the lowest in the combination group, compared to age-matched controls in the cortex (P < 0.05). Our data provide the first evidence

  13. Chronic endotoxin exposure produces airflow obstruction and lung dendritic cell expansion.

    PubMed

    Lai, Peggy S; Fresco, Jennifer M; Pinilla, Miguel A; Macias, Alvaro A; Brown, Ronald D; Englert, Joshua A; Hofmann, Oliver; Lederer, James A; Hide, Winston; Christiani, David C; Cernadas, Manuela; Baron, Rebecca M

    2012-08-01

    Little is known about the mechanisms of persistent airflow obstruction that result from chronic occupational endotoxin exposure. We sought to analyze the inflammatory response underlying persistent airflow obstruction as a result of chronic occupational endotoxin exposure. We developed a murine model of daily inhaled endotoxin for periods of 5 days to 8 weeks. We analyzed physiologic lung dysfunction, lung histology, bronchoalveolar lavage fluid and total lung homogenate inflammatory cell and cytokine profiles, and pulmonary gene expression profiles. We observed an increase in airway hyperresponsiveness as a result of chronic endotoxin exposure. After 8 weeks, the mice exhibited an increase in bronchoalveolar lavage and lung neutrophils that correlated with an increase in proinflammatory cytokines. Detailed analyses of inflammatory cell subsets revealed an expansion of dendritic cells (DCs), and in particular, proinflammatory DCs, with a reduced percentage of macrophages. Gene expression profiling revealed the up-regulation of a panel of genes that was consistent with DC recruitment, and lung histology revealed an accumulation of DCs in inflammatory aggregates around the airways in 8-week-exposed animals. Repeated, low-dose LPS inhalation, which mirrors occupational exposure, resulted in airway hyperresponsiveness, associated with a failure to resolve the proinflammatory response, an inverted macrophage to DC ratio, and a significant rise in the inflammatory DC population. These findings point to a novel underlying mechanism of airflow obstruction as a result of occupational LPS exposure, and suggest molecular and cellular targets for therapeutic development.

  14. 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

  15. 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.

  16. 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.

  17. Exposure of rats to a high but not low dose of ethanol during early postnatal life increases the rate of loss of optic nerve axons and decreases the rate of myelination

    PubMed Central

    HARRIS, SIMON J.; WILCE, PETER; BEDI, KULDIP S.

    2000-01-01

    Visual system abnormalities are commonly encountered in the fetal alcohol syndrome although the level of exposure at which they become manifest is uncertain. In this study we have examined the effects of either low (ETLD) or high dose (ETHD) ethanol, given between postnatal days 4–9, on the axons of the rat optic nerve. Rats were exposed to ethanol vapour in a special chamber for a period of 3 h per day during the treatment period. The blood alcohol concentration in the ETLD animals averaged ∼ 171 mg/dl and in the ETHD animals ∼ 430 mg/dl at the end of the treatment on any given day. Groups of 10 and 30-d-old mother-reared control (MRC), separation control (SC), ETLD and ETHD rats were anaesthetised with an intraperitoneal injection of ketamine and xylazine, and killed by intracardiac perfusion with phosphate-buffered glutaraldehyde. In the 10-d-old rat optic nerves there was a total of ∼ 145000–165000 axons in MRC, SC and ETLD animals. About 4% of these fibres were myelinated. The differences between these groups were not statistically significant. However, the 10-d-old ETHD animals had only about 75000 optic nerve axons (P < 0.05) of which about 2.8% were myelinated. By 30 d of age there was a total of between 75000–90000 optic nerve axons, irrespective of the group examined. The proportion of axons which were myelinated at this age was still significantly lower (P < 0.001) in the ETHD animals (∼ 77%) than in the other groups (about 98%). It is concluded that the normal stages of development and maturation of the rat optic nerve axons, as assessed in this study, can be severely compromised by exposure to a relatively high (but not low) dose of ethanol between postnatal d 4 and 9. PMID:11117631

  18. 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.

  19. 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. PMID:19820457

  20. 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.

  1. Dose-effect relationships, epidemiological analysis and the derivation of low dose risk.

    PubMed

    Leenhouts, H P; Chadwick, K H

    2011-03-01

    This paper expands on our recent comments in a letter to this journal about the analysis of epidemiological studies and the determination of low dose RBE of low LET radiation (Chadwick and Leenhouts 2009 J. Radiol. Prot. 29 445-7). Using the assumption that radiation induced cancer arises from a somatic mutation (Chadwick and Leenhouts 2011 J. Radiol. Prot. 31 41-8) a model equation is derived to describe cancer induction as a function of dose. The model is described briefly, evidence is provided in support of it, and it is applied to a set of experimental animal data. The results are compared with a linear fit to the data as has often been done in epidemiological studies. The article presents arguments to support several related messages which are relevant to epidemiological analysis, the derivation of low dose risk and the weighting factor of sparsely ionising radiations. The messages are: (a) cancer incidence following acute exposure should, in principle, be fitted to a linear-quadratic curve with cell killing using all the data available; (b) the acute data are dominated by the quadratic component of dose; (c) the linear fit of any acute data will essentially be dependent on the quadratic component and will be unrelated to the effectiveness of the radiation at low doses; consequently, (d) the method used by ICRP to derive low dose risk from the atomic bomb survivor data means that it is unrelated to the effectiveness of the hard gamma radiation at low radiation doses; (e) the low dose risk value should, therefore, not be used as if it were representative for hard gamma rays to argue for an increased weighting factor for tritium and soft x-rays even though there are mechanistic reasons to expect this; (f) epidemiological studies of chronically exposed populations supported by appropriate cellular radiobiological studies have the best chance of revealing different RBE values for different sparsely ionising radiations. PMID:21346287

  2. 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.

  3. 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.

  4. A report from the 2013 international symposium: the evaluation of the effects of low-dose radiation exposure in the life span study of atomic bomb survivors and other similar studies.

    PubMed

    Grant, E J; Ozasa, K; Ban, N; de González, A Berrington; Cologne, J; Cullings, H M; Doi, K; Furukawa, K; Imaoka, T; Kodama, K; Nakamura, N; Niwa, O; Preston, D L; Rajaraman, P; Sadakane, A; Saigusa, S; Sakata, R; Sobue, T; Sugiyama, H; Ullrich, R; Wakeford, R; Yasumura, S; Milder, C M; Shore, R E

    2015-05-01

    The RERF International Low-Dose Symposium was held on 5-6 December 2013 at the RERF campus in Hiroshima, Japan, to discuss the issues facing the Life Span Study (LSS) and other low-dose studies. Topics included the current status of low-dose risk detection, strategies for low-dose epidemiological and statistical research, methods to improve communication between epidemiologists and biologists, and the current status of radiological studies and tools. Key points made by the participants included the necessity of pooling materials over multiple studies to gain greater insight where data from single studies are insufficient; generating models that reflect epidemiological, statistical, and biological principles simultaneously; understanding confounders and effect modifiers in the current data; and taking into consideration less studied factors such as the impact of dose rate. It is the hope of all participants that this symposium be used as a trigger for further studies, especially those using pooled data, in order to reach a greater understanding of the health effects of low-dose radiation.

  5. A report from the 2013 international symposium: the evaluation of the effects of low-dose radiation exposure in the life span study of atomic bomb survivors and other similar studies.

    PubMed

    Grant, E J; Ozasa, K; Ban, N; de González, A Berrington; Cologne, J; Cullings, H M; Doi, K; Furukawa, K; Imaoka, T; Kodama, K; Nakamura, N; Niwa, O; Preston, D L; Rajaraman, P; Sadakane, A; Saigusa, S; Sakata, R; Sobue, T; Sugiyama, H; Ullrich, R; Wakeford, R; Yasumura, S; Milder, C M; Shore, R E

    2015-05-01

    The RERF International Low-Dose Symposium was held on 5-6 December 2013 at the RERF campus in Hiroshima, Japan, to discuss the issues facing the Life Span Study (LSS) and other low-dose studies. Topics included the current status of low-dose risk detection, strategies for low-dose epidemiological and statistical research, methods to improve communication between epidemiologists and biologists, and the current status of radiological studies and tools. Key points made by the participants included the necessity of pooling materials over multiple studies to gain greater insight where data from single studies are insufficient; generating models that reflect epidemiological, statistical, and biological principles simultaneously; understanding confounders and effect modifiers in the current data; and taking into consideration less studied factors such as the impact of dose rate. It is the hope of all participants that this symposium be used as a trigger for further studies, especially those using pooled data, in order to reach a greater understanding of the health effects of low-dose radiation. PMID:25811153

  6. 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).

  7. 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). PMID:25219894

  8. 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

  9. Subclinical decelerations during developing hypotension in preterm fetal sheep after acute on chronic lipopolysaccharide exposure.

    PubMed

    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

  10. Acceleration of atherogenesis in ApoE-/- mice exposed to acute or low-dose-rate ionizing radiation.

    PubMed

    Mancuso, Mariateresa; Pasquali, Emanuela; Braga-Tanaka, Ignacia; Tanaka, Satoshi; Pannicelli, Alessandro; Giardullo, Paola; Pazzaglia, Simonetta; Tapio, Soile; Atkinson, Michael J; Saran, Anna

    2015-10-13

    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

  11. 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

  12. Low-dose thioperamide injected into the cerebellar vermis of mice immediately after exposure to the elevated plus-maze impairs their avoidance behavior on re-exposure to the apparatus

    PubMed Central

    Costa, J.; Serafim, K.R.; Gianlorenço, A.C.L.; Mattioli, R.

    2013-01-01

    The present study investigated the effect of thioperamide (THIO), an H3 histaminergic receptor antagonist, microinjected into the cerebellar vermis on emotional memory consolidation in male Swiss albino mice re-exposed to the elevated plus-maze (EPM). We implanted a guide cannula into the cerebellar vermis using stereotactic surgery. On the third day after surgery, we performed behavioral tests for two consecutive days. On the first day (exposure), the mice (n=10/group) were exposed to the EPM and received THIO (0.06, 0.3, or 1.5 ng/0.1 µL) immediately after the end of the session. Twenty-four hours later, the mice were re-exposed to the EPM under the same experimental conditions, but without drug injection. A reduction in the exploration of the open arms upon re-exposure to the EPM (percentage of number of entries and time spent in open arms) compared with the initial exposure was used as an indicator of learning and memory. One-way analysis of variance (ANOVA) followed by the Duncan post hoc test was used to analyze the data. Upon re-exposure, exploratory activity in the open arms was reduced in the control group, and with the two highest THIO doses: 0.3 and 1.5 ng/0.1 µL. No reduction was seen with the lowest THIO dose (0.06 ng/0.1 µL), indicating inhibition of the consolidation of emotional memory. None of the doses interfered with the animals' locomotor activity. We conclude that THIO at the lowest dose (0.06 ng/0.1 µL) microinjected into the cerebellum impaired emotional memory consolidation in mice. PMID:24270913

  13. Low-dose thioperamide injected into the cerebellar vermis of mice immediately after exposure to the elevated plus-maze impairs their avoidance behavior on re-exposure to the apparatus.

    PubMed

    Costa, J; Serafim, K R; Gianlorenço, A C L; Mattioli, R

    2013-11-06

    The present study investigated the effect of thioperamide (THIO), an H3 histaminergic receptor antagonist, microinjected into the cerebellar vermis on emotional memory consolidation in male Swiss albino mice re-exposed to the elevated plus-maze (EPM). We implanted a guide cannula into the cerebellar vermis using stereotactic surgery. On the third day after surgery, we performed behavioral tests for two consecutive days. On the first day (exposure), the mice (n=10/group) were exposed to the EPM and received THIO (0.06, 0.3, or 1.5 ng/0.1 µL) immediately after the end of the session. Twenty-four hours later, the mice were re-exposed to the EPM under the same experimental conditions, but without drug injection. A reduction in the exploration of the open arms upon re-exposure to the EPM (percentage of number of entries and time spent in open arms) compared with the initial exposure was used as an indicator of learning and memory. One-way analysis of variance (ANOVA) followed by the Duncan post hoc test was used to analyze the data. Upon re-exposure, exploratory activity in the open arms was reduced in the control group, and with the two highest THIO doses: 0.3 and 1.5 ng/0.1 µL. No reduction was seen with the lowest THIO dose (0.06 ng/0.1 µL), indicating inhibition of the consolidation of emotional memory. None of the doses interfered with the animals' locomotor activity. We conclude that THIO at the lowest dose (0.06 ng/0.1 µL) microinjected into the cerebellum impaired emotional memory consolidation in mice.

  14. 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

  15. Chronic intrauterine exposure to endotoxin does not alter fetal nephron number or glomerular size.

    PubMed

    Ryan, Danica; Atik, Anzari; De Matteo, Robert; Harding, Richard; Black, Mary J

    2013-11-01

    A reduced nephron endowment early in life adversely impacts on long-term functional reserve in the kidney. A recent study has shown that acute exposure to chorioamnionitis during late gestation can adversely impact on nephrogenesis. The present study aimed to examine the effects of chronic, low-dose endotoxin exposure in utero, during the period of nephrogenesis, on nephron number and glomerular size in preterm lambs. Ewes were administered either endotoxin (lipopolysaccharide; 1 mg/day) or saline at 110-133 days of gestation (term approximately 147 days) via surgically implanted osmotic minipumps within the amniotic cavity. The ewes were induced to deliver preterm at 133 days gestation and the kidneys of the lambs were analysed at 8 weeks after term-equivalent age. Nephron number per kidney was determined using a combined optical disector and fractionator stereological approach; renal corpuscle size was also measured stereologically. At 8 weeks after term-equivalent age there was no significant effect of in utero exposure to endotoxin on bodyweight or kidney weight and there were no significant differences in nephron number, nephron density or renal corpuscle volume between groups. We conclude that chronic intrauterine inflammation during the period of nephrogenesis may not adversely impact on the number of nephrons formed within the kidney or on the volume of the renal corpuscle.

  16. 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

  17. 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. PMID:25644753

  18. Low-dose risk assessment for arsenic: a meta-analysis approach.

    PubMed

    Begum, Munni; Horowitz, John; Hossain, Md Irfan

    2015-03-01

    We conducted a meta-analysis to explore dose-response relationships for bladder and lung cancers when people are chronically exposed to low doses of arsenic. We searched electronic databases for articles published through 2010. Ten studies on bladder cancer and ingested arsenic exposure and five studies on lung cancer and ingested arsenic exposure fit our selection criteria. We also investigate the sensitivity of the absolute risk of lung and bladder cancer under different underlying prevalence measures. Males have a higher risk of bladder cancer than do females at all maximum contamination levels. The absolute risk of bladder cancer and lung cancer from ingested arsenic correlates highly with smoking rates. For a maximum contamination level of 10 µg/L, we estimate that there are about 2.91 additional bladder cancer cases per 100,000 people and, considering studies since 2000, we estimate that there are about 4.51 additional lung cancer cases per 100,000 people.

  19. Extrapolation from incomplete data to total or lifetime risks at low doses.

    PubMed Central

    Schneiderman, M A

    1981-01-01

    Both epidemiology and laboratory data can contribute to estimates of risks to humans of exposure to low doses of carcinogens. The sum of all these contributions does not permit us to make these estimates with certainty. In chronic disease epidemiology, in looking for possible excessive cancer risks, we sometimes fail to have an adequately long observation time or to observe a population sufficiently aged for cancers to appear in meaningful numbers. In studies of most human exposures, dose data are often lacking, beyond a vague "yes-no" or "lots, not much, hardly any." Thus, without a knowledge of what dose produced an observed result it becomes logically impossible to know what result some other (presumed) dose might yield. Animal data show some promise of being useful in extrapolating to low doses in man. However, several problems exist: (a) man is not a tailless, two-legged mouse, or featherless chicken--that is, we do not know if man is more or less sensitive than the laboratory animal; (b) the mathematical model used for extrapolation leads to large differences in estimates of response; (c) man is genetically heterogeneous and is usually exposed to many more hazards than is the laboratory animal. Thus, existing data, even from well-done studies, are inadequate if we want to make extrapolations in any detail or to apply to specific subgroups in the population. Any risk estimation we do may have to be stated in terms that point out the wide ranges of the estimates. PMID:7333258

  20. Multi-level effects of low dose rate ionizing radiation on southern toad, Anaxyrus [Bufo] terrestris

    DOE PAGESBeta

    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 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

  1. 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.

  2. 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

  3. 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. PMID:26284510

  4. 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.

  5. Tardive dyskinesia with low dose amisulpride.

    PubMed

    Tharoor, Hema; Padmavati, R

    2013-01-01

    In recent years, there has been an increasing trend to use amisulpride in the treatment of dysthymia and also as an adjunct treatment in patients with major depression. At low doses (50 mg), amisulpride preferentially blocks presynaptic auto receptors, enhances dopamine release, and therefore acts as a dopaminergic compound able to resolve the dopaminergic hypo activity that characterizes depression. Based on experimental data, amisulpride is the drug of choice for dopaminergic transmission disorders, both in depression and in schizophrenia. This case highlights the development of dyskinesia in a depressed patient treated with low dose amisulpride and fluvoxamine.

  6. 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.

  7. Etched track detectors and the low dose problem.

    PubMed

    Pálfalvi, J; Dám, A M; Bogdándi, E N; Polonyi, I; Szabó, J; Balásházy, I; Farkas, A

    2003-01-01

    The risk to human health of exposure to low-level radiation is not precisely known yet. One way of studying this is to carry out in vitro biological experiments with cell cultures and to extend the conclusions to biological models. To relate the macroscopically deteminable 'low dose' to the damage of cells caused by a certain type of ionising particle is nearly impossible. therefore the number of hits and the imparted energy are the significant quantities. They can be estimated by particle transport calculations and by direct measurements. The effect of low dose was investigated in radio-adaptation experiments when mono-layers of different unsynchronised cell cultures were irradiated by neutrons produced in the filtered beam of the Budapest Research Reactor (BRR). The energy deposition was investigated by replacing the mono-layers with etched track detectors of the CR-39 type. PMID:12678384

  8. Mitochondrial reactive oxygen species-mediated genomic instability in low-dose irradiated human cells through nuclear retention of cyclin D1.

    PubMed

    Shimura, Tsutomu; Kunugita, Naoki

    2016-06-01

    Mitochondria are associated with various radiation responses, including adaptive responses, mitophagy, the bystander effect, genomic instability, and apoptosis. We recently identified a unique radiation response in the mitochondria of human cells exposed to low-dose long-term fractionated radiation (FR). Such repeated radiation exposure inflicts chronic oxidative stresses on irradiated cells via the continuous release of mitochondrial reactive oxygen species (ROS) and decrease in cellular levels of the antioxidant glutathione. ROS-induced oxidative mitochondrial DNA (mtDNA) damage generates mutations upon DNA replication. Therefore, mtDNA mutation and dysfunction can be used as markers to assess the effects of low-dose radiation. In this study, we present an overview of the link between mitochondrial ROS and cell cycle perturbation associated with the genomic instability of low-dose irradiated cells. Excess mitochondrial ROS perturb AKT/cyclin D1 cell cycle signaling via oxidative inactivation of protein phosphatase 2A after low-dose long-term FR. The resulting abnormal nuclear accumulation of cyclin D1 induces genomic instability in low-dose irradiated cells. PMID:27078622

  9. Chronic exposure to low benzo[a]pyrene level causes neurodegenerative disease-like syndromes in zebrafish (Danio rerio).

    PubMed

    Gao, Dongxu; Wu, Meifang; Wang, Chonggang; Wang, Yuanchuan; Zuo, Zhenghong

    2015-10-01

    Previous epidemiological and animal studies report that exposure to environmental pollutant exposure links to neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Benzo[a]pyrene (BaP), a neurotoxic polycyclic aromatic hydrocarbon, has been increasingly released into the environment during recent decades. So far, the role of BaP on the development of neurodegenerative diseases remaind unclear. This study aimed to determine whether chronic exposure to low dose BaP would cause neurodegenerative disease-like syndromes in zebrafish (Danio rerio). We exposed zebrafish, from early embryogenesis to adults, to environmentally relevant concentrations of BaP for 230 days. Our results indicated that BaP decreased the brain weight to body weight ratio, locomotor activity and cognitive ability; induced the loss of dopaminergic neurons; and resulted in neurodegeneration. In addition, obvious cell apoptosis in the brain was found. Furthermore, the neurotransmitter levels of dopamine and 3,4-dihydroxyphenylacetic acid, the mRNA levels of the genes encoding dopamine transporter, Parkinson protein 7, phosphatase and tensin-induced putative kinase 1, ubiquitin carboxy-terminal hydrolase L1, leucine-rich repeat serine/threonine kinase 2, amyloid precursor protein b, presenilin 1 and presenilin 2 were significantly down-regulated by BaP exposure. These findings suggest that chronic exposure to low dose BaP could cause the behavioral, neuropathological, neurochemical, and genetic features of neurodegenerative diseases. This study provides clues that BaP may constitute an important environmental risk factor for neurodegenerative diseases in humans.

  10. Low-dose radiation: a cause of breast cancer

    SciTech Connect

    Land, C.E.

    1980-08-15

    It is likely that the breast is the organ most sensitive to radiation carcinogenesis in postpubertal women. Studies of different exposed populations have yielded remarkably consistent results, in spite of wide differences in underlying breast cancer rates and conditions of exposure. Excess risk is approximately proportional to dose, and is relatively independent of ionization density and fractionization of dose. This implies that the risk associated with low-dose exposures to ionizing radiation can be estimated with some confidence from higher-dose data. Excess risk is heavily dependent on age at exposure but relatively independent of population differences in normal risk. The temporal patterns after exposure of both radiation-induced and naturally occurring breast cancer are similar, suggesting a strong influence of factors other than radiation on radiation-induced breast cancer. Uncertainties remain about risks from exposures before puberty and after menopause.

  11. 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.

  12. 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.

  13. Low Dose Effects: Benefit or Harm?

    PubMed

    Woloschak, Gayle E

    2016-03-01

    This forum article discusses issues related to the effects of low dose radiation, an area that is under intense study but difficult to assess. Experiments with large-scale animal studies are included in this paper; these studies point to the need for international consortia to examine and balance the results of these large-scale studies and databases. PMID:26808889

  14. Chronic inhalation exposure of rats to nitromethane.

    PubMed

    Griffin, T B; Coulston, F; Stein, A A

    1996-07-01

    Male and female Long-Evans rats were housed in inhalation chambers and exposed to vapors of nitromethane (NM) at either 100 or 200 ppm. The animals were exposed 7 hr per day, 5 days per week for 2 years. Control groups of rats were also housed in a similar inhalation chamber, but NM was not introduced into the chamber. The animals were observed daily for signs of pharmacologic or toxicologic effect and body weights were recorded periodically. At the 2-year termination of the exposure period, clinical laboratory examinations (serum chemistry and hematology) were performed on selected animals and all surviving animals were sacrificed. All animals were necropsied and subjected to a thorough histopathologic examination. During the study there were no pharmacologic effects from exposure to NM at either 100 or 200 ppm. There was no effect on mortality on either sex at either exposure level. Body weights of male rats exposed to NM were not significantly different from those of control rats, but the body weights of female rats of both exposure groups were slightly less than their controls. There was no effect of exposure of rats of either sex to either level of NM on hematology. There were no clinically significant effects on serum chemistry. There were no effects of exposure to NM on organ weights. There were no significant differences in the nonneoplastic or neoplastic pathology related to exposure to NM. PMID:8812175

  15. Sub-chronic exposure to methylmercury at low levels decreases butyrylcholinesterase activity in rats.

    PubMed

    Valentini, Juliana; Vicentini, Juliana; Grotto, Denise; Tonello, Raquel; Garcia, Solange C; Barbosa, Fernando

    2010-02-01

    In this study, we examined the effects of low levels and sub-chronic exposure to methylmercury (MeHg) on butyrylcholinesterase (BuChE) activity in rats. Moreover, we examined the relationship between BuChE activity and oxidative stress biomarkers [delta-aminolevulinic acid dehydratase (delta-ALA-D) and malondialdehyde levels (MDA)] in the same animals. Rats were separated into three groups (eight animals per group): (Group I) received water by gavage; (Group II) received MeHg (30 microg/kg/day) by gavage; (Group III) received MeHg (100 microg/kg/day). The time of exposure was 90 days. BuChE and ALA-D activities were measured in serum and blood, respectively; whereas MDA levels were measured in plasma. We found BuChE and ALA-D activities decreased in groups II and III compared to the control group. Moreover, we found an interesting negative correlation between plasmatic BuChE activity and MDA (r = -0.85; p < 0.01) and a positive correlation between plasmatic BuChE activity and ALA-D activities (r = 0.78; p < 0.01), thus suggesting a possible relationship between oxidative damage promoted by MeHg exposure and the decrease of BuChE activity. In conclusion, long-term exposure to low doses of MeHg decreases plasmatic BuChE activity. Moreover, the decrease in the enzyme is strongly correlated with the oxidative stress promoted by the metal exposure. This preliminary finding highlights a possible mechanism for MeHg to reduce BuChE activity in plasma. Additionally, this enzyme could be an auxiliary biomarker on the evaluation of MeHg exposure.

  16. 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...

  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. Screening for lung cancer using low dose computed tomography.

    PubMed

    Tammemagi, Martin C; Lam, Stephen

    2014-01-01

    Screening for lung cancer with low dose computed tomography can reduce mortality from the disease by 20% in high risk smokers. This review covers the state of the art knowledge on several aspects of implementing a screening program. The most important are to identify people who are at high enough risk to warrant screening and the appropriate management of lung nodules found at screening. An accurate risk prediction model is more efficient than age and pack years of smoking alone at identifying those who will develop lung cancer and die from the disease. Algorithms are available for assessing people who screen positive to determine who needs additional imaging or invasive investigations. Concerns about low dose computed tomography screening include false positive results, overdiagnosis, radiation exposure, and costs. Further work is needed to define the frequency and duration of screening and to refine risk prediction models so that they can be used to assess the risk of lung cancer in special populations. Another important area is the use of computer vision software tools to facilitate high throughput interpretation of low dose computed tomography images so that costs can be reduced and the consistency of scan interpretation can be improved. Sufficient data are available to support the implementation of screening programs at the population level in stages that can be expanded when found to perform well to improve the outcome of patients with lung cancer. PMID:24865600

  19. Low dose monitors — the movements and causes

    NASA Astrophysics Data System (ADS)

    Cherekdjian, S.

    1993-04-01

    A previous paper [Nucl. Instr. and Meth. B55 (1991) 178] has demonstrated that the correct equipment specification and process procedures enable the reliable direct probing of low dose sheet resistance monitors. Utilizing this, we are able to characterize the instability of low dose monitors to process and ambient conditions. Several experiments are conducted to determine the origin of the movements. These movements were found to be either "short term", or "long term". The former is a result of the interaction of the wafer and its processing prior to measurement. While the latter is a slow change after processing. The correct specification of the wafers, wafer processing, and the condition of the four point probe tips enable the low dose measurement to be performed. The value of the initial result, "short term movement", is shown to be directly the consequence of wet chemistry and the ambient anneal condition. While the stability of the wafer after measurement, "long term movement", is found to be the electrical degradation of the surface of the silicon. A key factor in this stability problem is the exposure of the wafer to air, especially to moisture in the atmosphere. X-ray photo spectroscopy (XPS), and time of flight secondary ion mass Spectrometry (TOP SIMS) results give an insight to the complexity of the surface condition. These range from oxide growth, surface chemistry, and hydrogen injection.

  20. 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.

  1. 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

  2. Gamma radiation at a human relevant low dose rate is genotoxic in mice.

    PubMed

    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 RBC(CD24-)) 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

  3. Acute and chronic respiratory effects of sodium borate particulate exposures.

    PubMed Central

    Wegman, D H; Eisen, E A; Hu, X; Woskie, S R; Smith, R G; Garabrant, D H

    1994-01-01

    This study examined work-related chronic abnormality in pulmonary function and work-related acute irritant symptoms associated with exposure to borate dust in mining and processing operations. Chronic effects were examined by pulmonary function at the beginning and end of a 7-year interval. Time-specific estimates of sodium borate particulate exposures were used to estimate cumulative exposure during the study interval. Change in pulmonary function over the 7 years was found unrelated to the estimate of cumulative exposure during that interval. Exposure-response associations also were examined with respect to short-term peak exposures and incidence of five symptoms of acute respiratory irritation. Hourly measures of health outcome and continuous measures of particulate exposure were made on each subject throughout the day. Whenever a subject reported one of the irritant symptoms, a symptom intensity score was also recorded along with the approximate time of onset. The findings indicated that exposure-response relationships were present for each of the specific symptoms at several symptom intensity levels. The associations were present when exposure was estimated by both day-long and short-term (15-min) time-weighted average exposures. Associations persisted after taking account of smoking, age, and the presence of a common cold. No significant difference in response rate was found between workers exposed to different types of sodium borate dusts. PMID:7889871

  4. Psychologic sequelae of chronic toxic waste exposure.

    PubMed

    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. PMID:1738876

  5. 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

  6. Re-exposure of mallards to selenium after chronic exposure

    SciTech Connect

    Heinz, G.H. . Patuxent Wildlife Research Center)

    1993-09-01

    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, weight loss in survivors, selenium concentrations in the livers of survivors, or selenium concentrations in the livers of birds that died. When the data from the birds that had previously been exposed to 15 ppm selenium were combined in the livers of birds that had died on the 100-ppm selenium treatment did not differ from the concentrations in the livers of birds that had survived.

  7. Benign skin changes associated with chronic sunlight exposure.

    PubMed

    Goldberg, L H; Altman, A

    1984-07-01

    Chronic and heavy sun exposure will insidiously induce changes in human skin during the course of many years. These changes include wrinkles, atrophy, cutis rhomboidalis nuchae, yellow papules and plaques of the face, colloid milium, telangiectasis, diffuse erythema, diffuse brown pigmentation, ecchymoses, freckles, actinic lentigo, nevi, Favre-Racouchot syndrome, poikiloderma of Civatte, actinic keratosis, basal cell carcinoma, squamous cell carcinoma, melanoma, actinic lichen planus, actinic reticuloid, porphyria cutanea tarda, and erythropoietic protoporphyria. In particular, we describe the clinical appearance of the benign changes caused by chronic sunlight exposure.

  8. 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.

  9. Repeated exposure to low doses of kainic acid activates nuclear factor kappa B (NF-κB) prior to seizure in transgenic NF-κB/EGFP reporter mice.

    PubMed

    Miller, James A; Kirkley, Kelly A; Padmanabhan, Rachel; Liang, Li-Ping; Raol, Yogendra H; Patel, Manisha; Bialecki, Russell A; Tjalkens, Ronald B

    2014-09-01

    Predicting seizurogenic properties of pharmacologically active compounds is difficult due to the complex nature of the mechanisms involved and because of the low sensitivity and high variability associated with current behavioral-based methods. To identify early neuronal signaling events predictive of seizure, we exposed transgenic NF-κB/EGFP reporter mice to multiple low doses of kainic acid (KA), postulating that activation of the stress-responsive NF-κB pathway could be a sensitive indicator of seizurogenic potential. The sub-threshold dose level proximal to the induction of seizure was determined as 2.5mg/kg KA, using video EEG monitoring. Subsequent analysis of reporter expression demonstrated significant increases in NF-κB activation in the CA3 and CA1 regions of the hippocampus 24h after a single dose of 2.5mg/kg KA. This response was primarily observed in pyramidal neurons with little non-neuronal expression. Neuronal NF-κB/EGFP expression was observed in the absence of glial activation, indicating a lack of neurodegeneration-induced neuroinflammation. Protein expression of the immediate-early gene, Nurr1, increased in neurons in parallel to NF-κB activation, supporting that the sub-threshold doses of KA employed directly caused neuronal stress. Lastly, KA also stimulated NF-κB activation in organotypic hippocampal slice cultures established from NF-κB/EGFP reporter mice. Collectively, these data demonstrate the potential advantages of using genetically encoded stress pathway reporter models in the screening of seizurogenic properties of new pharamacologically active compounds.

  10. 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).

  11. 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.

  12. Chronic cadmium exposure: relation to male reproductive toxicity and subsequent fetal outcome.

    PubMed

    Zenick, H; Hastings, L; Goldsmith, M; Niewenhuis, R J

    1982-03-01

    Acute injections of high doses of Cd induce 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 contributions 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 sacrificed 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 significant 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.

  13. 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. PMID:19962437

  14. 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)

  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. Exposure to Chronic Community Violence: Resilience in African American Children

    ERIC Educational Resources Information Center

    Jones, Janine M.

    2007-01-01

    In many African American communities, violence and poverty are often part of daily living. As a result, children are at risk for difficulties in all aspect of their lives, particularly their emotional well-being. This study explored the relationship between exposure to chronic community violence and the development of complex post-traumatic stress…

  17. Increased chronic acceleration exposure enhances work capacity.

    PubMed

    Burton, R R; Smith, A H

    1997-10-01

    Adult male chickens adapted to 1.75 or 2.5 G from long term centrifugation, were maximally exercised on an animal treadmill at 1 g (Earth's gravity) and compared with the exercise capacities of control chickens raised at 1 g. The increased-G birds had statistically significantly greater exercise capacities than the controls during the first 3 weeks of the study after the initial exercise exposure. Thereafter however for the following two months of the study, there was no difference in either group's exercise capacities. This early increased work capacity was attributed to the increased-G birds improved ability to maximize their muscular strength with neurological adaptation. The increased-G birds lost body mass at a 31% greater rate during exercise than the controls although this difference was not statistically significant. This increased body mass loss was considered to have resulted from increased use of glycogen during exercise.

  18. [Low dose naltrexone for treatment of pain].

    PubMed

    Plesner, Karin Bruun; Vægter, Henrik Bjarke; Handberg, Gitte

    2015-10-01

    Recent years have seen an increasing interest in the use of low dose naltrexone (LDN) for off-label treatment of pain in diseases as fibromyalgia, multiple sclerosis and morbus Crohn. The evidence is poor, with only few randomized double-blind placebo-controlled studies. The studies currently available are reviewed in this paper. LDN could be a potentially useful drug in the future for the treatment of pain in fibromyalgia, but more studies are needed to verify that it is superior to placebo, and currently it cannot be recommended as first-line therapy. PMID:26509454

  19. 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. PMID:27418545

  20. 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.

  1. Silica exposure and chronic airflow limitation in pottery workers.

    PubMed

    Neukirch, F; Cooreman, J; Korobaeff, M; Pariente, R

    1994-01-01

    We assessed the relationship between exposure to silica dust and chronic airflow limitation in an epidemiological survey conducted among pottery workers and controls who were of the same socioeconomic status (average age: 35 y; 78% males). Data were collected by questionnaire for respiratory symptoms, allergy, respiratory history, smoking habits, and occupation. Lung function was measured with a computer-equipped Gauthier spirometer. We excluded subjects with silicosis or doubtful chest x-ray, and two exposure levels were defined. No differences were observed between exposed subjects and controls with respect to respiratory conditions. Mean pulmonary function values for men and women were significantly lower, after adjustment for age, height, and smoking habits, in even indirectly exposed pottery workers, compared with controls. These results suggest that exposure to silica dust is a risk factor for chronic airflow limitation and is independent of radiographic changes.

  2. Prenatal low-dose methylmercury exposure impairs neurite outgrowth and synaptic protein expression and suppresses TrkA pathway activity and eEF1A1 expression in the rat cerebellum.

    PubMed

    Fujimura, Masatake; Usuki, Fusako; Cheng, Jinping; Zhao, Wenchang

    2016-05-01

    Methylmercury (MeHg) is a highly neurotoxic environmental chemical that can cause developmental impairments. Human fetuses and neonates are particularly susceptible to MeHg toxicity; however, the mechanisms governing its effects in the developing brain are unclear. In the present study, we investigated the effects of prenatal and lactational MeHg exposure on the developing cerebellum in rats. We demonstrated that exposure to 5ppm MeHg decreased postnatal expression of pre- and postsynaptic proteins, suggesting an impairment in synaptic development. MeHg exposure also reduced neurite outgrowth, as shown by a decrease in the expression of the neurite marker neurofilament H. These changes were not observed in rats exposed to 1ppm MeHg. In order to define the underlying mechanism, we investigated the effects of MeHg exposure on the tropomyosin receptor kinase (Trk) A pathway, which plays important roles in neuronal differentiation and synapse formation. We demonstrated suppression of the TrkA pathway on gestation day 20 in rats exposed to 5ppm MeHg. In addition, down-regulation of eukaryotic elongation factor 1A1 (eEF1A1) was observed on postnatal day 1. eEF1A1 knockdown in differentiating PC12 cells impaired neurite outgrowth and synaptic protein expression, similar to the results of MeHg exposure in the cerebellum. These results suggest that suppression of the TrkA pathway and subsequent decreases in eEF1A1 expression induced by prenatal exposure to MeHg may lead to reduced neurite outgrowth and synaptic protein expression in the developing cerebellum.

  3. 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

  4. 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

  5. Chronic exposure to simulated space conditions predominantly affects cytoskeleton remodeling and oxidative stress response in mouse fetal fibroblasts.

    PubMed

    Beck, Michaël; Moreels, Marjan; Quintens, Roel; Abou-El-Ardat, Khalil; El-Saghire, Hussein; Tabury, Kevin; Michaux, Arlette; Janssen, Ann; Neefs, Mieke; Van Oostveldt, Patrick; De Vos, Winnok H; Baatout, Sarah

    2014-08-01

    Microgravity and cosmic rays as found in space are difficult to recreate on earth. However, ground-based models exist to simulate space flight experiments. In the present study, an experimental model was utilized to monitor gene expression changes in fetal skin fibroblasts of murine origin. Cells were continuously subjected for 65 h to a low dose (55 mSv) of ionizing radiation (IR), comprising a mixture of high‑linear energy transfer (LET) neutrons and low-LET gamma-rays, and/or simulated microgravity using the random positioning machine (RPM), after which microarrays were performed. The data were analyzed both by gene set enrichment analysis (GSEA) and single gene analysis (SGA). Simulated microgravity affected fetal murine fibroblasts by inducing oxidative stress responsive genes. Three of these genes are targets of the nuclear factor‑erythroid 2 p45-related factor 2 (Nrf2), which may play a role in the cell response to simulated microgravity. In addition, simulated gravity decreased the expression of genes involved in cytoskeleton remodeling, which may have been caused by the downregulation of the serum response factor (SRF), possibly through the Rho signaling pathway. Similarly, chronic exposure to low-dose IR caused the downregulation of genes involved in cytoskeleton remodeling, as well as in cell cycle regulation and DNA damage response pathways. Many of the genes or gene sets that were altered in the individual treatments (RPM or IR) were not altered in the combined treatment (RPM and IR), indicating a complex interaction between RPM and IR.

  6. 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

  7. 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.

  8. 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...

  9. 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...

  10. Culmination of Low-Dose Pesticide Effects

    PubMed Central

    2013-01-01

    Pesticides applied in agriculture can affect the structure and function of nontarget populations at lower doses and for longer timespans than predicted by the current risk assessment frameworks. We identified a mechanism for this observation. The populations of an aquatic invertebrate (Culex pipiens) exposed over several generations to repeated pulses of low concentrations of the neonicotinoid insecticide (thiacloprid) continuously declined and did not recover in the presence of a less sensitive competing species (Daphnia magna). By contrast, in the absence of a competitor, insecticide effects on the more sensitive species were only observed at concentrations 1 order of magnitude higher, and the species recovered more rapidly after a contamination event. The underlying processes are experimentally identified and reconstructed using a simulation model. We conclude that repeated toxicant pulse of populations that are challenged with interspecific competition may result in a multigenerational culmination of low-dose effects. PMID:23859631

  11. 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

  12. Risk of Low Dose/Low Dose Rate Ionizing Radiation to Humans Symposium at the EMS 2009 Annual Meeting - September 2006

    SciTech Connect

    Morgan, William F.; von Borstel, Robert C.; Brenner, David; Redpath, J. Leslie; Erickson, Barbra E.; Brooks, Antone L.

    2009-11-12

    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.

  13. 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.

  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. PMID:27279742

  15. 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

  16. Effects of Low-Dose Drinking Water Arsenic on Mouse Fetal and Postnatal Growth and Development

    PubMed Central

    Kozul-Horvath, Courtney D.; Zandbergen, Fokko; Jackson, Brian P.; Enelow, Richard I.; Hamilton, Joshua W.

    2012-01-01

    Background Arsenic (As) exposure is a significant worldwide environmental health concern. Chronic exposure via contaminated drinking water has been associated with an increased incidence of a number of diseases, including reproductive and developmental effects. The goal of this study was to identify adverse outcomes in a mouse model of early life exposure to low-dose drinking water As (10 ppb, current U.S. EPA Maximum Contaminant Level). Methodology and Findings C57B6/J pups were exposed to 10 ppb As, via the dam in her drinking water, either in utero and/or during the postnatal period. Birth outcomes, the growth of the F1 offspring, and health of the dams were assessed by a variety of measurements. Birth outcomes including litter weight, number of pups, and gestational length were unaffected. However, exposure during the in utero and postnatal period resulted in significant growth deficits in the offspring after birth, which was principally a result of decreased nutrients in the dam's breast milk. Cross-fostering of the pups reversed the growth deficit. Arsenic exposed dams displayed altered liver and breast milk triglyceride levels and serum profiles during pregnancy and lactation. The growth deficits in the F1 offspring resolved following separation from the dam and cessation of exposure in male mice, but did not resolve in female mice up to six weeks of age. Conclusions/Significance Exposure to As at the current U.S. drinking water standard during critical windows of development induces a number of adverse health outcomes for both the dam and offspring. Such effects may contribute to the increased disease risks observed in human populations. PMID:22693606

  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. Changes in the synaptic structure of hippocampal neurons and impairment of spatial memory in a rat model caused by chronic arsenite exposure.

    PubMed

    Jing, Jinfei; Zheng, Gang; Liu, Mingchao; Shen, Xuefeng; Zhao, Fang; Wang, Jiye; Zhang, Jianbin; Huang, Guanpeng; Dai, Peng; Chen, Yinglei; Chen, Jingyuan; Luo, Wenjing

    2012-10-01

    Many epidemiological studies and in vitro experiments have found that chronic arsenic exposure may influence memory formation. The goal of this study was to create an animal model of memory impairment induced by chronic arsenite exposure and to study the underlying mechanisms. Sixty male Sprague-Dawley (SD) male rats were randomly divided into a control group, a low-dose sodium arsenite exposure group and a high-dose sodium arsenite exposure group. Sodium arsenite was administered by adding it to drinking water for 3 months. Then, the spatial memory of the rats was examined with Morris water maze and Y maze. The concentration of arsenic in the blood and the brain was determined by an atomic fluorescence absorption spectrometer. The ultra-structure of hippocampal neurons was observed by an electron microscope. Timm staining was used for observing mossy fibers. We found that the concentration of arsenic in the blood and the brain increased in a dose-response manner (P<0.05). The performance of rats in the arsenite exposed group (15 mg/kg) was significantly impaired in the Morris water maze and Y maze tasks than those in the control group (P<0.05). Sodium arsenite exposure resulted in abnormal structural changes in the myelin sheaths of nerve fibers and decreases in the terminals of mossy fibers. Together, chronic sodium arsenite exposure through drinking water results in detrimental changes in the neuronal synapses, which may contribute to the arsenite-induced impairment of spatial memory.

  19. 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

  20. 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

    Gunderson, Mark P; Veldhoen, Nik; Skirrow, Rachel C; Macnab, Magnus K; Ding, Wei; van Aggelen, Graham; Helbing, Caren C

    2011-03-01

    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 48h exposure to 1 and 100μg/l of the herbicide atrazine (ATZ) and its major metabolite desethylatrazine (DEA), as well as 5ng/l of the estrogenic chemical, 17α-ethynylestradiol (EE(2)), and 673ng/l of the thyroid hormone, 3,5,3'-triiodothyronine (T(3)), 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 48h exposure to EE(2) but not T(3) 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.

  1. Analysis of cellular response by exposure to acute or chronic radiation in human lymphoblastoid TK-6 cells

    NASA Astrophysics Data System (ADS)

    Ohnishi, T.; Yasumoto, J.; Takahashi, A.; Ohnishi, K.

    To clarify the biological effects of low-dose rate radiation on human health for long-term stay in space, we analyzed the induction of apoptosis and apoptosis-related gene expression after irradiation with different dose-rate in human lymphoblastoid TK-6 cells harboring wild-type p53 gene. We irradiated TK-6 cells by X-ray at 1.5 Gy (1 Gy/min) and then sampled at 25 hr after culturing. We also irradiated by gamma-ray at 1.5 Gy (1 mGy/min) and then sampled immediately or 25 hr after irradiation. For DNA ladder analysis, we extracted DNA from these samples and electrophoresed with 2% agarose gel. In addition, we extracted mRNA from these samples for DNA-array analysis. mRNA from non-irradiated cells was used as a control. After labeling the cDNA against mRNA with [α -33P]-dCTP and hybridizing onto DNA array (Human Apoptosis Expression Array, R&D Systems), we scanned the profiles of the spots by a phosphorimager (BAS5000, FUJI FILM) and calculated using a NIH Image program. The data of each DNA-array were normalized with eight kinds of house keeping genes. We analyzed the expression level of apoptosis-related genes such as p53-related, Bcl-2 family, Caspase family and Fas-related genes. DNA ladders were obviously detected in the cells exposed to a high dose-rate radiation. We detected the induction of the gene expression of apoptosis-promotive genes. In contrast, almost no apoptosis was observed in the cells exposed to the chronic radiation at a low dose-rate. In addition, we detected the induction of the gene expression of apoptosis-suppressive genes as compared with apoptosis promotive-genes immediately after chronic irradiation. These results lead the importance of biological meaning of exposure to radiation at low dose-rate from an aspect of carcinogenesis. Finally, the effects of chronic irradiation become a highly important issue in space radiation biology for human health.

  2. 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.

  3. Chronic marijuana smoke exposure in the rhesus monkey. I. Plasma cannabinoid and blood carboxyhemoglobin concentrations and clinical chemistry parameters.

    PubMed

    Slikker, W; Paule, M G; Ali, S F; Scallet, A C; Bailey, J R

    1991-08-01

    This report is the first in a series about a large multidisciplinary study designed to determine whether chronic marijuana (MJ) smoke exposure results in residual behavioral and/or neuropathological alterations in the rhesus monkey. Prior to the initiation of a year of chronic MJ smoke exposure, 64 periadolescent male rhesus monkeys were trained for 1 year to perform five operant behavioral tasks and then divided, according to their performance in these tasks, into four exposure groups (n = 15-16/group): (1) a high dose (HI) group, exposed 7 days/week to the smoke of one standard MJ cigarette; (2) a low dose (LO) group, exposed on weekend days only to the smoke of a standard MJ cigarette; (3) an extracted MJ cigarette (EX) group, exposed 7 days/week to the smoke of one ethanol-extracted MJ cigarette; and (4) a sham group (SH), exposed 7 days/week to sham exposure conditions. Daily exposures for 1 year were accomplished using a mask that covered the subjects' nose and mouth. Average body weights (initially 3.7 +/- 0.5 kg, mean +/- SD) and rates of weight gain (approximately 0.1 kg/month) were the same for all groups throughout the entire experiment. During the first week of exposure, plasma concentrations of delta-9-tetrahydrocannabinol and 11-nor-9-carboxy-THC in the HI group were 59 +/- 7 (mean +/- SE) and 5.5 +/- 1.5 ng/ml, respectively, 45 min after MJ smoke administration and did not change significantly at similar times after exposure throughout the remainder of the year. Whole blood carboxyhemoglobin levels increased to approximately 13% 1 min after exposure to smoke in either the MJ or the EX groups. Comparison of blood chemistry and hematology values before, during, and after exposure indicated no differences for most parameters. During exposure, lymphocytes, alkaline phosphatase and gamma-glutamyl transferase were depressed in the HI group compared to in the SH group. During exposure, aspartate aminotransferase was elevated for both the HI and EX groups

  4. 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

  5. The stage-specific testicular germ cell apoptotic response to low-dose X-irradiation and 2,5-hexanedione combined exposure. I: Validation of the laser capture microdissection method for qRT-PCR array application.

    PubMed

    Catlin, Natasha R; Huse, Susan M; Boekelheide, Kim

    2014-12-01

    Over the past decade, laser capture microdissection (LCM) has grown as a tool for gene expression profiling of small numbers of cells from tumor samples and of specific cell populations in complex tissues. LCM can be used to study toxicant effects on selected cell populations within the testis at different stages of spermatogenesis. There are several LCM-related hurdles to overcome, including issues inherent to the method itself, as well as biases that result from amplifying the LCM-isolated RNA. Many technical issues associated with the LCM method are addressed here, including increasing RNA yield and obtaining more accurate quantification of RNA yields. We optimized the LCM method optimized to generate RNA quantities sufficient for quantitative reverse transcription polymerase chain reaction (qRT-PCR) array analysis without amplification and were able to validate the method through direct comparison of results from unamplified and amplified RNA from individual samples. The addition of an amplification step for gene expression studies using LCM RNA resulted in a bias, especially for low abundance transcripts. Although the amplification bias was consistent across samples, researchers should use caution when comparing results generated from amplified and unamplified LCM RNA. Here, we have validated the use of LCM-derived RNA with the qRT-PCR array, improving our ability to investigate cell-type and stage-specific responses to toxicant exposures.

  6. 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.

  7. 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. PMID:26808877

  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. Quantifying exploratory low dose compounds in humans with AMS

    PubMed Central

    Dueker, Stephen R.; Vuong, Le T.; Lohstroh, Peter N.; Giacomo, Jason A.; Vogel, John S.

    2010-01-01

    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 14C 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. PMID:21047543

  10. 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.

  11. Activation of NF-kappaB in bone marrow cells of BALB/cJ mice following exposure in vivo to low doses of (137)Cs gamma-rays.

    PubMed

    Rithidech, Kanokporn Noy; Tungjai, Montree; Arbab, Edgar; Simon, Sanford R

    2005-10-01

    We measured levels of NF-kappaB activation in bone marrow (BM) cells collected at 1 and 4 h from male BALB/cJ mice (10-12 weeks old) given a whole body dose of 0, 0.05, 0.1 and 1 Gy of (137)Cs gamma-rays (at the dose rate of 0.75 Gy/min). At each harvest time-point, BM cells were collected from five mice per dose of radiation. We used two methods for detecting NF-kappaB activation (1) the NF-kappaB/p65 transcription factor enzyme-linked immunosorbance assay (ELISA) and (2) immunofluorescence staining with NF-kappaB/p65 antibody. Results from ELISA indicated 2.0 and 2.8-fold increases in NF-kappaB activation in BM cells isolated at 1 h post-exposure of mice to 0.1 or 1.0 Gy. The immunofluorescence staining method showed similar results. In samples isolated 4 h post-irradiation, however, no activated NF-kappaB signal was found, regardless of the method of detection. The data also demonstrated that NF-kappaB was not activated in bone marrow cells collected either at 1 or 4 h from BALB/cJ mice exposed to a single dose of 0.05 Gy (137)Cs gamma-rays. Taken together, the results from our in vivo study indicate the involvement of NF-kappaB activation in early response to 0.1 and 1.0 Gy (but not 0.05 Gy) of (137)Cs gamma-rays. PMID:16052312

  12. Effects of Mild Chronic Intermittent Cold Exposure on Rat Organs.

    PubMed

    Wang, Xiaohui; Che, Honglei; Zhang, Wenbin; Wang, Jiye; Ke, Tao; Cao, Rui; Meng, Shanshan; Li, Dan; Weiming, Ouyang; Chen, Jingyuan; Luo, Wenjing

    2015-01-01

    Cold adaptation is a body's protective response to cold stress. Mild chronic intermittent cold (CIC) exposure has been used to generate animal models for cold adaptation studies. However, the effects of mild CIC exposure on vital organs are not completely characterized. In the present study, we exposed rats to mild CIC for two weeks, and then measured the body weights, the weights of brown adipose tissue (BAT), the levels of ATP and reactive oxygen species (ROS) in the brains, livers, hearts, muscles and BATs. Rats formed cold adaptation after exposure to CIC for two weeks. Compared to rats of the control group that were hosted under ambient temperature, rats exposed to mild CIC showed a lower average body weight, but a higher weight of brown adipose tissue (BAT). Rats exposed to CIC for two weeks also exhibited higher levels of ATP and ROS in all examined organs as compared to those of the control group. In addition, we determined the expression levels of cold-inducible RNA binding protein (Cirbp) and thioredoxin (TRX) in rat tissues after 2 weeks of CIC exposure. Both Cirbp and TRX were increased, suggesting a role of these two proteins for establishment of cold adaptation. Together, this study reveals the effects of mild CIC exposure on vital organs of rats during CIC exposure.

  13. Effects of Mild Chronic Intermittent Cold Exposure on Rat Organs

    PubMed Central

    Wang, Xiaohui; Che, Honglei; Zhang, Wenbin; Wang, Jiye; Ke, Tao; Cao, Rui; Meng, Shanshan; Li, Dan; Weiming, Ouyang; Chen, Jingyuan; Luo, Wenjing

    2015-01-01

    Cold adaptation is a body's protective response to cold stress. Mild chronic intermittent cold (CIC) exposure has been used to generate animal models for cold adaptation studies. However, the effects of mild CIC exposure on vital organs are not completely characterized. In the present study, we exposed rats to mild CIC for two weeks, and then measured the body weights, the weights of brown adipose tissue (BAT), the levels of ATP and reactive oxygen species (ROS) in the brains, livers, hearts, muscles and BATs. Rats formed cold adaptation after exposure to CIC for two weeks. Compared to rats of the control group that were hosted under ambient temperature, rats exposed to mild CIC showed a lower average body weight, but a higher weight of brown adipose tissue (BAT). Rats exposed to CIC for two weeks also exhibited higher levels of ATP and ROS in all examined organs as compared to those of the control group. In addition, we determined the expression levels of cold-inducible RNA binding protein (Cirbp) and thioredoxin (TRX) in rat tissues after 2 weeks of CIC exposure. Both Cirbp and TRX were increased, suggesting a role of these two proteins for establishment of cold adaptation. Together, this study reveals the effects of mild CIC exposure on vital organs of rats during CIC exposure. PMID:26327811

  14. 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.

  15. Cardiovascular Risks Associated with Low Dose Ionizing Particle Radiation

    DOE PAGESBeta

    Yan, Xinhua; Sasi, Sharath P.; Gee, Hannah; Lee, JuYong; Yang, Yongyao; Mehrzad, Raman; Onufrak, Jillian; Song, Jin; Enderling, Heiko; Agarwal, Akhil; et al

    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

  16. 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

  17. Increased oxidative stress following acute and chronic high altitude exposure.

    PubMed

    Jefferson, J Ashley; Simoni, Jan; Escudero, Elizabeth; Hurtado, Maria-Elena; Swenson, Erik R; Wesson, Donald E; Schreiner, George F; Schoene, Robert B; Johnson, Richard J; Hurtado, Abdias

    2004-01-01

    The generation of reactive oxygen species is typically associated with hyperoxia and ischemia reperfusion. Recent evidence has suggested that increased oxidative stress may occur with hypoxia. We hypothesized that oxidative stress would be increased in subjects exposed to high altitude hypoxia. We studied 28 control subjects living in Lima, Peru (sea level), at baseline and following 48 h exposure to high altitude (4300 m). To assess the effects of chronic altitude exposure, we studied 25 adult males resident in Cerro de Pasco, Peru (altitude 4300 m). We also studied 27 subjects living in Cerro de Pasco who develop excessive erythrocytosis (hematocrit > 65%) and chronic mountain sickness. Acute high altitude exposure led to increased urinary F(2)-isoprostane, 8-iso PGF(2 alpha) (1.31 +/- 0.8 microg/g creatinine versus 2.15 +/- 1.1, p = 0.001) and plasma total glutathione (1.29 +/- 0.10 micromol versus 1.37 +/- 0.09, p = 0.002), with a trend to increased plasma thiobarbituric acid reactive substance (TBARS) (59.7 +/- 36 pmol/mg protein versus 63.8 +/- 27, p = NS). High altitude residents had significantly elevated levels of urinary 8-iso PGF(2 alpha) (1.3 +/- 0.8 microg/g creatinine versus 4.1 +/- 3.4, p = 0.007), plasma TBARS (59.7 +/- 36 pmol/mg protein versus 85 +/- 28, p = 0.008), and plasma total glutathione (1.29 +/- 0.10 micromol versus 1.55 +/- 0.19, p < 0.0001) compared to sea level. High altitude residents with excessive erythrocytosis had higher levels of oxidative stress compared to high altitude residents with normal hematological adaptation. In conclusion, oxidative stress is increased following both acute exposure to high altitude without exercise and with chronic residence at high altitude.

  18. 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.

  19. 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

  20. 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

  1. 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

  2. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses.

    PubMed

    Vandenberg, Laura N; 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; Myers, John Peterson

    2012-06-01

    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

  3. 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.

  4. Chronic bisphenol A exposure alters behaviors of zebrafish (Danio rerio).

    PubMed

    Wang, Ju; Wang, Xia; Xiong, Can; Liu, Jian; Hu, Bing; Zheng, Lei

    2015-11-01

    The adult zebrafish (Danio rerio) were exposed to treated-effluent concentration of bisphenol A (BPA) or 17β-estradiol (E2) for 6 months to evaluate their effects on behavioral characteristics: motor behavior, aggression, group preference, novel tank test and light/dark preference. E2 exposure evidently dampened fish locomotor activity, while BPA exposure had no marked effect. Interestingly, BPA-exposed fish reduced their aggressive behavior compared with control or E2. Both BPA and E2 exposure induced a significant decrease in group preference, as well as a weaker adaptability to new environment, exhibiting lower latency to reach the top, more entries to the top, longer time spent in the top, fewer frequent freezing, and fewer erratic movements. Furthermore, the circadian rhythmicity of light/dark preference was altered by either BPA or E2 exposure. Our results suggest that chronic exposure of treated-effluent concentration BPA or E2 induced various behavioral anomalies in adult fish and enhanced ecological risk to wildlife. PMID:26204572

  5. 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.

  6. Chronic Exposure to Arsenic in the Drinking Water Alters the Expression of Immune Response Genes in Mouse Lung

    PubMed Central

    Kozul, Courtney D.; Hampton, Thomas H.; Davey, Jennifer C.; Gosse, Julie A.; Nomikos, Athena P.; Eisenhauer, Phillip L.; Weiss, Daniel J.; Thorpe, Jessica E.; Ihnat, Michael A.; Hamilton, Joshua W.

    2009-01-01

    Background Chronic exposure to drinking water arsenic is a significant worldwide environmental health concern. Exposure to As is associated with an increased risk of lung disease, which may make it a unique toxicant, because lung toxicity is usually associated with inhalation rather than ingestion. Objectives The goal of this study was to examine mRNA and protein expression changes in the lungs of mice exposed chronically to environmentally relevant concentrations of As in the food or drinking water, specifically examining the hypothesis that As may preferentially affect gene and protein expression related to immune function as part of its mechanism of toxicant action. Methods C57BL/6J mice fed a casein-based AIN-76A defined diet were exposed to 10 or 100 ppb As in drinking water or food for 5–6 weeks. Results Whole genome transcriptome profiling of animal lungs revealed significant alterations in the expression of many genes with functions in cell adhesion and migration, channels, receptors, differentiation and proliferation, and, most strikingly, aspects of the innate immune response. Confirmation of mRNA and protein expression changes in key genes of this response revealed that genes for interleukin 1β, interleukin 1 receptor, a number of toll-like receptors, and several cytokines and cytokine receptors were significantly altered in the lungs of As-exposed mice. Conclusions These findings indicate that chronic low-dose As exposure at the current U.S. drinking-water standard can elicit effects on the regulation of innate immunity, which may contribute to altered disease risk, particularly in lung. PMID:19654921

  7. Does the Sympathetic Nervous System Adapt to Chronic Altitude Exposure?

    PubMed

    Sander, Mikael

    2016-01-01

    During continued exposure to hypobaric hypoxia in acclimatizing lowlanders increasing norepinephrine levels indirectly indicate sympathoexcitation, and in a few subjects serial measurements have suggested some adaptation over time. A few studies have provided direct microneurographic evidence for markedly increased muscle sympathetic nervous activity (MSNA) after 1-50 days of exposure of lowlanders to altitudes of 4100-5260 m above sea level. Only one study has provided two MSNA-measurements over time (10 and 50 days) in altitude (4100 m above sea level) and continued robust sympathoexcitation without adaptation was found in acclimatizing lowlanders. In this study, norepinephrine levels during rest and exercise also remained highly elevated over time. In comparison, acute exposure to hypoxic breathing (FiO2 0.126) at sea level caused no change in sympathetic nervous activity, although the same oxygen saturation in arterial blood (around 90 %) was present during acute (FiO2 0.126) and chronic hypoxic exposure (4100 m above sea level). These findings strongly suggest that the chemoreflex-mechanisms underlying acute hypoxia-induced increases in MSNA are sensitized over time. Collectively, the MSNA data suggests that sensitization of the sympathoexcitatory chemoreflex is evident but not complete within the first 24 h, but is complete after 10 days of altitude exposure. After return from high altitude to sea level the MSNA remains significantly elevated for at least 5 days but completely normalized after 3 months. The few MSNA measurements in high altitude natives have documented high sympathetic activity in all subjects studied. Because serial measurements of MSNA in high altitude natives during sea level exposure are lacking, it is unclear whether the sympathetic nervous system have somehow adapted to lifelong altitude exposure. PMID:27343109

  8. 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.

  9. 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.

  10. 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.

  11. 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. PMID:27090425

  12. 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.

  13. 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.

  14. 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. PMID:24366315

  15. 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.

  16. 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

  17. Chronic Alcohol Exposure Renders Epithelial Cells Vulnerable to Bacterial Infection

    PubMed Central

    Wood, Stephen; Pithadia, Ravi; Rehman, Tooba; Zhang, Lijuan; Plichta, Jennifer; Radek, Katherine A.; Forsyth, Christopher; Keshavarzian, Ali; Shafikhani, Sasha H.

    2013-01-01

    Despite two centuries of reports linking alcohol consumption with enhanced susceptibility to bacterial infections and in particular gut-derived bacteria, there have been no studies or model systems to assess the impact of long-term alcohol exposure on the ability of the epithelial barrier to withstand bacterial infection. It is well established that acute alcohol exposure leads to reduction in tight and adherens junctions, which in turn leads to increases in epithelial cellular permeability to bacterial products, leading to endotoxemia and a variety of deleterious effects in both rodents and human. We hypothesized that reduced fortification at junctional structures should also reduce the epithelial barrier’s capacity to maintain its integrity in the face of bacterial challenge thus rendering epithelial cells more vulnerable to infection. In this study, we established a cell-culture based model system for long-term alcohol exposure to assess the impact of chronic alcohol exposure on the ability of Caco-2 intestinal epithelial cells to withstand infection when facing pathogenic bacteria under the intact or wounded conditions. We report that daily treatment with 0.2% ethanol for two months rendered Caco-2 cells far more susceptible to wound damage and cytotoxicity caused by most but not all bacterial pathogens tested in our studies. Consistent with acute alcohol exposure, long-term ethanol exposure also adversely impacted tight junction structures, but in contrast, it did not affect the adherens junction. Finally, alcohol-treated cells partially regained their ability to withstand infection when ethanol treatment was ceased for two weeks, indicating that alcohol’s deleterious effects on cells may be reversible. PMID:23358457

  18. Chronic alcohol exposure renders epithelial cells vulnerable to bacterial infection.

    PubMed

    Wood, Stephen; Pithadia, Ravi; Rehman, Tooba; Zhang, Lijuan; Plichta, Jennifer; Radek, Katherine A; Forsyth, Christopher; Keshavarzian, Ali; Shafikhani, Sasha H

    2013-01-01

    Despite two centuries of reports linking alcohol consumption with enhanced susceptibility to bacterial infections and in particular gut-derived bacteria, there have been no studies or model systems to assess the impact of long-term alcohol exposure on the ability of the epithelial barrier to withstand bacterial infection. It is well established that acute alcohol exposure leads to reduction in tight and adherens junctions, which in turn leads to increases in epithelial cellular permeability to bacterial products, leading to endotoxemia and a variety of deleterious effects in both rodents and human. We hypothesized that reduced fortification at junctional structures should also reduce the epithelial barrier's capacity to maintain its integrity in the face of bacterial challenge thus rendering epithelial cells more vulnerable to infection. In this study, we established a cell-culture based model system for long-term alcohol exposure to assess the impact of chronic alcohol exposure on the ability of Caco-2 intestinal epithelial cells to withstand infection when facing pathogenic bacteria under the intact or wounded conditions. We report that daily treatment with 0.2% ethanol for two months rendered Caco-2 cells far more susceptible to wound damage and cytotoxicity caused by most but not all bacterial pathogens tested in our studies. Consistent with acute alcohol exposure, long-term ethanol exposure also adversely impacted tight junction structures, but in contrast, it did not affect the adherens junction. Finally, alcohol-treated cells partially regained their ability to withstand infection when ethanol treatment was ceased for two weeks, indicating that alcohol's deleterious effects on cells may be reversible. PMID:23358457

  19. A Low-Dose Ipsilateral Lung Restriction Improves 3-D Conformal Planning for Partial Breast Radiation Therapy

    SciTech Connect

    Mitchell, Tracy; Truong, Pauline T.; Salter, Lee; Graham, Cathy; Gaffney, Helene; Beckham, Wayne; Olivotto, Ivo A.

    2011-04-01

    In trials of 3D conformal external beam partial breast radiotherapy (PBRT), the dosimetrist must balance the priorities of achieving high conformity to the target versus minimizing low-dose exposure to the normal structures. This study highlights the caveat that in the absence of a low-dose lung restriction, the use of relatively en-face fields may meet trial-defined requirements but expose the ipsilateral lung to unnecessary low-dose radiation. Adding a low-dose restriction that {<=}20% of the ipsilateral lung should receive 10% of the prescribed dose resulted in successful plans in 88% of cases. This low-dose lung limit should be used in PBRT planning.

  20. 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. PMID:27538709

  1. Chronic Exposure to Diquat Causes Reproductive Toxicity in Female Mice

    PubMed Central

    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. PMID:26785375

  2. 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. PMID:26785375

  3. 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.

  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. Ultra-low-dose vaginal estrogen tablets for the treatment of postmenopausal vaginal atrophy.

    PubMed

    Simon, J A; Maamari, R V

    2013-08-01

    Vaginal atrophy is a common chronic condition affecting up to 57% of postmenopausal women. The decrease in estrogen following cessation of menses can lead to bothersome symptoms that include vaginal dryness and irritation, pain and burning during urination (dysuria), urinary tract infections, and pain (dyspareunia) and bleeding during sexual activities. These symptoms can be safely and effectively managed with the use of local estrogen therapy, which reduces the risks associated with long-term systemic hormone therapy. The ultra-low-dose 10 μg estradiol vaginal tablet is the lowest approved dose available and has an annual estradiol exposure of only 1.14 mg. Its development addresses recommendations from regulatory agencies and women's health societies regarding the use of the lowest hormonal dose. The 10 μg vaginal tablet displays minimal estradiol absorption, causes no increased risk of endometrial hyperplasia or carcinoma, and provides significant symptom relief. The clinical evidence presented here may offer greater reassurance to health-care professionals and postmenopausal women that vaginal atrophy can be treated safely and effectively.

  6. 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. PMID:25455892

  7. Low-Dose Nonlinear Effects of Smoking on Coronary Heart Disease Risk

    PubMed Central

    Cox, Louis Anthony (Tony)

    2012-01-01

    Some recent discussions of adverse human health effects of active and passive smoking have suggested that low levels of exposure are disproportionately dangerous, so that “The effects of even brief (minutes to hours) passive smoking are often nearly as large (averaging 80% to 90%) as chronic active smoking” (Barnoya and Glantz, 2005). Recent epidemiological evidence (Teo et al., 2006) suggests a more linear relation. This paper reexamines the empirical relation between self-reported low levels of active smoking and risk of coronary heart disease (CHD) in public-domain data from the National Health and Nutrition Examination Survey (NHANES). Consistent with biological evidence on J-shaped and U-shaped relations between smoking-associated risk factors and CHD risks, we find that low levels of active smoking do not appear to be associated with increased CHD risk. Several methodological challenges in epidemiology may explain how model-derived estimates can predict low-dose linear or concave dose-response estimates, even if the empirical (i.e., data-based) relation does not show a clear increased risk at the lowest doses. PMID:22740784

  8. Effect of chronic exposure to welding light on Calabar welders.

    PubMed

    Davies, K G; Asanga, U; Nku, C O; Osim, E E

    2007-01-01

    It was generally observed that welders in Calabar, Nigeria did not always wear their protective goggles during welding. Since chronic exposure to welding light can impair vision this study was done to assess the effect of exposure to welding light on ocular function of welders in Calabar, Nigeria. There were 195 subjects comprising 110 welders (test) and 85 control subjects. Both groups were all male and had similar age range. The tests employed were clinical examination for ocular disorders, assessment of visual acuity, and opthalmoscopy. Test questionnaire was also used to record information on length of service, precautionary measures at work place, age and past ocular illnesses. The study also compared incidence of ocular disorders between the two groups of welders (arc and carbide welders). The mean ages of the welders and their control were not significantly different (27.53 +/- 10.0 vs 27.78 +/- 8.5 yrs respectively). There was a significantly [P < 0.01] higher incidence of pingueculum, cataract, allergic conjunctivitis, corneal opacity, and keratoconjunctivitis (arc eye) in welders than in their control subjects. However, visual acuity, incidence of pterygium and glaucoma were similar. Between the two groups of welders, the incidence of pterygium, corneal opacity and keratoconjunctivitis was significantly [P < 0.01] higher in arc welders than carbide welders. The incidence of pingueculum and glaucoma were however, similar. In conclusion, chronic exposure to welding light without adequate precaution may cause ocular disorders. Arc welding is more dangerous to ocular function than carbide welding. Length of service and age are predisposing factors to ocular disorders in the welding business.

  9. 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.

  10. Effects of acute low doses of gamma-radiation on erythrocytes membrane.

    PubMed

    Mahmoud, Sherif S; El-Sakhawy, Eman; Abdel-Fatah, Eman S; Kelany, Adel M; Rizk, Rizk M

    2011-03-01

    It is believed that any dose of ionizing radiation may damage cells and that the mutated cells could develop into cancer cells. Additionally, results of research performed over the past century on the effects of low doses of ionizing radiation on biological organisms show beneficial health effects, called hormesis. Much less is known about the cellular response to low doses of ionizing radiation, such as those typical for medical diagnostic procedures, normal occupational exposures or cosmic-ray exposures at flight altitudes. Extrapolating from the effects observed at higher doses to predict changes in cells after low-dose exposure is problematic. We examined the biological effects of low doses (0.01-0.3 Gy) of γ-radiation on the membrane characteristics of erythrocytes of albino rats and carried out osmotic fragility tests and Fourier transform infrared spectroscopy (FTIR). Our results indicate that the lowest three doses in the investigated radiation range, i.e., 0.01, 0.025 and 0.05 Gy, resulted in positive effects on the erythrocyte membranes, while a dose of 0.1 Gy appeared to represent the limiting threshold dose of those positive effects. Doses higher than 0.1 Gy were associated with the denaturation of erythrocyte proteins. PMID:20865271

  11. 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.

  12. Zebrafish reproductive toxicity induced by chronic perfluorononanoate exposure.

    PubMed

    Zhang, Wei; Sheng, Nan; Wang, Minhui; Zhang, Hongxia; Dai, Jiayin

    2016-06-01

    Perfluoroalkyl acids (PFAAs) are a group of anthropogenic compounds that have been widely used in consumer products for over 50 years. One of the most dominant PFAAs is perfluorononanoate (PFNA), a compound detected ubiquitously in aquatic ecosystems. While PFNA is suspected of being an endocrine disruptor, the mechanisms behind PFNA-induced reproductive disorders are poorly understood. The aim of this study was to investigate the reproduction-related effects and possible mechanisms of PFNA on adult zebrafish (Danio rerio) following 180 days of exposure at different concentrations (0.01, 0.1, 1mg/L). PFNA concentration in the gonads of zebrafish was tested by HPLC-MS/MS after chronic exposure to study possible inconsistent accumulation between the genders. The results showed that the accumulation of PFNA in the male gonads was almost one-fold higher than that in the female gonads, indicating a possible higher PFAA gonad burden for male zebrafish. Significant reductions in the male gonadosomatic index (GSI) and female egg production were observed. In addition, the decreased 72h hatching rate displayed an evident dosage effect, indicating that maternal exposure to PFNA might impair offspring developmental success. To investigate how PFNA exposure affects the hypothalamic-pituitary-gonadal-liver axis (HPGL axis), the transcriptional levels of genes were measured by real-time PCR. The disrupted expression of genes, such as ERα, ERβ, FSHR, LHR, StAR, and 17βHSD, indicated the possible interference of PFNA on the HPGL axis function and sex hormone synthesis. Furthermore, testosterone (T) and estradiol (E2) levels in serum and VTG content in the liver were detected to clarify the influences of PFNA on sex hormone levels. Except for the increase in serum estrogen levels, as an estrogen analogue, PFNA also induced the synthesis of biomarker protein vitellogenin (VTG) in the adult male liver. The results of this study indicate that chronic exposure to PFNA can lead to

  13. Chronic exposure to simulated space conditions predominantly affects cytoskeleton remodeling and oxidative stress response in mouse fetal fibroblasts.

    PubMed

    Beck, Michaël; Moreels, Marjan; Quintens, Roel; Abou-El-Ardat, Khalil; El-Saghire, Hussein; Tabury, Kevin; Michaux, Arlette; Janssen, Ann; Neefs, Mieke; Van Oostveldt, Patrick; De Vos, Winnok H; Baatout, Sarah

    2014-08-01

    Microgravity and cosmic rays as found in space are difficult to recreate on earth. However, ground-based models exist to simulate space flight experiments. In the present study, an experimental model was utilized to monitor gene expression changes in fetal skin fibroblasts of murine origin. Cells were continuously subjected for 65 h to a low dose (55 mSv) of ionizing radiation (IR), comprising a mixture of high‑linear energy transfer (LET) neutrons and low-LET gamma-rays, and/or simulated microgravity using the random positioning machine (RPM), after which microarrays were performed. The data were analyzed both by gene set enrichment analysis (GSEA) and single gene analysis (SGA). Simulated microgravity affected fetal murine fibroblasts by inducing oxidative stress responsive genes. Three of these genes are targets of the nuclear factor‑erythroid 2 p45-related factor 2 (Nrf2), which may play a role in the cell response to simulated microgravity. In addition, simulated gravity decreased the expression of genes involved in cytoskeleton remodeling, which may have been caused by the downregulation of the serum response factor (SRF), possibly through the Rho signaling pathway. Similarly, chronic exposure to low-dose IR caused the downregulation of genes involved in cytoskeleton remodeling, as well as in cell cycle regulation and DNA damage response pathways. Many of the genes or gene sets that were altered in the individual treatments (RPM or IR) were not altered in the combined treatment (RPM and IR), indicating a complex interaction between RPM and IR. PMID:24859186

  14. Human Physiological Responses to Acute and Chronic Cold Exposure

    NASA Technical Reports Server (NTRS)

    Stocks, Jodie M.; Taylor, Nigel A. S.; Tipton, Michael J.; Greenleaf, John E.

    2001-01-01

    When inadequately protected humans are exposed to acute cold, excessive body heat is lost to the environment and unless heat production is increased and heat loss attenuated, body temperature will decrease. The primary physiological responses to counter the reduction in body temperature include marked cutaneous vasoconstriction and increased metabolism. These responses, and the hazards associated with such exposure, are mediated by a number of factors which contribute to heat production and loss. These include the severity and duration of the cold stimulus; exercise intensity; the magnitude of the metabolic response; and individual characteristics such as body composition, age, and gender. Chronic exposure to a cold environment, both natural and artificial, results in physiological alterations leading to adaptation. Three quite different, but not necessarily exclusive, patterns of human cold adaptation have been reported: metabolic, hypothermic, and insulative. Cold adaptation has also been associated with an habituation response, in which there is a desensitization, or damping, of the normal response to a cold stress. This review provides a comprehensive analysis of the human physiological and pathological responses to cold exposure. Particular attention is directed to the factors contributing to heat production and heat loss during acute cold stress, and the ability of humans to adapt to cold environments.

  15. Responses to Low Doses of Ionizing Radiation in Biological Systems

    PubMed Central

    Feinendegen, Ludwig E.; Pollycove, Myron; Sondhaus, Charles A.

    2004-01-01

    Biological tissues operate through cells that act together within signaling networks. These assure coordinated cell function in the face of constant exposure to an array of potentially toxic agents, externally from the environment and endogenously from metabolism. Living tissues are indeed complex adaptive systems. To examine tissue effects specific for low-dose radiation, (1) absorbed dose in tissue is replaced by the sum of the energies deposited by each track event, or hit, in a cell-equivalent tissue micromass (1 ng) in all micromasses exposed, that is, by the mean energy delivered by all microdose hits in the exposed micromasses, with cell dose expressing the total energy per micromass from multiple microdoses; and (2) tissue effects are related to cell damage and protective cellular responses per average microdose hit from a given radiation quality for all such hits in the exposed micromasses. The probability of immediate DNA damage per low-linear-energy-transfer (LET) average micro-dose hit is extremely small, increasing over a certain dose range in proportion to the number of hits. Delayed temporary adaptive protection (AP) involves (a) induced detoxification of reactive oxygen species, (b) enhanced rate of DNA repair, (c) induced removal of damaged cells by apoptosis followed by normal cell replacement and by cell differentiation, and (d) stimulated immune response, all with corresponding changes in gene expression. These AP categories may last from less than a day to weeks and be tested by cell responses against renewed irradiation. They operate physiologically against nonradiogenic, largely endogenous DNA damage, which occurs abundantly and continually. Background radiation damage caused by rare microdose hits per micromass is many orders of magnitude less frequent. Except for apoptosis, AP increasingly fails above about 200 mGy of low-LET radiation, corresponding to about 200 microdose hits per exposed micromass. This ratio appears to exceed

  16. 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)

  17. [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.

  18. 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 phosphory