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Sample records for mice dosed feed

  1. Independent feeding and metabolic actions of orexins in mice.

    Science.gov (United States)

    Lubkin, M; Stricker-Krongrad, A

    1998-12-18

    Orexin-A and orexin-B (OX peptides) are two putative products of a newly discovered secreted protein encoded by a mRNA restricted to neuronal cell bodies of the lateral hypothalamus (LH). Because the activation of the LH can induce changes in energy balance, we wanted to investigate the actions of OX peptides on energy metabolism in mice. We injected male C57BL/6J mice with different doses (1, 3, and 10 nmol) of orexin-A and orexin-B into the third ventricle (i3vt). A single i3vt injection of orexin-A 3 h into the light period slightly stimulated feeding at the lowest dose only over the following 4 h (11 +/- 09 mg/mouse vs 80 +/- 13 mg/mouse, p energy utilization using indirect calorimetry. Single i3vt injection 3 h after light on, or just before dark onset, or in 4-h fasted mice resulted in increases in the metabolic rate. These effects were associated with decreases or increases in the respiratory quotient regarding the time of injection or the underlying metabolic state of the mice. The present findings provide direct evidence that OX peptides are more likely to be involved in the control of energy metabolism than of food intake in mice. Copyright 1998 Academic Press.

  2. Genetic effects of feeding irradiated wheat to mice

    International Nuclear Information System (INIS)

    Vijayalaxmi

    1976-01-01

    The effects of feeding irradiated wheat in mice on bone marrow and testis chromosomes, germ cell numbers and dominant lethal mutations were investigated. Feeding of freshly irradiated wheat resulted in significantly increased incidence of polyploid cells in bone marrow, aneuploid cells in testis, reduction in number of spermatogonia of types A, B and resting primary spermatocytes as well as a higher mutagenic index. Such a response was not observed when mice were fed stored irradiated wheat. Also there was no difference between the mice fed un-irradiated wheat and stored irradiated wheat. (author)

  3. Effects of feeding lactobacillus GG on lethal irradiation in mice

    International Nuclear Information System (INIS)

    Dong, M.Y.; Chang, T.W.; Gorbach, S.L.

    1987-01-01

    Mice exposed to 1400 rads of total body irradiation experienced 80%-100% mortality in 2 wk. Bacteremia was demonstrated in all dead animals. Feeding Lactobacillus GG strain reduced Pseudomonas bacteremia and prolonged survival time in animals colonized with this organism. In animals not colonized with Pseudomonas, feeding Lactobacillus GG also produced some reduction in early deaths, and there was less Gram-negative bacteremia in these animals compared with controls

  4. Effects of proton radiation dose, dose rate and dose fractionation on hematopoietic cells in mice

    International Nuclear Information System (INIS)

    Ware, J.H.; Rusek, A.; Sanzari, J.; Avery, S.; Sayers, C.; Krigsfeld, G.; Nuth, M.; Wan, X.S.; Kennedy, A.R.

    2010-01-01

    The present study evaluated the acute effects of radiation dose, dose rate and fractionation as well as the energy of protons in hematopoietic cells of irradiated mice. The mice were irradiated with a single dose of 51.24 MeV protons at a dose of 2 Gy and a dose rate of 0.05-0.07 Gy/min or 1 GeV protons at doses of 0.1, 0.2, 0.5, 1, 1.5 and 2 Gy delivered in a single dose at dose rates of 0.05 or 0.5 Gy/min or in five daily dose fractions at a dose rate of 0.05 Gy/min. Sham-irradiated animals were used as controls. The results demonstrate a dose-dependent loss of white blood cells (WBCs) and lymphocytes by up to 61% and 72%, respectively, in mice irradiated with protons at doses up to 2 Gy. The results also demonstrate that the dose rate, fractionation pattern and energy of the proton radiation did not have significant effects on WBC and lymphocyte counts in the irradiated animals. These results suggest that the acute effects of proton radiation on WBC and lymphocyte counts are determined mainly by the radiation dose, with very little contribution from the dose rate (over the range of dose rates evaluated), fractionation and energy of the protons.

  5. Effects of proton radiation dose, dose rate and dose fractionation on hematopoietic cells in mice.

    Science.gov (United States)

    Ware, J H; Sanzari, J; Avery, S; Sayers, C; Krigsfeld, G; Nuth, M; Wan, X S; Rusek, A; Kennedy, A R

    2010-09-01

    The present study evaluated the acute effects of radiation dose, dose rate and fractionation as well as the energy of protons in hematopoietic cells of irradiated mice. The mice were irradiated with a single dose of 51.24 MeV protons at a dose of 2 Gy and a dose rate of 0.05-0.07 Gy/min or 1 GeV protons at doses of 0.1, 0.2, 0.5, 1, 1.5 and 2 Gy delivered in a single dose at dose rates of 0.05 or 0.5 Gy/min or in five daily dose fractions at a dose rate of 0.05 Gy/min. Sham-irradiated animals were used as controls. The results demonstrate a dose-dependent loss of white blood cells (WBCs) and lymphocytes by up to 61% and 72%, respectively, in mice irradiated with protons at doses up to 2 Gy. The results also demonstrate that the dose rate, fractionation pattern and energy of the proton radiation did not have significant effects on WBC and lymphocyte counts in the irradiated animals. These results suggest that the acute effects of proton radiation on WBC and lymphocyte counts are determined mainly by the radiation dose, with very little contribution from the dose rate (over the range of dose rates evaluated), fractionation and energy of the protons.

  6. NTP technical report on the toxicity studies of Castor Oil (CAS No. 8001-79-4) in F344/N Rats and B6C3F1 Mice (Dosed Feed Studies).

    Science.gov (United States)

    Irwin, R

    1992-03-01

    Castor oil is a natural oil derived from the seeds of the castor bean, Ricinus communis. It is comprised largely of triglycerides with a high ricinolin content. Toxicity studies with castor oil were performed by incorporating the material at concentrations as high as 10% in diets given to F344/N rats and B6C3F1 mice of both sexes for 13 weeks. Genetic toxicity studies also were performed and were negative for mutation induction in Salmonella typhimurium, for induction of sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells, and for induction of micronuclei in the peripheral blood erythrocytes of mice evaluated at the end of the 13-week studies. Exposure to castor oil at dietary concentrations as high as 10% in 13-week studies did not affect survival or body weight gains of rats or mice (10 per sex and dose). There were no biologically significant effects noted in hematologic analyses in rats. Mild increases in total bile acids and in serum alkaline phosphatase were noted at various times during the studies in rats receiving the higher dietary concentrations of castor oil. Liver weights were increased in male rats receiving the 10% dietary concentration and in male and female mice receiving diets containing 5% or 10% castor oil. However, there were no histopathologic lesions associated with these liver changes, nor were there any compound-related morphologic changes in any organ in rats or mice. No significant changes were noted in a screening for male reproductive endpoints, including sperm count and motility, and no changes were observed in the length of estrous cycles of rats or mice given diets containing castor oil. Thus, no significant adverse effects of castor oil administration were noted in these studies. Synonyms: Ricinus Oil, oil of Palma Christi, tangantangan oil, phorboyl, Neoloid.

  7. The effect of animal feed from irradiated palm oil sludge on antibody forming of mice

    International Nuclear Information System (INIS)

    Suharni Sadi; Umar, Hasibuan; Jenny, M.; Adria, P.M.; Murni Indrawatmi

    1998-01-01

    In this experiment, 3 kinds of animal feed were, e.q. control (commercial product), non irradiated and irradiated palm oil sludge by using 6 0Co source with a 4 kGy dose. BALB-C mice of 3 months old were used, each group contains 5 animals. Before conducting the experiment the animals were injected with antibiotic to free them from Enterobacteriaceae. The animals were observed every 2 weeks by weighting them, blood were analyzed and after 10 weeks their antibody were analyzed. Animal feed were in the form of pellets and each animal was feed 5 g of pellets. The results were as follows, antibody formed by C (control), N (non irradiated sludge) and, R (irradiated sludge) were 37; 36.5; and 36.2 mg/nl, respectively. Apparently pellets which were made of palm oil sludge and commercial product produced not significantly different level of antibody. (author)

  8. PER1 Phosphorylation Specifies Feeding Rhythm in Mice

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    Zhiwei Liu

    2014-06-01

    Full Text Available Organization of circadian behavior, physiology, and metabolism is important for human health. An S662G mutation in hPER2 has been linked to familial advanced sleep-phase syndrome (FASPS. Although the paralogous phosphorylation site S714 in PER1 is conserved in mice, its specific function in circadian organization remains unknown. Here, we find that the PER1S714G mutation accelerates the molecular feedback loop. Furthermore, hPER1S714G mice, but not hPER2S662G mice, exhibit peak time of food intake that is several hours before daily energy expenditure peaks. Both the advanced feeding behavior and the accelerated clock disrupt the phase of expression of several key metabolic regulators in the liver and adipose tissue. Consequently, hPER1S714G mice rapidly develop obesity on a high-fat diet. Our studies demonstrate that PER1 and PER2 are linked to different downstream pathways and that PER1 maintains coherence between the circadian clock and energy metabolism.

  9. Effects of low dose radiation on tumor-bearing mice

    International Nuclear Information System (INIS)

    Feng Li; Hou Dianjun; Huang Shanying; Deng Daping; Wang Linchao; Cheng Yufeng

    2007-01-01

    Objective: To explore the effects of low-dose radiation on tumor-bearing mice and radiotherapy induced by low-dose radiation. Methods: Male Wistar mice were implanted with Walker-256 sarcoma cells in the right armpit. On day 4, the mice were given 75 mGy whole-body X-ray radiation. From the fifth day, tumor volume was measured, allowing for the creation of a graph depicting tumor growth. Lymphocytes activity in mice after whole-body X-ray radiation with LDR was determinned by FCM. Cytokines level were also determined by ELISA. Results: Compared with the radiotherapy group, tumor growth was significantly slower in the mice pre-exposed to low-dose radiation (P<0.05), after 15 days, the average tumor weight in the mice pre- exposed to low-dose radiation was also significantly lower (P<0.05). Lymphocytes activity and the expression of the CK in mice after whole-body y-ray radiation with LDR increased significantly. Conclusions: Low-dose radiation can markedly improve the immune function of the lymphocyte, inhibit the tumor growth, increase the resistant of the high-dose radiotherapy and enhance the effect of radiotherapy. (authors)

  10. Psychological stress exposure to aged mice causes abnormal feeding patterns with changes in the bout number.

    Science.gov (United States)

    Yamada, Chihiro; Mogami, Sachiko; Hattori, Tomohisa

    2017-11-09

    Stress responses are affected by aging. However, studies on stress-related changes in feeding patterns with aging subject are minimal. We investigated feeding patterns induced by two psychological stress models, revealing characteristics of stress-induced feeding patterns as "meal" and "bout" (defined as the minimum feeding behavior parameters) in aged mice. Feeding behaviors of C57BL/6J mice were monitored for 24 h by an automatic monitoring device. Novelty stress reduced the meal amount over the 24 h in both young and aged mice, but as a result of a time course study it was persistent in aged mice. In addition, the decreased bout number was more pronounced in aged mice than in young mice. The 24-h meal and bout parameters did not change in either the young or aged mice following water avoidance stress (WAS). However, the meal amount and bout number increased in aged mice for 0-6 h after WAS exposure but remained unchanged in young mice. Our findings suggest that changes in bout number may lead to abnormal stress-related feeding patterns and may be one tool for evaluating eating abnormality in aged mice.

  11. Dose rate effectiveness in radiation-induced teratogenesis in mice

    International Nuclear Information System (INIS)

    Kato, F.; Ootsuyama, A.; Norimura, T.

    2000-01-01

    To investigate the role of p53 gene in tissue repair of teratogenic injury, we compared incidence of radiation-induced malformations in homozygous p53(-/-) mice, heterozygous p53(+/-) mice and wild-type p53(+/+) mice. After X-irradiation with 2 Gy at high dose rate on 9.5 days of gestation, p53(-/-) mice showed higher incidences of anomalies and higher resistance to prenatal deaths than p53(+/+) mice. This reciprocal relationship of radiosensitivity to anomalies and deaths supports the notion that embryos or fetuses have a p53-dependent 'guardian' that aborts cells bearing radiation-induced teratogenic DNA damage. In fact, after X-irradiation, the number of apoptotic cells was greatly increased in p53(+/+) fetuses but not in p53(-/-) fetuses. The same dose of γ-ray exposure at low dose rate on 9.5-10.5 day of gestation produced significant reduction of radiation-induced malformation in p53(+/+) and p53(+/-) mice, remained teratogenic for p53(-/-) mice. These results suggest that complete elimination of teratogenic damage from irradiated tissues requires the concerted cooperation of two mechanisms; proficient DNA repair and the p53-dependent apoptotic tissue repair. When concerted DNA repair and apoptosis functions efficiently, there is a threshold dose-rate for radiation-induced malformations. (author)

  12. Absorbed dose to mice in prolonged irradiation by low-dose rate ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Shiragai, Akihiro [National Inst. of Radiological Sciences, Chiba (Japan); Saitou, Mikio; Kudo, Iwao [and others

    2000-07-01

    In this paper, the dose absorbed by mice was evaluated as a preliminary study of the late effects of prolonged continuous irradiation of mice with low-dose rate ionizing radiation. Eight-week-old male and female SPF C3H/HeN mice in three irradiation rooms were exposed to irradiation at 8000, 400, and 20 mGy, respectively, using a {sup 137}Cs {gamma}-source. Nine racks were arranged in a circle approximately 2.5 m from the source in each room, and 10 cages were arranged on the 4 shelves of each rack. Dose distributions, such as in air at the source level, in the three rooms were estimated by using ionization chambers, and the absorbed dose distributions in the room and relative dose distributions in the cages in relation to the distance of the cage center were examined. The mean abdomen doses of the mice measured by TLD were compared with the absorbed doses in the cages. The absorbed dose distributions showed not only inverse-inverse-square-law behavior with distance from the source, but geometric symmetry in every room. The inherent scattering and absorption in each room are responsible for such behavior and asymmetry. Comparison of relative dose distributions revealed cage positions that are not suitable for experiments with high precision doses, but all positions can be used for prolonged continuous irradiation experiments if the position of the cages is rotated regularly. The mean abdomen doses of the mice were similar in each cage. The mean abdomen doses of the mice and the absorbed doses in a cage were almost the same in all cages. Except for errors concerning the positions of the racks and cages, the uncertainties in the exposure doses were estimated to be about {+-}12% for 8000 mGy group, 17% for 400 mGy group, and 35% for 20 mGy group. (K.H.)

  13. Carcinogenesis in mice after low doses and dose rates

    International Nuclear Information System (INIS)

    Ullrich, R.L.

    1979-01-01

    The results from the experimental systems reported here indicate that the dose-response curves for tumor induction in various tissues cannot be described by a single model. Furthermore, although the understanding of the mechanisms involved in different systems is incomplete, it is clear that very different mechanisms for induction are involved. For some tumors the mechanism of carcinogenesis may be mainly a result of direct effects on the target cell, perhaps involving one or more mutations. While induction may occur, in many instances, through such direct effects, the eventual expression of the tumor can be influenced by a variety of host factors including endocrine status, competence of the immune system, and kinetics of target and interacting cell populations. In other tumors, indirect effects may play a major role in the initiation or expression of tumors. Some of the hormone-modulated tumors would fall into this class. Despite the complexities of the experimental systems and the lack of understanding of the types of mechanisms involved, in nearly every example the tumorigenic effectiveness per rad of low-LET radiation tends to decrease with decreasing dose rate. For some tumor types the differences may be small or may appear only with very low dose rates, while for others the dose-rate effects may be large

  14. Anti-tumor effect of low dose radiation in mice

    International Nuclear Information System (INIS)

    Fan Zhengping; Lu Jiaben; Zhu Bingchai

    1997-01-01

    The author reports the effects of the total body irradiation of low dose radiation (LDR) and/or the local irradiation of large dose on average tumor weights and tumor inhibitory rates in 170 mice inoculated S 180 sarcoma cell, and the influence of LDR on average longevity in 40 tumor-bearing animals. Results show (1) LDR in the range of 75∼250 mGy can inhibit tumor growth to some extent; (2) fractionated irradiation of 75 mGy and local irradiation of 10 Gy may produce a synergism in tumor growth inhibition; and (3)LDR may enhance average longevity in ascitic tumor-bearing mice

  15. A study on mice exposure dose for low-dose gamma-irradiation using glass dosimeter

    Energy Technology Data Exchange (ETDEWEB)

    Noh, Sung Jin; Kim, Hyo Jin; Kim, Hyun; Jeong, Dong Hyeok; Son, Tae Gen; Kim, Jung Ki; Yang, Kwang Mo; Kang, Yeong Rok [Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan (Korea, Republic of); Nam, Sang Hee [Dept. of Biomedical Engineering, Inje University, Gimhae (Korea, Republic of)

    2015-12-15

    The low dose radiation is done for a long period, thus researchers have to know the exact dose distribution for the irradiated mouse. This research has been conducted in order to find out methods in transmitting an exact dose to mouse in a mouse irradiation experiment carried out using {sup 137}C{sub s} irradiation equipment installed in the DIRAMS (Dongnam Institution of Radiological and Medical Sciences) research center. We developed a single mouse housing cage and shelf with adjustable geometric factors such as distance and angle from collimator. The measurement of irradiated dose showed a maximal 42% difference of absorbed dose from the desired dose in the conventional irradiation system, whereas only 6% difference of the absorbed dose was measured in the self-developed mouse apartment system. In addition, multi mice housing showed much difference of the absorbed dose in between head and body, compared to single mouse housing in the conventional irradiation system. This research may allow further research about biological effect assessment for the low dose irradiation using the self-developed mouse apartment to provide more exact doses which it tries to transmit, and to have more reliability for the biological analysis results.

  16. Aspartame administered in feed, beginning prenatally through life span, induces cancers of the liver and lung in male Swiss mice.

    Science.gov (United States)

    Soffritti, Morando; Belpoggi, Fiorella; Manservigi, Marco; Tibaldi, Eva; Lauriola, Michelina; Falcioni, Laura; Bua, Luciano

    2010-12-01

    Aspartame (APM) is a well-known intense artificial sweetener used in more than 6,000 products. Among the major users of aspartame are children and women of childbearing age. In previous lifespan experiments conducted on Sprague-Dawley rats we have shown that APM is a carcinogenic agent in multiple sites and that its effects are increased when exposure starts from prenatal life. The aim of this study is to evaluate the potential of APM to induce carcinogenic effects in mice. Six groups of 62-122 male and female Swiss mice were treated with APM in feed at doses of 32,000, 16,000, 8,000, 2,000, or 0  ppm from prenatal life (12 days of gestation) until death. At death each animal underwent complete necropsy and all tissues and organs of all animals in the experiment were microscopically examined. APM in our experimental conditions induces in males a significant dose-related increased incidence of hepatocellular carcinomas (P < 0.01), and a significant increase at the dose levels of 32,000  ppm (P < 0.01) and 16,000  ppm (P < 0.05). Moreover, the results show a significant dose-related increased incidence of alveolar/bronchiolar carcinomas in males (P < 0.05), and a significant increase at 32,000  ppm (P < 0.05). The results of the present study confirm that APM is a carcinogenic agent in multiple sites in rodents, and that this effect is induced in two species, rats (males and females) and mice (males). No carcinogenic effects were observed in female mice. Am. J. Ind. Med. 53:1197-1206, 2010. © 2010 Wiley-Liss, Inc.

  17. Metabolic adaptations to short-term every-other-day feeding in long-living Ames dwarf mice.

    Science.gov (United States)

    Brown-Borg, Holly M; Rakoczy, Sharlene

    2013-09-01

    Restrictive dietary interventions exert significant beneficial physiological effects in terms of aging and age-related disease in many species. Every other day feeding (EOD) has been utilized in aging research and shown to mimic many of the positive outcomes consequent with dietary restriction. This study employed long living Ames dwarf mice subjected to EOD feeding to examine the adaptations of the oxidative phosphorylation and antioxidative defense systems to this feeding regimen. Every other day feeding lowered liver glutathione (GSH) concentrations in dwarf and wild type (WT) mice but altered GSH biosynthesis and degradation in WT mice only. The activities of liver OXPHOS enzymes and corresponding proteins declined in WT mice fed EOD while in dwarf animals, the levels were maintained or increased with this feeding regimen. Antioxidative enzymes were differentially affected depending on the tissue, whether proliferative or post-mitotic. Gene expression of components of liver methionine metabolism remained elevated in dwarf mice when compared to WT mice as previously reported however, enzymes responsible for recycling homocysteine to methionine were elevated in both genotypes in response to EOD feeding. The data suggest that the differences in anabolic hormone levels likely affect the sensitivity of long living and control mice to this dietary regimen, with dwarf mice exhibiting fewer responses in comparison to WT mice. These results provide further evidence that dwarf mice may be better protected against metabolic and environmental perturbations which may in turn, contribute to their extended longevity. © 2013.

  18. CXCL14 deficiency in mice attenuates obesity and inhibits feeding behavior in a novel environment.

    Directory of Open Access Journals (Sweden)

    Kosuke Tanegashima

    Full Text Available BACKGROUND: CXCL14 is a chemoattractant for macrophages and immature dendritic cells. We recently reported that CXCL14-deficient (CXCL14(-/- female mice in the mixed background are protected from obesity-induced hyperglycemia and insulin resistance. The decreased macrophage infiltration into visceral adipose tissues and the increased insulin sensitivity of skeletal muscle contributed to these phenotypes. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we performed a comprehensive study for the body weight control of CXCL14(-/- mice in the C57BL/6 background. We show that both male and female CXCL14(-/- mice have a 7-11% lower body weight compared to CXCL14(+/- and CXCL14(+/+ mice in adulthood. This is mainly caused by decreased food intake, and not by increased energy expenditure or locomotor activity. Reduced body weight resulting from the CXCL14 deficiency was more pronounced in double mutant CXCL14(-/-ob/ob and CXCL14(-/-A(y mice. In the case of CXCL14(-/-A(y mice, oxygen consumption was increased compared to CXCL14(+/-A(y mice, in addition to the reduced food intake. In CXCL14(-/- mice, fasting-induced up-regulation of Npy and Agrp mRNAs in the hypothalamus was blunted. As intracerebroventricular injection of recombinant CXCL14 did not change the food intake of CXCL14(-/- mice, CXCL14 could indirectly regulate appetite. Intriguingly, the food intake of CXCL14(-/- mice was significantly repressed when mice were transferred to a novel environment. CONCLUSIONS/SIGNIFICANCE: We demonstrated that CXCL14 is involved in the body weight control leading to the fully obese phenotype in leptin-deficient or A(y mutant mice. In addition, we obtained evidence indicating that CXCL14 may play an important role in central nervous system regulation of feeding behavior.

  19. Response of Intestinal Bacterial Flora to the Long-term Feeding of Aflatoxin B1 (AFB1) in Mice.

    Science.gov (United States)

    Yang, Xiai; Liu, Liangliang; Chen, Jing; Xiao, Aiping

    2017-10-12

    In order to investigate the influence of aflatoxin B1 (AFB1) on intestinal bacterial flora, 24 Kunming mice (KM mice) were randomly placed into four groups, which were labeled as control, low-dose, medium-dose, and high-dose groups. They were fed intragastrically with 0.4 mL of 0 mg/L, 2.5 mg/L, 4 mg/L, or 10 mg/L of AFB1 solutions, twice a day for 2 months. The hypervariable region V3 + V4 on 16S rDNA of intestinal bacterial flora was sequenced by the use of a high-flux sequencing system on a Miseq Illumina platform; then, the obtained sequences were analyzed. The results showed that, when compared with the control group, both genera and phyla of intestinal bacteria in the three treatment groups decreased. About one third of the total genera and one half of the total phyla remained in the high-dose group. The dominant flora were Lactobacillus and Bacteroides in all groups. There were significant differences in the relative abundance of intestinal bacterial flora among groups. Most bacteria decreased as a whole from the control to the high-dose groups, but several beneficial and pathogenic bacterial species increased significantly with increasing dose of AFB1. Thus, the conclusion was that intragastric feeding with 2.5~10 mg/mL AFB1 for 2 months could decrease the majority of intestinal bacterial flora and induce the proliferation of some intestinal bacteria flora.

  20. Visualizing non infectious and infectious Anopheles gambiae blood feedings in naive and saliva-immunized mice.

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    Valerie Choumet

    Full Text Available BACKGROUND: Anopheles gambiae is a major vector of malaria and lymphatic filariasis. The arthropod-host interactions occurring at the skin interface are complex and dynamic. We used a global approach to describe the interaction between the mosquito (infected or uninfected and the skin of mammals during blood feeding. METHODS: Intravital video microscopy was used to characterize several features during blood feeding. The deposition and movement of Plasmodium berghei sporozoites in the dermis were also observed. We also used histological techniques to analyze the impact of infected and uninfected feedings on the skin cell response in naive mice. RESULTS: The mouthparts were highly mobile within the skin during the probing phase. Probing time increased with mosquito age, with possible effects on pathogen transmission. Repletion was achieved by capillary feeding. The presence of sporozoites in the salivary glands modified the behavior of the mosquitoes, with infected females tending to probe more than uninfected females (86% versus 44%. A white area around the tip of the proboscis was observed when the mosquitoes fed on blood from the vessels of mice immunized with saliva. Mosquito feedings elicited an acute inflammatory response in naive mice that peaked three hours after the bite. Polynuclear and mast cells were associated with saliva deposits. We describe the first visualization of saliva in the skin by immunohistochemistry (IHC with antibodies directed against saliva. Both saliva deposits and sporozoites were detected in the skin for up to 18 h after the bite. CONCLUSION: This study, in which we visualized the probing and engorgement phases of Anopheles gambiae blood meals, provides precise information about the behavior of the insect as a function of its infection status and the presence or absence of anti-saliva antibodies. It also provides insight into the possible consequences of the inflammatory reaction for blood feeding and pathogen

  1. Visualizing non infectious and infectious Anopheles gambiae blood feedings in naive and saliva-immunized mice.

    Science.gov (United States)

    Choumet, Valerie; Attout, Tarik; Chartier, Loïc; Khun, Huot; Sautereau, Jean; Robbe-Vincent, Annie; Brey, Paul; Huerre, Michel; Bain, Odile

    2012-01-01

    Anopheles gambiae is a major vector of malaria and lymphatic filariasis. The arthropod-host interactions occurring at the skin interface are complex and dynamic. We used a global approach to describe the interaction between the mosquito (infected or uninfected) and the skin of mammals during blood feeding. Intravital video microscopy was used to characterize several features during blood feeding. The deposition and movement of Plasmodium berghei sporozoites in the dermis were also observed. We also used histological techniques to analyze the impact of infected and uninfected feedings on the skin cell response in naive mice. The mouthparts were highly mobile within the skin during the probing phase. Probing time increased with mosquito age, with possible effects on pathogen transmission. Repletion was achieved by capillary feeding. The presence of sporozoites in the salivary glands modified the behavior of the mosquitoes, with infected females tending to probe more than uninfected females (86% versus 44%). A white area around the tip of the proboscis was observed when the mosquitoes fed on blood from the vessels of mice immunized with saliva. Mosquito feedings elicited an acute inflammatory response in naive mice that peaked three hours after the bite. Polynuclear and mast cells were associated with saliva deposits. We describe the first visualization of saliva in the skin by immunohistochemistry (IHC) with antibodies directed against saliva. Both saliva deposits and sporozoites were detected in the skin for up to 18 h after the bite. This study, in which we visualized the probing and engorgement phases of Anopheles gambiae blood meals, provides precise information about the behavior of the insect as a function of its infection status and the presence or absence of anti-saliva antibodies. It also provides insight into the possible consequences of the inflammatory reaction for blood feeding and pathogen transmission.

  2. Presence of pups suppresses hunger-induced feeding in virgin adult mice of both sexes.

    Science.gov (United States)

    Han, Ying; Li, Xing-Yu; Wang, Shao-Ran; Wei, Yi-Chao; Xu, Xiao-Hong

    2017-10-24

    Despite recent progress on neural pathways underlying individual behaviors, how an animal balances and prioritizes behavioral outputs remains poorly understood. While studying the relationship between hunger-induced feeding and pup-induced maternal behaviors in virgin female mice, we made the unexpected discovery that presence of pups strongly delayed and decreased food consumption. Strikingly, presence of pups also suppressed feeding induced by optogenetic activation of Agrp neurons. Such a suppressive effect inversely correlated with the extents of maternal behaviors, but did not rely on the display of these behaviors, and was also present in virgin males. Furthermore, chemogenetic activation of Vglut2+ neurons in the medial preoptic area (mPOA), a region critical for maternal behaviors and motivation, was sufficient to suppress hunger-induced feeding. However, muscimol inhibition of the mPOA, while disrupting maternal behaviors, did not prevent pup suppression of feeding, indicating that neural pathways in other brain regions may also mediate such an effect. Together, these results provide novel insights into neural coordination of pup care and feeding in mice and organizations of animal behaviors in general. Copyright © 2017. Published by Elsevier Ltd.

  3. Every-other-day feeding extends lifespan but fails to delay many symptoms of aging in mice.

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    Xie, Kan; Neff, Frauke; Markert, Astrid; Rozman, Jan; Aguilar-Pimentel, Juan Antonio; Amarie, Oana Veronica; Becker, Lore; Brommage, Robert; Garrett, Lillian; Henzel, Kristin S; Hölter, Sabine M; Janik, Dirk; Lehmann, Isabelle; Moreth, Kristin; Pearson, Brandon L; Racz, Ildiko; Rathkolb, Birgit; Ryan, Devon P; Schröder, Susanne; Treise, Irina; Bekeredjian, Raffi; Busch, Dirk H; Graw, Jochen; Ehninger, Gerhard; Klingenspor, Martin; Klopstock, Thomas; Ollert, Markus; Sandholzer, Michael; Schmidt-Weber, Carsten; Weiergräber, Marco; Wolf, Eckhard; Wurst, Wolfgang; Zimmer, Andreas; Gailus-Durner, Valerie; Fuchs, Helmut; Hrabě de Angelis, Martin; Ehninger, Dan

    2017-07-24

    Dietary restriction regimes extend lifespan in various animal models. Here we show that longevity in male C57BL/6J mice subjected to every-other-day feeding is associated with a delayed onset of neoplastic disease that naturally limits lifespan in these animals. We compare more than 200 phenotypes in over 20 tissues in aged animals fed with a lifelong every-other-day feeding or ad libitum access to food diet to determine whether molecular, cellular, physiological and histopathological aging features develop more slowly in every-other-day feeding mice than in controls. We also analyze the effects of every-other-day feeding on young mice on shorter-term every-other-day feeding or ad libitum to account for possible aging-independent restriction effects. Our large-scale analysis reveals overall only limited evidence for a retardation of the aging rate in every-other-day feeding mice. The data indicate that every-other-day feeding-induced longevity is sufficiently explained by delays in life-limiting neoplastic disorders and is not associated with a more general slowing of the aging process in mice.Dietary restriction can extend the life of various model organisms. Here, Xie et al. show that intermittent periods of fasting achieved through every-other-day feeding protect mice against neoplastic disease but do not broadly delay organismal aging in animals.

  4. Transcriptome profiling of mice testes following low dose irradiation

    DEFF Research Database (Denmark)

    Belling, Kirstine C.; Tanaka, Masami; Dalgaard, Marlene Danner

    2013-01-01

    ABSTRACT: BACKGROUND: Radiotherapy is used routinely to treat testicular cancer. Testicular cells vary in radio-sensitivity and the aim of this study was to investigate cellular and molecular changes caused by low dose irradiation of mice testis and to identify transcripts from different cell types...... in the adult testis. METHODS: Transcriptome profiling was performed on total RNA from testes sampled at various time points (n = 17) after 1 Gy of irradiation. Transcripts displaying large overall expression changes during the time series, but small expression changes between neighbouring time points were...... selected for further analysis. These transcripts were separated into clusters and their cellular origin was determined. Immunohistochemistry and in silico quantification was further used to study cellular changes post-irradiation (pi). RESULTS: We identified a subset of transcripts (n = 988) where changes...

  5. Sensitivity to low-dose radiation in radiosensitive ''wasted'' mice

    International Nuclear Information System (INIS)

    Paunesku, T.; Protic, M.; Woloschak, G. E.

    1999-01-01

    Mice homozygous for the autosomal recessive wasted mutation (wst/wst) have abnormalities in T-lymphocytes and in the anterior motor neuron cells of the spinal cord, leading to sensitivity to low doses of ionizing radiation, hind limb paralysis, and immunodeficiency. This defect results in a failure to gain weight by 20 days and death at 28 days of age. The wasted mutation (previously mapped to mouse chromosome 2) is shown to be a 3-bp deletion in a T-cell-specific (and perhaps motor-neuron-specific) regulatory region (promoter) of the proliferating cell nuclear antigen (PCNA) gene on mouse chromosome 2. A regulatory element is also shown to be important in PCNA expression in T-lymphocytes and motor neuron cells afflicted by the 3-bp deletion in the PCNA promoter. The model is as follows: Absence of PCNA expression in the thymuses (and motor neurons) of wasted mice causes cellular apoptosis; this absence of expression is mediated by a positive transactor that can bind to the wild-type but not the wasted mutant PCNA promoter; the bound protein induces late expression of PCNA in T-lymphocytes and prevents onset of radiation sensitivity in the cells

  6. Entrainment to feeding but not to light: circadian phenotype of VPAC2 receptor-null mice.

    Science.gov (United States)

    Sheward, W John; Maywood, Elizabeth S; French, Karen L; Horn, Jacqueline M; Hastings, Michael H; Seckl, Jonathan R; Holmes, Megan C; Harmar, Anthony J

    2007-04-18

    The master clock driving mammalian circadian rhythms is located in the suprachiasmatic nuclei (SCN) of the hypothalamus and entrained by daily light/dark cycles. SCN lesions abolish circadian rhythms of behavior and result in a loss of synchronized circadian rhythms of clock gene expression in peripheral organs (e.g., the liver) and of hormone secretion (e.g., corticosterone). We examined rhythms of behavior, hepatic clock gene expression, and corticosterone secretion in VPAC2 receptor-null (Vipr2-/-) mice, which lack a functional SCN clock. Unexpectedly, although Vipr2-/- mice lacked robust circadian rhythms of wheel-running activity and corticosterone secretion, hepatic clock gene expression was strongly rhythmic, but advanced in phase compared with that in wild-type mice. The timing of food availability is thought to be an important entrainment signal for circadian clocks outside the SCN. Vipr2-/- mice consumed food significantly earlier in the 24 h cycle than wild-type mice, consistent with the observed timing of peripheral rhythms of circadian gene expression. When restricted to feeding only during the daytime (RF), mice develop rhythms of activity and of corticosterone secretion in anticipation of feeding time, thought to be driven by a food-entrainable circadian oscillator, located outside the SCN. Under RF, mice of both genotypes developed food-anticipatory rhythms of activity and corticosterone secretion, and hepatic gene expression rhythms also became synchronized to the RF stimulus. Thus, food intake is an effective zeitgeber capable of coordinating circadian rhythms of behavior, peripheral clock gene expression, and hormone secretion, even in the absence of a functional SCN clock.

  7. Low dose radiation exposure and atherosclerosis in ApoE{sup -/-} mice

    Energy Technology Data Exchange (ETDEWEB)

    Mitchel, R.E.J. [Atomic Energy of Canada Limited, Chalk River, ON (Canada); Hasu, M. [Univ. of Ottawa, Department of Pathology and Lab. Medicine, and Cellular and Molecular Medicine, Ottawa, ON (Canada); Univ. of Ottawa Heart Inst., Vascular Biology Group, Ottawa, ON (Canada); Bugden, M.; Wyatt, H. [Atomic Energy of Canada Limited, Chalk River, ON (Canada); Little, M. [Imperial Coll., Faculty of Medicine, St. Marys Campus, London (United Kingdom); Hildebrandt, G. [Univ. Hospital, Dept. of Radiotherapy, Rostock (Germany); Priest, N.D. [Atomic Energy of Canada Limited, Chalk River, ON (Canada); Whitman, S.C. [Univ. of Ottawa, Department of Pathology and Lab. Medicine, and Cellular and Molecular Medicine, Ottawa, ON (Canada); Univ. of Ottawa Heart Inst., Vascular Biology Group, Ottawa, ON (Canada)

    2010-07-01

    The hypothesis that single low dose exposures (0.025-0.5 Gy) to low LET radiation, given at either high (240 mGy/min) or low (1 mGy/min) dose rate, would promote aortic atherosclerosis was tested in female C57BI/6 mice genetically predisposed to this disease (ApoE-/-). Mice were exposed either at early stage disease (2 months of age) and examined 3 or 6 months later, or at late stage disease (8 months of age) and examined 2 or 4 months later. Compared to unexposed controls, all doses given at low or high dose rate at early stage disease had significant inhibitory effects on lesion growth and, at 25 or 50 mGy, on lesion frequency. No dose given at low dose rate had any effect on total serum cholesterol, but this was elevated by every dose given at high dose rate. Exposures at low dose rate had no effect on the percentage of lesion lipids contained within macrophages, and, at either high or low dose rate, had no significant effect on lesion severity. Exposure at late stage disease, to any dose at high dose rate, had no significant effect on lesion frequency, but at low dose rate some doses produced a small transient increase in this frequency. Exposure to low doses at low, but not high dose rate, significantly, but transiently reduced average lesion size, and at either dose rate transiently reduced lesion severity. Exposure to any dose at low dose rate (but not high dose rate) resulted in large and persistent decreases in serum cholesterol. These data indicate that a single low dose exposure, depending on dose and dose rate, generally protects against various measures of atherosclerosis in genetically susceptible mice. This result contrasts with the known, generally detrimental effects of high doses on this disease in the same mice, suggesting that a linear extrapolation of risk from high doses is not appropriate. (author)

  8. Low dose radiation exposure and atherosclerosis in ApoE-/- mice

    International Nuclear Information System (INIS)

    Mitchel, R.E.J.; Hasu, M.; Bugden, M.; Wyatt, H.; Little, M.; Hildebrandt, G.; Priest, N.D.; Whitman, S.C.

    2010-01-01

    The hypothesis that single low dose exposures (0.025-0.5 Gy) to low LET radiation, given at either high (240 mGy/min) or low (1 mGy/min) dose rate, would promote aortic atherosclerosis was tested in female C57BI/6 mice genetically predisposed to this disease (ApoE-/-). Mice were exposed either at early stage disease (2 months of age) and examined 3 or 6 months later, or at late stage disease (8 months of age) and examined 2 or 4 months later. Compared to unexposed controls, all doses given at low or high dose rate at early stage disease had significant inhibitory effects on lesion growth and, at 25 or 50 mGy, on lesion frequency. No dose given at low dose rate had any effect on total serum cholesterol, but this was elevated by every dose given at high dose rate. Exposures at low dose rate had no effect on the percentage of lesion lipids contained within macrophages, and, at either high or low dose rate, had no significant effect on lesion severity. Exposure at late stage disease, to any dose at high dose rate, had no significant effect on lesion frequency, but at low dose rate some doses produced a small transient increase in this frequency. Exposure to low doses at low, but not high dose rate, significantly, but transiently reduced average lesion size, and at either dose rate transiently reduced lesion severity. Exposure to any dose at low dose rate (but not high dose rate) resulted in large and persistent decreases in serum cholesterol. These data indicate that a single low dose exposure, depending on dose and dose rate, generally protects against various measures of atherosclerosis in genetically susceptible mice. This result contrasts with the known, generally detrimental effects of high doses on this disease in the same mice, suggesting that a linear extrapolation of risk from high doses is not appropriate. (author)

  9. Low-Dose Radiation Exposure and Atherosclerosis in ApoE(-/-) Mice

    NARCIS (Netherlands)

    Mitchel, R. E. J.; Hasu, M.; Bugden, M.; Wyatt, H.; Little, M. P.; Gola, A.; Hildebrandt, G.; Priest, N. D.; Whitman, S. C.

    The hypothesis that single low-dose exposures (0.025-0.5 Gy) to low-LET radiation given at either high (about 150 mGy/min) or low (1 mGy/min) dose rate would promote aortic atherosclerosis was tested in female C57BL/6J mice genetically predisposed to this disease (ApoE(-/-)). Mice were exposed

  10. Growth and development of male "little" mice assessed with Parks' theory of feeding and growth.

    Science.gov (United States)

    Puche, Rodolfo C; Alloatti, Rosa; Chapo, Gustavo

    2002-01-01

    This work was designed to characterize the appetite kinetics and growth of male C57BL/6J (lit) mice. Those variables were assessed with Parks' function of ad libitum feeding and growth. Heterozygous mice (lit/+) attained their mature weight at 12-15 weeks of age, peak growth rate (3.5 g/week) at 5 weeks and displayed the normal decay of food conversion efficiency as a function of age. The homozygous genotype has a chronic defect in the synthesis and secretion of growth hormone (GH). Homozygous mice could not be assessed with Park's function. From the 4th to the 15th week of age, body weight increased linearly and exhibited constant food conversion efficiency. Food intake of both genotypes was commensurate with their body weights. Lit/lit mice became progressively obese. At 40 weeks of age, body fat of lit/lit mice was fivefold that of lit/+ and their body weight was similar to their heterozygous controls. The chronic deficiency of growth hormone produced a lower bone mass (compared to heterozygous controls). Bone mass of both genotypes attained maturity at 12-15 weeks with a maximum growth rate at 5 weeks. Body weight and bone mass grow harmoniously in lit/+ but not in lit/lit mice.

  11. Every-other-day feeding extends lifespan but fails to delay many symptoms of aging in mice

    DEFF Research Database (Denmark)

    Xie, Kan; Neff, Frauke; Markert, Astrid

    2017-01-01

    that every-other-day feeding-induced longevity is sufficiently explained by delays in life-limiting neoplastic disorders and is not associated with a more general slowing of the aging process in mice.Dietary restriction can extend the life of various model organisms. Here, Xie et al. show that intermittent...... periods of fasting achieved through every-other-day feeding protect mice against neoplastic disease but do not broadly delay organismal aging in animals....

  12. Hard-Diet Feeding Recovers Neurogenesis in the Subventricular Zone and Olfactory Functions of Mice Impaired by Soft-Diet Feeding

    Science.gov (United States)

    Utsugi, Chizuru; Miyazono, Sadaharu; Osada, Kazumi; Sasajima, Hitoshi; Noguchi, Tomohiro; Matsuda, Mitsuyoshi; Kashiwayanagi, Makoto

    2014-01-01

    The subventricular zone (SVZ) generates an immense number of neurons even during adulthood. These neurons migrate to the olfactory bulb (OB) and differentiate into granule cells and periglomerular cells. The information broadcast by general odorants is received by the olfactory sensory neurons and transmitted to the OB. Recent studies have shown that a reduction of mastication impairs both neurogenesis in the hippocampus and brain functions. To examine these effects, we first measured the difference in Fos-immunoreactivity (Fos-ir) at the principal sensory trigeminal nucleus (Pr5), which receives intraoral touch information via the trigeminal nerve, when female adult mice ingested a hard or soft diet to explore whether soft-diet feeding could mimic impaired mastication. Ingestion of a hard diet induced greater expression of Fos-ir cells at the Pr5 than did a soft diet or no diet. Bromodeoxyuridine-immunoreactive (BrdU-ir) structures in sagittal sections of the SVZ and in the OB of mice fed a soft or hard diet were studied to explore the effects of changes in mastication on newly generated neurons. After 1 month, the density of BrdU-ir cells in the SVZ and OB was lower in the soft-diet-fed mice than in the hard-diet-fed mice. The odor preferences of individual female mice to butyric acid were tested in a Y-maze apparatus. Avoidance of butyric acid was reduced by the soft-diet feeding. We then explored the effects of the hard-diet feeding on olfactory functions and neurogenesis in the SVZ of mice impaired by soft-diet feeding. At 3 months of hard-diet feeding, avoidance of butyric acid was reversed and responses to odors and neurogenesis were recovered in the SVZ. The present results suggest that feeding with a hard diet improves neurogenesis in the SVZ, which in turn enhances olfactory function at the OB. PMID:24817277

  13. Effects of Bifidobacterium Breve Feeding Strategy and Delivery Modes on Experimental Allergic Rhinitis Mice.

    Directory of Open Access Journals (Sweden)

    Jian-jun Ren

    Full Text Available Different delivery modes may affect the susceptibility to allergic diseases. It is still unknown whether early intervention with probiotics would counteract this effect.The effect of different delivery modes on immune status and nasal symptoms was investigated on established allergic rhinitis (AR mouse model. In addition, the immunoregulatory effects and mechanisms of different feeding manners with Bifidobacterium breve(B. breve were examined.Live lyophilized B. breve was orally administered to BALB/c mice born via vaginal delivery(VD or cesarean delivery (CD for 8 consecutive weeks, after which they were sensitized by ovalbumin(OVA to establish experimental AR. Nasal symptoms, serum immunoglobulins, cytokines, splenic percentages of CD4(+CD25(+Foxp3(+ regulatory T(Treg cells and nasal eosinophil infiltration were evaluated.Compared with VD mice, mice delivered via CD demonstrated more serious nasal symptoms, higher concentrations of OVA-specific immunoglobulin (Ig E, more nasal eosinophils and lower percentages of splenic CD4(+CD25(+Foxp3(+Treg cells after establishing experimental AR. These parameters were reversed by administering B. breves hortly after birth. However, the effect of B. breve did not differ between different delivery modes.CD aggravates the nasal symptoms of AR mice compared to VD. This is the first report that oral administration of B. breve shortly after birth can significantly alleviate the symptoms of AR mice born via both deliveries, probably via activation of the regulatory capacity of CD4(+CD25(+Foxp3(+Treg cells.

  14. Effects of Bifidobacterium Breve Feeding Strategy and Delivery Modes on Experimental Allergic Rhinitis Mice.

    Science.gov (United States)

    Ren, Jian-jun; Yu, Zhao; Yang, Feng-Ling; Lv, Dan; Hung, Shi; Zhang, Jie; Lin, Ping; Liu, Shi-Xi; Zhang, Nan; Bachert, Claus

    2015-01-01

    Different delivery modes may affect the susceptibility to allergic diseases. It is still unknown whether early intervention with probiotics would counteract this effect. The effect of different delivery modes on immune status and nasal symptoms was investigated on established allergic rhinitis (AR) mouse model. In addition, the immunoregulatory effects and mechanisms of different feeding manners with Bifidobacterium breve(B. breve) were examined. Live lyophilized B. breve was orally administered to BALB/c mice born via vaginal delivery(VD) or cesarean delivery (CD) for 8 consecutive weeks, after which they were sensitized by ovalbumin(OVA) to establish experimental AR. Nasal symptoms, serum immunoglobulins, cytokines, splenic percentages of CD4(+)CD25(+)Foxp3(+) regulatory T(Treg) cells and nasal eosinophil infiltration were evaluated. Compared with VD mice, mice delivered via CD demonstrated more serious nasal symptoms, higher concentrations of OVA-specific immunoglobulin (Ig) E, more nasal eosinophils and lower percentages of splenic CD4(+)CD25(+)Foxp3(+)Treg cells after establishing experimental AR. These parameters were reversed by administering B. breves hortly after birth. However, the effect of B. breve did not differ between different delivery modes. CD aggravates the nasal symptoms of AR mice compared to VD. This is the first report that oral administration of B. breve shortly after birth can significantly alleviate the symptoms of AR mice born via both deliveries, probably via activation of the regulatory capacity of CD4(+)CD25(+)Foxp3(+)Treg cells.

  15. Lactobacillus paracasei feeding improves the control of secondary experimental meningococcal infection in flu-infected mice.

    Science.gov (United States)

    Belkacem, Nouria; Bourdet-Sicard, Raphaëlle; Taha, Muhamed-Kkeir

    2018-04-10

    The use of probiotics to improve anti-microbial defence, such as for influenza infections, is increasingly recommended. However, no data are available on the effect of probiotics on flu-associated secondary bacterial infections. There is strong evidence of a spatiotemporal association between influenza virus infection and invasive Neisseria meningitidis. We thus investigated the effect of feeding mice Lactobacillus paracasei CNCM I-1518 in a mouse model of sequential influenza-meningococcal infection. We intranasally infected BALB/c mice with a strain of influenza A virus (IAV) H3N2 that was first adapted to mice. Seven days later, a secondary bacterial infection was induced by intranasal administration of bioluminescent N. meningitidis. During the experiment, mice orally received either L. paracasei CNCM I-1518 or PBS as a control. The effect of L. paracasei administration on secondary bacterial infection by N. meningitidis was evaluated. Oral consumption of L. paracasei CNCM I-1518 reduced the weight loss of infected mice and lowered the bioluminescent signal of infecting meningococci. This improvement was associated with higher recruitment of inflammatory myeloid cells, such as interstitial monocytes and dendritic cells, to the lungs. Our data highlight the role of the gut-lung axis. L. paracasei CNCM I-1518 may boost the defence against IAV infection and secondary bacterial infection, which should be further studied and validated in clinical trials.

  16. High-fat feeding rather than obesity drives taxonomical and functional changes in the gut microbiota in mice

    NARCIS (Netherlands)

    Xiao, Liang; Sonne, Si Brask; Feng, Qiang; Chen, Ning; Xia, Zhongkui; Li, Xiaoping; Fang, Zhiwei; Zhang, Dongya; Fjære, Even; Midtbø, Lisa Kolden; Derrien, Muriel; Hugenholtz, Floor; Tang, Longqing; Li, Junhua; Zhang, Jianfeng; Liu, Chuan; Hao, Qin; Vogel, Ulla Birgitte; Mortensen, Alicja; Kleerebezem, Michiel; Licht, Tine Rask; Yang, Huanming; Wang, Jian; Li, Yingrui; Arumugam, Manimozhiyan; Wang, Jun; Madsen, Lise; Kristiansen, Karsten

    2017-01-01

    BACKGROUND: It is well known that the microbiota of high-fat (HF) diet-induced obese mice differs from that of lean mice, but to what extent, this difference reflects the obese state or the diet is unclear. To dissociate changes in the gut microbiota associated with high HF feeding from those

  17. Differential sensitivity of long-sleep and short-sleep mice to high doses of cocaine.

    Science.gov (United States)

    de Fiebre, C M; Ruth, J A; Collins, A C

    1989-12-01

    The cocaine sensitivity of male and female long-sleep (LS) and short-sleep (SS) mice, which have been selectively bred for differential ethanol-induced "sleep-time," was examined in a battery of behavioral and physiological tests. Differences between these two mouse lines were subtle and were seen primarily at high doses. At high doses, SS mice were more sensitive than LS mice, particularly to cocaine-induced hypothermia; however, significant hypothermia was not seen except at doses which were very near to the seizure threshold. During a 60-min test of locomotor activity, LS mice showed greater stimulation of Y-maze activity by 20 mg/kg cocaine than SS mice. Consistent with the finding of subtle differences in sensitivity to low doses of cocaine. LS and SS mice did not differ in sensitivity to cocaine inhibition of synaptosomal uptake of [3H]-dopamine, [3H]-norepinephrine or [3H]-5-hydroxytryptamine. However, consistent with the finding of differential sensitivity to high doses of cocaine, SS mice were more sensitive to the seizure-producing effects of the cocaine and lidocaine, a local anesthetic. It is hypothesized that the differential sensitivity of these mouse lines to high doses of cocaine is due to differential sensitivity to cocaine's actions on systems that regulate local anesthetic effects. Selective breeding for differential duration of alcohol-induced "sleep-time" may have resulted in differential ion channel structure or function in these mice.

  18. Estimated dose to in-tank equipment: Phase 1 waste feed delivery

    International Nuclear Information System (INIS)

    Claghorn, R.D.

    1998-01-01

    This analysis estimates the radiation dose to the equipment that will be submerged in double-shell tank waste. The results of this analysis are intended to be the basis for specifications for in-tank equipment. The scope of this analysis is limited to the new equipment required for the delivery of waste feed to Phase 1 private contractors. Phase 1 refers to the first of a two-phase plan to privatize the remediation of Hanford's tank waste. The focus of this analysis is on waste feed delivery because of the extraordinarily high cost of any failure that would lead to the interruption of a steady flow of feed to the private contractors

  19. The Effect Of Inoculation Dose Of trypanosoma Evansi On Blood Value In Animal Hosts f Mice

    International Nuclear Information System (INIS)

    Arifin, M.

    2002-01-01

    An experiment was carried out to obtain the information and its relation between a number of parasites and pathogenity in mice. The pathogenity of T. evansi was depend on the exchange of blood value of infected mice. The parasites was irradiated by gamma rays 6 O C o with the dose of and 300 Gy. The dose of inoculation were 1 x 10 5 , 5 x 10 5 and 1 x 10 6 parasites per mice. The results obtained showed that a number of parasites were inoculated caused the drop of blood value of mice. The number of parasites and irradiation were also significant effect to the blood value (P<0.01)

  20. Long-term feeding studies in mice fed a diet containing irradiated fish. I

    International Nuclear Information System (INIS)

    Petten, L.E. van; Calkins, J.E.; McConnell, R.F.; Gottschalk, H.M.; Elias, P.S.

    1980-01-01

    A wholesomeness feeding study was carried out in mice fed equal amounts of cod or redfish, comprising 45% of the diet. Three groups of animals received either irradiated [1.75 kGy (175 krad)] fish, non-irradiated fish or stock ration. A 90-day subchronic study, a multigeneration reproduction, a dominant lethality and a teratology study were carried out together with an 80-week oncogenic study on the F 1 generation. No adverse effects were noted on growth, reproduction and litter behaviour, in relation to dominant lethality, teratogenicity or oncogenicity. (Auth.)

  1. Radioprotective effect of RSP-CM on mice irradiated with different doses

    International Nuclear Information System (INIS)

    Zhang Xia; Yang Rujun; Zhang Xin; Yang Yunfang; Jin Zhijun; Xiang Yingsong

    2000-01-01

    Objective: To investigate the radioprotective effects of cytokines on hematopoietic impairment of irradiated mice. Methods: Using RSP-CM and LP3-CM respectively originated GM-CSF and G-CSF to treat ICR mice irradiated with different doses of 60 Co γ-rays. The 30-day survival rate of mice, the mean survival days of dead mice were determined and the numbers of peripheral white blood cells and BMC of part of the mice were counted. At the same time, GM clonogenic activity of BM was assayed. Results:RSP-CM could effectively raise 30-day survival rate of mice irradiated with 7.5 Gy. However, LP3-CM had no obvious effect. Judging from the comparative survival ratio, only the RSP-CM treated group showed protective effect on the 8.0 Gy -irradiated mice. The 8.5 Gy-irradiated mice all died within 30 days, indicating that GM-CSF had weak effect on higher dose-irradiated mice. Conclusion: GM-CSF can stimulate the hematopoietic system of irradiated mice, and has dose-effect and time-effect relations. M-CSF used singly has no obvious effect

  2. High-fat feeding rather than obesity drives taxonomical and functional changes in the gut microbiota in mice

    DEFF Research Database (Denmark)

    Xiao, Liang; Sonne, Si Brask; Feng, Qiang

    2017-01-01

    feeding rather than obesity development led to distinct changes in the gut microbiota. We observed a robust increase in alpha diversity, gene count, abundance of genera known to be butyrate producers, and abundance of genes involved in butyrate production in Sv129 mice compared to BL6 mice fed either a LF......Background: It is well known that the microbiota of high-fat (HF) diet-induced obese mice differs from that of lean mice, but to what extent, this difference reflects the obese state or the diet is unclear. To dissociate changes in the gut microbiota associated with high HF feeding from those......-induced obesity, but in Sv129 mice accentuates obesity.Results: Using HiSeq-based whole genome sequencing, we identified taxonomic and functional differences in the gut microbiota of the two mouse strains fed regular low-fat or HF diets with or without supplementation with the COX-inhibitor, indomethacin. HF...

  3. The growth and development of Schistosoma mansoni in mice exposed to sublethal doses of radiation

    International Nuclear Information System (INIS)

    Aitken, R.; Wilson, R.A.

    1989-01-01

    The maturation of Schistosoma mansoni was studied in mice exposed to various sublethal doses of radiation. Although the treatment of mice with 500 rads of radiation prior to infection did not alter parasite maturation, doses in excess of 500 rads led to a reduction in worm burden. This could not be attributed to a delay in the arrival of parasites in the hepatic portal system. Worms developing in mice treated with 800 rads commenced egg-laying about 1 wk later than worms in intact mice, and the rate of egg deposition appeared to be lower in irradiated hosts. The data demonstrate that exposure of C57BL/6 mice to doses of radiation in excess of 500 rads impairs their ability to carry infections of S. mansoni. The findings do not support the hypothesis that primary worm burdens in the mouse are controlled by a host immune response

  4. Effects of low dose rate irradiation on induction of myeloid leukemia in mice

    International Nuclear Information System (INIS)

    Furuse, Takeshi

    1999-01-01

    We investigated the induction of myeloid leukemia and other kinds of neoplasias in C3H male mice irradiated at several dose rate levels. We compared the incidence of neoplasias among these groups, obtained dose and dose rate effectiveness factors (DDREF) for myeloid leukemia. C3H/He male mice were exposed to whole body gamma-ray irradiation at 8 weeks of age. All mice were maintained for their entire life span and teh pathologically examined after their death. Radiation at a high dose-rate of 882 mGy/min (group H), a medium dose-rate of 95.6 mGy/min (group M), and low dose-rates of 0.298 mGy/min (group L-A), 0.067 mGy/min (group L-B) or 0.016 mGy/min (group L-C) were delivered from 137 Cs sources. The mice in group L were irradiated continuously for 22 hours daily up to total doses of 1, 2, 3, 4, 10 Gy over a period of 3 days to 200 days. As for the induction of neoplasias, myeloid leukemia developed significantly more frequently in irradiated groups than in unirradiated groups. The time distribution of mice dying from myeloid leukemia did not show a difference between groups H and L. The incidence of myeloid leukemia showed a greater increase in the high dose-rate groups than in the low and medium dose-rate groups in the dose range over 2 Gy, it also showed significant increases in the groups irradiated with 1 Gy of various dose rate, but the difference between these groups was not clear. These dose effect curves had their highest values on each curve at about 3 Gy. We obtained DDREF values of 2-3 by linear fittings for their dose response curves of dose ranges in which leukemia incidences were increasing. (author)

  5. Low dose diagnostic radiation does not increase cancer risk in cancer prone mice

    Energy Technology Data Exchange (ETDEWEB)

    Boreham, D., E-mail: dboreham@nosm.ca [Northern Ontario School of Medicine, ON (Canada); Phan, N., E-mail: nghiphan13@yahoo.com [Univ. of Ottawa, Ottawa, ON (Canada); Lemon, J., E-mail: lemonja@mcmaster.ca [McMaster Univ., Hamilton, ON (Canada)

    2014-07-01

    The increased exposure of patients to low dose diagnostic ionizing radiation has created concern that these procedures will result in greater risk of carcinogenesis. However, there is substantial evidence that shows in many cases that low dose exposure has the opposite effect. We have investigated whether CT scans can modify mechanisms associated with carcinogenesis in cancer-prone mice. Cancer was induced in Trp53+/- mice with an acute high dose whole-body 4 Gy γ-radiation exposure. Four weeks following the cancer-inducing dose, weekly whole-body CT scans (10 mGy/scan, 75 kVp X-rays) were given for ten consecutive weeks adding an additional radiation burden of 0.1 Gy. Short-term biological responses and subsequent lifetime cancer risk were investigated. Five days following the last CT scan, there were no detectable differences in the spontaneous levels of DNA damage in blood cells (reticulocytes). In fact, CT scanned mice had significantly lower constitutive levels of oxidative DNA damage and cell death (apoptosis), compared to non-CT scanned mice. This shows that multiple low dose radiation exposures modified the radio response and indicates protective processes were induced in mice. In mice treated with the multiple CT scans following the high cancer-inducing 4 Gy dose, tumour latency was increased, significantly prolonging lifespan. We conclude that repeated CT scans can reduce the cancer risk of a prior high-dose radiation exposure, and delay the progression of specific types of radiation-induced cancers in Trp53+/-mice. This research shows for the first time that low dose exposure long after cancer initiation events alter risk and reduce cancer morbidity. Cancer induction following low doses does not follow a linear non-threshold model of risk and this model should not be used to extrapolate risk to humans following low dose exposure to ionizing radiation. (author)

  6. Induction of oral tolerance with micro-doses of ovomucoid depends on the length of the feeding period

    DEFF Research Database (Denmark)

    Kjær, Tanja; Frøkiær, Hanne

    2002-01-01

    Oral administration of antigen induces antigen-specific immunologic tolerance, which is known to be dose-dependent. We studied the influence of continuous oral administration of nanogram and microgram doses of antigen on oral tolerance induction. Mice were continuously exposed to varying doses (1...

  7. High-fat feeding rather than obesity drives taxonomical and functional changes in the gut microbiota in mice.

    Science.gov (United States)

    Xiao, Liang; Sonne, Si Brask; Feng, Qiang; Chen, Ning; Xia, Zhongkui; Li, Xiaoping; Fang, Zhiwei; Zhang, Dongya; Fjære, Even; Midtbø, Lisa Kolden; Derrien, Muriel; Hugenholtz, Floor; Tang, Longqing; Li, Junhua; Zhang, Jianfeng; Liu, Chuan; Hao, Qin; Vogel, Ulla Birgitte; Mortensen, Alicja; Kleerebezem, Michiel; Licht, Tine Rask; Yang, Huanming; Wang, Jian; Li, Yingrui; Arumugam, Manimozhiyan; Wang, Jun; Madsen, Lise; Kristiansen, Karsten

    2017-04-08

    It is well known that the microbiota of high-fat (HF) diet-induced obese mice differs from that of lean mice, but to what extent, this difference reflects the obese state or the diet is unclear. To dissociate changes in the gut microbiota associated with high HF feeding from those associated with obesity, we took advantage of the different susceptibility of C57BL/6JBomTac (BL6) and 129S6/SvEvTac (Sv129) mice to diet-induced obesity and of their different responses to inhibition of cyclooxygenase (COX) activity, where inhibition of COX activity in BL6 mice prevents HF diet-induced obesity, but in Sv129 mice accentuates obesity. Using HiSeq-based whole genome sequencing, we identified taxonomic and functional differences in the gut microbiota of the two mouse strains fed regular low-fat or HF diets with or without supplementation with the COX-inhibitor, indomethacin. HF feeding rather than obesity development led to distinct changes in the gut microbiota. We observed a robust increase in alpha diversity, gene count, abundance of genera known to be butyrate producers, and abundance of genes involved in butyrate production in Sv129 mice compared to BL6 mice fed either a LF or a HF diet. Conversely, the abundance of genes involved in propionate metabolism, associated with increased energy harvest, was higher in BL6 mice than Sv129 mice. The changes in the composition of the gut microbiota were predominantly driven by high-fat feeding rather than reflecting the obese state of the mice. Differences in the abundance of butyrate and propionate producing bacteria in the gut may at least in part contribute to the observed differences in obesity propensity in Sv129 and BL6 mice.

  8. Dietary Feeding of Grape Seed Extract Prevents Intestinal Tumorigenesis in APCmin/+ Mice

    Directory of Open Access Journals (Sweden)

    Balaiya Velmurugan

    2010-01-01

    Full Text Available Chemopreventive effects and associated mechanisms of grape seed extract (GSE against intestinal/colon cancer development are largely unknown. Herein, we investigated GSE efficacy against intestinal tumorigenesis in APCmin/+ mice. Female APCmin/+ mice were fed control or 0.5% GSE (wt/wt mixed AIN-76A diet for 6 weeks. At the end of the experiment, GSE feeding decreased the total number of intestinal polyps by 40%. The decrease in polyp formation in the small intestine was 42%, which was mostly in its middle (51% and distal (49% portions compared with the proximal one. GSE also decreased polyp growth where the number of polyps of 1 to 2 mm in size decreased by 42% and greater than 2 mm in size by 71%, without any significant change in polyps less than 1 mm in size. Immunohistochemical analyses of small intestinal tissue samples revealed a decrease (80%–86% in cell proliferation and an increase (four- to eight-fold in apoptosis. GSE feeding also showed decreased protein levels of cyclooxygenase-2 (COX-2 (56%–64%, inducible nitric oxide synthase (iNOS (58%–60%, and β-catenin (43%–59% but an increased Cip1/p21-positive cells (1.9- to 2.6-fold. GSE also decreased cyclin D1 and c-Myc protein levels in small intestine. Together, these findings show the chemopreventive potential of GSE against intestinal polyp formation and growth in APCmin/+ mice, which was accompanied with reduced cell proliferation and increased apoptosis together with down-regulation in COX-2, iNOS, β-catenin, cyclin D1, and c-Myc expression, but increased Cip1/p21. In conclusion, the present study suggests potential usefulness of GSE for the chemoprevention of human intestinal/colorectal cancer.

  9. Toxicity bioassay in mice exposed to low dose-rate radiation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Joog Sun; Gong, Eun Ji; Heo, Kyu; Yang, Kwang Mo [Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan (Korea, Republic of)

    2013-04-15

    The systemic effect of radiation increases in proportion to the dose amount and rate. The association between accumulated radiation dose and adverse effects, which is derived according to continuous low dose-rate radiation exposure, is not clearly elucidated. Our previous study showed that low dose-rate radiation exposure did not cause adverse effects in BALB/c mice at dose levels of ≤2 Gy, but the testis weight decreased at a dose of 2 Gy. In this study, we studied the effects of irradiation at the low dose rate (3.49 mGy/h) in the testes of C57BL/6 mice. Mice exposed to a total dose of 0.02, 0.2, and 2 Gy were found to be healthy and did not show any significant changes in body weight and peripheral blood components. However, mice irradiated with a dose of 2 Gy had significantly decreased testis weight. Further, histological studies and sperm evaluation also demonstrated changes consistent with the findings of decreased testis weight. In fertile patients found to have arrest of sperm maturation, the seminiferous tubules lack the DNMT1 and HDAC1 protein. The decrease of DNMT1 and HDAC1 in irradiated testis may be the part of the mechanism via which low dose-rate irradiation results in teticular injury. In conclusion, despite a low dose-rate radiation, our study found that when mice testis were irradiated with 2 Gy at 3.49 mGy/h dose rate, there was significant testicular and sperm damage with decreased DNMT1 and HDAC1 expression.

  10. Bioassay in BALB/c mice exposed to low dose rate radiation

    Energy Technology Data Exchange (ETDEWEB)

    Km, Sung Dae; Gong, Eun Ji; Bae, Min Ji; Yang, Kwang Mo; Kim, Joong Sun [Dongnam Institute of Radiological and Medical Sciences, Suwon (Korea, Republic of)

    2012-09-15

    The present study was performed to investigate the toxicity of low-dose-rate irradiation in BALB/c mice. Twenty mice of each sex were randomly assigned to four groups of five mice each and were exposed to 0 (sham), 0.02, 0.2, or 2 Gy, equivalents to low-dose-rate irradiation to 3.49 mGy{center_dot}h{sup -1}. Urine, blood, and blood biochemistry were analyzed, and organ weight was measured. The low-dose-rate irradiation did not induce any toxicologically significant changes in mortality, clinical signs, body weight, food and water consumption, urinalysis, and serum biochemistry. However, the weights of reproductive organs including the testis, ovary, and uterus decreased in a dose-dependent manner. Irradiation at 2 Gy significantly decreased the testis, ovary, and uterus weights, but did not change the weights of other organs. There were no adverse effects on hematology in any irradiated group and only the number of neutrophils increased dose dependently. The low-dose-rate irradiation exposure did not cause adverse effects in mice at dose levels of 2 Gy or less, but the reproductive systems of male and female mice showed toxic effects.

  11. Mechanism of suppressive effect of low dose radiation on cancer cell dissemination in mice

    International Nuclear Information System (INIS)

    Fu Haiqing; Li Xiuyi; Chen Yubing; Zhang Yingchun; Liu Shuzheng

    1997-01-01

    Influence of low dose radiation on immunity in C57 BL/6 mice injected with cancer cells was studied. In mice given 75 mGy WBI 24 h before injection of Lewis lung carcinoma cells or B 16 melanoma cells, the percentage of S-phase thymocytes and CD 3+ thymocytes, the splenic NK cell activity, IL-2 secretion and γIFN secretion were found to be potentiated 2∼8 day after irradiation in comparison with the sham-irradiation mice. The results suggest that low dose radiation might suppress cancer cell dissemination via the enhancement of immune reactivity

  12. Replacing Fish Oil with Vegetable Oils in Salmon Feed Increases Hepatic Lipid Accumulation and Reduces Insulin Sensitivity in Mice

    DEFF Research Database (Denmark)

    Midtbø, Lisa Kolden

    Background: Due to a growing global aquaculture production, fish oil (FO) and fish meal (FM) are partly replaced with vegetable ingredients in aqua feed for Atlantic salmon. These replacements in the feed lead to an altered fatty acid composition in the salmon fillet. We aimed to investigate how...... these changes affects obesity development and insulin sensitivity in mice eating the salmon. In addition, we wanted to investigate how the background diet affects the antiobesity effect of FO. Results: Western diets (WDs) were produced containing salmon fed either FO (WD-FO), or with partly replacement (80......%) of FO with different vegetable oils (VOs); rape seed oil (WDRO), olive oil (WD-OO) or soybean oil (WD-SO). These diets were given to C57BL/6J mice, and mice had higher hepatic lipid accumulation and lower insulin sensitivity when given WD-SO compared with WD-FO. Mice given WD-SO had higher hepatic...

  13. Effects of low-dose rate irradiation on two types of type II diabetes model mice

    International Nuclear Information System (INIS)

    Nomura, Takaji; Sakai, Kazuo

    2004-01-01

    The effects of low-dose rate gamma-irradiation were investigated in two mouse strains - C57BL/KsJ-db/db (db mouse) and AKITA (AKITA mouse)-for type II diabetes mellitus. Both strains develop the developed type II diabetes by about 8 weeks of age due to dysfunction of the insulin/insulin receptor. The db Mouse' shows obese and exhibits hyperinsulinism, and the onset of Type II diabetes like resembles that for Westerners. On the other hand, the AKITA mouse has exhibits disordered insulin secretion, and the diabetes such as resembles that of Asians. Ten-week old female mice, in groups of 8 or 12, were irradiated at 0.65 mGy/hr in the low-dose rate irradiation facility in the Low Dose Radiation Research Center. The level of urine glucose was measured with test slips. The urine glucose levels of all of the mice were highly elevated the beginning of the irradiation. In the irradiated group of db mice, three mice showed decrease in glucose level compare to the level of non-irradiated diabetes mice after 35, 52 or 80 weeks of irradiation. All had maintained a normal level thereafter. No such improvement in diabetes was ever observed in the 12 mice of in the non-irradiated control group. The AKITA mice, however, did not decrease the glucose level regardless of the irradiation. Both the db mice and AKITA mice had their lives prolonged their life by the irradiation. The survival rate of db mice at the age of 90 weeks was 75% in the irradiated group, but 50% in the non-irradiated group. The average life span was 104 weeks in the irradiated group and 87 weeks in the control group. Furthermore, a marked difference was furthermore observed in the appearance of the coat hair, skin, and tail; appearances were well preserved in the irradiated group. The average life span in the irradiated AKITA mice was also longer than that for the non-irradiated mice, 51 weeks and 41 weeks in the irradiated and non-irradiated group respectively. These results suggest that the low-dose irradiation

  14. Late effects of chronic low dose-rate γ-rays irradiation on mice

    International Nuclear Information System (INIS)

    Tanaka, Satoshi; Sasagawa, Sumiko; Ichinohe, Kazuaki; Matsumoto, Tsuneya; Otsu, Hiroshi; Sato, Fumiaki

    2002-01-01

    To evaluate late biological effects of chronic low dose-rate radiation, we are conducting two experiments. Experiment 1 - Late effects of chronic low dose-rate g-rays irradiation on SPF mice, using life-span and pathological changes as parameters. Continuous irradiation with g-rays for 400 days was performed using 137 Cs γ-rays at dose-rates of 20 mGy/day, 1 mGy/day and 0.05 mGy/day with accumulated doses equivalent to 8,000 mGy, 400 mGy and 20 mGy, respectively. All mice were kept until they died a natural death. As of 2002 March 31, 3,999 of the total 4,000 mice have died. Preliminary analyses of data show that 20 mGy/day suggested a shortened life span in both sexes. Partial results show that the most common lethal neoplasms in the pooled data of non-irradiated control and irradiated male mice, in order of frequency, were neoplasms of the lymphohematopoietic system, liver, and lung. In female mice, neoplasms of the lymphohematopoietic system, soft tissue, and endocrine system were common. Experiment 2 - Effects on the progeny of chronic low dose-rate g-ray irradiated SPF mice: pilot study, was started in 1999 and is currently in progress. (author)

  15. Effects of low dose radiation on antioxidant enzymes after radiotherapy of tumor-bearing mice

    International Nuclear Information System (INIS)

    Li Jin; Gao Gang; Wang Qin; Tang Weisheng; Liu Xiaoqiu; Wang Zhiquan

    2005-01-01

    Objective: To search for effects of low dose radiation on the activities of antioxidant enzymes after radiotherapy of tumor-bearing mice. Methods: Superoxide dismutase (SOD), glutathione-S-transferase (GST) and catalase (CAT) were all determined by chemical colorimetry. Results: Low dose radiation increase the activities of antioxidant enzymes superoxide dismutase (SOD), glutathione-S-transferase (GST) and catalase (CAT) in serum of tumor-bearing mice more markedly than those in the unirradiated controls. The activities of antioxidant enzymes SOD, GST, CAT in serum of tumor-bearing mice (d 5 , d 3 ) irradiated with 5cGy 6h before 2.0 Gy radiation are obviously higher than those of the group (c 3 , c 5 ) given with radiotherapy only. Conclusion: The increase in the activities of antioxidant enzymes in serum of tumor-bearing mice triggered by low dose radiation could partly contribute to the protective mechanism. (authors)

  16. Gender Differences in Response to Prolonged Every-Other-Day Feeding on the Proliferation and Apoptosis of Hepatocytes in Mice.

    Science.gov (United States)

    Piotrowska, Katarzyna; Tarnowski, Maciej; Zgutka, Katarzyna; Pawlik, Andrzej

    2016-03-19

    Intermittent fasting decreases glucose and insulin levels and increases insulin sensitivity and lifespan. Decreased food intake influences the liver. Previous studies have shown gender differences in response to various types of caloric restriction, including every-other-day (EOD) feeding, in humans and rodents. Our goal was to show the influence of prolonged EOD feeding on the morphology, proliferation and apoptosis of livers from male and female mice. After nine months of an EOD diet, the livers from male and female mice were collected. We examined their morphology on histological slides using the Hematoxilin and Eosine (H_E) method and Hoechst staining of cell nuclei to evaluate the nuclear area of hepatocytes. We also evaluated the expression of mRNA for proto-oncogens, pro-survival proteins and apoptotic markers using Real Time Polimerase Chain Reaction (PCR). We noted increased lipid content in the livers of EOD fed female mice. EOD feeding lead to a decrease of proliferation and apoptosis in the livers of female and male mice, which suggest that tissue maintenance occurred during EOD feeding. Our experiment revealed sex-specific expression of mRNA for proto-oncogenes and pro-survival and pro-apoptotic genes in mice as well as sex-specific responses to the EOD treatment.

  17. Gender Differences in Response to Prolonged Every-Other-Day Feeding on the Proliferation and Apoptosis of Hepatocytes in Mice

    Directory of Open Access Journals (Sweden)

    Katarzyna Piotrowska

    2016-03-01

    Full Text Available Intermittent fasting decreases glucose and insulin levels and increases insulin sensitivity and lifespan. Decreased food intake influences the liver. Previous studies have shown gender differences in response to various types of caloric restriction, including every-other-day (EOD feeding, in humans and rodents. Our goal was to show the influence of prolonged EOD feeding on the morphology, proliferation and apoptosis of livers from male and female mice. After nine months of an EOD diet, the livers from male and female mice were collected. We examined their morphology on histological slides using the Hematoxilin and Eosine (H_E method and Hoechst staining of cell nuclei to evaluate the nuclear area of hepatocytes. We also evaluated the expression of mRNA for proto-oncogens, pro-survival proteins and apoptotic markers using Real Time Polimerase Chain Reaction (PCR. We noted increased lipid content in the livers of EOD fed female mice. EOD feeding lead to a decrease of proliferation and apoptosis in the livers of female and male mice, which suggest that tissue maintenance occurred during EOD feeding. Our experiment revealed sex-specific expression of mRNA for proto-oncogenes and pro-survival and pro-apoptotic genes in mice as well as sex-specific responses to the EOD treatment.

  18. Metabolic effects of feeding high doses of propanol and propylacetate to lactating Holstein cows

    DEFF Research Database (Denmark)

    Raun, Birgitte Marie Løvendahl; Kristensen, Niels Bastian

    2012-01-01

    Three lactating Holstein cows implanted with ruminal cannulas and permanent indwelling catheters in major splanchnic blood vessels were used to investigate alcohol metabolism and metabolic effects of feeding high doses of propanol and propylacetate. Cows were fed three diets control (basal ration......; C), propanol (C plus 50 g propanol/kg DM; P), and propylacetate (C plus 50 g propanol/kg DM and 15 g propylacetate/kg DM; PPA) in a 3 × 3 Latin square design with 14 d period. Daily rations were fed in three equally sized portions at 8 hour intervals and 8 hourly sets of ruminal fluid, arterial...

  19. Restricted temporal access to food and anorexia in mice: Microstructure of eating within feeding opportunities.

    Science.gov (United States)

    Rowland, Neil E; Cervantez, Melissa; Robertson, Kimberly L

    2016-01-01

    Intake and body weight were recorded in a closed economy as male and female C57BL/6 mice progressed through either fixed interval (FI) or fixed unit price (FUP) schedules of cost for 20-mg food pellets. Access to food was constrained to four 40 min food opportunities (FOs) per day, spaced 4-h apart through the dark phase. Nose poke responses and pellet deliveries were collected at 10-s resolution to allow pellet-by-pellet analysis. In the FI protocol, mice maintained adequate food intake and body weight through the study, even though at the highest FI (50-s) they spent the entire 40-min FOs engaged in eating at or near the maximum rate allowed by the schedule. In the FUP protocol, mice greatly reduced their intake and lost weight at the highest FUP (50 responses/pellet). The analysis of response and pellet distributions showed these mice were not filling the FOs with responding and ate less at dusk (FO #1) and dawn (FO #4) than at FOs #2 and 3 in the middle of the night. The principal, and unexpected, sex difference was that females tended to eat more than males despite lower body weight, but behavioral changes as a function of feeding cost or schedule were qualitatively similar in both sexes. These results show that slow eating as imposed by an FI is not sufficient to produce hypophagia and, in the FUP protocol, hypophagia cannot be explained by slowed eating due to response requirements. We discuss the role of effort or time in FUP-induced anorexia, and suggest this murine model may emulate some aspects of human anorexia nervosa better than current activity-based protocols. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Apoptosis of bone marrow leukemia cells in mice after low dose radiation at different time

    International Nuclear Information System (INIS)

    Li Guangyu; Yu Mingming; Li Xianjun; Liu Zhixiang

    2007-01-01

    Objective: To investigate the apoptosis of bone marrow leukemia cell in mice after low dose radiation (LDR) at different time and the experimental basis for LDR auxiliary therapy on leukemia. Methods: WEHI-3 cells were injected into BALB/c mice through tail veins to make an experimental mice model of myelornonocytic leukemia. 60 leukemia mice models were divided half-and half. 30 mice models in experimental group were irradiated with LDR of 75mGy at the same time while the others 30 in the control group were not. 6 mice models with LDR and 6 mice models without LDR would be killed at the time the 1st day, the 2nd day, the 3rd day, the 5th day- and the l0th day after LDR in order to extract bone marrow samples. The apoptosis percentage of leukemia cells in bone marrow was examined. Results: The apoptosis percentage of leukemia cells in experimental group was increasing after LDR and went to top on the 2nd day and the 3rd day. The apoptosis percentage of leukemia cells was remarkably different between experimental and control group, all P<0.05. Conclusion: LDR could significantly increase the apoptosis percentage of bone marrow leukemia cells in mice. Its mechanism is remarkably different in kill and wound of big dose radiation to tumour cells. It is probably related to of the increase immune exciting response as to promote some cytokine secretion, in leukemia mice. (authors)

  1. Low-dose radiation-induced adaptive response in bone marrow cells of mice

    International Nuclear Information System (INIS)

    Farooqi, Zeba; Kesavan, P.C.

    1993-01-01

    Using bone marrow cells of whole body irradiated mice, the cytogenetic adaptive response induced by low conditioning doses of gamma-rays was investigated. The conditioning doses (0.025 and 0.05 Gy) were given at a dose-rate of 1.67 Gy/min. The challenging dose of 1 Gy was given at a dose-rate of 0.045 Gy/s. The challenging dose was given at different time intervals after the conditioning dose. The time intervals between the conditioning dose and challenging dose were 2, 7.5, 13, 18.5 and 24 h. When the time interval between the conditioning dose and the challenging dose was 2 h, both conditioning doses (0.025 and 0.05 Gy) reduced the frequency of MNPCEs and chromosomal aberrations in the bone marrow cells. The data collected at different time intervals (7.5, 13, 18.5 h) reveal that the radioadaptive response persisted for a longer time when the lower conditioning dose (0.025 Gy) was given. With the higher conditioning dose (0.05 Gy), the radioadaptive response disappeared after a time interval of 13 h. When the time interval between the conditioning dose and the challenging doses was 18.5 or 24 h, only the lower conditioning dose appeared effective in inducing the radioadaptive response

  2. High-fat feeding increases hepatic vitamin C synthesis and its circulatory mobilization in mice

    DEFF Research Database (Denmark)

    Christensen, Britt Tranberg; Hansen, Axel Jacob Kornerup; Lykkesfeldt, Jens

    2014-01-01

    , glucose and vitC concentrations. Hepatic vitC concentration and gulonolactone oxidase (GLO) capacity, as a measure of vitC de novo biosynthesis, were analyzed in liver homogenates. RESULTS: HF diet significantly increased plasma concentrations of vitC compared with a control diet low in fat (P ... to modulate their vitC homeostasis during high-fat (HF) feeding. METHODS: Twenty-five male 5-week-old C57BL/6 mice were fed high- or low-fat diets for 14 weeks. An oral glucose tolerance test (OGTT) was performed after 12 weeks of intervention. Terminal fasting plasma samples were analyzed for insulin.......05). Hepatic de novo biosynthesis of vitC was upregulated (P glucose and insulin concentrations...

  3. Effect of chamomile supplements to feeding doses on antimicrobial parameters in poultry

    Directory of Open Access Journals (Sweden)

    Zuzana Jakubcova

    2014-07-01

    Full Text Available Due to a ban of use of antibiotic growth promoters in the poultry industry it is necessary to look for alternative solutions. The use of some herbs showing antimicrobial effects can be one of such alternatives. In this experiment, effects of three different concentrations of chamomile (Matricaria chamomilla extract, (0.3%; 0.6% and 1.2% in feeding doses on the microbial population in the gastrointestinal tract of growing broiler chickens were studied. The main attention was paid to the population of Clostridium perfringens and to numbers of coliform microbes. Clostridia were cultivated under anaerobic conditions at 46 °C on the Tryptone Sulfite Neomycin (TSN agar for a period of 24 hours. Coliform microbes were grown on the violet red bile lactose (VRBL agar at 37 °C for a period of 24 hours. The experiment lasted 39 days and involved 80 chicks that were slaughtered in the course of their growth period at the age of 18, 25, 32 and 39 days; there were 5 chicks in each group. The obtained results indicated that increasing doses of chamomile in the feeding ration decreased numbers of coliform microbes in the digestive tract of chicks and also reduced the population of C. perfingens.

  4. Dose effects of dietary phytosterols on cholesterol metabolism: a controlled feeding study.

    Science.gov (United States)

    Racette, Susan B; Lin, Xiaobo; Lefevre, Michael; Spearie, Catherine Anderson; Most, Marlene M; Ma, Lina; Ostlund, Richard E

    2010-01-01

    Phytosterol supplementation of 2 g/d is recommended by the National Cholesterol Education Program to reduce LDL cholesterol. However, the effects of different intakes of phytosterol on cholesterol metabolism are uncertain. We evaluated the effects of 3 phytosterol intakes on whole-body cholesterol metabolism. In this placebo-controlled, crossover feeding trial, 18 adults received a phytosterol-deficient diet (50 mg phytosterols/2000 kcal) plus beverages supplemented with 0, 400, or 2000 mg phytosterols/d for 4 wk each, in random order. All meals were prepared in a metabolic kitchen; breakfast and dinner on weekdays were eaten on site. Primary outcomes were fecal cholesterol excretion and intestinal cholesterol absorption measured with stable-isotope tracers and serum lipoprotein concentrations. Phytosterol intakes (diet plus supplements) averaged 59, 459, and 2059 mg/d during the 3 diet periods. Relative to the 59-mg diet, the 459- and 2059-mg phytosterol intakes significantly (P phytosterol dose (-8.9 +/- 2.3%); a trend was observed with the 459-mg/d dose (-5.0 +/- 2.1%; P = 0.077). Dietary phytosterols in moderate and high doses favorably alter whole-body cholesterol metabolism in a dose-dependent manner. A moderate phytosterol intake (459 mg/d) can be obtained in a healthy diet without supplementation. This trial was registered at clinicaltrials.gov as NCT00860054.

  5. Dose effects of dietary phytosterols on cholesterol metabolism: a controlled feeding study123

    Science.gov (United States)

    Lin, Xiaobo; Lefevre, Michael; Spearie, Catherine Anderson; Most, Marlene M; Ma, Lina; Ostlund, Richard E

    2010-01-01

    Background: Phytosterol supplementation of 2 g/d is recommended by the National Cholesterol Education Program to reduce LDL cholesterol. However, the effects of different intakes of phytosterol on cholesterol metabolism are uncertain. Objective: We evaluated the effects of 3 phytosterol intakes on whole-body cholesterol metabolism. Design: In this placebo-controlled, crossover feeding trial, 18 adults received a phytosterol-deficient diet (50 mg phytosterols/2000 kcal) plus beverages supplemented with 0, 400, or 2000 mg phytosterols/d for 4 wk each, in random order. All meals were prepared in a metabolic kitchen; breakfast and dinner on weekdays were eaten on site. Primary outcomes were fecal cholesterol excretion and intestinal cholesterol absorption measured with stable-isotope tracers and serum lipoprotein concentrations. Results: Phytosterol intakes (diet plus supplements) averaged 59, 459, and 2059 mg/d during the 3 diet periods. Relative to the 59-mg diet, the 459- and 2059-mg phytosterol intakes significantly (P phytosterol dose (−8.9 ± 2.3%); a trend was observed with the 459-mg/d dose (−5.0 ± 2.1%; P = 0.077). Conclusions: Dietary phytosterols in moderate and high doses favorably alter whole-body cholesterol metabolism in a dose-dependent manner. A moderate phytosterol intake (459 mg/d) can be obtained in a healthy diet without supplementation. This trial was registered at clinicaltrials.gov as NCT00860054. PMID:19889819

  6. Ameliorative effects of low dose/low dose-rate irradiation on reactive oxygen species-related diseases model mice

    International Nuclear Information System (INIS)

    Nomura, Takaharu

    2008-01-01

    Living organisms have developed complex biological system which protects themselves against environmental radiation, and irradiation with proper dose, dose-rate and irradiation time can stimulate their biological responses against oxidative stress evoked by the irradiation. Because reactive oxygen species are involved in various human diseases, non-toxic low dose/low dose-rate radiation can be utilized for the amelioration of such diseases. In this study, we used mouse experimental models for fatty liver, nephritis, diabetes, and ageing to elucidate the ameliorative effect of low dose/low dose-rate radiation in relation to endogenous antioxidant activity. Single irradiation at 0.5 Gy ameliorates carbon tetrachloride-induced fatty liver. The irradiation increases hepatic anti-oxidative system involving glutathione and glutathione peroxidase, suggesting that endogenous radical scavenger is essential for the ameliorative effect of low dose radiation on carbon tetrachloride-induced fatty liver. Single irradiation at 0.5 Gy ameliorates ferric nitrilotriacetate-induced nephritis. The irradiation increases catalase and decreases superoxide dismutase in kidney. The result suggests that low dose radiation reduced generation of hydroxide radical generation by reducing cellular hydroperoxide level. Single irradiation at 0.5 Gy at 12 week of age ameliorates incidence of type I diabetes in non-obese diabetic (NOD) mice through the suppression of inflammatory activity of splenocytes, and resultant apoptosis of β-cells in pancreas. The irradiation activities of superoxide dismutase and catalase, which coordinately diminish intracellular reactive oxygen species. Continuous irradiation at 0.70 mGy/hr from 10 week of age elongates life span, and suppresses alopecia in type II diabetesmice. The irradiation improved glucose clearance without affecting insulin-resistance, and increased pancreatic catalase activity. The results suggest that continuous low dose-rate irradiation protect

  7. The ERa-PI3K cascade in proopiomelanocortin progenitor neurons regulates feeding and glucose balance in female mice

    Science.gov (United States)

    Estrogens act upon estrogen receptor (ER)a to inhibit feeding and improve glucose homeostasis in female animals. However, the intracellular signals that mediate these estrogenic actions remain unknown. Here, we report that anorexigenic effects of estrogens are blunted in female mice that lack ERa sp...

  8. Ultra-low dose of Mycobacterium tuberculosis aerosol creates partial infection in mice.

    Science.gov (United States)

    Saini, Divey; Hopkins, Gregory W; Seay, Sarah A; Chen, Ching-Ju; Perley, Casey C; Click, Eva M; Frothingham, Richard

    2012-03-01

    A murine low dose (LD) aerosol model is commonly used to test tuberculosis vaccines. Doses of 50-400 CFU (24h lung CFU) infect 100% of exposed mice. The LD model measures progression from infection to disease based on organ CFU at defined time points. To mimic natural exposure, we exposed mice to an ultra-low dose (ULD) aerosol. We estimated the presented dose by sampling the aerosol. Female C57BL/6 mice were exposed to Mycobacterium tuberculosis H37Rv aerosol at 1.0, 1.1, 1.6, 5.4, and 11 CFU presented dose, infecting 27%, 36%, 36%, 100%, and 95% of mice, respectively. These data are compatible with a stochastic infection event (Poisson distribution, weighted R(2)=0.97) or with a dose-response relationship (sigmoid distribution, weighted R(2)=0.97). Based on the later assumption, the ID50 was 1.6CFU presented dose (95% confidence interval, 1.2-2.1). We compared organ CFU after ULD and LD aerosols (5.4 vs. 395CFU presented dose). Lung burden was 30-fold lower in the ULD model at 4 weeks (3.4 vs. 4.8 logs, pLD aerosols had greater within-group CFU variability. Exposure to ULD aerosols leads to infection in a subset of mice, and to persistently low organ CFU. The ULD aerosol model may resemble human pulmonary tuberculosis more closely than the standard LD model, and may be used to identify host or bacterial factors that modulate the initial infection event. Copyright © 2011 Elsevier Ltd. All rights reserved.

  9. Pathomorphology of spleen lymphocyte apoptosis in large dose 60Co γ-irradiated mice

    International Nuclear Information System (INIS)

    Gao Linlu; Cui Yufang; Yang Hong; Xia Guowei; Peng Ruiyun; Gao Yabing; Wang Dewen

    2000-01-01

    Objective: The aim of the authors was to investigate the pathomorphology changes of spleen lymphocyte apoptosis after 60 Co γ-irradiation. Methods: The mice were irradiated with 6, 9, 12, 15 and 20 Gy of 60 Co γ-rays. At different times after irradiation, the mice were sacrificed and the pathological changes of spleen lymphocyte were observed by light and transmission electron microscopies. Results: Spleen lymphocyte decreased evidently and the peak of apoptosis in spleen lymphocyte was dependent on radiation dose and the time after irradiation. Conclusion: After γ-irradiation with large doses, pathological changes of spleen lymphocyte apoptosis in mice can be divided into obviously different stages. The main causes of death of spleen lymphocytes are different in different dose groups

  10. Artificial Feeds Given in Different Dose to the Growth and Feed Consumption of Semah Fish Seed (Tor Douronensis in Order to Domestication

    Directory of Open Access Journals (Sweden)

    . Sunarto

    2009-01-01

    Full Text Available Semah fish (Tor douronensis is a kind of freshwater fish pertained as a wild fish that almost extint and rare, therefore, it is necessary to preserve through the culture activity. Meanwhile, in fish culture effort, feed is considers as an important factor.  Thus, feed must meet a proper quality and quantity due to the fish maintenance, growth, and reproduction requirement. Test feed employed in this research was an artificial feed in form of pellet which was consists of 40% protein by dose tested of 3%, 6%, 9% and 12% of biomass weight. The result indicated that daily growth rate was ranged between 1.44-1.99% by highest growth achieved at feed dose 6% and from the quadratic regression analysis achieved optimal dose by 6.18%.  Daily feed comsumption rate of semah fish seed was ranged between 2.69-10.19% per day.  Feed efficiency was ranged between 13.85-54.09%, and survival rate was 100%. Keywords: dose, growth, feed comsumption, semah fish, Tor douronensis   ABSTRAK Ikan semah (Tor douronensis adalah jenis ikan air tawar yang tergolong jenis ikan liar yang hampir punah dan sudah langka, karena itu perlu upaya pelestariannya dengan usaha pembudidayaan. Dalam usaha budidaya ikan, pakan merupakan salah satu faktor penting. Oleh sebab itu pakan harus berkualitas dengan kuantitas yang tepat sesuai dengan kebutuhan ikan untuk pertumbuhannya, pemeliharaan tubuh dan reproduksi. Pakan uji yang digunakan dalam penelitian ini adalah pakan buatan berupa pelet yang mengandung  protein 40% dengan dosis pakan yang diuji 3%, 6%, 9% dan 12% dari bobot biomassa. Hasil menunjukkan laju pertumbuhan harian berkisar antara 1,99-1,44% dengan pertumbuhan tertinggi dicapai pada dosis pakan 6% dan dari analisis regresi kwadratik diperoleh dosis optimum sebesar 6,18%. Laju konsumsi harian benih ikan semah selama penelitian ini berkisar antara 2,69-10,19 %/hari. Efesiensi pakan berkisar antara 54,09-13,85%, dan tingkat kelangsungan hidup 100% Kata kunci: dosis

  11. The effects of low dose radiation (LDR) on mice of immune function

    International Nuclear Information System (INIS)

    Feng Li; Deng Daping

    2007-01-01

    Objective: To find out the Effects of Low Dose Radiation(LDR) on mice of immune function. Methods: Through flow cytometry to observe and analyse the effects of the leukomonocyte. Through immunohistochemistry to study IL-2, TNF-α. Results: At dose of 100mGy the stimulative effect on CD 4 + cells, CD 8 + cells and NK activity was higher than that at other doses. At dose of 500mGy leukomonocyte activity was lower. At dose of 100mGy, the colorations about IL-2, TNF-α deepen. Conclusion: LDR could stimulate immune function, especially at dose of 100mGy. while at dose of 500mGy, radiation could restrain the leukomonocyte activity. (authors)

  12. Effect of Variable Doses of Zinc Oxide Nanoparticles on Male Albino Mice Behavior.

    Science.gov (United States)

    Zahra, Javeria; Iqbal, Shahid; Zahra, Kiran; Javed, Zulha; Shad, Muhammad Aslam; Akbar, Atif; Ashiq, Muhammad Naeem; Iqbal, Furhan

    2017-02-01

    Zinc oxide nanoparticles (ZnO NPs) have diverse utility these days ranging from being part of nanosensors to be ingredient of cosmetics. Present study was designed to report the effect of variable doses of ZnO NPs on selected aspects of male albino mice behavior. Nano particles were synthesized by sol-gel auto-combustion method (Data not shown here). 10 week old male albino mice were divided into four experimental groups; group A, B and C were orally supplemented with 50 (low dose), 300 (medium dose) and 600 mg/ml solvent/kg body weight (high dose) of ZnO NPs for 4 days. Group D (control) orally received 0.2 M sodium phosphate buffer (solvent for ZnO NPs) for the same duration. A series of neurological tests (Rota rod, open field, novel object and light-dark box test) were conducted in all groups and performance was compared between ZnO NPs treated and control group. Muscular functioning during rota rod test was significantly improved in all ZnO NPs treated mice as compared to control group. While no significant differences in open field, novel object and light-dark box test performance were observed when data from studied parameters of specific ZnO NPs treatment were compared with the control group indicating that applied doses of ZnO NPs did not affect the exploratory, anxiolytic behavior and object recognition capability of adult male albino mice.

  13. Effect of feeding graded doses of Citrinin on clinical and teratology in female Wistar rats.

    Science.gov (United States)

    Singh, N D; Sharma, A K; Patil, R D; Rahman, S; Leishangthem, G D; Kumar, M

    2014-02-01

    Citrinin is the one of the well-known mycotoxins, which is possibly spread all over the world. The graded doses of citrinin (1, 3 and 5 ppm CIT in feed) in female Wistar rats 10 weeks prior to mating, during mating and during organogenesis resulted in resorptions and post implantation losses, decreased fetal body weights and crown-rump lengths in fetuses of all groups. Various developmental anomalies recorded in fetuses of treated rats included gross (wrist drop, curled tail, stretched forelimb, subcutaneous haematoma), skeletal (incomplete ossification of skull bones, incomplete fusion of vertebral bodies, complete and partial agenesis of sternaebrae, metacarpals, metatarsals and phalanges, fused ribs and swing out ribs) and visceral (internal and external hydrocephalus, cerebellar hypoplasia, microphthalmia, roundening of heart, contracted kidneys, dilated renal pelvis and cryptorchid testes). The results suggest that CIT has adverse effects on fetal development which may be due to the longer bioavailability of citrinin in the animals.

  14. Effect of prolonged irradiation by low dose-rate ionizing radiation on the hemopoiesis of mice

    Energy Technology Data Exchange (ETDEWEB)

    Yanai, Takanori; Shirata, Katsutoshi; Saitou, Mikio; Tanaka, Satoshi; Onodera, Junichi; Otsu, Hiroshi; Sato, Fumiaki [Institute for Environmental Sciences, Department of Radiobiology, Rokkasho, Aomori (Japan)

    1999-07-01

    To evaluate effects of prolonged irradiation by low dose-rate ionizing radiation on the hemopoiesis of mice, SPF C3H/HeN female mice were irradiated by {sup 137}Cs {gamma}-rays with doses of 1-8 Gy at the dose rate of 20 mGy (22 h-day){sup -1}. After irradiation, the number of hemopoietic cells contained in bone marrow was determined by the methods of CFU-S and CFU-GM assay, and the number of peripheral blood cells was counted. It was shown that the day 12-CFU-S, which is in the earlier stage of differentiation, decreased as the dose increased. Decreases of the numbers of day 7-CFU-S and CFU-GM were also observed. However, there were no remarkable changes in the number of peripheral blood cells. (author)

  15. Effect of prolonged irradiation by low dose-rate ionizing radiation on the hemopoiesis of mice

    Energy Technology Data Exchange (ETDEWEB)

    Yanai, Takanori; Shirata, Katsutoshi; Yamada, Yutaka; Saitou, Mikio; Izumi, Jun; Tanaka, Satoshi; Otsu, Hiroshi; Sato, Fumiaki [Institute for Environmental Sciences, Rokkasho, Aomori (Japan)

    2000-07-01

    For evaluation of effects of prolonged irradiation by low dose-rate ionizing radiation on the hemopoiesis of mice, SPF C3H/HeN female mice were irradiated with {sup 137}Cs {gamma}-rays with doses of 1-4 Gy at the dose rate of 20 mGy/22h-day. After irradiation, the number of hemopoietic cells contained in spleen was determined by the methods of CFU-S and CFU-GM assay, and the number of peripheral blood cells was counted. It was shown that the number of CFU-S colonies on day 12, which is in the earlier stage of differentiation, decreased as dose increased. No remarkable changes in the number of peripheral blood cells, however, were observed. (author)

  16. Effect of myostatin depletion on weight gain, hyperglycemia, and hepatic steatosis during five months of high-fat feeding in mice.

    Directory of Open Access Journals (Sweden)

    Kerri Burgess

    Full Text Available The marked hypermuscularity in mice with constitutive myostatin deficiency reduces fat accumulation and hyperglycemia induced by high-fat feeding, but it is unclear whether the smaller increase in muscle mass caused by postdevelopmental loss of myostatin activity has beneficial metabolic effects during high-fat feeding. We therefore examined how postdevelopmental myostatin knockout influenced effects of high-fat feeding. Male mice with ubiquitous expression of tamoxifen-inducible Cre recombinase were fed tamoxifen for 2 weeks at 4 months of age. This depleted myostatin in mice with floxed myostatin genes, but not in control mice with normal myostatin genes. Some mice were fed a high-fat diet (60% of energy for 22 weeks, starting 2 weeks after cessation of tamoxifen feeding. Myostatin depletion increased skeletal muscle mass ∼30%. Hypermuscular mice had ∼50% less weight gain than control mice over the first 8 weeks of high-fat feeding. During the subsequent 3 months of high-fat feeding, additional weight gain was similar in control and myostatin-deficient mice. After 5 months of high-fat feeding, the mass of epididymal and retroperitoneal fat pads was similar in control and myostatin-deficient mice even though myostatin depletion reduced the weight gain attributable to the high-fat diet (mean weight with high-fat diet minus mean weight with low-fat diet: 19.9 g in control mice, 14.1 g in myostatin-deficient mice. Myostatin depletion did not alter fasting blood glucose levels after 3 or 5 months of high-fat feeding, but reduced glucose levels measured 90 min after intraperitoneal glucose injection. Myostatin depletion also attenuated hepatic steatosis and accumulation of fat in muscle tissue. We conclude that blocking myostatin signaling after maturity can attenuate some of the adverse effects of a high-fat diet.

  17. Neural correlates of food anticipatory activity in mice subjected to once- or twice-daily feeding periods.

    Science.gov (United States)

    Rastogi, Ashutosh; Mintz, Eric M

    2017-10-01

    In rodents, restricted food access to a limited period each day at a predictable time results in the appearance of food anticipatory activity (FAA). Two shorter periods of food access each day can result in two FAA bouts. In this study, we examine FAA under 12:12 and 18:6 photoperiods in mice (Mus musculus) with one or two food access periods per day and measure the activation of the suprachiasmatic, dorsomedial and arcuate nuclei by assaying Fos protein expression, while making use of tissue-type plasminogen activator knockout mice to assess the role of neural plasticity in adaptation to restricted feeding cycles. Long days were utilised to allow for temporal separation of two restricted feeding periods during the light phase. Mice fed twice per day generally divided FAA into two distinct bouts, with mice lacking tissue-type plasminogen activator showing reduced FAA. Increases in Fos expression in response to one restricted feeding period per day were seen in the dorsomedial and arcuate nuclei in both 12:12 and 18:6 conditions, with an increase seen in the SCN in only the 12:12 condition. These increases were eliminated or reduced in the two feeding time conditions (done in 18:6 only). Both activity patterns and Fos expression differed for single restricted feeding times between 18:6 and 12:12 photoperiods. Fos activation was lower during RF in 18:6 than 12:12 across all three brain regions, a pattern not reflective of changes in FAA. These data suggest that involvement of these regions in FAA may be influenced by photoperiodic context. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  18. Life span and tumorigenesis in mice exposed to continuous low dose-rate gamma-rays

    International Nuclear Information System (INIS)

    Tanaka, Satoshi; Braga-Tanaka III, Ignacia; Takabatake, Takashi; Ichinohe, Kazuaki; Tanaka, Kimio; Matsumoto, Tsuneya; Sato, Fumiaki

    2004-01-01

    Two experiments were conducted to evaluate late biological effects of chronic low dose-rate radiation. 1: Late effects of chronic low dose-rate gamma-ray irradiation on SPF mice, using life span and pathological changes as parameters. Continuous irradiation for approximately 400 days was performed using 137 Cs gamma-rays at dose-rates of 20 mGy/day, 1 mGy/day and 0.05 mGy/day with accumulated doses equivalent to 8000 mGy, 400 mGy and 20 mGy, respectively. All mice were kept until their natural death. Statistical analyses show that the life spans of the both sexes irradiated at 20 mGy/day (p<0.0001) and of females irradiated at 1 mGy/day (p<0.05) were significantly shorter than those of the control group. There was no evidence of lengthened life span in mice continuously exposed to very low dose-rates of gama-rays. Pathodological examinations showed that the most frequently observed lethal neoplasms in males were malignant lymphomas, liver, lung, and soft tissue neoplasms, whereas, in females, malignant lymphomas and soft tissue neoplasms were common. No significant difference in the causes of death and mortality rates between groups. Hematopoietic neoplasms (malignant lymphoma and myeloid leukemia), liver, lung and soft tissue neoplasms, showed a tendency to appear at a younger age in both sexes irradiated at 20 mGy/day. Experiment 2: effects on the progeny of chronic low dose-rate gamma-ray irradiated SPF mice: preliminary study. No significant difference was observed between non-irradiated group and irradiated group with regards to litter size, sex ratio and causes of death in F1 and F2 mice. (author)

  19. Genotoxic effects of high dose rate X-ray and low dose rate gamma radiation in ApcMin/+ mice.

    Science.gov (United States)

    Graupner, Anne; Eide, Dag M; Brede, Dag A; Ellender, Michele; Lindbo Hansen, Elisabeth; Oughton, Deborah H; Bouffler, Simon D; Brunborg, Gunnar; Olsen, Ann Karin

    2017-10-01

    Risk estimates for radiation-induced cancer in humans are based on epidemiological data largely drawn from the Japanese atomic bomb survivor studies, which received an acute high dose rate (HDR) ionising radiation. Limited knowledge exists about the effects of chronic low dose rate (LDR) exposure, particularly with respect to the application of the dose and dose rate effectiveness factor. As part of a study to investigate the development of colon cancer following chronic LDR vs. acute HDR radiation, this study presents the results of genotoxic effects in blood of exposed mice. CBAB6 F1 Apc +/+ (wild type) and Apc Min/+ mice were chronically exposed to estimated whole body absorbed doses of 1.7 or 3.2 Gy 60 Co-γ-rays at a LDR (2.2 mGy h -1 ) or acutely exposed to 2.6 Gy HDR X-rays (1.3 Gy min -1 ). Genotoxic endpoints assessed in blood included chromosomal damage (flow cytometry based micronuclei (MN) assay), mutation analyses (Pig-a gene mutation assay), and levels of DNA lesions (Comet assay, single-strand breaks (ssb), alkali labile sites (als), oxidized DNA bases). Ionising radiation (ca. 3 Gy) induced genotoxic effects dependent on the dose rate. Chromosomal aberrations (MN assay) increased 3- and 10-fold after chronic LDR and acute HDR, respectively. Phenotypic mutation frequencies as well as DNA lesions (ssb/als) were modulated after acute HDR but not after chronic LDR. The Apc Min/+ genotype did not influence the outcome in any of the investigated endpoints. The results herein will add to the scant data available on genotoxic effects following chronic LDR of ionising radiation. Environ. Mol. Mutagen. 58:560-569, 2017. © 2017 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society. © 2017 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.

  20. Transgenic Mice Expressing Yeast CUP1 Exhibit Increased Copper Utilization from Feeds

    Science.gov (United States)

    Chen, Zhenliang; Liao, Rongrong; Zhang, Xiangzhe; Wang, Qishan; Pan, Yuchun

    2014-01-01

    Copper is required for structural and catalytic properties of a variety of enzymes participating in many vital biological processes for growth and development. Feeds provide most of the copper as an essential micronutrient consumed by animals, but inorganic copper could not be utilized effectively. In the present study, we aimed to develop transgenic mouse models to test if copper utilization will be increased by providing the animals with an exogenous gene for generation of copper chelatin in saliva. Considering that the S. cerevisiae CUP1 gene encodes a Cys-rich protein that can bind copper as specifically as copper chelatin in yeast, we therefore constructed a transgene plasmid containing the CUP1 gene regulated for specific expression in the salivary glands by a promoter of gene coding pig parotid secretory protein. Transgenic CUP1 was highly expressed in the parotid and submandibular salivary glands and secreted in saliva as a 9-kDa copper-chelating protein. Expression of salivary copper-chelating proteins reduced fecal copper contents by 21.61% and increased body-weight by 12.97%, suggesting that chelating proteins improve the utilization and absorbed efficacy of copper. No negative effects on the health of the transgenic mice were found by blood biochemistry and histology analysis. These results demonstrate that the introduction of the salivary CUP1 transgene into animals offers a possible approach to increase the utilization efficiency of copper and decrease the fecal copper contents. PMID:25265503

  1. Radioimmunotherapy for liver micrometastases in mice. Pharmacokinetics, dose estimation, and long-term effect

    International Nuclear Information System (INIS)

    Saga, Tsuneo; Sakahara, Harumi; Nakamoto, Yuji; Sato, Noriko; Zhao, Songji; Iida, Yasuhiko; Konishi, Junji; Kuroki, Masahide; Endo, Keigo

    1999-01-01

    The pharmacokinetics of a therapeutic dose of 131 I-labeled antibody and the absorbed dose in liver micrometastases of human colon cancer LS174T in female BALB/c nu/nu mice were investigated, along with the long-term therapeutic effect. Mice with liver micrometastases were given an intravenous injection of 131 I-labeled anti-carcinoembryonic antigen (CEA) antibody F33-104 (8.88 MBq/40 μg). The biodistribution of the antibody was determined 1, 2, 4, 6, and 10 days later. The absorbed dose was estimated for three hypothetical tumor diameters; 1,000, 500, and 300 μm. Autoradiography showed a homogeneous distribution of radioactivity in the micrometastases, and a high uptake was maintained until day 6 (24.0% injected dose (ID)/g on day 1 to 17.8% ID/g on day 6), but decreased thereafter. The absorbed doses in the 1,000-, 500-, and 300-μm tumors were calculated to be 19.1, 12.0, and 8.2 Gy, respectively. The intravenous injection of the 131 I-labeled antibody also showed a dose-dependent therapeutic effect (all mice of the nontreated group died, with a mean survival period of 4 weeks; 3 of the 8 mice that received 9.25 MBq survived up to 120 days with no sign of liver metastasis). These data give further evidence that micrometastasis is a good target of radioimmunotherapy, and that an absorbed dose of less than 20 Gy can effectively control small metastatic lesions. (author)

  2. Exposure to low-dose barium by drinking water causes hearing loss in mice.

    Science.gov (United States)

    Ohgami, Nobutaka; Hori, Sohjiro; Ohgami, Kyoko; Tamura, Haruka; Tsuzuki, Toyonori; Ohnuma, Shoko; Kato, Masashi

    2012-10-01

    We continuously ingest barium as a general element by drinking water and foods in our daily life. Exposure to high-dose barium (>100mg/kg/day) has been shown to cause physiological impairments. Direct administration of barium to inner ears by vascular perfusion has been shown to cause physiological impairments in inner ears. However, the toxic influence of oral exposure to low-dose barium on hearing levels has not been clarified in vivo. We analyzed the toxic influence of oral exposure to low-dose barium on hearing levels and inner ears in mice. We orally administered barium at low doses of 0.14 and 1.4 mg/kg/day to wild-type ICR mice by drinking water. The doses are equivalent to and 10-fold higher than the limit level (0.7 mg/l) of WHO health-based guidelines for drinking water, respectively. After 2-week exposure, hearing levels were measured by auditory brain stem responses and inner ears were morphologically analyzed. After 2-month exposure, tissue distribution of barium was measured by inductively coupled plasma mass spectrometry. Low-dose barium in drinking water caused severe hearing loss in mice. Inner ears including inner and outer hair cells, stria vascularis and spiral ganglion neurons showed severe degeneration. The Barium-administered group showed significantly higher levels of barium in inner ears than those in the control group, while barium levels in bone did not show a significant difference between the two groups. Barium levels in other tissues including the cerebrum, cerebellum, heart, liver and kidney were undetectably low in both groups. Our results demonstrate for the first time that low-dose barium administered by drinking water specifically distributes to inner ears resulting in severe ototoxicity with degeneration of inner ears in mice. Copyright © 2012 Elsevier Inc. All rights reserved.

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

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Suk Chul [Radiation Health Research Institute, Korea Hydro and Nuclear Power Co., Ltd., 388-1, Ssangmun-dong, Dobong-gu, Seoul 132-703 (Korea, Republic of); Lee, Kyung-Mi [Global Research Lab, BAERI Institute, Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul 136-705 (Korea, Republic of); Kang, Yu Mi [Radiation Health Research Institute, Korea Hydro and Nuclear Power Co., Ltd., 388-1, Ssangmun-dong, Dobong-gu, Seoul 132-703 (Korea, Republic of); Kim, Kwanghee [Global Research Lab, BAERI Institute, Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul 136-705 (Korea, Republic of); Kim, Cha Soon; Yang, Kwang Hee; Jin, Young-Woo [Radiation Health Research Institute, Korea Hydro and Nuclear Power Co., Ltd., 388-1, Ssangmun-dong, Dobong-gu, Seoul 132-703 (Korea, Republic of); Kim, Chong Soon [Department of Nuclear Medicine, Haeundae Paik Hospital, Inje University, Busan 612-030 (Korea, Republic of); Kim, Hee Sun, E-mail: hskimdvm@khnp.co.kr [Radiation Health Research Institute, Korea Hydro and Nuclear Power Co., Ltd., 388-1, Ssangmun-dong, Dobong-gu, Seoul 132-703 (Korea, Republic of)

    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.

  4. Three months of high-fructose feeding fails to induce excessive weight gain or leptin resistance in mice.

    Directory of Open Access Journals (Sweden)

    Erik J Tillman

    Full Text Available High-fructose diets have been implicated in obesity via impairment of leptin signaling in humans and rodents. We investigated whether fructose-induced leptin resistance in mice could be used to study the metabolic consequences of fructose consumption in humans, particularly in children and adolescents. Male C57Bl/6 mice were weaned to a randomly assigned diet: high fructose, high sucrose, high fat, or control (sugar-free, low-fat. Mice were maintained on their diets for at least 14 weeks. While fructose-fed mice regularly consumed more kcal and expended more energy, there was no difference in body weight compared to control by the end of the study. Additionally, after 14 weeks, both fructose-fed and control mice displayed similar leptin sensitivity. Fructose-feeding also did not change circulating glucose, triglycerides, or free fatty acids. Though fructose has been linked to obesity in several animal models, our data fail to support a role for fructose intake through food lasting 3 months in altering of body weight and leptin signaling in mice. The lack of impact of fructose in the food of growing mice on either body weight or leptin sensitivity over this time frame was surprising, and important information for researchers interested in fructose and body weight regulation.

  5. 2-deoxyglucose tissue levels and insulin levels following tolazamide dosing in normal and obese mice

    International Nuclear Information System (INIS)

    Skillman, C.A.; Fletcher, H.P.

    1986-01-01

    The effect of tolazamide (TZ), a sulfonylurea, on 14 C-2-deoxyglucose ( 14 C-2DG) tissue distribution and insulin levels of normal and obese mice was investigated using an in vivo physiological method. Acute doses of TZ (50 mg/kg ip) increased 14 C-2DG levels in gastrocnemius muscle and retroperitoneal fat and produced a transient elevation of insulin which most likely accounts for the increased 14 C-2DG levels in muscle and fat. The results demonstrate that the in vivo 14 C-2DG method produced results consistent with known actions of sulfonylureas on in vitro hexose assimilation in muscle and fat. Subchronic treatment (7 days) with TZ 50 mg/kg ip twice daily did not result in increased insulin-stimulated 14 C-2DG tissue levels in normal mice when compared to saline treated controls. However, insulin levels were lower in mice treated subchronically with TZ compared to saline controls suggesting an enhancement of insulin action. Viable yellow obese mice represent a model of maturity onset obesity presenting with insulin resistance. The insulin resistance of this obese strain appears to reside in the fat tissue as assessed by comparing 14 C-2DG tissue levels of obese mice with lean littermate controls. Subchronic TZ treatment had no effect on 14 C-2DG uptake in fat or muscle tissue of viable yellow obese mice and did not alter their plasma insulin levels. It appears that genetically obese viable mice may be resistant to subchronic treatment with TZ. (author)

  6. Dose-dependent effects of celecoxib on CB-1 agonist-induced antinociception in the mice

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Zarrindast

    2009-04-01

    Full Text Available "nObjective: Endocannabinoid produce analgesia that is comparable which of opioids. The mechanism of antinociceptive effects of (∆ - 9 tetrahydrocannabinol (THC is suggested to be through cyclooxygenase (COX pathway. In the present work, the effect of two extreme dose ranges of celecoxib (mg/kg and ng/kg, a cyclooxygenase-2 (COX-2 antagonist, on arachidonylcyclopropylamide (ACPA, a selective CB1 agonist induced antinociception in mice was examined. "nMethods: We have investigated the interaction between celecoxib, at the doses of mg/kg (50, 100, 200 and 400 i.p.  and ultra low dose (ULD (25 and 50 ng/kg, i.p., on the antinociceptive effect of intracerebroventricular (i.c.v. administration of ACPA (0.004, 0.0625 and 1 μg/mice, using formalin test in mice. "nResults: I.C.V. administration of ACPA induced antinociception. Intraperitoneal administration of celecoxib (mg/kg and its ULD (ng/kg attenuated and potentiated, ACPA antinociceptive effects, respectively. "nConclusion: It is concluded that the mg/kg doses of COX-2 antagonist showed opposite effects compare to the ultra-low dose of the drug.

  7. Dissociable effects of Sry and sex chromosome complement on activity, feeding and anxiety-related behaviours in mice.

    Science.gov (United States)

    Kopsida, Eleni; Lynn, Phoebe M; Humby, Trevor; Wilkinson, Lawrence S; Davies, William

    2013-01-01

    Whilst gonadal hormones can substantially influence sexual differentiation of the brain, recent findings have suggested that sex-linked genes may also directly influence neurodevelopment. Here we used the well-established murine 'four core genotype' (FCG) model on a gonadally-intact, outbred genetic background to characterise the contribution of Sry-dependent effects (i.e. those arising from the expression of the Y-linked Sry gene in the brain, or from hormonal sequelae of gonadal Sry expression) and direct effects of sex-linked genes other than Sry ('sex chromosome complement' effects) to sexually dimorphic mouse behavioural phenotypes. Over a 24 hour period, XX and XY gonadally female mice (lacking Sry) exhibited greater horizontal locomotor activity and reduced food consumption per unit bodyweight than XX and XY gonadally male mice (possessing Sry); in two behavioural tests (the elevated plus and zero mazes) XX and XY gonadally female mice showed evidence for increased anxiety-related behaviours relative to XX and XY gonadally male mice. Exploratory correlational analyses indicated that these Sry-dependent effects could not be simply explained by brain expression of the gene, nor by circulating testosterone levels. We also noted a sex chromosome complement effect on food (but not water) consumption whereby XY mice consumed more over a 24hr period than XX mice, and a sex chromosome complement effect in a third test of anxiety-related behaviour, the light-dark box. The present data suggest that: i) the male-specific factor Sry may influence activity and feeding behaviours in mice, and ii) dissociable feeding and anxiety-related murine phenotypes may be differentially modulated by Sry and by other sex-linked genes. Our results may have relevance for understanding the molecular underpinnings of sexually dimorphic behavioural phenotypes in healthy men and women, and in individuals with abnormal sex chromosome constitutions.

  8. Dissociable effects of Sry and sex chromosome complement on activity, feeding and anxiety-related behaviours in mice.

    Directory of Open Access Journals (Sweden)

    Eleni Kopsida

    Full Text Available Whilst gonadal hormones can substantially influence sexual differentiation of the brain, recent findings have suggested that sex-linked genes may also directly influence neurodevelopment. Here we used the well-established murine 'four core genotype' (FCG model on a gonadally-intact, outbred genetic background to characterise the contribution of Sry-dependent effects (i.e. those arising from the expression of the Y-linked Sry gene in the brain, or from hormonal sequelae of gonadal Sry expression and direct effects of sex-linked genes other than Sry ('sex chromosome complement' effects to sexually dimorphic mouse behavioural phenotypes. Over a 24 hour period, XX and XY gonadally female mice (lacking Sry exhibited greater horizontal locomotor activity and reduced food consumption per unit bodyweight than XX and XY gonadally male mice (possessing Sry; in two behavioural tests (the elevated plus and zero mazes XX and XY gonadally female mice showed evidence for increased anxiety-related behaviours relative to XX and XY gonadally male mice. Exploratory correlational analyses indicated that these Sry-dependent effects could not be simply explained by brain expression of the gene, nor by circulating testosterone levels. We also noted a sex chromosome complement effect on food (but not water consumption whereby XY mice consumed more over a 24hr period than XX mice, and a sex chromosome complement effect in a third test of anxiety-related behaviour, the light-dark box. The present data suggest that: i the male-specific factor Sry may influence activity and feeding behaviours in mice, and ii dissociable feeding and anxiety-related murine phenotypes may be differentially modulated by Sry and by other sex-linked genes. Our results may have relevance for understanding the molecular underpinnings of sexually dimorphic behavioural phenotypes in healthy men and women, and in individuals with abnormal sex chromosome constitutions.

  9. Dose-specific transcriptional responses in thyroid tissue in mice after 131I administration

    International Nuclear Information System (INIS)

    Rudqvist, Nils; Schüler, Emil; Parris, Toshima Z.; Langen, Britta; Helou, Khalil; Forssell-Aronsson, Eva

    2015-01-01

    Introduction: In the present investigation, microarray analysis was used to monitor transcriptional activity in thyroids in mice 24 h after 131 I exposure. The aims of this study were to 1) assess the transcriptional patterns associated with 131 I exposure in normal mouse thyroid tissue and 2) propose biomarkers for 131 I exposure of the thyroid. Methods: Adult BALB/c nude mice were i.v. injected with 13, 130 or 260 kBq of 131 I and killed 24 h after injection (absorbed dose to thyroid: 0.85, 8.5, or 17 Gy). Mock-treated mice were used as controls. Total RNA was extracted from thyroids and processed using the Illumina platform. Results: In total, 497, 546, and 90 transcripts were regulated (fold change ≥ 1.5) in the thyroid after 0.85, 8.5, and 17 Gy, respectively. These were involved in several biological functions, e.g. oxygen access, inflammation and immune response, and apoptosis/anti-apoptosis. Approximately 50% of the involved transcripts at each absorbed dose level were dose-specific, and 18 transcripts were commonly detected at all absorbed dose levels. The Agpat9, Plau, Prf1, and S100a8 gene expression displayed a monotone decrease in regulation with absorbed dose, and further studies need to be performed to evaluate if they may be useful as dose-related biomarkers for 131I exposure. Conclusion: Distinct and substantial differences in gene expression and affected biological functions were detected at the different absorbed dose levels. The transcriptional profiles were specific for the different absorbed dose levels. We propose that the Agpat9, Plau, Prf1, and S100a8 genes might be novel potential absorbed dose-related biomarkers to 131 I exposure of thyroid. Advances in knowledge: During the recent years, genomic techniques have been developed; however, they have not been fully utilized in nuclear medicine and radiation biology. We have used RNA microarrays to investigate genome-wide transcriptional regulations in thyroid tissue in mice after low

  10. Feeding period restriction alters the expression of peripheral circadian rhythm genes without changing body weight in mice.

    Directory of Open Access Journals (Sweden)

    Hagoon Jang

    Full Text Available Accumulating evidence suggests that the circadian clock is closely associated with metabolic regulation. However, whether an impaired circadian clock is a direct cause of metabolic dysregulation such as body weight gain is not clearly understood. In this study, we demonstrate that body weight gain in mice is not significantly changed by restricting feeding period to daytime or nighttime. The expression of peripheral circadian clock genes was altered by feeding period restriction, while the expression of light-regulated hypothalamic circadian clock genes was unaffected by either a normal chow diet (NCD or a high-fat diet (HFD. In the liver, the expression pattern of circadian clock genes, including Bmal1, Clock, and Per2, was changed by different feeding period restrictions. Moreover, the expression of lipogenic genes, gluconeogenic genes, and fatty acid oxidation-related genes in the liver was also altered by feeding period restriction. Given that feeding period restriction does not affect body weight gain with a NCD or HFD, it is likely that the amount of food consumed might be a crucial factor in determining body weight. Collectively, these data suggest that feeding period restriction modulates the expression of peripheral circadian clock genes, which is uncoupled from light-sensitive hypothalamic circadian clock genes.

  11. Suppression of carcinogenesis in mice by adaptive responses to low dose rate irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Sakai, Kazuo; Iwasaki, Toshiyasu; Hoshi, Yuko; Nomura, Takaharu; Ina, Yasuhiro; Tanooka, Hiroshi [Central Research Institute of Electric Power Industry, Low Dose Radiation Research Center, Komae, Tokyo (Japan)

    2003-07-01

    Effects of prolonged low-dose-rate irradiation on the process of carcinogenesis were examined in mice treated with chemical carcinogen or irradiated with high doses of X-rays. Female ICR mice, 5 week-old, 35 in each group, were exposed to gamma-rays from a {sup 137}Cs source in the long-term low dose rate irradiation facility at CRIEPI. The dose rate was 2.6 mGy/hr (A), 0.96 mGy/hr (B), or 0.30 mGy/hr (C). Thirty-five days later, the mice were injected into the groin with 0.5 mg of methylcholanthrene (MC) dissolved in olive oil and irradiation was continued. Cumulative tumor incidences after 216 days following MC injection were 89% in group A, 76% in group B, and 94% in group C. That in non-irradiated control group was 94%. The difference in the tumor incidence between the control and position B was statistically significant, indicating the suppressive effect of the low dose rate irradiation on the process of MC-induced carcinogenesis with an optimum dose rate around 1 mGy/hr. In B6C3F1 mice, although the suppression of tumor incidence was not observed, there was a significant delay in tumor appearance in the irradiated mice between 100-150 days after MC injection. A group of 20 female C57BL/6N mice, 5 weeks old, were exposed to gamma-rays at 0.95 mGy/hr for 5 weeks. Then, they were exposed weekly to 1.8 Gy whole body X-irradiation (300 kVp) for consecutive 4 weeks to induce thymic lymphoma. Another group received only the fractionated irradiation. The first mouse died from thymic lymphoma appeared 89 days after the last irradiation in the group received only the fractionated irradiation, while 110 days in the group combined with the low dose rate irradiation. (author)

  12. Low-dose cadmium exposure exacerbates polyhexamethylene guanidine-induced lung fibrosis in mice.

    Science.gov (United States)

    Kim, Min-Seok; Kim, Sung-Hwan; Jeon, Doin; Kim, Hyeon-Young; Han, Jin-Young; Kim, Bumseok; Lee, Kyuhong

    2018-01-01

    Cadmium (Cd) is a toxic metal present in tobacco smoke, air, food, and water. Inhalation is an important route of Cd exposure, and lungs are one of the main target organs for metal-induced toxicity. Cd inhalation is associated with an increased risk of pulmonary diseases. The present study aimed to assess the effects of repeated exposure to low-dose Cd in a mouse model of polyhexamethylene guanidine (PHMG)-induced lung fibrosis. Mice were grouped into the following groups: vehicle control (VC), PHMG, cadmium chloride (CdCl 2 ), and PHMG + CdCl 2 . Animals in the PHMG group exhibited increased numbers of total cells and inflammatory cells in the bronchoalveolar lavage fluid (BALF) accompanied by inflammation and fibrosis in lung tissues. These parameters were exacerbated in mice in the PHMG + CdCl 2 group. In contrast, mice in the CdCl 2 group alone displayed only minimal inflammation in pulmonary tissue. Expression of inflammatory cytokines and fibrogenic mediators was significantly elevated in lungs of mice in the PHMG group compared with that VC. Further, expression of these cytokines and mediators was enhanced in pulmonary tissue in mice administered PHMG + CdCl 2 . Data demonstrate that repeated exposure to low-dose Cd may enhance the development of PHMG-induced pulmonary fibrosis.

  13. Anti-tumor effect of total body irradiation of low doses on WHT/Ht mice

    International Nuclear Information System (INIS)

    Miyamoto, Miyako; Sakamoto, Kiyohiko

    1987-01-01

    The effect of low dose (0.05 - 1.0 Gy) of total body irradiation (TBI) on non-tumor bearing and tumor bearing mice were investigated. Mice received TBI of 0.1 Gy during 6 - 12 hours before tumor cell inoculation demonstrated to need larger number of tumor cells (approximately 2.5 times) for 50 per cent tumor incidence, compared to recipient mice not to receive TBI. On the other hand, in tumor bearing mice given 0.1 Gy of TBI only tumor cell killing effect was not detected, however enhancement of tumor cell killing effect and prolonged growth delay were observed when tumor bearing mice were treated with 0.1 Gy of TBI in combined with local irradiation on tumors, especially cell killing effect was remarkable in dose range over 6 Gy of local exposure. The mechanism of the effect of 0.1 Gy TBI is considered to be host mediated reactions from the other our experimental results. (author)

  14. Effect of radiation dose on the recovery of aerobic and anaerobic bacteria from mice

    International Nuclear Information System (INIS)

    Brook, Itzhak; Walker, R.I.; MacVittie, T.J.

    1986-01-01

    The presence of aerobic and anaerobic bacteria in the blood, spleen, and liver was investigated in mice that were exposed to 7, 8, 9 or 10 Gy 60 Co radiation. Microorganisms were detected more often in animals exposed to higher doses of radiation. The number of mice that were culture positive and the number of isolates in one site increased with increasing dose. Bacteria were recovered in mice killed at various times after radiation, in 3 of 100 mice exposed to 7 Gy, in 13 of 100 irradiated with 8 Gy, in 23 of 90 exposed to 9 Gy, and in 34 of 87 irradiated with 10 Gy. The predominant organisms recovered were Escherichia coli, anerobic Gram-positive cocci, Proteus mirabilis, Staphylococcus aureus, and Bacteroides spp. Escherichia coli and anaerobes were more often isolated in animals exposed to 10 Gy, while S. aureus was more often recovered in those irradiated with 9 Gy. These data demonstrate a relationship between the dose of radiation and the rate of infection due to enteric aerobic and anaerobic bacteria

  15. Effect of radiation dose on the recovery of aerobic and anaerobic bacteria from mice

    Energy Technology Data Exchange (ETDEWEB)

    Brook, I.; Walker, R.I.; MacVittie, T.J.

    1986-01-01

    The presence of aerobic and anaerobic bacteria in the blood, spleen, and liver was investigated in mice that were exposed to 7, 8, 9, or 10 Gy /sup 60/Co radiation. Microorganisms were detected more often in animals exposed to higher doses of radiation. The number of mice that were culture positive and the number of isolates in one site increased with increasing dose. Bacteria were recovered in mice killed at various times after radiation, in 3 of 100 mice exposed to 7 Gy, in 13 of 100 irradiated with 8 Gy, in 23 of 90 exposed to 9 Gy, and in 34 of 87 irradiated with 10 Gy. The predominant organisms recovered were Escherichia coli, anerobic Gram-positive cocci, Proteus mirabilis, Staphylococcus aureus, and Bacteroides spp. Escherichia coli and anaerobes were more often isolated in animals exposed to 10 Gy, while S. aureus was more often recovered in those irradiated with 9 Gy. These data demonstrate a relationship between the dose of radiation and the rate of infection due to entire aerobic and anaerobic bacteria. Reprints.

  16. Single oral dose toxicity test of platycodin d, a saponin from platycodin radix in mice.

    Science.gov (United States)

    Lee, Won-Ho; Gam, Cheol-Ou; Ku, Sae-Kwang; Choi, Seong-Hun

    2011-12-01

    The object of this study was to evaluate the single oral dose toxicity of platycodin D, a saponin from the root of Platycodon grandiflorum in male and female mice. Platycodin D was administered to female and male mice as an oral dose of 2000, 1000, 500, 250 and 125 mg/kg (body wt.). Animals were monitored for the mortality and changes in body weight, clinical signs and gross observation during 14 days after treatment, upon necropsy, organ weight and histopathology of 14 principle organs were examined. As the results, no platycodin D treatment related mortalities, clinical signs, changes on the body and organ weights, gross and histopathological observations against 14 principle organs were detected up to 2000 mg/kg in both female and male mice. Therefore, LD50 (50% lethal dose) and approximate LD of playtcodin D after single oral treatment in female and male mice were considered over 2000 mg/kg - the limited dosages recommended by KFDA Guidelines [2009-116, 2009], respectively.

  17. Unscheduled DNA synthesis in spleen cells of mice exposed to low doses of total body irradiation

    International Nuclear Information System (INIS)

    Tuschl, H.; Kovac, R.; Hruby, E.

    1983-07-01

    Unscheduled DNA synthesis was induced by UV irradiation of spleen cells obtained from C 57 Bl mice after repeated total body irradiation of 0.05 Gy 60 Co (0.00125 Gy/mice) and determined autoradiographically. An enhancement in the ability for repair of UV induced DNA lesions was observed in cells of gamma irradiated animals. While the amount of 3 H-thymidine incorporated per cell was increased, the percentage of labeled cells remained unchanged. The present results are compared with previous data on low dose radiation exposure in men. (Author) [de

  18. Growth performance and feed utilization of keureling (Tor tambra fingerlings fed a formulated diet with different doses of vitamin E (alpha-tocopherol

    Directory of Open Access Journals (Sweden)

    Muchlisin Zainal A.

    2016-03-01

    Full Text Available The objective of the present study was to determine the optimum dosage of vitamin E (alpha-tocopherol in the diet of keureling, Tor tambra (Val. fingerlings for optimal growth performance and feed utilization. Five doses of vitamin E were tested: 0 mg kg−1 feed (control; 150 mg kg−1 feed; 300 mg kg−1 feed; 450 mg kg−1 feed; 600 mg kg−1. The feed ratio was 5% body weight, which was delivered twice daily at 08:00 and 17:00 for 60 days. The results showed that higher growth performance, feeding conversion ratios, feed efficiency, protein retention, and protein digestibility were obtained at 600 mg kg−1 feed, but the value was not significantly different from the other doses. The optimal dose in terms of the hepatosomatic index and survival rate was 300 mg kg−1. Hence, it was concluded that the optimum, most economical dose of vitamin E supplement for keureling (T. tambra was 150 mg kg−1 feed, because this value was not significantly different from the doses of 300 and 600 mg kg−1 feed.

  19. Bone cancer from radium: canine dose response explains data for mice and humans

    International Nuclear Information System (INIS)

    Raabe, O.G.; Book, S.A.; Parks, N.J.

    1980-01-01

    Analysis of lifetime studies of 243 beagles with skeletal burdens of radium-226 shows that the distribution of bone cancers clusters about a linear function of the logarithms of radiation dose rate to the skeleton and time from exposure until death. Similar relations displaced by species-dependent response ratios also provide satisfactory descriptions of the reported data on deaths from primary bone cancers in people and mice exposed to radium-226. The median cumulative doses (or times) leading to death from bone tumors are 2.9 times larger for dogs than for mice and 3.6 times larger for people than for dogs. These response ratios are well correlated with the normal life expectancies. The cumulative radiation dose required to give significant risk of bone cancer is found to be much less at lower dose rates than at higher rates, but the time required for the tumors to be manifested is longer. At low dose rates, this time exceeds the normal life-span and appears as a practical threshold, which for bone cancer is estimated to occur at an average cumulative radiation dose to the skeleton of about 50 to 110 rads for the three species

  20. Limiting values for the RBE of fission neutrons at low doses for life shortening in mice

    International Nuclear Information System (INIS)

    Storer, J.B.; Mitchell, T.J.

    1984-01-01

    The authors have analyzed recently published data on the effects of low doses of fission neutrons on the mean survival times of mice. The analysis for single-dose exposures was confined to doses of 20 rad or less, while for fractionated exposures only total doses of 80 rad or less were considered. They fitted the data to the frequently used power function model: life shortening = βD/sup γ/, where D is the radiation dose. They show that, at low doses per fraction, either the effects are not additive or the dose-effect curve for single exposures cannot show a greater negative curvature than about the 0.9 power of dose. Analysis of the data for γ rays showed that an exponent of 1.0 gave an acceptable fit. They conclude that at neutron doses of 20 rad or less the RBE for life shortening is constant and ranges from 13 to 22 depending on mouse strain and sex

  1. Effect of dose on lead retention and distribution in suckling and adult female mice

    International Nuclear Information System (INIS)

    Keller, C.A.; Doherty, R.A.

    1980-01-01

    Single doses of lead (trace to 445 mg/kg) were administered per os to suckling and adult mice. Both groups exhibited dose-independent lead retention when doses of 4 to 445 mg/kg were administered. However, developmental differences in the fraction of initial dose (FID) retained were evident for all doses administered. A much larger FID was retained in both age groups following administration of carrier-free 203 Pb. The results are consistent with a mechanism of gastrointestinal lead absorption comprising two or more processes. Developmental differences were also observed in organ lead concentration relative to whole body concentration for kidneys, skull and brain 6 days following lead administration. Lead retentions (relative to whole body retention) in brain and in bone were linearly related to dose of lead administered in both suckling and adult age groups. Though uptake of lead into brain and into femur was observed to be directly related to dose over a wide range, relative blood lead concentrations were not linearly correlated with dose administered. The relationships between lead concentrations of blood and organ(s) were also shown to be nonlinear relative to dose. However, blood lead concentration was found to be a reliable indicator of kidney and liver lead concentrations following an acute lead exposure

  2. The Protective Effects of Oral Low-dose Quercetin on Diabetic Nephropathy in Hypercholesterolemic Mice

    Directory of Open Access Journals (Sweden)

    Isabele Beserra Santos Gomes

    2015-09-01

    Full Text Available Aims: Diabetic nephropathy (DN is one of the major causes of end-stage renal disease, and the incidence of DN is increasing worldwide. Considering our previous report indicating that chronic treatment with oral low-dose quercetin (10 mg/Kg demonstrated renoprotective, anti-oxidative and anti-apoptotic effects in the C57BL/6J model of diabetic nephropathy, we investigated whether this flavonoid could also have beneficial effects in concurrent DN and spontaneous atherosclerosis using the apolipoprotein E-deficient mouse (apoE-/-. Methods: DN was induced by streptozotocin (100 mg/kg/day, for 3 days in adult apoE-/-mice. Six weeks later, the mice were divided into the following groups: diabetic apoE-/- mice treated with quercetin (DQ, 10 mg/kg/day, 4 weeks, diabetic ApoE-/- mice treated with vehicle (DV and non-treated non-diabetic (ND mice.Results: Quercetin treatment caused a reduction in polyuria (~30%, glycemia (~25%, abolished the hypertriglyceridemia and had significant effects on renal function, including decreased proteinuria (~15% and creatininemia (~30%, which were accompanied by beneficial effects on the renal structural changes, including normalization of the index of glomerulosclerosis and kidney weight.Conclusions: Our data revealed that quercetin treatment significantly reduced DN in hypercholesterolemic mice by inducing biochemical and morphological modifications. Thus, this translational study highlights the importance of quercetin as a potential nutraceutical for the management of DN, including in diabetes associated with dyslipidemia.

  3. Radionuclides in Animal Feed (Poultry) 'Assessment of Radiation Dose'

    Energy Technology Data Exchange (ETDEWEB)

    Algadi, S.; Salih, I. [Radiation Safety Institute (Sudan)

    2014-07-01

    In this work a comprehensive study has been carried out for the determination of presents evaluation of effective dose due to consumption of chicken fed by fodders collected from four major Sudanese companies (Hader, Koudjs, Wifi and Preconex SPN.V). The concentrations of radionuclides in the thirty two (32) feed samples have been determined by gamma spectrometry using NaI(Tl) detector. Radionuclides observed were: Pb-212 (daughter of Th-238), Pb-214, Bi-214 (daughters of U-238), Cs-137 and K-40 concentration. In additives the activity concentration of these radionuclides has found in the following ranges: 0.81 - 22.06 Bq/kg, 0.59 - 32.07 Bq/kg, 0.64 - 15.77 Bq/kg, 0.01 - 2.02 Bq/kg and 33.58 - 204.61 Bq/kg respectively. In feed concentrates activity concentration ranges has: 0.73 - 13.79 Bq/kg, 0.33 - 20.04 Bq/kg, 0.01 - 1.67 Bq/kg, 0.01 - 0.28 Bq/kg, 26.86 - 99.21 Bq/kg respectively. In fodders the activity concentration ranges has: 1.25 - 1.52 Bq/kg, 0.12 - 1.24 Bq/kg, 0.51 - 1.25 Bq/kg, 0.01 - 0.61 Bq/kg, 11.94 - 127.88 Bq/kg respectively. The 'animal product' activity concentration ranges has: 0.31 - 1.65 Bq/kg, 0.22 - 1.11 Bq/kg, 0.26 - 1.07 Bq/kg, 0.03 - 0.51 Bq/kg, 14.07 - 79.93 Bq/kg respectively. High concentrations (233.3 Bq/Kg) has typically found in toxo(additive); the lowest concentration (27.9 Bq/Kg ) has found in concentrate for layers and animal product. The total average effective dose due to the different feed-stuff has estimated and found to be 5.89x10{sup -6}±3.11x10{sup -6}mSv/y and 13.9 x 10{sup -7} ± 7.24 x 10{sup -7}mSv/y for age categories 7-12 y and >17 y respectively. If compared with the limits - Radioactivity Levels Permitted in foodstuffs Part 1 the Saudi Standards, Metrology and quality (300 Bq/Kg) and ICRP,FAO organization (5 mSv/y) - these values are very low. Document available in abstract form only. (authors)

  4. Association between Caesarean Delivery and Isolated Doses of Formula Feeding in Cow Milk Allergy.

    Science.gov (United States)

    Gil, Francisco; Amezqueta, Ana; Martinez, Diana; Aznal, Elena; Etayo, Veronica; Durá, Teodoro; Sánchez-Valverde, Félix

    2017-01-01

    Cow milk allergy (CMA) is the most common food allergy in breastfed infants. The aim of this study is to verify whether certain perinatal factors may influence the development of CMA immunoglobulin E (IgE)+. A retrospective, observational study of case and control groups was carried out. Information was collected of patients with CMA IgE+ from our department during the years 1990-2013. Patients of the same age and sex were recruited for the control group. Information on the following variables was collected: sex, age, pregnancy tolerance, duration of pregnancy, type of delivery, isolated doses of formula feeding in hospital (FFH), duration of breastfeeding, and family history of allergy (defined as ≥1 first-degree family member with allergic disease). Statistical analysis was performed using multivariate logistic regression techniques. A total of 211 cases were included in this study. Multivariate analysis showed an influence of duration of breastfeeding, FFH to be a risk factor (OR 4.94; 95% CI 2.68-9.08), especially in caesarean delivery (OR 11.82; 95% CI 2.64-47.50), and prematurity (OR 0.29; 95% CI 0.09-0.92) to be a protective factor. Perinatal factors play a key role in the development of CMA IgE+, with an influence of breastfeeding duration, FFH and caesarean delivery as risk factors and prematurity as a protective factor. While family history had no important role, environmental factors were more decisive. © 2017 S. Karger AG, Basel.

  5. NTP technical report on the toxicity studies of Cupric Sulfate (CAS No. 7758-99-8) Administered in Drinking Water and Feed to F344/N Rats and B6C3F1 Mice.

    Science.gov (United States)

    Hebert, Charles

    1993-07-01

    Cupric sulfate is an inorganic salt which is widely used in industry, agriculture, and veterinary medicine. Its applications include use as an algicide in potable waters and as a feed additive and therapeutic agent in swine, sheep, and cattle. Because copper salts are found in human water supplies, toxicity studies of cupric sulfate pentahydrate were conducted in male and female F344/N rats and B6C3F1 mice by the drinking water (2-week studies only) and dosed feed routes (2-week and 13-week studies). Animals were evaluated for hematology, clinical chemistry, urinalysis, reproductive toxicity, tissue metal accumulation, and histopathology. In the 2-week drinking water studies, groups of five rats and five mice per sex received cupric sulfate at concentrations of 300 to 30,000 ppm for 15 days. One female rat, one male mouse, and three female mice in the 3000 ppm groups and all rats and mice in the 10,000 and 30,000 ppm groups died before the end of the studies. The remaining mice and rats in the 3000 ppm groups gained little or lost weight. Water consumption in the three highest dose groups of both species was reduced by more than 65%. Clinical signs observed in these groups were typical of those seen in moribund animals and were attributed to dehydration. The only gross or microscopic change specifically related to cupric sulfate toxicity was an increase in the size and number of cytoplasmic protein droplets in the epithelium of the renal proximal convoluted tubule in male rats from the 300 and 1000-ppm groups. In the 2-week feed studies, groups of five rats and five mice per sex were fed diets containing 1000 to 16,000 ppm cupric sulfate. No chemical-related deaths occurred in any dose group. Compared to the controls, rats and mice in the two highest dose groups had reduced body weight gains which were attributed to decreased feed consumption. Hyperplasia with hyperkeratosis of the squamous epithelium on the limiting ridge of the forestomach was seen in rats and

  6. Oral feeding with polyunsaturated fatty acids fosters hematopoiesis and thrombopoiesis in healthy and bone marrow-transplanted mice.

    Science.gov (United States)

    Limbkar, Kedar; Dhenge, Ankita; Jadhav, Dipesh D; Thulasiram, Hirekodathakallu V; Kale, Vaijayanti; Limaye, Lalita

    2017-09-01

    Hematopoietic stem cells play the vital role of maintaining appropriate levels of cells in blood. Therefore, regulation of their fate is essential for their effective therapeutic use. Here we report the role of polyunsaturated fatty acids (PUFAs) in regulating hematopoiesis which has not been explored well so far. Mice were fed daily for 10 days with n-6/n-3 PUFAs, viz. linoleic acid (LA), arachidonic acid (AA), alpha-linolenic acid and docosahexanoic acid (DHA) in four separate test groups with phosphate-buffered saline fed mice as control set. The bone marrow cells of PUFA-fed mice showed a significantly higher hematopoiesis as assessed using side population, Lin-Sca-1 + ckit+, colony-forming unit (CFU), long-term culture, CFU-spleen assay and engraftment potential as compared to the control set. Thrombopoiesis was also stimulated in PUFA-fed mice. A combination of DHA and AA was found to be more effective than when either was fed individually. Higher incorporation of PUFAs as well as products of their metabolism was observed in the bone marrow cells of PUFA-fed mice. A stimulation of the Wnt, CXCR4 and Notch1 pathways was observed in PUFA-fed mice. The clinical relevance of this study was evident when bone marrow-transplanted recipient mice, which were fed with PUFAs, showed higher engraftment of donor cells, suggesting that the bone marrow microenvironment may also be stimulated by feeding with PUFAs. These data indicate that oral administration of PUFAs in mice stimulates hematopoiesis and thrombopoiesis and could serve as a valuable supplemental therapy in situations of hematopoietic failure. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Influence of conditioned psychological stress on immunological recovery in mice exposed to low-dose x irradiation

    International Nuclear Information System (INIS)

    Sato, K.; Flood, J.F.; Makinodan, T.

    1984-01-01

    A study was initiated to determine the effects of psychological stress on the immune response in BALB/c mice recovering from exposure to a low dose of ionizing radiation. Mice were first subjected to conditioning training for 12 days, then exposed to 200 R, subjected to psychological stress for 14 days, and assessed for peak anti-sheep RBC response. The seven treatment groups included two unirradiated groups and five irradiated groups. Mice exposed to 200 R and then subjected to conditioned psychological stress responded less vigorously to antigenic stimulation than those of the other irradiated groups. The psychological stress imposed upon these mice did not influence the antibody-forming capacity of unirradiated mice. These results indicate that a psychological stress which did not affect the immunological activity of unirradiated mice can curtail the immunological recovery of mice exposed to low doses of ionizing radiation

  8. Dose imprecision and resistance: free-choice medicated feeds in industrial food animal production in the United States.

    Science.gov (United States)

    Love, David C; Davis, Meghan F; Bassett, Anna; Gunther, Andrew; Nachman, Keeve E

    2011-03-01

    Industrial food animal production employs many of the same antibiotics or classes of antibiotics that are used in human medicine. These drugs can be administered to food animals in the form of free-choice medicated feeds (FCMF), where animals choose how much feed to consume. Routine administration of these drugs to livestock selects for microorganisms that are resistant to medications critical to the treatment of clinical infections in humans. In this commentary, we discuss the history of medicated feeds, the nature of FCMF use with regard to dose delivery, and U.S. policies that address antimicrobial drug use in food animals. FCMF makes delivering a predictable, accurate, and intended dose difficult. Overdosing can lead to animal toxicity; underdosing or inconsistent dosing can result in a failure to resolve animal diseases and in the development of antimicrobial-resistant microorganisms. The delivery of antibiotics to food animals for reasons other than the treatment of clinically diagnosed disease, especially via free-choice feeding methods, should be reconsidered.

  9. Tritium metabolism in newborn mice and estimation of the accumulated dose

    Energy Technology Data Exchange (ETDEWEB)

    Saito, M; Ishida, M R

    1986-01-01

    Suckling mice received tritium from their mothers who were supplied with tritiated water as drinking water. After weaning, the offspring were sacrificed and the tritium concentration was determined for various organs and various molecular components including acid soluble component, lipid, RNA, DNA and protein. The accumulated dose for the period between 3 and 41 weeks after birth was calculated for various organs and the contributions of the acid insoluble components to the total dose estimated. The per cent contribution of the acid insoluble components to the total dose was organ specific and was between about 17% and 42%. The result indicates that the inhomogeneous distribution of tritium in subcellular structures needs to be taken into account. The contribution of organically bound tritium to dose is then comparable to that of tritium in the free water component.

  10. Recovery from diabetes in neonatal mice after a low-dose streptozotocin treatment

    International Nuclear Information System (INIS)

    Kataoka, Masateru; Kawamuro, Yuki; Shiraki, Nobuaki; Miki, Rika; Sakano, Daisuke; Yoshida, Tetsu; Yasukawa, Takanori; Kume, Kazuhiko; Kume, Shoen

    2013-01-01

    Highlights: ► We monitored long-term beta cell regeneration in neonatal mice treated with low dose STZ. ► Low-dose STZ neonatal female mice recovered blood glucose in 150 days. ► Glucose intolerance of the STZ treated mice significantly improved in 150 days. -- Abstract: Administration of streptozotocin (STZ) induces destruction of β-cells and is widely used as an experimental animal model of type I diabetes. In neonatal rat, after low-doses of STZ-mediated destruction of β-cells, β-cells regeneration occurs and reversal of hyperglycemia was observed. However, in neonatal mice, β-cell regeneration seems to occur much slowly compared to that observed in the rat. Here, we described the time dependent quantitative changes in β-cell mass during a spontaneous slow recovery of diabetes induced in a low-dose STZ mice model. We then investigated the underlying mechanisms and analyzed the cell source for the recovery of β-cells. We showed here that postnatal day 7 (P7) female mice treated with 50 mg/kg STZ underwent the destruction of a large proportion of β-cells and developed hyperglycemia. The blood glucose increased gradually and reached a peak level at 500 mg/dl on day 35–50. This was followed by a spontaneous regeneration of β-cells. A reversal of non-fasting blood glucose to the control value was observed within 150 days. However, the mice still showed impaired glucose tolerance on day 150 and day 220, although a significant improvement was observed on day 150. Quantification of the β-cell mass revealed that the β-cell mass increased significantly between day 100 and day 150. On day 150 and day 220, the β-cell mass was approximately 23% and 48.5% of the control, respectively. Of the insulin-positive cells, 10% turned out to be PCNA-positive proliferating cells. Our results demonstrated that, β-cell duplication is one of the cell sources for β-cell regeneration

  11. Recovery from diabetes in neonatal mice after a low-dose streptozotocin treatment

    Energy Technology Data Exchange (ETDEWEB)

    Kataoka, Masateru; Kawamuro, Yuki; Shiraki, Nobuaki [Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto 860-0811 (Japan); Miki, Rika; Sakano, Daisuke [Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto 860-0811 (Japan); The Global COE Cell Fate Regulation Research and Education Unit, Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto 860-0811 (Japan); Yoshida, Tetsu; Yasukawa, Takanori; Kume, Kazuhiko [Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto 860-0811 (Japan); Kume, Shoen, E-mail: skume@kumamoto-u.ac.jp [Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto 860-0811 (Japan); The Global COE Cell Fate Regulation Research and Education Unit, Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto 860-0811 (Japan)

    2013-01-18

    Highlights: ► We monitored long-term beta cell regeneration in neonatal mice treated with low dose STZ. ► Low-dose STZ neonatal female mice recovered blood glucose in 150 days. ► Glucose intolerance of the STZ treated mice significantly improved in 150 days. -- Abstract: Administration of streptozotocin (STZ) induces destruction of β-cells and is widely used as an experimental animal model of type I diabetes. In neonatal rat, after low-doses of STZ-mediated destruction of β-cells, β-cells regeneration occurs and reversal of hyperglycemia was observed. However, in neonatal mice, β-cell regeneration seems to occur much slowly compared to that observed in the rat. Here, we described the time dependent quantitative changes in β-cell mass during a spontaneous slow recovery of diabetes induced in a low-dose STZ mice model. We then investigated the underlying mechanisms and analyzed the cell source for the recovery of β-cells. We showed here that postnatal day 7 (P7) female mice treated with 50 mg/kg STZ underwent the destruction of a large proportion of β-cells and developed hyperglycemia. The blood glucose increased gradually and reached a peak level at 500 mg/dl on day 35–50. This was followed by a spontaneous regeneration of β-cells. A reversal of non-fasting blood glucose to the control value was observed within 150 days. However, the mice still showed impaired glucose tolerance on day 150 and day 220, although a significant improvement was observed on day 150. Quantification of the β-cell mass revealed that the β-cell mass increased significantly between day 100 and day 150. On day 150 and day 220, the β-cell mass was approximately 23% and 48.5% of the control, respectively. Of the insulin-positive cells, 10% turned out to be PCNA-positive proliferating cells. Our results demonstrated that, β-cell duplication is one of the cell sources for β-cell regeneration.

  12. Chemical protection against long term effects in mice exposed to supralethal doses of X rays

    International Nuclear Information System (INIS)

    Maisin, J.R.

    1982-01-01

    Our results demonstrate that mixtures of radioprotectors increase the degree of protection against the short and the long term effects compared with that obtained with each substance given separately. The most potent mixtures of radioprotectors (AET, MEA, Cyst, GSH, 5-HT) yield for the long term survival a dose reduction factor of 2.1. Pulmonary lesions are most often the cause of death in protected mice irradiated with 13.5 Gy or more. At the time of death signs of sclerosis and atrophy in several tissues are associated with these lung lesions in most mice and increase with dose and time after exposure. The tissues most affected are the kidney, the alimentary tract, the liver and the lymphoid tissues [fr

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

    Science.gov (United States)

    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. © 2013 Wiley Periodicals, Inc.

  14. Stimulatory effect of low dose radiation on the immune function in tumor-bearing mice

    International Nuclear Information System (INIS)

    Zhang Ying; Li Xiujuan; Li Xiuyi; Liu Shuzheng

    1999-01-01

    Objective: The author aims at investigating the effect of whole body irradiation (WBI) with low dose radiation on immune function in tumor-bearing mice. Methods: C57BL/6J mine implanted with Lewis lung carcinoma cells in the right thighs were used as an experimental animal model. WBI with 75 mGy X-rays was given at the 10 th day after implantation and immunological parameters were detected 18 hours after irradiation. The immunological parameters included the spontaneous incorporation of 3 H-TdR into thymocytes, the number of splenocytes, the reaction of splenocytes to ConA and LPS, the splenic production of IL-2, the cytotoxic activities of natural killer (NK) and lymphokine activated killer cells (LAK) as well as specific cytotoxic T lymphocytes (CTL). Results: The immunological parameters of irradiated tumor-bearing mice were significantly increased compared with those of sham-irradiated tumor-bearing mice (P<0.05∼0.01). Conclusion: Low dose radiation could significantly increase the immune function of tumor-bearing mice, and this stimulatory effect may be of some potential significance in tumor therapy

  15. Dose-dependent adverse effects of salinomycin on male reproductive organs and fertility in mice.

    Directory of Open Access Journals (Sweden)

    Olajumoke Omolara Ojo

    Full Text Available Salinomycin is used as an antibiotic in animal husbandry. Its implication in cancer therapy has recently been proposed. Present study evaluated the toxic effects of Salinomycin on male reproductive system of mice. Doses of 1, 3 or 5 mg/kg of Salinomycin were administered daily for 28 days. Half of the mice were sacrificed after 24 h of the last treatment and other half were sacrificed 28 days after withdrawal of treatment. Effects of SAL on body and reproductive organ weights were studied. Histoarchitecture of testis and epididymis was evaluated along with ultrastructural changes in Leydig cells. Serum and testicular testosterone and luteinizing hormones were estimated. Superoxide dismutase, reduced glutathione, lipid peroxidation, catalase and lactate dehydrogenase activities were measured. Spermatozoa count, morphology, motility and fertility were evaluated. Expression patterns of steroidogenic acute regulatory protein (StAR and cytochrome P450 side chain cleavage proteins (CYP11A1 were assessed by Western blotting. Salinomycin treatment was lethal to few mice and retarded body growth in others with decreased weight of testes and seminal vesicles in a dose dependent manner. Seminiferous tubules in testes were disrupted and the epithelium of epididymis showed frequent occurrence of vacuolization and necrosis. Leydig cells showed hypertrophied cytoplasm with shrunken nuclei, condensed mitochondria, proliferated endoplasmic reticulum and increased number of lipid droplets. Salinomycin decreased motility and spermatozoa count with increased number of abnormal spermatozoa leading to infertility. The testosterone and luteinizing hormone levels were decreased in testis but increased in serum at higher doses. Depletion of superoxide dismutase and reduced glutathione with increased lipid peroxidation in both testis and epididymis indicated generation of oxidative stress. Suppressed expression of StAR and CYP11A1 proteins indicates inhibition of

  16. High-fat feeding rather than obesity drives taxonomical and functional changes in the gut microbiota in mice

    DEFF Research Database (Denmark)

    Xiao, Liang; Sonne, Si Brask; Feng, Qiang

    2017-01-01

    Background: It is well known that the microbiota of high-fat (HF) diet-induced obese mice differs from that of lean mice, but to what extent, this difference reflects the obese state or the diet is unclear. To dissociate changes in the gut microbiota associated with high HF feeding from those...... associated with obesity, we took advantage of the different susceptibility of C57BL/6JBomTac (BL6) and 129S6/SvEvTac (Sv129) mice to diet-induced obesity and of their different responses to inhibition of cyclooxygenase (COX) activity, where inhibition of COX activity in BL6 mice prevents HF diet......-induced obesity, but in Sv129 mice accentuates obesity.Results: Using HiSeq-based whole genome sequencing, we identified taxonomic and functional differences in the gut microbiota of the two mouse strains fed regular low-fat or HF diets with or without supplementation with the COX-inhibitor, indomethacin. HF...

  17. Effect of low dose radiation on thymocyte cytosol and nuclei protein synthesis in mice

    International Nuclear Information System (INIS)

    Meng Qingyong; Chen Shali; Liu Shuzheng

    2003-01-01

    Objective: To the effect of low dose radiation on thymocyte cytosol and nuclei protein synthesis in mice. Methods: The expression of proteins was analyzed by gel filtration with Sephadex G-100 and HPLC based on separation of proteins on thymocyte cytosol and nuclei after whole-body irradiation with 75 mGy X-rays and sham-irradiation, and their biological activity was examined by mouse splenocyte proliferation and chromosome aberration of human peripheral blood lymphocytes. Results: HPLC analysis showed that there was a marked increase in expression of 61.4 kD protein in the extract of thymocyte cytosol and 30.4 kD protein in the extract of thymocyte nuclei in comparison with the corresponding fractions from the sham-irradiated control mice. These protein fractions from the thymocyte cytosol and nuclei of the irradiated mice showed both stimulating effect on normal T cell proliferation and protective effect on chromosome damage induced by high dose radiation. Conclusion: These findings might have implications in study of mechanism of immunoenhancement and cytogenetic adaptive response induced by low dose radiation

  18. Inflammatory Signals shift from adipose to liver during high fat feeding and influence the development of steatohepatitis in mice

    Directory of Open Access Journals (Sweden)

    Greenfeder Scott

    2011-03-01

    Full Text Available Abstract Background Obesity and inflammation are highly integrated processes in the pathogenesis of insulin resistance, diabetes, dyslipidemia, and non-alcoholic fatty liver disease. Molecular mechanisms underlying inflammatory events during high fat diet-induced obesity are poorly defined in mouse models of obesity. This work investigated gene activation signals integral to the temporal development of obesity. Methods Gene expression analysis in multiple organs from obese mice was done with Taqman Low Density Array (TLDA using a panel of 92 genes representing cell markers, cytokines, chemokines, metabolic, and activation genes. Mice were monitored for systemic changes characteristic of the disease, including hyperinsulinemia, body weight, and liver enzymes. Liver steatosis and fibrosis as well as cellular infiltrates in liver and adipose tissues were analyzed by histology and immunohistochemistry. Results Obese C57BL/6 mice were fed with high fat and cholesterol diet (HFC for 6, 16 and 26 weeks. Here we report that the mRNA levels of macrophage and inflammation associated genes were strongly upregulated at different time points in adipose tissues (6-16 weeks and liver (16-26 weeks, after the start of HFC feeding. CD11b+ and CD11c+ macrophages highly infiltrated HFC liver at 16 and 26 weeks. We found clear evidence that signals for IL-1β, IL1RN, TNF-α and TGFβ-1 are present in both adipose and liver tissues and that these are linked to the development of inflammation and insulin resistance in the HFC-fed mice. Conclusions Macrophage infiltration accompanied by severe inflammation and metabolic changes occurred in both adipose and liver tissues with a temporal shift in these signals depending upon the duration of HFC feeding. The evidences of gene expression profile, elevated serum alanine aminotransferase, and histological data support a progression towards nonalcoholic fatty liver disease and steatohepatitis in these HFC-fed mice within the

  19. Investigation of wholesomeness of feeding low-irradiated diet to mice. Part of a coordinated programme on the wholesomeness of the process of food irradiation

    International Nuclear Information System (INIS)

    Baev, I.A.

    1980-06-01

    Studies are carried out on the wholesomeness of irradiated food with special reference to gamma irradiation (0.75 kGy) maize, (1 kGy) walnuts and (2 kGy) prune-plums. These include physico-chemical changes in the food constituents as well as toxicity and mutagenic effects on animals after long-term feeding test. The results indicate an increase of the carbonyl compounds after irradiation in all studied foodstuffs, but there is not significant difference in the number of the new-formed carbonyl compounds when compared with controls. Biomedical investigation are carried out to define any toxicity, consideration being given to both direct effects in adult or growing organisms and to effect in their progeny. Effects of gamma irradiated diet, including maize, walnuts and prune-plums, exposed to the above mentioned doses fed to three consecutive generations of mice have been studied. A 35% addition of irradiated feed to standard diet is shown to produce no deleterious effects as judged by mean litter size, body weight at weaning, adult body weight and organ weight, haematological measures and some enzyme activities

  20. Direct and transgenerational effects of low doses of perinatal di-(2-ethylhexyl phthalate (DEHP on social behaviors in mice.

    Directory of Open Access Journals (Sweden)

    Kayla M Quinnies

    Full Text Available Di-(2-ethylhexyl phthalate (DEHP is an endocrine disrupting chemical commonly used as a plasticizer in medical equipment, food packaging, flooring, and children's toys. DEHP exposure during early development has been associated with adverse neurobehavioral outcomes in children. In animal models, early exposure to DEHP results in abnormal development of the reproductive system as well as altered behavior and neurodevelopment. Based on these data, we hypothesized that developmental exposure to DEHP would decrease social interactions and increase anxiety-like behaviors in mice in a dose-dependent manner, and that the effects would persist over generations. C57BL/6J mice consumed one of three DEHP doses (0, 5, 40, and 400 μg/kg body weight throughout pregnancy and during the first ten days of lactation. The two higher doses yielded detectable levels of DEHP metabolites in serum. Pairs of mice from control, low, and high DEHP doses were bred to create three dose lineages in the third generation (F3. Average anogenital index (AGI: anogenital distance/body weight was decreased in F1 males exposed to the low dose of DEHP and in F1 females exposed to the highest dose. In F1 mice, juvenile pairs from the two highest DEHP dose groups displayed fewer socially investigative behaviors and more exploratory behaviors as compared with control mice. The effect of DEHP on these behaviors was reversed in F3 mice as compared with F1 mice. F1 mice exposed to low and medium DEHP doses spent more time in the closed arms of the elevated plus maze than controls, indicating increased anxiety-like behavior. The generation-dependent effects on behavior and AGI suggest complex mechanisms by which DEHP directly impacts reproductive and neurobehavioral development and influences germline-inherited traits.

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

    Science.gov (United States)

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

    2017-07-01

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

  2. Dose and time relationships of the radioprotector WR-2721 on locomotor activity in mice

    International Nuclear Information System (INIS)

    Landauer, M.R.; Davis, H.D.; Dominitz, J.A.; Weiss, J.F.

    1987-01-01

    The effects of the radioprotector S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) on locomotor activity were evaluated in CD2F1 male mice. Separate groups of animals (N = 10/group) received an IP injection of vehicle, 25, 50, 100, 200, or 400 mg/kg of WR-2721 immediately before testing. Horizontal and vertical activity were measured using a Digiscan automated animal activity monitor. The latency to onset and duration of action of each dose of the radioprotector were recorded. For both behavioral measures, a significant reduction was observed in activity at doses of 200 and 400 mg/kg. A dose of 200 mg/kg had a 12- to 14-min latency to onset and significantly reduced behavioral activity for 3 hr. Mice injected with 400 mg/kg exhibited locomotor deficits within 8-10 min and were affected for up to 9 hr. The ED50 for horizontal and vertical activities at 1 hr postinjection were determined to be 271 and 105 mg/kg, respectively. The results demonstrate that significant reductions in locomotor activity are exhibited at doses of 200 mg/kg or more and that vertical activity was more sensitive to the disruptive effects of WR-2721 than was horizontal activity

  3. Caffeine protects mice against whole-body lethal dose of {gamma}-irradiation

    Energy Technology Data Exchange (ETDEWEB)

    George, K.C.; Hebbar, S.A.; Kale, S.P.; Kesavan, P.C. [Biosciences Group, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085 (India)

    1999-06-01

    Administration of caffeine (1,3,7-trimethylxanthine), a major component of coffee, to Swiss mice at doses of 80 or 100 mg/kg body weight 60 min prior to whole-body lethal dose of {gamma}-irradiation (7.5 Gy) resulted in the survival of 70 and 63% of animals, respectively, at the above doses in contrast to absolutely no survivors (LD-100/25 days) in the group exposed to radiation alone. Pre-treatment with a lower concentration of caffeine (50 mg/kg) did not confer any radioprotection. The protection exerted by caffeine (80 mg/kg), however, was reduced from 70 to 50% if administered 30 min prior to irradiation. The trend statistics reveal that a dose of 80 mg/kg administered 60 min before whole-body exposure to 7.5 Gy is optimal for maximal radioprotection. However, caffeine (80 mg/kg) administered within 3 min after irradiation offered no protection. While there is documentation in the literature that caffeine is an antioxidant and radioprotector against the toxic pathway of radiation damage in a wide range of cells and organisms, this is the first report demonstrating unequivocally its potent radioprotective action in terms of survival of lethally whole-body irradiated mice. (author)

  4. Homeopathic Doses of Gelsemium sempervirens Improve the Behavior of Mice in Response to Novel Environments

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    Paolo Bellavite

    2011-01-01

    Full Text Available Gelsemium sempervirens is used in homeopathy for treating patients with anxiety related symptoms, however there have been few experimental studies evaluating its pharmacological activity. We have investigated the effects of homeopathic doses of G. sempervirens on mice, using validated behavioral models. Centesimal (CH dilutions/dynamizations of G. sempervirens, the reference drug diazepam (1 mg/kg body weight or a placebo (solvent vehicle were intraperitoneally delivered to groups of mice of CD1 strain during 8 days, then the effects were assessed by the Light-Dark (LD choice test and by the Open-Field (OF exploration test, in a fully blind manner. In the LD test, the mean time spent in the illuminated area by control and placebo-treated animals was 15.98%, for mice treated with diazepam it increased to 19.91% (P = .047, while with G. sempervirens 5 CH it was 18.11% (P = .341, non-significant. The number of transitions between the two compartments increased with diazepam from 6.19 to 9.64 (P < .001 but not with G. Sempervirens. In the OF test, G. sempervirens 5 CH significantly increased the time spent and the distance traveled in the central zone (P = .009 and P = .003, resp., while diazepam had no effect on these OF test parameters. In a subsequent series of experiments, G. sempervirens 7 and 30 CH also significantly improved the behavioral responses of mice in the OF test (P < .01 for all tested variables. Neither dilutions of G. sempervirens affected the total distance traveled, indicating that the behavioral effect was not due to unspecific changes in locomotor activity. In conclusion, homeopathic doses of G. sempervirens influence the emotional responses of mice to novel environments, suggesting an improvement in exploratory behavior and a diminution of thigmotaxis or neophobia.

  5. Effects of a single high dose of 55Fe in mice

    International Nuclear Information System (INIS)

    Laissue, J.A.; Burlington, H.; Cronkite, E.P.; Heldman, B.; Reincke, U.

    1979-01-01

    High doses of 55 Fe induced cytocide in maturing erythroid cells, due to the short-range deposition of decay energy. Organ damage at the time of death was evaluated in a group of 45 female mice of the C 57 BL/6 J strain given a single i.v. injection of 2,800 μCi, 1,400 μCi or 700 μCi of 55 FeCl 3 when 10 to 14 weeks old. A corresponding amount of cold iron was given to control animals by the same route. Radioiron-treated mice died spontaneously, or were killed when moribund. Mice given 2,800 μCi died after a median survival time of 27 days with severe depletion of hemopoietic cells in bone marrow and spleen, marked atrophy of lymphoid tissues and mild liver damage. After 1,400 μCi or 700 μCi, the median survival time was 117 and 439, respectively. In contrast, median survival was 847 days in control animals allowed to survive. In the two lower 55 Fe-dose groups, there was a dose-dependent pancytopenia. Atrophy of lymphoid tissues was moderate, and signs of liver damage slight. The degree of organ hemosiderosis in experimental and control animals was slight to moderate. Organ damage associated with deposition of cold iron was not apparent in tissue sections. Morphological signs of damage to non-hemopoietic organs such as the liver were not conspicuous. Direct radiation damage, primarily to the erythroid series, and competition for stem cells between the heavily depleted erythroid and the other hemopoietic cell lines must be considered among the possible factors leading to pancytopenia. Out of 14 55 Fe-treated mice who survived longer than 300 days developed tumors of hemopoietic and lymphoid tissues, or osteosarcomas. (orig./MG) [de

  6. Numerical variation of cell lysosomes of the proximal convoluted tubules of mice Kidneys submitted to different X-ray doses

    International Nuclear Information System (INIS)

    Silva Lapa, R. de C.R. da; Pacheco, I.P.; Segreto, C.

    1984-01-01

    The number of cell lysosomes of the proximal convoluted tubules of mice Kidneys (Mus musculus) before and after whole-body irradiation with different X-ray doses is confronted. The mice were sacrificed after 72 hours and the cortex fragments were conduct to electron microscopy. A statistically significant numerical reduction of the lysosomas was observed in 72 hours. (M.A.C.) [pt

  7. The effect of low dose rate on metabolomic response to radiation in mice

    International Nuclear Information System (INIS)

    Goudarzi, Maryam; Mak, Tytus D.; Chen, Congju; Smilenov, Lubomir B.; Brenner, David J.; Fornace, Albert J.

    2014-01-01

    Metabolomics has been shown to have utility in assessing responses to exposure by ionizing radiation (IR) in easily accessible biofluids such as urine. Most studies to date from our laboratory and others have employed γ-irradiation at relatively high dose rates (HDR), but many environmental exposure scenarios will probably be at relatively low dose rates (LDR). There are well-documented differences in the biologic responses to LDR compared to HDR, so an important question is to assess LDR effects at the metabolomics level. Our study took advantage of a modern mass spectrometry approach in exploring the effects of dose rate on the urinary excretion levels of metabolites 2 days after IR in mice. A wide variety of statistical tools were employed to further focus on metabolites, which showed responses to LDR IR exposure (0.00309 Gy/min) distinguishable from those of HDR. From a total of 709 detected spectral features, more than 100 were determined to be statistically significant when comparing urine from mice irradiated with 1.1 or 4.45 Gy to that of sham-irradiated mice 2 days post-exposure. The results of this study show that LDR and HDR exposures perturb many of the same pathways such as TCA cycle and fatty acid metabolism, which also have been implicated in our previous IR studies. However, it is important to note that dose rate did affect the levels of particular metabolites. Differences in urinary excretion levels of such metabolites could potentially be used to assess an individual's exposure in a radiobiological event and thus would have utility for both triage and injury assessment. (orig.)

  8. Oral repeated-dose systemic and reproductive toxicity of 6:2 fluorotelomer alcohol in mice

    Directory of Open Access Journals (Sweden)

    Pushkor Mukerji

    2015-01-01

    Full Text Available 6:2 fluorotelomer alcohol (6:2 FTOH was evaluated for potential systemic repeated-dose and reproductive toxicity in mice. 6:2 FTOH was administered by oral gavage to CD-1 mice as a suspension in 0.5% aqueous methylcellulose with 0.1% Tween-80 at dosages of 1, 5, 25, or 100 mg/kg/day. The no-observed-adverse-effect level (NOAEL for systemic toxicity was 25 mg/kg/day (males and 5 mg/kg/day (females, based on effects at higher doses on mortality, clinical observations, body weight, nutritional parameters, hematology (red and white blood cell, clinical chemistry (liver-related, liver weights, and histopathology (liver, teeth, reproductive tract, and mammary gland. However, 6:2 FTOH was not a selective reproductive toxicant. The NOAEL for reproductive toxicity was >100 mg/kg/day; no effects on reproductive outcome were observed at any dosage. The NOAEL for viability and growth of the offspring was 25 mg/kg/day, based on clinical signs of delayed maturation in pups, and reductions in pup survival and pup body weight during lactation at 100 mg/kg/day. While the severity of the effects was generally greater in mice than previously reported in CD rats, the overall NOAELs were identical in both species, 5 mg/kg/day for systemic toxicity and 25 mg/kg/day for offspring viability/growth. 6:2 FTOH was not a selective reproductive toxicant in either species; no effects on reproductive outcome occurred at any dose level, and any effects observed in offspring occurred at dose levels that induced mortality and severe toxicity in maternal animals.

  9. Mice lacking natural killer T cells are more susceptible to metabolic alterations following high fat diet feeding.

    Directory of Open Access Journals (Sweden)

    Brittany V Martin-Murphy

    Full Text Available Current estimates suggest that over one-third of the adult population has metabolic syndrome and three-fourths of the obese population has non-alcoholic fatty liver disease (NAFLD. Inflammation in metabolic tissues has emerged as a universal feature of obesity and its co-morbidities, including NAFLD. Natural Killer T (NKT cells are a subset of innate immune cells that abundantly reside within the liver and are readily activated by lipid antigens. There is general consensus that NKT cells are pivotal regulators of inflammation; however, disagreement exists as to whether NKT cells exert pathogenic or suppressive functions in obesity. Here we demonstrate that CD1d(-/- mice, which lack NKT cells, were more susceptible to weight gain and fatty liver following high fat diet (HFD feeding. Compared with their WT counterparts, CD1d(-/- mice displayed increased adiposity and greater induction of inflammatory genes in the liver suggestive of the precursors of NAFLD. Calorimetry studies revealed a significant increase in food intake and trends toward decreased metabolic rate and activity in CD1d(-/- mice compared with WT mice. Based on these findings, our results suggest that NKT cells play a regulatory role that helps to prevent diet-induced obesity and metabolic dysfunction and may play an important role in mechanisms governing cross-talk between metabolism and the immune system to regulate energy balance and liver health.

  10. Incorporation and metabolism of tritium in pregnant mice and their offspring after feeding organically labelled tritiated milk powder during pregnancy

    International Nuclear Information System (INIS)

    Bruwaene, R. van; Gerber, G.B.; Kirchmann, R.; Maes, J.; Fagniart, E.

    1982-01-01

    Food mixed from equal amounts of organically labelled tritiated milk powder and normal food pellets was given to mice during pregnancy and lactation. At birth, some new-born were swapped with those from non-exposed mothers to compare separately accumulation and metabolism during pregnancy and lactation. Young mice were sacrificed at different time after birth, and tritium activity in different organs was determined. Tritium activity was also determined in maternal organs at various times during and after the 42 days feeding period. The activity per g in some tissues of the young, particularly in fat, exceeded that of the food given, probably as a result of the high activity and low metabolic dilution of the fats in the food. Young mice contaminated during lactation and pregnancy contained still detectible activity at an age of 2 months. Activity was nearly the same in mice receiving tritium only during lactation as in those receiving it also during pregnancy. Dilution was more marked due to rapid growth when tritium application was discontinued at birth. Tritium water was replaced most rapidly, organic tritium in brain turned over most slowly with and additional metabolic component of a half life in the order of 1 month. Organic tritium in liver displayed an intermediate half life. (author)

  11. Hepatic Effects of Pharmacological Doses of Hydroxy-Cobalamin[c-lactam] in Mice.

    Directory of Open Access Journals (Sweden)

    Patrizia Haegler

    Full Text Available The vitamin B12 analog hydroxy-cobalamin[c-lactam] (HCCL impairs hepatic mitochondrial protein synthesis and function of the electron transport chain in rats. We aimed to establish an in vivo model for mitochondrial dysfunction in mice, which could be used to investigate hepatotoxicity of mitochondrial toxicants. In a first step, we performed a dose-finding study in mice treated with HCCL 0.4 mg/kg and 4 mg/kg i.p. for two to four weeks. The plasma methylmalonate concentration was strongly increased at 4 mg/kg starting at three weeks of treatment. We subsequently treated mice daily with 4 mg/kg HCCL i.p. for three weeks and characterized liver function and histology as well as liver mitochondrial function. We found an increase in liver weight in HCCL-treated mice, which was paralleled by hepatocellular accumulation of triglycerides. In liver homogenate of HCCL-treated mice, the complex I activity of the electron transport chain was reduced, most likely explaining hepatocellular triglyceride accumulation. The activity of CPT1 was not affected by methylmalonyl-CoA in isolated liver mitochondria. Despite impaired complex I activity, mitochondrial superoxide anion production was not increased and the hepatocellular glutathione (GSH pool was maintained. Finally, the mitochondrial DNA content was not altered with HCCL treatment. In conclusion, treatment of mice with HCCL is associated with increased liver weight explained by hepatocellular triglyceride accumulation. Hepatocellular fat accumulation is most likely a consequence of impaired activity of the mitochondrial electron transport chain. The impairment of complex I activity is not strong enough to result in ROS accumulation and reduction of the GSH stores.

  12. Concentration of metallothionein in mice livers after a small dose of irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Saitou, Mikio; Yanai, Takanori; Hasegawa, Hidenao; Otsu, Hiroshi; Sato, Fumiaki [Inst. for Environmental Sciences, Rokkasho, Aomori (Japan); Akata, Naofumi; Kanaiwa-Kudo, Shouko; Matsumoto, Tsuneya; Noda, Yuko

    1998-12-01

    This study was made to determine whether metallothionein (MT) is induced by a small dose (0.5 Gy) irradiation. One hundred B6C3F1/Nrs mice of each sex, 8-10 weeks old, were used in the sham study (unirradiated controls) and experimental (irradiated) groups. Eighty mice of each sex were given acute whole body irradiation with {sup 197}Cs{gamma}-rays under SPF conditions; two doses of 0.5 and 5.0 Gy at 30 cm distance from the source at the rate of 0.563 Gy/min. Twenty mice of each sex were used in the sham study. Every ten male and female mouse was killed by cervical dislocation on days 1, 7, 14 and 21 after irradiation. The same numbers of male and female control mice were killed on days 0 and 21. Livers were removed immediately after death, and concentration of MT was examined. In both the males and females, the MT concentration of the 5 Gy-group peaked on the first day after irradiation, and there was no difference in comparison with the control values between the 7th and 21st days. In contrast, on no day did the MT concentration for the 0.5 Gy-group showed a significant difference from the control group. The time dependency patterns of the female and male mice also showed no significant differences for 5 Gy- and 0.5 Gy-groups, but the mean values of the MT concentration was lower in the males than in the females on the 1st day. Results of the direct quantitation of MT by the enzyme-linked immunoabsorbent assay (ELISA) also showed peak MT accumulation on the 1st day for both male and female mice. These were also shown by the atomic absorption spectrometry (AAS) and the inductively coupled plasma mass spectrometry (ICP-MS) analyses. But peak heights for the males and females showed a tendency inverse to that of the AAS and ICP-MS analyses. This discrepancy is attributable to the technical problem encountered in the experiment. On the basis of our findings, MT does not seem to be related to acquired radioresistance in mice. (K.H.)

  13. Low and high dose rate heavy ion radiation-induced intestinal and colonic tumorigenesis in APC1638N/+ mice

    Science.gov (United States)

    Suman, Shubhankar; Kumar, Santosh; Moon, Bo-Hyun; Fornace, Albert J.; Datta, Kamal

    2017-05-01

    Ionizing radiation (IR) is a recognized risk factor for colorectal cancer (CRC) and astronauts undertaking long duration space missions are expected to receive IR doses in excess of permissible limits with implications for colorectal carcinogenesis. Exposure to IR in outer space occurs at low doses and dose rates, and energetic heavy ions due to their high linear energy transfer (high-LET) characteristics remain a major concern for CRC risk in astronauts. Previously, we have demonstrated that intestinal tumorigenesis in a mouse model (APC1638N/+) of human colorectal cancer was significantly higher after exposure to high dose rate energetic heavy ions relative to low-LET γ radiation. The purpose of the current study was to compare intestinal tumorigenesis in APC1638N/+ mice after exposure to energetic heavy ions at high (50 cGy/min) and relatively low (0.33 cGy/min) dose rate. Male and female mice (6-8 weeks old) were exposed to either 10 or 50 cGy of 28Si (energy: 300 MeV/n; LET: 70 keV/μm) or 56Fe (energy: 1000 MeV/n; LET: 148 keV/μm) ions at NASA Space Radiation Laboratory in Brookhaven National Laboratory. Mice (n = 20 mice/group) were euthanized and intestinal and colon tumor frequency and size were counted 150 days after radiation exposure. Intestinal tumorigenesis in male mice exposed to 56Fe was similar for high and low dose rate exposures. Although male mice showed a decreasing trend at low dose rate relative to high dose rate exposures, the differences in tumor frequency between the two types of exposures were not statistically significant after 28Si radiation. In female mice, intestinal tumor frequency was similar for both radiation type and dose rates tested. In both male and female mice intestinal tumor size was not different after high and low dose rate radiation exposures. Colon tumor frequency in male and female mice after high and low dose rate energetic heavy ions was also not significantly different. In conclusion, intestinal and colonic tumor

  14. Effects of low dose rate irradiation on life span prolongation of human premature-aging syndrome model mice

    International Nuclear Information System (INIS)

    Nomura, Takaharu

    2006-01-01

    We previously showed that Type II diabetes model mice prolonged of their life span by life long low dose rate irradiation. We also found that antioxidant function in variety tissues of some strain of mice were enhancement after low dose/low dose rate irradiation. The prolongation of life span might depend on certain damaged level of reactive oxygen species. We thought the effect of the prolongation was due to the enhancement of the antioxidant activities after irradiation. We investigated whether the enhancement of antioxidant activities after low dose rate irradiation had an effect on life span prolongation. Four-week-old female human premature-aging syndrome model mice, kl/kl (klotho) mice, which the life span of this model mouse is about 65 days, were irradiated with gamma rays at 0.35, 0.70 or 1.2 mGy/hr. The 0.70 mGy/hr-irradiated group remarkably effected on the prolongation of their life span. Some mice of the group were extremely survived for about and more 100 days. Antioxidant activities in the irradiated groups were enhancement by low dose rate irradiation, however the dependence of the dose rates were not clearly difference. These results suggest that the antioxidant activities in this model mouse were enhanced by the low dose rate irradiation, and may make it possible to prolong the life span of this mouse. (author)

  15. Sodium fusidate ameliorates the course of diabetes induced in mice by multiple low doses of streptozotocin

    DEFF Research Database (Denmark)

    Nicoletti, F; Di Marco, R; Conget, I

    2000-01-01

    We studied the effects of the immunosuppressant sodium fusidate (fusidin) on murine immunoinflammatory diabetes mellitus (DM) induced by multiple low doses of streptozotocin (SZ). Fusidin was given by gavage to three strains of mice (C57KsJ, C57BL/6, CD1) at doses 10 or 100 mg/kg body weight every...... induced in vivo by ConA, reducing the levels of IFN-gamma, IL-2 and TNF-alpha and augmenting the level of IL-6. However, only the inhibitory effect of the drug on the synthesis/release of IFN-gamma seemed to be causally related to its capacity to counteract the SZ-induced DM. In fact, the disease...... other day. The drug was administered as an early or late prophylactic regime starting either 1 day prior to the first or after the fifth and last injection of SZ. In both situations the largest dose of fusidin successfully reduced the clinical, chemical and histological signs of DM, the treated mice...

  16. Prenatal irradiation and spatial memory in mice: investigation of dose-response relationship

    International Nuclear Information System (INIS)

    Sienkiewicz, Z.J.; Haylock, R.G.E.; Saunders, R.D.

    1994-01-01

    Pregnant CD1 mice were exposed on gestational day 18 to 250 kV X-rays at 0.1, 0.25, 0.35 and 0.5 Gy. The performances of 10 adult male offspring from each exposure condition were investigated on a spatial discrimination learning task in a radial arm maze. An impairment in the performance of this task was found which showed a correlation with dose. Compared with sham exposed control mice, performance was not significantly affected with irradiation at 0.1 Gy and was slightly but non-significantly reduced at 0.25 Gy. Irradiation at 0.35 Gy caused a significant impairment in performance, and exposure at 0.5 Gy resulted in a still larger impairment. The overall association between dose and behavioural impairment was best described by a linear relationship without a threshold, although at doses lower than about 0.25 Gy any impairment would appear to be too small to be detectable. (Author)

  17. Humoral response to blastospores and mycelium in mice injected with different doses of Candida albicans.

    Science.gov (United States)

    Mesón, O E; Valdez, J C; de Alderete, N G; Sirena, A; Perdigón, G

    1992-01-01

    An indirect immunofluorescence assay was carry out to determine the IgM and IgG antibody responses to yeast and mycelial forms of Candida albicans in mice injected with a 5 x 5(5) and 5 x 10(7) live cells suspensions. Prior adsorption of the serum samples with heat-killed blastospores enabled us to follow the specific antimycelial response which were detected considerably later than expected. Slow level of antibodies were obtained within an infection of 5 x 10(5) cell for both antibody classes and for yeast and mycelial forms. When a 5 x 10(7) cell dose was used for inoculation, maximum titers of antibodies to blastospores and mycelium in non-adsorbed sera appeared almost simultaneously (days 15 and 13, respectively). When serum samples from mice infected with the same dose were previously adsorbed with blastospores, the antimycelium antibodies for both types of Igs, were detected delayed during the infection course. In this case the higher titer for IgG appeared on day 33 and on day 23 for IgM. We suggest that the high titer obtained with the blastospore forms for the 5 x 10(7) cell dose may be due to a major immunogenicity of this forms, for to induce an immune response in the host, or that the delay in the antimycelium antibodies detection could be due to that a blastospore form is the predominant in the infection early stages. Implications of this fact for pathogenesis are discussed.

  18. Radioprotective effects in mice by a single dose of subcutaneous administration of cobaltous chloride post γ-rays irradiation with a sublethal dose

    International Nuclear Information System (INIS)

    Izumo, Yoshiro; Ogata, Hiromitsu

    1993-01-01

    Radioprotective effects were investigated in mice which received subcutaneously a single dose of each inorganic metal: Co, Cu, Rb, Sr, Mo and W 24 hours post irradiation of 60 Co γ-rays with a sublethal dose. The effects were observed in mice injected with Co at an optimum dosage of 20 mg/kg·body weight. Then to elucidate mechanisms of the effects, mice were injected with Co containing the radioactive tracer ( 60 Co) following the radiation exposure, measured elimination of the radioactivity for 7 days, then sacrificed and divided to some tissues and organs. The radioactivity in whole body during this period resulted in a markedly higher retention than that for mice injected with [ 60 Co] alone, as well as liver in the organs. These higher retentions appeared to be related to the radioprotective effects. (author)

  19. Phenotypic characterization of thymic prelymphoma cells of B10 mice treated with split-dose irradiation

    International Nuclear Information System (INIS)

    Muto, M.; Kubo, E.; Kamisaku, H.; Sado, T.

    1990-01-01

    Using an intrathymic injection assay on B10 Thy-1 congenic mice, it was demonstrated that thymic prelymphoma cells first developed within the thymuses from 4 to 8 days after split-dose irradiation and were detected in more than 63% of the test donor thymuses when examined at 21 and 31 days after irradiation. Moreover, some mice (25%) at 2 mo after split-dose irradiation had already developed thymic lymphomas in their thymuses. To characterize these thymic prelymphoma cells, the thymocytes from B10 Thy-1.1 mice 1 mo after irradiation were stained with anti-CD4 and anti-CD8 mAb and were sorted into four subpopulations. These fractionated cells were injected into the recipient thymuses to examine which subpopulation contained thymic prelymphoma cells. The results indicated that thymic prelymphoma cells existed mainly in CD4- CD8- and CD4- CD8+ thymocyte subpopulations and also in CD4+ CD8+ subpopulation. T cell lymphomas derived from CD4- CD8- prelymphoma cells had mainly CD4- CD8- or CD4- CD8+ phenotypes. T cell lymphomas developed from CD4- CD8+ prelymphoma cells mainly expressed CD4- CD8+ or CD4+ CD8+ phenotype. T cell lymphomas originating from CD4+ CD8+ prelymphoma cells were mainly CD4+ CD8+ but some CD4- CD8+ or CD4+ CD8- cells were also present. These thymic prelymphoma cells were further characterized phenotypically in relation to their expression of the marker defined by the mAb against J11d marker and TL-2 (thymus-leukemia) Ag, which is not expressed on normal thymocytes of B10.Thy-1.2 or B10.Thy-1.1 strain, but appears on the thymocytes of lymphomagenic irradiated mice. The results indicated that the prelymphoma cells existed in J11d+, TL-2+ cells

  20. Antilipogenic and Anti-Inflammatory Activities of Codonopsis lanceolata in Mice Hepatic Tissues after Chronic Ethanol Feeding

    Directory of Open Access Journals (Sweden)

    Areum Cha

    2012-01-01

    Full Text Available This study evaluated the antilipogenic and anti-inflammatory effects of Codonopsis lanceolata (C. lanceolata root extract in mice with alcohol-induced fatty liver and elucidated its underlying molecular mechanisms. Ethanol was introduced into the liquid diet by mixing it with distilled water at 5% (wt/v, providing 36% of the energy, for nine weeks. Among the three different fractions prepared from the C. lanceolata root, the C. lanceolata methanol extract (CME exhibited the most remarkable attenuation of alcohol-induced fatty liver with respect to various parameters such as hepatic free fatty acid concentration, body weight loss, and hepatic accumulations of triglyceride and cholesterol. The hepatic gene and protein expression levels were analysed via RT-PCR and Western blotting, respectively. CME feeding significantly restored the ethanol-induced downregulation of the adiponectin receptor (adipoR 1 and of adipoR2, along with their downstream molecules. Furthermore, the study data showed that CME feeding dramatically reversed ethanol-induced hepatic upregulation of toll-like receptor- (TLR- mediated signaling cascade molecules. These results indicate that the beneficial effects of CME against alcoholic fatty livers of mice appear to be with adenosine- and adiponectin-mediated regulation of hepatic steatosis and TLR-mediated modulation of hepatic proinflammatory responses.

  1. MOSFET assessment of radiation dose delivered to mice using the Small Animal Radiation Research Platform (SARRP).

    Science.gov (United States)

    Ngwa, Wilfred; Korideck, Houari; Chin, Lee M; Makrigiorgos, G Mike; Berbeco, Ross I

    2011-12-01

    The Small Animal Radiation Research Platform (SARRP) is a novel isocentric irradiation system that enables state-of-the-art image-guided radiotherapy research to be performed with animal models. This paper reports the results obtained from investigations assessing the radiation dose delivered by the SARRP to different anatomical target volumes in mice. Surgically implanted metal oxide semiconductor field effect transistors (MOSFET) dosimeters were employed for the dose assessment. The results reveal differences between the calculated and measured dose of -3.5 to 0.5%, -5.2 to -0.7%, -3.9 to 0.5%, -5.9 to 2.5%, -5.5 to 0.5%, and -4.3 to 0% for the left kidney, liver, pancreas, prostate, left lung, and brain, respectively. Overall, the findings show less than 6% difference between the delivered and calculated dose, without tissue heterogeneity corrections. These results provide a useful assessment of the need for tissue heterogeneity corrections in SARRP dose calculations for clinically relevant tumor model sites.

  2. Effect of dose rate on intestinal tolerance in mice. Implications in radiotherapy

    International Nuclear Information System (INIS)

    Wambersie, A.; Stienon-Smoes, M.R.; Octave-Prignot, M.

    1978-01-01

    Effect of dose rate on intestinal tolerance after 60 Co irradiation was studied in BALB/c mice. Intestinal tolerance was assessed from LD50, after selective abdominal irradiation and after total body irradiation. Three dose rates were compared, corresponding to irradiation times of about 15-20 minutes ('acute irradiation' taken as reference), 5-6 hours and 10-15 hours. Irradiations were performed simultaneously, with three telecobaltherapy units, the dose rates being adjusted with lead shields and by increasing the distances. Comparison of the experimental data already published indicates that, for some biological systems and effects, additional dose necessary to reach a given effect when passing from 'acute' to 'continuous low dose rate' irradiation is comparable to that expected when considering only repair of sublethal lesions. For other biological systems and effects, it is necessary to consider, besides repair of sublethal lesions, other mechanisms such as cell distribution and, for tumours, the oxygen effect. A differential effect then appears to be possible. However, as far as the clinical applications are concerned, a general agreement is not yet reached on the exact shape of the iso-effect curves as a function of irradiation time for the effects relevant to radiation therapy [fr

  3. Dose-response relationship for life-shortening and carcinogenesis in mice irradiated at day 7 postnatal age with dose range below 1 Gy of gamma rays

    International Nuclear Information System (INIS)

    Sasaki, Shunsaku; Fukuda, Nobuo

    2006-01-01

    This study was designed to elucidate the dose-response relationships for life-shortening and tumorigenic effect in the dose range below 1 Gy of gamma rays delivered during the infant period. Female B6C3F 1 mice were irradiated with 0.10, 0.48 or 0.95 Gy at 7 days of age. All irradiated mice were allowed to live out their entire life span together with a simultaneously ongoing control group under a specific pathogen-free condition. Shortening of the mean life span was 1.58% in mice irradiated with 0.10 Gy, which was statistically significant. The coefficient of the linear dose-response relationship for life-shortening was 11.21% Gy -1 . The attributable death fraction for all causes of death in 0.10 Gy group reached 0.092. The excess relative risk for death rate from all causes was 0.102 in the group irradiated with 0.10 Gy. The coefficient of the linear dose-response relationship of the excess relative risk for death rate from all causes was 1.30 Gy -1 . The mean number of types of solid tumors at the time of death in mice irradiated with 0.10 Gy was distinctly larger than that in the control group. The excess relative risk for death rate from solid tumors was 0.45 in mice irradiated with 0.10 Gy. The coefficient of the linear dose-response relationship of excess relative risk for death rate from solid tumors was 4.52 Gy -1 . Increase in incidences of the pituitary, ovarian and adrenal tumors was observed in mice irradiated with 0.10 Gy. The results of the present study showed that infant mice are susceptible to solid tumor induction, especially of the endocrine organs. (author)

  4. Effects of low dose radiation on kidney function and morphology of diabetic mice

    International Nuclear Information System (INIS)

    Zhang Chi; Li Xiaokun; Gong Shouliang; Meng Tao; Li Cai; Cai Lu

    2010-01-01

    Objective: To study the effect of low dose radiation (LDR) on the kidney function and morphology in C57BL/6J mice with diabetic nephropathy (DN) induced by streptozotocin (STZ) and illuminate the protective function of LDR on kidney damage caused by diabetes mellitus (DM). Methods: The healthy and right age C57BL/6J mice were divided into 4 groups including control, DM, LDR and DM/LDR. The mice in DM and DM/LDR groups were injected intraperitoneally with STZ to set up DM models. The mice in DM/LDR and LDR groups were irradiated with 25 mGy X-rays every other day for 4 weeks. The changes of blood glucose level, urine index level and the morphology of glomerular were detected at 2, 4, 8, 12, 16 weeks after radiation. Results: The blood glucose levels of mice in DM and DM/LDR groups after STZ-induced DM model preparation were higher than those in LDR and control groups (P<0.05). After treated with LDR for 2 weeks, the blood glucose level in DM/LDR group was supressed and significantly lower than that in DM group (P<0.05). Moreover the the change had been kept to 16 weeks. In addition, compared with DM group, the level of urine micro albumin(MALB) in DM/LDR group was decreased and the urine creatinine (Cre) level was increased. Compared with DM group, the morphological results showed that the glomerular mesangial expansion and mesangial cell proliferation were significantly supressed in DM/LDR group (P<0.05). Conclusion: LDR can promote the decease of blood glucose level efficiently, relief the change of kidney function, supress and delay the pathological changes of DN. (authors)

  5. Recovery Effect and Life Prolong Effect of Long Term Low-Dose Rate Irradiation on Type II Diabetes Model Mice

    International Nuclear Information System (INIS)

    Nomura, T.; Makino, N.; Oda, T.; Suzuki, I.; Sakai, K

    2004-01-01

    The effects of low-dose rate gamma-irradiation were investigated on model mice for type II diabetes mellitus, C57BL/KsJ-db/db. The mice develop the type II diabetes by 10 weeks of age due to obesity and are characterized by hyperinsulinemia. Female 10-week old mice, a group of 12 mice, were irradiated at 0.65 mGy/hr from 137-Cs (370 GBq). The urine glucose levels of all of the mice were strongly positive at the beginning of the irradiation. In the irradiated group, the decrease in the glucose level was observed in 3 mice. Such recovery from the diabetes was never observed in 12 mice of non-irradiated control group. There is no systematic difference in the change of body weight, food assumption, and amount of drinking water, between the irradiated group and the non-irradiated group or between the recovered mice and the non-recovered mice. The survival was better in the irradiated group: the surviving fraction at the age of 90 weeks was 75% in the irradiated group, while 40% in the non-irradiated. Marked difference was also observed in the appearance of the coat hair, skin, and tail; better condition was kept in the irradiated group. In the irradiated mice mortality was delayed and the healthy appearance was prolonged in the irradiated mice by about 20 ? 30 weeks compared with the non-irradiated mice. These results suggest that the low-dose irradiation modified the condition of the diabetic mice, which lead not only to the recovery of the diabetes, but also to the suppression of the aging process. (Author)

  6. Role of Immunomodulators in Tumor Regression in Mice Exposed to Fractionated Low Dose of Gamma Radiation

    International Nuclear Information System (INIS)

    Rokaya Elsayed Maaroaf Elsayed

    2015-01-01

    Immunotherapy is one of the most promising approaches of cancer treatment. The present study was designed to examine the role of irradiated tumor cell lysate vaccine, IFNα-2b and low dose of gamma irradiation as immunomodulators either alone or combined in tumor regression. Ehrlich ascite carcinoma (EAC) cells and 9 groups of female mice were used. Mice were immunized intramuscularly by tumor cell lysate vaccine one time/week for 3 weeks in the right thigh of mice. After two weeks from last immunization, all mice were challenged with normal viable EAC cells at count of 2.5 ×10 6 /mouse in the opposite left thigh for Ehrlich carcinoma (EC) production. Mice were subcutaneously injected with 10.000 units of IFNα-2b 3 times/week for 4 weeks and others were exposed to fractionated dose of γ- radiation (0.5 Gy/day x 4, day after day). Tumor size, serum tumor markers (TNF-α and CEA), tumor DNA fragmentation and Caspase-3 were evaluated. Oxidative stress (MDA and NO) markers and antioxidants (GSH, GPX and SOD) were determined in spleen and tumor tissues. Histopathological examinations, apoptosis and necrosis in spleen and tumor tissues were also examined. The results revealed significant inhibition in tumor size throughout the observation period either for treatments with vaccine or IFNα-2b either alone or combined with γ-irradiation. DNA fragmentation and Caspase-3 enzyme activities were significantly elevated in immunized mice as compared with EC group along with diminished tumor size while, tumor markers were significantly decreased. MDA and NO were significantly increased in tumor tissue.while, tumor GSH content, GPX and SOD activities were significantly decreased. Combined treatments of female mice bearing EC with IFN-α-2b, tumor cell lysate vaccine and low dose of γ-radiation cause a highly significant decrease in serum TNF-α and CEA levels, increase in Cas-3 activity, no DNA fragmentation, significant increase in MDA, decrease in SOD activity and decreased

  7. The ERα-PI3K Cascade in Proopiomelanocortin Progenitor Neurons Regulates Feeding and Glucose Balance in Female Mice.

    Science.gov (United States)

    Zhu, Liangru; Xu, Pingwen; Cao, Xuehong; Yang, Yongjie; Hinton, Antentor Othrell; Xia, Yan; Saito, Kenji; Yan, Xiaofeng; Zou, Fang; Ding, Hongfang; Wang, Chunmei; Yan, Chunling; Saha, Pradip; Khan, Sohaib A; Zhao, Jean; Fukuda, Makoto; Tong, Qingchun; Clegg, Deborah J; Chan, Lawrence; Xu, Yong

    2015-12-01

    Estrogens act upon estrogen receptor (ER)α to inhibit feeding and improve glucose homeostasis in female animals. However, the intracellular signals that mediate these estrogenic actions remain unknown. Here, we report that anorexigenic effects of estrogens are blunted in female mice that lack ERα specifically in proopiomelanocortin (POMC) progenitor neurons. These mutant mice also develop insulin resistance and are insensitive to the glucose-regulatory effects of estrogens. Moreover, we showed that propyl pyrazole triol (an ERα agonist) stimulates the phosphatidyl inositol 3-kinase (PI3K) pathway specifically in POMC progenitor neurons, and that blockade of PI3K attenuates propyl pyrazole triol-induced activation of POMC neurons. Finally, we show that effects of estrogens to inhibit food intake and to improve insulin sensitivity are significantly attenuated in female mice with PI3K genetically inhibited in POMC progenitor neurons. Together, our results indicate that an ERα-PI3K cascade in POMC progenitor neurons mediates estrogenic actions to suppress food intake and improve insulin sensitivity.

  8. Phytosterol Feeding Causes Toxicity in ABCG5/G8 Knockout Mice

    Science.gov (United States)

    McDaniel, Allison L.; Alger, Heather M.; Sawyer, Janet K.; Kelley, Kathryn L.; Kock, Nancy D.; Brown, J. Mark; Temel, Ryan E.; Rudel, Lawrence L.

    2014-01-01

    Plant sterols, or phytosterols, are very similar in structure to cholesterol and are abundant in typical diets. The reason for poor absorption of plant sterols by the body is still unknown. Mutations in the ABC transporters G5 and G8 are known to cause an accumulation of plant sterols in blood and tissues (sitosterolemia). To determine the significance of phytosterol exclusion from the body, we fed wild-type and ABCG5/G8 knockout mice a diet enriched with plant sterols. The high-phytosterol diet was extremely toxic to the ABCG5/G8 knockout mice but had no adverse effects on wild-type mice. ABCG5/G8 knockout mice died prematurely and developed a phenotype that included high levels of plant sterols in many tissues, liver abnormalities, and severe cardiac lesions. This study is the first to report such toxic effects of phytosterol accumulation in ABCG5/G8 knockout mice. We believe these new data support the conclusion that plant sterols are excluded from the body because they are toxic when present at high levels. PMID:23380580

  9. Effects of split fast neutron doses on the liver cells of albino Swiss mice

    International Nuclear Information System (INIS)

    Abdelmeguid, N.; Ramadan, A.A.; El-Khatib, A.M.

    1990-01-01

    The effect of neutron doses from a compact D-T neutron generator on the liver cells of adult male and female albino Swiss mice was investigated. Fast neutrons (14.5 MeV) were delivered to the whole body in a single dose or in two, four, six or eight equal doses separated by 3-day intervals. The lowest dose, 100 rem, was given over an exposure time of 6 hours and was then steadily raised to 912 rem over an exposure time of 48 hours. During exposure the neutron flux was controlled by the activation foil technique. The animals were killed for testing after each irradiation. Histological examination of the hepatocytes with a light microscope showed marked degenerative changes only after the longer irradiation periods (24, 36 and 48 h). Electron microscopy showed cytological (cytoplasmic and nuclear) changes in the hepatocytes after only 12 hours' irradiation. Densitometric scans of electron micrographs of control and 12 h-irradiated livers indicated that the control hepatocyte interphase nucleus contains approximately 72% heterochromatin, while the irradiated nucleus contains only 64% heterochromatin. (author). 13 figs., 1 tab., 18 refs

  10. Induction of colonic aberrant crypts in mice by feeding apparent N-nitroso compounds derived from hot dogs

    Science.gov (United States)

    Davis, Michael E; Lisowyj, Michal P; Zhou, Lin; Wisecarver, James L; Gulizia, James M; Shostrom, Valerie K; Naud, Nathalie; Corpet, Denis E; Mirvish, Sidney S

    2012-01-01

    Nitrite-preserved meats (e.g., hot dogs) may help cause colon cancer because they contain N-nitroso compounds. We tested whether purified hot-dog-derived total apparent N-nitroso compounds (ANC) could induce colonic aberrant crypts, which are putative precursors of colon cancer. We purified ANC precursors in hot dogs and nitrosated them to produce ANC. In preliminary tests, CF1 mice received 1 or 3 i.p. injections of 5mg azoxymethane (AOM)/kg. In Experiments 1 and 2, female A/J mice received ANC in diet. In Experiment 1, ANC dose initially dropped sharply because the ANC precursors had mostly decomposed but, later in Experiment 1 and throughout Experiment 2, ANC remained at 85 nmol/g diet. Mice were killed after 8 (AOM tests) or 17–34 (ANC tests) wk. Median numbers of aberrant crypts in the distal 2 cm of the colon for 1 and 3 AOM injections, CF1 controls, ANC (Experiment 1), ANC (Experiment 2),and untreated A/J mice were 31, 74, 12, 20, 12, and 5–6, with P ANC tests. Experiment 2 showed somewhat increased numbers of colonic mucin-depleted foci in the ANC-treated group. We conclude that hot-dog-derived ANC induced significant numbers of aberrant crypts in the mouse colon. PMID:22293095

  11. Effect of cholecystokinin on feeding is attenuated in monosodium glutamate obese mice

    Czech Academy of Sciences Publication Activity Database

    Maletínská, Lenka; Toma, Resha Shamas; Pirnik, Z.; Kiss, A.; Slaninová, Jiřina; Haluzík, M.; Železná, Blanka

    2006-01-01

    Roč. 136, č. 1/3 (2006), s. 58-63 ISSN 0167-0115 R&D Projects: GA ČR(CZ) GA303/05/0614 Institutional research plan: CEZ:AV0Z40550506; CEZ:AV0Z50520514 Keywords : monosodium glutamate * obesity * cholecistokinin * feeding behavior Subject RIV: CE - Biochemistry Impact factor: 2.442, year: 2006

  12. N-Acetyl Cysteine does not prevent liver toxicity from chronic low dose plus sub-acute high dose paracetamol exposure in young or old mice

    Science.gov (United States)

    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

    2016-01-01

    Paracetamol is an analgesic commonly used by people of all ages, which is well documented to cause severe hepatotoxicity with acute over-exposures. The risk of hepatotoxicity from non-acute 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 non-acute 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 sub-acute paracetamol over-exposure, 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 (1.33g/kg food) or control diet for 6 weeks. Mice were then dosed orally 8 times over 3 days with additional paracetamol (250mg/kg) or saline, followed by either one or two doses of oral NAC (1200mg/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. Sub-acute 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 sub-acute 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 sub-acute paracetamol toxicity. PMID:26821200

  13. Neurobeachin, a Regulator of Synaptic Protein Targeting, Is Associated with Body Fat Mass and Feeding Behavior in Mice and Body-Mass Index in Humans

    Science.gov (United States)

    Olszewski, Pawel K.; Rozman, Jan; Jacobsson, Josefin A.; Rathkolb, Birgit; Strömberg, Siv; Hans, Wolfgang; Klockars, Anica; Alsiö, Johan; Risérus, Ulf; Becker, Lore; Hölter, Sabine M.; Elvert, Ralf; Ehrhardt, Nicole; Gailus-Durner, Valérie; Fuchs, Helmut; Fredriksson, Robert; Wolf, Eckhard; Klopstock, Thomas; Wurst, Wolfgang; Levine, Allen S.; Marcus, Claude; Hrabě de Angelis, Martin; Klingenspor, Martin; Schiöth, Helgi B.; Kilimann, Manfred W.

    2012-01-01

    Neurobeachin (Nbea) regulates neuronal membrane protein trafficking and is required for the development and functioning of central and neuromuscular synapses. In homozygous knockout (KO) mice, Nbea deficiency causes perinatal death. Here, we report that heterozygous KO mice haploinsufficient for Nbea have higher body weight due to increased adipose tissue mass. In several feeding paradigms, heterozygous KO mice consumed more food than wild-type (WT) controls, and this consumption was primarily driven by calories rather than palatability. Expression analysis of feeding-related genes in the hypothalamus and brainstem with real-time PCR showed differential expression of a subset of neuropeptide or neuropeptide receptor mRNAs between WT and Nbea+/− mice in the sated state and in response to food deprivation, but not to feeding reward. In humans, we identified two intronic NBEA single-nucleotide polymorphisms (SNPs) that are significantly associated with body-mass index (BMI) in adult and juvenile cohorts. Overall, data obtained in mice and humans suggest that variation of Nbea abundance or activity critically affects body weight, presumably by influencing the activity of feeding-related neural circuits. Our study emphasizes the importance of neural mechanisms in body weight control and points out NBEA as a potential risk gene in human obesity. PMID:22438821

  14. Effects of Long-Term Feeding of the Polyphenols Resveratrol and Kaempferol in Obese Mice

    Science.gov (United States)

    Montero, Mayte; de la Fuente, Sergio; Fonteriz, Rosalba I.; Moreno, Alfredo; Alvarez, Javier

    2014-01-01

    The effect of the intake of antioxidant polyphenols such as resveratrol and others on survival and different parameters of life quality has been a matter of debate in the last years. We have studied here the effects of the polyphenols resveratrol and kaempferol added to the diet in a murine model undergoing long-term hypercaloric diet. Using 50 mice for each condition, we have monitored weight, survival, biochemical parameters such as blood glucose, insulin, cholesterol, triglycerides and aspartate aminotransferase, neuromuscular coordination measured with the rotarod test and morphological aspect of stained sections of liver and heart histological samples. Our data show that mice fed since they are 3-months-old with hypercaloric diet supplemented with any of these polyphenols reduced their weight by about 5–7% with respect to the controls fed only with hypercaloric diet. We also observed that mice fed with any of the polyphenols had reduced levels of glucose, insulin and cholesterol, and better marks in the rotarod test, but only after 1 year of treatment, that is, during senescence. No effect was observed in the rest of the parameters studied. Furthermore, although treatment with hypercaloric diets induced large changes in the pattern of gene expression in liver, we found no significant changes in gene expression induced by the presence of any of the polyphenols. Thus, our data indicate that addition of resveratrol or kaempferol to mice food produces an initial decrease in weight in mice subjected to hypercaloric diet, but beneficial effects in other parameters such as blood glucose, insulin and cholesterol, and neuromuscular coordination, only appear after prolonged treatments. PMID:25386805

  15. In vivo variation of micronuclei in BALB/c mice after low and high doses of gamma radiation

    International Nuclear Information System (INIS)

    Strain, D.; Allen, B.J.

    1996-01-01

    Full text: An adaptive response to ionising radiation exists if a low level or priming dose reduces the effect of a subsequent high or challenge dose. This has been demonstrated in vitro using the frequency of micronuclei formation as a measure of radiation-induced DNA damage. The objective of this project was to use the same approach with an animal model to investigate the existence of an in vivo adaptive response. The experimental design involved priming doses of 0.005 or 0.01 Gy and a challenge dose of 4 Gy administered 1, 2, 4, 8 or 16 hours after the priming dose. Ten mice at a time were housed in a perspex animal cage and irradiated using Co-60 gamma radiation. For every time point (1, 2, 4, 8 or 16 hours), there were four treatment groups of 5 mice for statistical analysis. The first group acted as a non-irradiated control (0 Gy). The second group of mice received only the priming dose (0.005 Gy), while the third group of mice received only the challenge dose (4 Gy). The fourth group of mice received both the priming and challenge doses 0.005 Gy + 4 Gy). The process was repeated for the second priming dose of 0.01 Gy. A total of 200 mice were used. The animals were sacrificed by cervical dislocation 24 hours after receiving the challenge dose. Both femora were removed and cleared of adhering muscle tissue. The bone marrow cells of five mice were collected and the nucleated cells removed using filtration through a mixed cellulose column incorporating a self-locking filter. The cell suspension was placed onto microscope slides using a cytocentrifuge, air-dried and then stained for the micronuclei. Then the slides were coded, and reticulocytes were scored for the presence or absence of micronuclei. Approximately 2500 cells were scored for each treatment point, and the number of micronuclei counted ranged from 3 to 125 in this sample size. While it appears that the adaptive response may be present in 2 of 9 groups of mice pre-exposed to 0.005 or 0.01 Gy, this

  16. Hepatic lipid profiling of deer mice fed ethanol using 1H and 31P NMR spectroscopy: A dose-dependent subchronic study

    International Nuclear Information System (INIS)

    Fernando, Harshica; Bhopale, Kamlesh K.; Boor, Paul J.; Ansari, G.A. Shakeel; Kaphalia, Bhupendra S.

    2012-01-01

    % ethanol. Only small increases were observed for allylic and diallylic protons, FAMEs and unsaturations in ADH + deer mice fed 3.5% ethanol vs. pair-fed controls. PCA of NMR data showed increased clustering by gradual separation of ethanol-fed ADH − deer mice groups from their respective pair-fed control groups and corresponding ethanol-fed ADH + deer mice groups. Our data indicate that dose of ethanol and hepatic ADH deficiency are two key factors involved in initiation and progression of alcoholic fatty liver disease. Further studies on characterization of individual lipid entities and associated metabolic pathways altered in our deer mouse model after different durations of ethanol feeding could be important to delineate mechanism(s) and identify potential biomarker candidate(s) of early stage ALD. -- Highlights: ► Dose-dependent ethanol-induced fatty liver was studied in deer mouse model. ► A NMR-based lipidomic approach with histology and dry lipid weights was used. ► We used principal component analysis (PCA) to analyze the NMR lipidomic data. ► Dose-dependent clustering patterns by PCA were compared among the groups.

  17. Hepatic lipid profiling of deer mice fed ethanol using {sup 1}H and {sup 31}P NMR spectroscopy: A dose-dependent subchronic study

    Energy Technology Data Exchange (ETDEWEB)

    Fernando, Harshica; Bhopale, Kamlesh K.; Boor, Paul J.; Ansari, G.A. Shakeel; Kaphalia, Bhupendra S., E-mail: bkaphali@utmb.edu

    2012-11-01

    also mildly increased in ADH{sup −} deer mice fed 1 or 2% ethanol. Only small increases were observed for allylic and diallylic protons, FAMEs and unsaturations in ADH{sup +} deer mice fed 3.5% ethanol vs. pair-fed controls. PCA of NMR data showed increased clustering by gradual separation of ethanol-fed ADH{sup −} deer mice groups from their respective pair-fed control groups and corresponding ethanol-fed ADH{sup +} deer mice groups. Our data indicate that dose of ethanol and hepatic ADH deficiency are two key factors involved in initiation and progression of alcoholic fatty liver disease. Further studies on characterization of individual lipid entities and associated metabolic pathways altered in our deer mouse model after different durations of ethanol feeding could be important to delineate mechanism(s) and identify potential biomarker candidate(s) of early stage ALD. -- Highlights: ► Dose-dependent ethanol-induced fatty liver was studied in deer mouse model. ► A NMR-based lipidomic approach with histology and dry lipid weights was used. ► We used principal component analysis (PCA) to analyze the NMR lipidomic data. ► Dose-dependent clustering patterns by PCA were compared among the groups.

  18. Effects on the glucose metabolism in type II diabetes model mice treated with dose-rates irradiation

    International Nuclear Information System (INIS)

    Nomura, Takaharu; Sakai, Kazuo

    2004-01-01

    The effects of low-dose rate gamma-irradiation on the type II diabetes mellitus were investigated in C57BL/KsJ-ab/db (db mouse). This mouse develops the type II diabetes within 8 weeks of the birth due to a dysfunction of the insulin receptors. As a result the db mouse shows obese and exhibits hyperinsulinism. Ten-week old female mice (12 mice in each group) were irradiated with gamma-rays at 0.35 mGy/hr, 0.65 mGy/hr or 1.2 mGy/hr in the low-dose rate irradiation facility in the Low Dose Radiation Research Center. The level of plasma glucose and insulin was measured. After 2 weeks irradiation, the glucose level slightly increased, however the difference between the irradiated mice and non-irradiated groups was not significant. The plasma insulin concentration decreased in the non-irradiated group to half of the initial level. In the irradiated group, it also decreased but in the group of 0.65 mGy/hr and 0.35 mGy/hr, it was significantly differed from that in the non-irradiated group. In the glucose tolerance test, plasma glucose level increased shortly after 0.1 mg/head glucose injection by mouth and reached to a peak at 90-120 min after the injection. The glucose level of the non-irradiated mice was slightly higher than that of irradiated mice. The plasma insulin level of non-irradiated group was enhanced after the injection and maintained the level during the test. However the levels of irradiated mice were decreased at 30-60 min after the injection. Both the level of non-irradiated an irradiated was almost same but the non-irradiated one was a little high. In all of mice, the plasma insulin level was highly elevated right after the 0.05 units/head insulin injection by i.p. and the levels were also gradually decreased. The level of the non-irradiated group was slowly decreased and was higher than the irradiated mice. The plasma glucose levels of all mice did not change after the test; however, the levels of irradiated mice were slightly lower than that of non

  19. A study of microscopic dose rate distribution of 99Tcm-MIBI in the liver of mice

    International Nuclear Information System (INIS)

    Wang Mingxi; Zhang Liang'an; Wang Yong; Dai Guangfu

    2002-01-01

    Objective: A microdosimetry model was tried to develop an accurate way to evaluate absorbed dose rates in target cell nuclei from radiopharmaceuticals. Methods: Microscopic frozen section autoradiography was used to determine the subcellular locations of 99 Tc m -MIBI relative to the tissue histology in the liver of mice after injection of 99 Tc m -MIBI via tail for two hours, and a mathematical model was developed to evaluate the microscopic dose rates in cell nuclei. The Medical Internal Radiation Dose (MIRD) schema was also used to evaluate the dose rates at the same time, and a comparison of the results of the two methods was conducted to determine which method is better to accurately estimate microscopic dose rates. Results: The spatial distribution of 99 Tc m -MIBI in the liver of mice at subcellular level was not uniform, and the differences between the microdosimetry model and MIRD schema were significant (P 99 Tc m -labeled pharmaceuticals at the microscopic level

  20. Effects of low dose radiation on differentiation, activation and apoptosis of thymocytes in mice

    International Nuclear Information System (INIS)

    Su Xu; Zhang Yingchun; Wan Hong; Liu Shuzheng

    1997-01-01

    Objective: To elucidate the possible mechanism of immunoenhancement after low dose radiation (LDR), the differentiation, activation and apoptosis of thymocytes following low dose irradiation were studied. Method: Kunming mice were whole-body irradiated (WBI) with low dose X-rays. The expressions of CD4, CD8, TCR, CD3, IL-2R, (Ca 2+ ) i , Bcl-2 Bax and apoptosis of thymocytes were analyzed by flow cytometry. Results: It was found that the ratio of T H /T S showed no significant changes after LDR. Thymocyte apoptosis was not increased after LDR. The increase of Bcl-2/Bax ratio after LDR might be one of its mechanisms. LDR could expedites the process of differentiation of, and facilitate the signal transduction in, thymocytes. Conclusion: The results indicate that the mechanism of immunoenhancement might be related to the expedition of the maturation, differentiation and activation of thymocytes, thus up-regulating the capability of supplying more mature T lymphocytes to the periphery by the thymus after LDR

  1. Suppressing effect of low-dose ionizing radiation on incidence of type I diabetes of NOD mice

    International Nuclear Information System (INIS)

    Nomura, T.; Makino, N.; Oda, T.; Sakai, K.

    2002-01-01

    In the present study we examined the effects of 0.5 Gy of ionizing radiation, given acutely or chronically, on the incidence of type I diabetes in non-obese diabetic mice was examined. NOD mice are characterized by a progressive loss of insulin-producing cells in the pancreas by autoimmune mechanisms. The results suggest that the suppressive effects on the onset of he diabetes by the low dose irradiation are explain by the induction of the antioxidative activity

  2. Effects of acute sublethal gamma radiation exposure on aggressive behavior in male mice: A dose-response study

    International Nuclear Information System (INIS)

    Maier, D.M.; Landauer, M.R.

    1989-01-01

    The resident-intruder paradigm was used to assess the effects of gamma radiation (0, 3, 5, 7 Gray [Gy] cobalt-60) on aggressive offensive behavior in resident male mice over a 3-month period. The defensive behavior of nonirradiated intruder mice was also monitored. A dose of 3 Gy had no effect on either the residents' offensive behavior or the defensive behavior of the intruders paired with them. Doses of 5 and 7 Gy produced decreases in offensive behavior of irradiated residents during the second week postirradiation. The nonirradiated intruders paired with these animals displayed decreases in defensive behavior during this time period, indicating a sensitivity to changes in the residents' behavior. After the third week postirradiation, offensive and defensive behavior did not differ significantly between irradiated mice and sham-irradiated controls. This study suggests that sublethal doses of radiation can temporarily suppress aggressive behavior but have no apparent permanent effect on that behavior

  3. Concentrating carbohydrates before sleep improves feeding regulation and metabolic and inflammatory parameters in mice.

    Science.gov (United States)

    Sofer, Sigal; Eliraz, Abraham; Madar, Zecharia; Froy, Oren

    2015-10-15

    New evidance highlights the importance of food timing. Recently, we showed that a low-calorie diet with carbohydrates eaten mostly at dinner changed diurnal hormone secretion and led to greater weight loss and improved metabolic status in obese people. Herein, we set out to test whether concentrated-carbohydrates diet (CCD), in which carbohydrates are fed only before sleep, leads to an improved metabolic status in mouse hypothalamus and peripheral tissues. Diet-induced obese mice were given concentrated or distributed carbohydrate diet for 6 weeks. Obese mice fed CCD ate 8.3% less, were 9.3% leaner and had 39.7% less fat mass. Leptin, ghrelin and adiponectin displayed altered secretion. In addition, these mice exhibited an improved biochemical and inflammatory status. In the hypothalamus, anorexigenic signals were up-regulated and orexigenic signals were down-regulated. In peripheral tissues, CCD promoted adiponectin signaling, repressed gluconeogenesis, enhanced lipid oxidation and lowered inflammation, thus ameliorating the major risk factors of obesity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  4. Therapy of Pelizaeus-Merzbacher disease in mice by feeding a cholesterol-enriched diet.

    Science.gov (United States)

    Saher, Gesine; Rudolphi, Fabian; Corthals, Kristina; Ruhwedel, Torben; Schmidt, Karl-Friedrich; Löwel, Siegrid; Dibaj, Payam; Barrette, Benoit; Möbius, Wiebke; Nave, Klaus-Armin

    2012-07-01

    Duplication of PLP1 (proteolipid protein gene 1) and the subsequent overexpression of the myelin protein PLP (also known as DM20) in oligodendrocytes is the most frequent cause of Pelizaeus-Merzbacher disease (PMD), a fatal leukodystrophy without therapeutic options. PLP binds cholesterol and is contained within membrane lipid raft microdomains. Cholesterol availability is the rate-limiting factor of central nervous system myelin synthesis. Transgenic mice with extra copies of the Plp1 gene are accurate models of PMD. Dysmyelination followed by demyelination, secondary inflammation and axon damage contribute to the severe motor impairment in these mice. The finding that in Plp1-transgenic oligodendrocytes, PLP and cholesterol accumulate in late endosomes and lysosomes (endo/lysosomes), prompted us to further investigate the role of cholesterol in PMD. Here we show that cholesterol itself promotes normal PLP trafficking and that dietary cholesterol influences PMD pathology. In a preclinical trial, PMD mice were fed a cholesterol-enriched diet. This restored oligodendrocyte numbers and ameliorated intracellular PLP accumulation. Moreover, myelin content increased, inflammation and gliosis were reduced and motor defects improved. Even after onset of clinical symptoms, cholesterol treatment prevented disease progression. Dietary cholesterol did not reduce Plp1 overexpression but facilitated incorporation of PLP into myelin membranes. These findings may have implications for therapeutic interventions in patients with PMD.

  5. Dose dependent transfer of 203lead to milk and tissue uptake in suckling offspring studied in rats and mice

    International Nuclear Information System (INIS)

    Palminger Hallen, I.; Oskarsson, A.

    1993-01-01

    The dose-dependent transfer of 203 Pb to milk and uptake in suckling rats and mice during a three-day nursing period was studied. On day 14 of lactation, the dams were administered a single intravenous dose of lead, labelled with 203 Pb, in four or five doses from 0.0005 to 2.0 mg Pb/kg b.wt. There was a linear relationship between Pb levels in plasma and milk of both species. The Pb milk: plasma ratios at 24 hr after administration were 119 and 89 in mice and rats, respectively. At 72 hr the Pb milk: plasma ratio had decreased to 72 in mice and 35 in rats. The tissue levels of lead in the suckling rats and mice were also linearly correlated with lead concentration in milk at 72 hr, showing that milk could be used as an indicator of lead exposure to the suckling offspring. It is concluded that lead is transported into rat and mouse milk to a very high extent and the excretion into milk is more efficient in mice than in rats. On the other hand, rat pups had higher lead levels in tissues than mice pups, which might be due to a higher bioavailability and/or a lower excretion of lead in rat pups. Thus, lead in breast milk could be used as a biological indicator of lead exposure in the mother as well as in the suckling offspring. (au) (38 refs.)

  6. Influences of reduced masticatory sensory input from soft-diet feeding upon spatial memory/learning ability in mice.

    Science.gov (United States)

    Tsutsui, Keisuke; Kaku, Masato; Motokawa, Masahide; Tohma, Yuiko; Kawata, Toshitsugu; Fujita, Tadashi; Kohno, Shinya; Ohtani, Junji; Tenjoh, Kaoru; Nakano, Mao; Kamada, Hiroko; Tanne, Kazuo

    2007-02-01

    It has been reported that reduction of masticatory afferent stimulation might influence learning and memory function. In order to clarify the influences of reduced masticatory sensory input on spatial memory/learning ability and neuropathological changes, we conducted the Morris water maze experiment and investigated the number of hippocampal neurons in association with the differences in masticatory afferent stimuli from hard- and soft-diet feeding in mice. The water maze experiment showed no significant difference in learning ability between 180-day-old solid- and powderdiet groups. Meanwhile, the ability was significantly reduced in the 360-day-old powder-diet group as compared with the age-matched solid-diet group. The total number of pyramidal cells in the hippocampal CA1 and CA3 regions was significantly smaller in 360-day-old powder-diet group than in the remaining groups. These results demonstrate that reduction of masticatory afferent stimuli due to long-term soft-diet feeding may induce neuron loss in the hippocampus and reduced memory/learning ability.

  7. Effect of continuous exposure to very low dose rates of gamma rays on life span and neoplasia in mice

    International Nuclear Information System (INIS)

    Tanaka, I.B. III; Tanaka, Satoshi; Ichinohe, Kazuaki; Matsumoto, Tsuneya; Otsu, Hiroshi; Oghiso, Yoichi; Sato, Fumiaki; Matsushita, Satoru

    2008-01-01

    Late effects of continuous exposure to ionizing radiation are potential hazards to workers in radiation facilities as well as to the general public. In the recent years, low-dose-rate and low-dose effects have become a serious concern. Using a total of 4,000 mice, we studied the late biological effects of chronic exposure to low-dose-rate radiation on life span and neoplasia. Two thousand male and 2000 female 8-week-old specific pathogen free (SPF) B6C3F1 mice were randomly divided into 4 groups, one non-irradiated (control) and three irradiated. The irradiated groups were exposed to 137 Cs gamma rays at dose-rates of 21, 1.1 and 0.05 mGy day -1 for approximately 400 days with total doses equivalent to 8000, 400 and 20 mGy, respectively. All mice were kept under SPF conditions until natural death and pathological examination was performed to determine the cause of death. Statistical analyses showed that the life spans of mice of both sexes irradiated with 21 mGy day -1 (P -1 (P 86.7% of all deaths. Compared to the non-irradiated controls, incidences of lethal neoplasms were significantly increased for myeloid leukaemia and hemangiosarcoma in males, soft tissue neoplasms and malignant granulosa cell tumors in females exposed to 21 mGy day -1 . The number of multiple primary neoplasms per mouse was significantly increased in mice irradiated at 21 mGy day -1 . Our results suggest that life shortening in mice continuously exposed to low dose-rate gamma rays is due to early death from a variety of neoplasms and not from increased incidence of specific lethal neoplasms. (author)

  8. Low-Dose Radiation-Induced Adaptive Response in Polychromatic Mice Erythrocyte as Measured by Acridine Orange Stained Micronuleus Assay

    International Nuclear Information System (INIS)

    Hee-Sun, K.; Kwang-Hee, Y.; Cha-Soom, K.; Jung-Mi, C.; Gu-Choul, S.; Suk-Young, P.; Kyoung-H, C.; Chong-Soom, K.; Young-Khi, L.; Jae-Ho, W.

    2004-01-01

    The effect of conditioning pretreatment with 0.01Gy of gamma rays on micronucleated polychromatic erythrocyte (MN-PCE) induction by 2Gy of g-rays was determined in peripheral blood of C3H/He mice. The timing of their administration of challenge doses was 6hr. The response was determined by scoring of Acridine orange dye stained MN-PCEs. The results indicate that low dose gamma ray pretreatment does protect against MN-PCE induction by the challenge g-ray dose. Introduction: An adaptive response induced by low doses of ionizing radiation in vivo reported. Some research team reports that a reduction on MN-PCE of mice caused by the pretreatment was observed [1- 4]. However, there was variability in the amount of the response depending on the time and adaptive dose [3]. This is important because the variation of MN-PCE frequency with time could lead to differences in the interpretation. In this study, differences in the biological effects within the priming dose ranges are discussed. Materials and Methods: Specific pathogen free 5-week-old C3H/He mice, purchased from Shizuoka Laboratory Center (Japan), were kept in clean and conventional environment. When 6 weeks old, the animal were whole body irradiated using irradiator of IBL-437 (137Cs, 0.8Gy/min). After various time intervals, the two groups were administrated to adaptation dose and challenge dose of 0.01Gy and 2Gy, respectively. For experiments, sham-irradiated, only adaptive and challenge dose irradiated groups were run concurrently. Smears were stained and scored using Acridine orange dye method [2]. Statistically significant differences in MN-PCE frequency were determined by comparing tie individual values at each group with the respective control values (challenge dose irradiated group) by using the paired ttest. Results and Discussions: Induced MN by the challenge dose (2Gy) after the pretreatment with 0.01Gy is low to the one induced by the challenge dose alone. In the present study, this estimation for the

  9. RBE/absorbed dose relationship of d(50)-Be neutrons determined for early intestinal tolerance in mice

    International Nuclear Information System (INIS)

    Gueulette, J.; Wambersie, A.

    1978-01-01

    RBE/absorbed dose relationship of d(50)-Be neutrons (ref.: 60 Co) was determined using intestinal tolerance in mice (LD50) after single and fractionated irradiation. RBE is 1.8 for a single fraction (about 1000 rad 60 Co dose); it increases when decreasing dose and reaches the plateau value of 2.8 for a 60 Co dose of about 200 rad. This RBE value is used for the clinical applications with the cyclotron 'Cyclone' at Louvain-la-Neuve [fr

  10. Frequencies of aneuploidy and dominant lethal mutations in young female mice induced by low dose γ-rays

    International Nuclear Information System (INIS)

    Yao Suyan; Zhang Chaoyang; Dai Lianlian; Gao Changwen

    1991-01-01

    Relationship between aneuploidy, dominant lethal mutations and doses in young feral mice induced by low dose γ-rays was examined. The results suggest that the frequencies of aneuploidy of embryos increased at 0.15 Gy, but increases at over 0.50 Gy after irradiation in groups. The frequencies of aneuploidy and dominant lethal mutations increased with increasing doses and fitted linear relationship. This dose-response relationship of trisomic was not significant. The frequency of dominant lethal mutations induced by 60 Co γ irradiation is 5.59%. The effect of dominant lethal mutation is higher than that of the aneuploidy

  11. Regulatory Forum Opinion Piece*: Retrospective Evaluation of Doses in the 26-week Tg.rasH2 Mice Carcinogenicity Studies: Recommendation to Eliminate High Doses at Maximum Tolerated Dose (MTD) in Future Studies.

    Science.gov (United States)

    Paranjpe, Madhav G; Denton, Melissa D; Vidmar, Tom J; Elbekai, Reem H

    2015-07-01

    High doses in Tg.rasH2 carcinogenicity studies are usually set at the maximum tolerated dose (MTD), although this dose selection strategy has not been critically evaluated. We analyzed the body weight gains (BWGs), mortality, and tumor response in control and treated groups of 29 Tg.rasH2 studies conducted at BioReliance. Based on our analysis, it is evident that the MTD was exceeded at the high and/or mid-doses in several studies. The incidence of tumors in high doses was lower when compared to the low and mid-doses of both sexes. Thus, we recommend that the high dose in male mice should not exceed one-half of the estimated MTD (EMTD), as it is currently chosen, and the next dose should be one-fourth of the EMTD. Because females were less sensitive to decrements in BWG, the high dose in female mice should not exceed two-third of EMTD and the next dose group should be one-third of EMTD. If needed, a third dose group should be set at one-eighth EMTD in males and one-sixth EMTD in females. In addition, for compounds that do not show toxicity in the range finding studies, a limit dose should be applied for the 26-week carcinogenicity studies. © 2014 by The Author(s).

  12. Beneficial effects of high dose taurine treatment in juvenile dystrophic mdx mice are offset by growth restriction.

    Science.gov (United States)

    Terrill, Jessica R; Pinniger, Gavin J; Nair, Keshav V; Grounds, Miranda D; Arthur, Peter G

    2017-01-01

    Duchenne Muscular Dystrophy (DMD) is a fatal muscle wasting disease manifested in young boys, for which there is no current cure. We have shown that the amino acid taurine is safe and effective at preventing dystropathology in the mdx mouse model for DMD. This study aimed to establish if treating growing mdx mice with a higher dose of taurine was more effective at improving strength and reducing inflammation and oxidative stress. Mice were treated with a dose of taurine estimated to be 16 g/kg/day, in drinking water from 1-6 weeks of age, after which in vivo and ex vivo muscle strength was assessed, as were measures of inflammation, oxidative stress and taurine metabolism. While the dose did decrease inflammation and protein oxidation in dystrophic muscles, there was no improvement in muscle strength (in contrast with benefits observed with the lower dose) and growth of the young mice was significantly restricted. We present novel data that a high taurine dose increases the cysteine content of both mdx liver and plasma, a possible result of down regulation of the taurine synthesis pathway in the liver (which functions to dispose of excess cysteine, which is toxic). These data caution that a high dose of taurine can have adverse effects and may be less efficacious than lower taurine doses. Therefore, monitoring of taurine dosage needs to be considered in future pre-clinical trials, in anticipation of using taurine as a clinical therapy for growing DMD boys (and other conditions).

  13. Experimental study of low dose radiation stimulate the haematogenesis reconstitution of the recipient after bone marrow transplantation in mice

    International Nuclear Information System (INIS)

    Zhang Liyuan; Yang Shun; Zhang Ye; Zhang Mingzhi; Jiang Jiagui; Jiang Jianping

    2007-01-01

    Objective: To investigate if low dose radiation can stimulate the haematogenesis reconstitution of the recipient after bone marrow transplantation in mice. Methods: Bone marrow cells were irradiated in vitro by different low dose radiation and then cultured in vitro. 3 H-TdR incorporation was used to measure the reproductive activity of cells, and then the radiation dose with the best stimulating effect was determined. The donator myeloid cells were exposed to low dose radiation before the recipient mice received bone marrow transplantation; then the irradiated myeloid cells were infused to the recipient; and lastly, the counts of peripheral blood cells (PBC) and bone marrow mononuclear cells (BMMNC) were monitored in order to observe the effect of low dose radiation on haematogenesis reconstitution of the recipient animal after bone marrow transplantation. Results: The reproductive activity of the bone marrow cells irradiated by 6 and 8 cGy could be improved significantly in vitro. When the recipient mice received bone marrow transplantation of the myeloid cells after low dose radiation, the counts of BMMNC and PBC were higher than those in the control group (P<0.05). Conclusions: Low dose radiation can stimulate the haematogenesis reconstitution of the recipient after bone marrow transplantation. (authors)

  14. Beneficial effects of high dose taurine treatment in juvenile dystrophic mdx mice are offset by growth restriction.

    Directory of Open Access Journals (Sweden)

    Jessica R Terrill

    Full Text Available Duchenne Muscular Dystrophy (DMD is a fatal muscle wasting disease manifested in young boys, for which there is no current cure. We have shown that the amino acid taurine is safe and effective at preventing dystropathology in the mdx mouse model for DMD. This study aimed to establish if treating growing mdx mice with a higher dose of taurine was more effective at improving strength and reducing inflammation and oxidative stress. Mice were treated with a dose of taurine estimated to be 16 g/kg/day, in drinking water from 1-6 weeks of age, after which in vivo and ex vivo muscle strength was assessed, as were measures of inflammation, oxidative stress and taurine metabolism. While the dose did decrease inflammation and protein oxidation in dystrophic muscles, there was no improvement in muscle strength (in contrast with benefits observed with the lower dose and growth of the young mice was significantly restricted. We present novel data that a high taurine dose increases the cysteine content of both mdx liver and plasma, a possible result of down regulation of the taurine synthesis pathway in the liver (which functions to dispose of excess cysteine, which is toxic. These data caution that a high dose of taurine can have adverse effects and may be less efficacious than lower taurine doses. Therefore, monitoring of taurine dosage needs to be considered in future pre-clinical trials, in anticipation of using taurine as a clinical therapy for growing DMD boys (and other conditions.

  15. Dietary feeding of flavokawain A, a Kava chalcone, exhibits a satisfactory safety profile and its association with enhancement of phase II enzymes in mice

    Directory of Open Access Journals (Sweden)

    Xuesen Li

    2014-01-01

    Full Text Available Flavokawain A (FKA, a major chalcone in the Kava plant, has recently demonstrated promising anti-cancer activities. A systematic evaluation of FKA's safety profile has not been reported before. In this study, male FVB/N mice were fed with an AIN-76A diet or AIN-76A diet supplemented with 0.6% (6 g/kg food FKA or 0.6% commercial kava root extract (KRE for three weeks. Dietary feeding of FKA did not affect food consumption and body weight. Histopathological examination of liver, kidney, colon, lung, heart, spleen, and thymus revealed no signs of FKA-induced toxicity. Biochemical serum analysis and histological examination confirmed normal organ function in FKA-treated mice. The cytotoxicity profile showed FKA had minimal side effects on bone marrow and small intestinal epithelial cells compared with Adriamycin. In addition, oral feeding of FKA increased activities of both glutathione S-transferase and quinone reductase in the liver, lung, prostate and bladder tissues of mice. In comparison, dietary feeding of 0.6% KRE increased liver/body weight ratio and decreased spleen, thymus, and testis/body weight ratios, as well as induced nodular proliferation in liver tissues. Therefore, dietary feeding FKA showed no adverse effects on major organ function and homeostasis in mice, suggesting the potential of FKA for chemoprevention study of human cancers.

  16. A single subconvulsant dose of domoic acid at mid-gestation does not cause temporal lobe epilepsy in mice.

    Science.gov (United States)

    Demars, Fanny; Clark, Kristen; Wyeth, Megan S; Abrams, Emily; Buckmaster, Paul S

    2018-05-01

    Harmful blooms of domoic acid (DA)-producing algae are a problem in oceans worldwide. DA is a potent glutamate receptor agonist that can cause status epilepticus and in survivors, temporal lobe epilepsy. In mice, one-time low-dose in utero exposure to DA was reported to cause hippocampal damage and epileptiform activity, leading to the hypothesis that unrecognized exposure to DA from contaminated seafood in pregnant women can damage the fetal hippocampus and initiate temporal lobe epileptogenesis. However, development of epilepsy (i.e., spontaneous recurrent seizures) has not been tested. In the present study, long-term seizure monitoring and histology was used to test for temporal lobe epilepsy following prenatal exposure to DA. In Experiment One, the previous study's in utero DA treatment protocol was replicated, including use of the CD-1 mouse strain. Afterward, mice were video-monitored for convulsive seizures from 2 to 6 months old. None of the CD-1 mice treated in utero with vehicle or DA was observed to experience spontaneous convulsive seizures. After seizure monitoring, mice were evaluated for pathological evidence of temporal lobe epilepsy. None of the mice treated in utero with DA displayed the hilar neuron loss that occurs in patients with temporal lobe epilepsy and in the mouse pilocarpine model of temporal lobe epilepsy. In Experiment Two, a higher dose of DA was administered to pregnant FVB mice. FVB mice were tested as a potentially more sensitive strain, because they have a lower seizure threshold, and some females spontaneously develop epilepsy. Female offspring were monitored with continuous video and telemetric bilateral hippocampal local field potential recording at 1-11 months old. A similar proportion of vehicle- and DA-treated female FVB mice spontaneously developed epilepsy, beginning in the fourth month of life. Average seizure frequency and duration were similar in both groups. Seizure frequency was lower than that of positive

  17. Dose-response models for the radiation-induction of skin tumours in mice

    International Nuclear Information System (INIS)

    Papworth, D.G.; Hulse, E.V.

    1983-01-01

    Extensive data on radiation-induced skin tumours in mice were examined using 8 models, all based on the concept that incidences of radiation-induced tumours depend on a combination of two radiation effects: a tumour induction process and the loss of reproductive integrity by the potential tumour cells. Models with and without a threshold were used, in spite of theoretical objections to threshold models. No model fitted well both the epidermal and the dermal tumour data and models which proved to be statistically satisfactory for some of the data were rejected for biological reasons. It is concluded that, for skin tumours, dose-response curves depending on a combination of cancer induction and loss of cellular reproductive integrity are distorted by some special, relatively radio-resistant, factor which we have previously postulated as being involved in radiation skin carcinogenesis. (author)

  18. Toxicology and carcinogenesis studies of nitrofurantoin (CAS No. 67-20-9) in F344/n rats and B6C3F1 mice (feed studies). Technical report

    Energy Technology Data Exchange (ETDEWEB)

    French, J.E.

    1989-09-01

    Two-year toxicology and carcinogenesis studies were conducted by administering diets containing 0, 600, or 1,300 ppm nitrofurantoin to groups of 50 female rats for 103 weeks. Groups of 50 male rats and 50 mice of each sex were fed diets containing 0, 1,300 or 2,500 ppm for 103 weeks. Under the conditions of these 2-year feed studies, there was some evidence of carcinogenic activity of nitrofurantoin for male F344/N rats as shown by increased incidences of uncommon kidney tubular cell neoplasms. Uncommon osteosarcomas of the bone and neoplasms of the subcutaneous tissue were observed in dosed male rats. Incidences of interstitial cell adenomas of the testis and neoplasms of the preputial gland were decreased in the 2,500-ppm group of male rats. There was no evidence of carcinogenic activity of nitrofurantoin for female F344/N rats fed diets containing 600 ppm or 1,300 ppm for 2 years. Female rats may have been able to tolerate higher doses. There was no evidence of carcinogenic activity of nitrofurantoin for male B6C3F(1) mice fed diets containing 1,300 ppm or 2,500 ppm for 2 years. There was clear evidence of carcinogenic activity of nitrofurantoin for female B6C3F(1) mice as shown by increased incidences of tubular adenomas, benign mixed tumors, and granulosa cell tumors of the ovary.

  19. A chronic low dose of Δ9-tetrahydrocannabinol (THC) restores cognitive function in old mice.

    Science.gov (United States)

    Bilkei-Gorzo, Andras; Albayram, Onder; Draffehn, Astrid; Michel, Kerstin; Piyanova, Anastasia; Oppenheimer, Hannah; Dvir-Ginzberg, Mona; Rácz, Ildiko; Ulas, Thomas; Imbeault, Sophie; Bab, Itai; Schultze, Joachim L; Zimmer, Andreas

    2017-06-01

    The balance between detrimental, pro-aging, often stochastic processes and counteracting homeostatic mechanisms largely determines the progression of aging. There is substantial evidence suggesting that the endocannabinoid system (ECS) is part of the latter system because it modulates the physiological processes underlying aging. The activity of the ECS declines during aging, as CB1 receptor expression and coupling to G proteins are reduced in the brain tissues of older animals and the levels of the major endocannabinoid 2-arachidonoylglycerol (2-AG) are lower. However, a direct link between endocannabinoid tone and aging symptoms has not been demonstrated. Here we show that a low dose of Δ 9 -tetrahydrocannabinol (THC) reversed the age-related decline in cognitive performance of mice aged 12 and 18 months. This behavioral effect was accompanied by enhanced expression of synaptic marker proteins and increased hippocampal spine density. THC treatment restored hippocampal gene transcription patterns such that the expression profiles of THC-treated mice aged 12 months closely resembled those of THC-free animals aged 2 months. The transcriptional effects of THC were critically dependent on glutamatergic CB1 receptors and histone acetylation, as their inhibition blocked the beneficial effects of THC. Thus, restoration of CB1 signaling in old individuals could be an effective strategy to treat age-related cognitive impairments.

  20. Effects of Low-Dose Non-Caloric Sweetener Consumption on Gut Microbiota in Mice

    Directory of Open Access Journals (Sweden)

    Takashi Uebanso

    2017-06-01

    Full Text Available Abstract: Non-caloric artificial sweeteners (NASs provide sweet tastes to food without adding calories or glucose. NASs can be used as alternative sweeteners for controlling blood glucose levels and weight gain. Although the consumption of NASs has increased over the past decade in Japan and other countries, whether these sweeteners affect the composition of the gut microbiome is unclear. In the present study, we examined the effects of sucralose or acesulfame-K ingestion (at most the maximum acceptable daily intake (ADI levels, 15 mg/kg body weight on the gut microbiome in mice. Consumption of sucralose, but not acesulfame-K, for 8 weeks reduced the relative amount of Clostridium cluster XIVa in feces. Meanwhile, sucralose and acesulfame-K did not increase food intake, body weight gain or liver weight, or fat in the epididymis or cecum. Only sucralose intake increased the concentration of hepatic cholesterol and cholic acid. Moreover, the relative concentration of butyrate and the ratio of secondary/primary bile acids in luminal metabolites increased with sucralose consumption in a dose-dependent manner. These results suggest that daily intake of maximum ADI levels of sucralose, but not acesulfame-K, affected the relative amount of the Clostridium cluster XIVa in fecal microbiome and cholesterol bile acid metabolism in mice.

  1. Methadone ameliorates multiple-low-dose streptozotocin-induced type 1 diabetes in mice

    International Nuclear Information System (INIS)

    Amirshahrokhi, K.; Dehpour, A.R.; Hadjati, J.; Sotoudeh, M.; Ghazi-Khansari, M.

    2008-01-01

    Type 1 diabetes is an autoimmune disease characterized by inflammation of pancreatic islets and destruction of β cells by the immune system. Opioids have been shown to modulate a number of immune functions, including T helper 1 (Th1) and T helper 2 (Th2) cytokines. The immunosuppressive effect of long-term administration of opioids has been demonstrated both in animal models and humans. The aim of this study was to determine the effect of methadone, a μ-opioid receptor agonist, on type 1 diabetes. Administration of multiple low doses of streptozotocin (STZ) (MLDS) (40mg/kg intraperitoneally for 5 consecutive days) to mice resulted in autoimmune diabetes. Mice were treated with methadone (10mg/kg/day subcutaneously) for 24days. Blood glucose, insulin and pancreatic cytokine levels were measured. Chronic methadone treatment significantly reduced hyperglycemia and incidence of diabetes, and restored pancreatic insulin secretion in the MLDS model. The protective effect of methadone can be overcome by pretreatment with naltrexone, an opioid receptor antagonist. Also, methadone treatment decreased the proinflammatory Th1 cytokines [interleukin (IL)-1β, tumor necrosis factor-α and interferon-γ] and increased anti-inflammatory Th2 cytokines (IL-4 and IL-10). Histopathological observations indicated that STZ-mediated destruction of β cells was attenuated by methadone treatment. It seems that methadone as an opioid agonist may have a protective effect against destruction of β cells and insulitis in the MLDS model of type 1 diabetes

  2. Long-term feeding studies in mice fed a diet containing irradiated fish. II

    International Nuclear Information System (INIS)

    Benson, H.G.; Miller, T.J.; Gottschalk, H.M.; Elias, P.S.

    1980-01-01

    Three groups of mice (Fsub(2b) generation of Part I study) were fed for 90 days, either stock ration or diets containing 45% fish, either non-irradiated or irradiated with 1.75 kGy. Equal amounts of cod and redfish (ocean perch) constituted the fish portion of the diet. Haematological and clinical chemical examinations revealed no treatment-related effects. There were no untoward terminal gross or histopathological changes. An initial lag in weight gain of males fed fish diets was attibuted to reduced food consumption, due to the difference in texture of the fish diets compared with the stock ration. (Auth.)

  3. Effects of low dose γ-rays irradiation on yield of tumor-infiltrating lymphocytes in mice

    International Nuclear Information System (INIS)

    Zou Huawei; Su Liaoyuan; Tian Hailin

    1998-01-01

    It is confirmed that low dose irradiation can inhibit tumor growth. In order to know tumor growth inhibiting mechanism, the changes of tumor-infiltrating lymphocytes (TIL) were investigated after exposing to tumor-bring mice. The mice were exposed to different doses, then , EAC cells were transplanted at the 3,6,9 and 24h hour. Ten days later TILs increased obviously caused by of 5-10 cGy γ-rays irradiation. The most obvious increasing occurred in the group in which cells was exposed irradiation for 6 hours at 10 cGy dose. A low dose radiation can make the yield of TILs increased. I might be correlated to the mechanism of tumor growth inhibiting

  4. Chronic UVA (365-nm) irradiation induced scratching in hairless mice: dose-time dependency and the effect of ketanserin

    International Nuclear Information System (INIS)

    Laat, J.M.T. de; Groenendijk, M.; Vloten, W.A. van; Gruijl, F.R. de; Seite, S.

    1997-01-01

    In a study on the dose-response relationship for longwave UVA (UVA1; 340-400 nm) carcinogenesis in hairless mice scratch marks appeared after months of daily exposure as an unwanted side effect. Tumor induction in the highest of the 4 tested dose groups (receiving a daily dose of 430 kJ/m 2 of 365-nm radiation) could not be determined because extensive scarification occurred prior to the development of any tumors. The induction of scratch marks could be scored and quantified in all 4 dose groups tested. The UVA1 dose-dependencies for the induction of tumors and scratch marks were compared. We found that the induction of scratch marks depended mainly on the cumulative UVA1 exposure, whereas tumor induction showed a lesser dose-dependency. An attempt was made to prevent the apparent pruritogenic effect of UVA1 irradiation and to understand its mechanism. The influence of ketanserin, a serotonin/histamine antagonist, on the UVA1 induction of scratch marks was tested in groups of 8 mice daily irradiated with 430 kJ/m 2 . No difference was found between treated and untreated animals. Histological examination of skin biopsies from irradiated mice from the 430-kJ/m 2 dose group from the UVA1 carcinogenic experiment, showed no changes in numbers of mast cells or other inflammatory features when compared to skin biopsies from unirradiated control mice. This indicated that UVA1-induced scratching is not mediated through mast cell release of serotonin and/or histamine. An adequate therapeutic treatment which can prevent UVA1-induced scratching would enable us to test tumor induction with UVA1 over a larger dose range, and may provide additional insight in how this radiation damages the skin. It remains conjectural whether there exists and analogous UVA-induced pruritus in human skin. (au)

  5. Threshold dose to developing central nerve system of rats and mice from prenatal exposure to tritiated water

    International Nuclear Information System (INIS)

    Zhou Xiangyan; Wang Bing; Gao Weimin; Lu Huimin

    1999-01-01

    Objective: To study the threshold dose to the developing central nerve system of rats and mice from prenatal exposure to tritiated water. methods: Pregnant adult C 57 BL/6J strain mice and Wistar strain rats were irradiated with beta-rays from HTO by a single intraperitoneal injection on the 12.5 th and 13 th days of gestation. The activities of HTO were 24.09, 48.18 and 144.54 ( x 10 4 Bq/g bw), respectively. Fifty-six parameters including postnatal growth, neutro-behavior, pathology of brain, neuropeptide contents, changes of hippocampal neurons, Ca 2+ conductance of hippocampal neurons etc were used to test the teratogenic threshold dose the lowest dose was different from that of the control). Results: Of the observed 56 parameters of rats and mice 80.4% indicated that the threshold doses for prenatal HTO exposure ranged from 0.030 Gy to 0.092 Gy, and the other 19.6% showed the threshold doses from 0.093 to 0.300 Gy. Conclusions: There exists threshold dose from the low level tritiated water irradiation of the developing central nerve system

  6. Tissue distribution and elimination of BDE 47 in mice following a single oral dose

    Energy Technology Data Exchange (ETDEWEB)

    Staskal, D. [Curriculum in Toxicology, Chapel Hill, NC (United States); Diliberto, J.; DeVito, M.; Birnbaum, L. [US EPA, ORD, NHEERL, ETD, RTP (United States)

    2004-09-15

    2,2',4,4'-Tetrabromodiphenyl ether (BDE 47) is a polybrominated diphenyl ether (PBDE) congener which is part of a class of brominated flame retardants (BFRs) commonly used in a variety of highly flammable consumer goods. Concern for the effects of PBDEs has increased significantly in recent years as their presence has been detected in environmental samples and in human tissues at steadily increasing concentrations. Despite its small contribution to the PBDE global production and usage, BDE 47 is the major congener found in environmental samples and human tissue. Limited toxicology studies suggest that BDE 47 is a developmental neurotoxicant and an endocrine disruptor however, several data gaps exist and must be investigated in order to evaluate the human health risk of BDE 47. This study investigated basic toxicokinetic properties of BDE 47 in female C57BL/6J mice. Here we report the effect of time on the absorption, distribution, and excretion following a single, oral dose of 14C-labeled BDE 47. Animals were administered 1.0mg BDE 47/kg bw, a dose chosen based on previous studies. Distribution and elimination were monitored at several time points ranging from 1 hour to 21 days following exposure. Data from these basic toxicokinetic studies will be applied to studies investigating the toxicokinetics of BDE 47 in a developmental model as well as in the development of a physiologically-based pharmacokinetic (PBPK) model.

  7. Ethanol metabolism, oxidative stress, and endoplasmic reticulum stress responses in the lungs of hepatic alcohol dehydrogenase deficient deer mice after chronic ethanol feeding

    Energy Technology Data Exchange (ETDEWEB)

    Kaphalia, Lata [Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 775555 (United States); Boroumand, Nahal [Department of Pathology, The University of Texas Medical Branch, Galveston, TX 775555 (United States); Hyunsu, Ju [Department of Preventive Medicine and Community Health, The University of Texas Medical Branch, Galveston, TX 775555 (United States); Kaphalia, Bhupendra S., E-mail: bkaphali@utmb.edu [Department of Pathology, The University of Texas Medical Branch, Galveston, TX 775555 (United States); Calhoun, William J. [Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 775555 (United States)

    2014-06-01

    ethanol feeding causes oxidative stress, ER stress and inflammation in lungs of ADH– deer mice. • Chronic ethanol feeding generates FAEEs (nonoxidative metabolites of ethanol) in lungs of ADH– deer mice. • Chronic ethanol feeding induces CYP2E1 in the lungs of ADH– deer mice. • Lack of ER homeostasis due to a prolonged ethanol feeding could trigger inflammation.

  8. Ethanol metabolism, oxidative stress, and endoplasmic reticulum stress responses in the lungs of hepatic alcohol dehydrogenase deficient deer mice after chronic ethanol feeding

    International Nuclear Information System (INIS)

    Kaphalia, Lata; Boroumand, Nahal; Hyunsu, Ju; Kaphalia, Bhupendra S.; Calhoun, William J.

    2014-01-01

    ethanol feeding causes oxidative stress, ER stress and inflammation in lungs of ADH– deer mice. • Chronic ethanol feeding generates FAEEs (nonoxidative metabolites of ethanol) in lungs of ADH– deer mice. • Chronic ethanol feeding induces CYP2E1 in the lungs of ADH– deer mice. • Lack of ER homeostasis due to a prolonged ethanol feeding could trigger inflammation

  9. Changes of chromosome aberration rate and micronucleus frequency along with accumulated dose in continuously irradiated mice with a low dose rate of γ-rays

    International Nuclear Information System (INIS)

    Tanaka, Kimio; Izumi, Jun; Yanai, Takanori; Ichinohe, Kazuaki; Matsumoto, Tsuneya

    2003-01-01

    Chromosome aberrations in chronically exposed workers in nuclear facilities and medical radiologists have been reported. However chronological change of chromosome aberration rates along with accumulated dose has not been well studied. Chromosome aberrations and micronuclei in spleen lymphocytes were observed serially in mice continuously irradiated with a low dose rate of 20 mGy/day up to 400 days. Chromosome aberration rates were rapidly increased to 11.1% at 1 Gy, while micronucleus incidence increased at 5 Gy. After these doses their increase rates were saturated. Micronucleus incidence in bone marrow erythroblasts was higher than in spleen cells. These chronological changes of cytogenetic aberrations seem to be induced through a balance between developments of chromosome aberrations and micronuclei, and life span of spleen lymphocytes. These results will be helpful for risk assessment in low dose rate radiation exposure. (author)

  10. Effects of irradiation at different dose rates on the onset of type I diabetes in model mice

    International Nuclear Information System (INIS)

    Nomura, Takashi; Sakai, Kazuo

    2003-01-01

    We previously demonstrated that low-dose irradiation (0.5 Gy) increased the level of antioxidants and decreased the level of lipid peroxide in normal mice. We also found that 0.5 Gy-irradiation of NOD mice suppressed the onset of type I diabetes. These results were obtained by the irradiation at high dose rate. The aim of the present study is to examine the effects at the low dose rate. The mice were acutely irradiated with 0.5 Gy of X-rays (300 kVp) at 94.2 Gy/hr at 10, 11, 12, 13 or 14 weeks of age, or chronically irradiated with 0.5 Gy of 137 Cs γ-rays at 0.95 mGy/hr starting at 10,11,12,13 or 14 weeks of age. When irradiated at 12th week with the high dose rate X-rays, the onset of diabetes suppressed, and the increase in the specific activity of superoxide dismutase (SOD) in pancreas was observed. On the other hand, the low dose rate γ-rays delivered from 12th week of age to 14th was less effective in the suppression of the incidence of diabetes than the high dose rate X-rays at the 12-14 weeks of age. Furthermore, the significant increase in pancreatic SOD activity was not observed after the low dose irradiation. Splenic macrophage activities of superoxide generation were not affected by the high dose rate irradiation nor the low dose rate irradiation. (author)

  11. Proposed mechanistic description of dose-dependent BDE-47 urinary elimination in mice using a physiologically based pharmacokinetic model

    Energy Technology Data Exchange (ETDEWEB)

    Emond, Claude, E-mail: claude.emond@umontreal.ca [BioSimulation Consulting Inc., Newark, DE (United States); Departments of Environmental and Occupational Health, Medicine Faculty, University of Montreal, Montreal, Quebec (Canada); Sanders, J. Michael, E-mail: sander10@mail.nih.gov [National Cancer Institute, Research Triangle Park, NC (United States); Wikoff, Daniele, E-mail: dwikoff@toxstrategies.com [ToxStrategies, Austin, TX (United States); Birnbaum, Linda S., E-mail: birnbaumls@niehs.nih.gov [National Cancer Institute, Research Triangle Park, NC (United States)

    2013-12-01

    Polybrominated diphenyl ethers (PBDEs) have been used in a wide variety of consumer applications as additive flame retardants. In North America, scientists have noted continuing increases in the levels of PBDE congeners measured in human serum. Some recent studies have found that PBDEs are associated with adverse health effects in humans, in experimental animals, and wildlife. This laboratory previously demonstrated that urinary elimination of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) is saturable at high doses in mice; however, this dose-dependent urinary elimination has not been observed in adult rats or immature mice. Thus, the primary objective of this study was to examine the mechanism of urinary elimination of BDE-47 in adult mice using a physiologically based pharmacokinetic (PBPK) model. To support this objective, additional laboratory data were collected to evaluate the predictions of the PBPK model using novel information from adult multi-drug resistance 1a/b knockout mice. Using the PBPK model, the roles of mouse major urinary protein (a blood protein carrier) and P-glycoprotein (an apical membrane transporter in proximal tubule cells in the kidneys, brain, intestines, and liver) were investigated in BDE-47 elimination. The resulting model and new data supported the major role of m-MUP in excretion of BDE-47 in the urine of adult mice, and a lesser role of P-gp as a transporter of BDE-47 in mice. This work expands the knowledge of BDE-47 kinetics between species and provides information for determining the relevancy of these data for human risk assessment purposes. - Highlights: • We report the first study on PBPK model on flame retardant in mice for BDE-47. • We examine mechanism of urinary elimination of BDE-47 in mice using a PBPK model. • We investigated roles of m-MUP and P-gp as transporters in urinary elimination.

  12. Adaptive response of spermatogenic cell apoptosis selectively induced by low dose X-ray irradiation in mice

    International Nuclear Information System (INIS)

    Liu Guangwei; Dong Lihua; Liu Yang; Lv Zhe; Liu Shuchun; Gong Shouliang

    2003-01-01

    Objective: The adaptive response of spermatogenic cell apoptosis induced by whole-body X-ray irradiation at low doses was studied in mice. Methods: Kunming male mice were irradiated with an inductive dose (D1:75 mGy) and/or a challenging dose (D2:1.0, 2.0 or 3.0 Gy). Different kinds of spermatogenic cells were separated using density gradient centrifugation and their apoptotic percentages were analysed using flow cytometry (FCM). Results: When the mice were irradiated with D1 6 h before irradiation with D2, the apoptotic percentages of the spermatogonia and spermatocytes declined rapidly as compared with those in the groups irradiated with D2 only, and those of spermatids and spermatozoa showed no significant changes. When the interval times between D1 and D2 was 3, 6, 12 or 24 h, the apoptotic percentages in spermatogonia and spermatocytes reduced early, significantly and continued for a longer duration after smaller D2(1.0 and 2.0 Gy) irradiation, while the apoptotic percentages did not change after larger D2(3.0 Gy) irradiation. Conclusion: The adaptive response of apoptosis in spermatogonia and spermatocytes could be selectively induced by low dose X-ray irradiation. The adaptive response could be closely related to the D2 dose and interval time between D1 and D2

  13. Clinically relevant doses of lidocaine and bupivacaine do not impair cutaneous wound healing in mice.

    Science.gov (United States)

    Waite, A; Gilliver, S C; Masterson, G R; Hardman, M J; Ashcroft, G S

    2010-06-01

    Lidocaine and bupivacaine are commonly infiltrated into surgical cutaneous wounds to provide local anaesthesia after surgical procedures. However, very little is known about their effects on cutaneous wound healing. If an inhibitory effect is demonstrated, then the balance between the benefits of postoperative local anaesthesia and the negatives of impaired cutaneous wound healing may affect the decision to use local anaesthesia or not. Furthermore, if a difference in the rate of healing of lidocaine- and bupivacaine-treated cutaneous wounds is revealed, or if an inhibitory effect is found to be dose-dependent, then this may well influence the choice of agent and its concentration for clinical use. Immediately before incisional wounding, we administered lidocaine and bupivacaine intradermally to adult female mice, some of which had been ovariectomized to act as a model of post-menopausal women (like post-menopausal women, ovariectomized mice heal wounds poorly, with increased proteolysis and inflammation). Day 3 wound tissue was analysed histologically and tested for expression of inflammatory and proteolytic factors. On day 3 post-wounding, wound areas and extent of re-epithelialization were comparable between the control and local anaesthetic-treated animals, in both intact and ovariectomized groups. Both tested drugs significantly increased wound activity of the degradative enzyme matrix metalloproteinase-2 relative to controls, while lidocaine also increased wound neutrophil numbers. Although lidocaine and bupivacaine influenced local inflammatory and proteolytic factors, they did not impair the rate of healing in either of two well-established models (mimicking normal human wound healing and impaired age-related healing).

  14. Comparison of distribution and toxicity following repeated oral dosing of different vanadium oxide nanoparticles in mice

    Energy Technology Data Exchange (ETDEWEB)

    Park, Eun-Jung, E-mail: pejtoxic@hanmail.net [Myunggok Eye Research Institute, Konyang University, Daejeon 302-718 (Korea, Republic of); Lee, Gwang-Hee [School of Civil, Environmental, and Architectural Engineering, Korea University, Seoul 136-713 (Korea, Republic of); Yoon, Cheolho [Seoul Center, Korea Basic Science Institute, Seoul 126-16 (Korea, Republic of); Kim, Dong-Wan, E-mail: dwkim1@korea.ac.kr [School of Civil, Environmental, and Architectural Engineering, Korea University, Seoul 136-713 (Korea, Republic of)

    2016-10-15

    Vanadium is an important ultra-trace element derived from fuel product combustion. With the development of nanotechnology, vanadium oxide nanoparticles (VO NPs) have been considered for application in various fields, thus the possibility of release into the environment and human exposure is also increasing. Considering that verification of bioaccumulation and relevant biological responses are essential for safe application of products, in this study, we aimed to identify the physicochemical properties that determine their health effects by comparing the biological effects and tissue distribution of different types of VO NPs in mice. For this, we prepared five types of VO NPs, commercial (C)-VO{sub 2} and -V{sub 2}O{sub 5} NPs and synthetic (S)-VO{sub 2}, -V{sub 2}O{sub 3,} and -V{sub 2}O{sub 5} NPs. While the hydrodynamic diameter of the two types of C-VO NPs was irregular and impossible to measure, those of the three types of S-VO NPs was in the range of 125–170 nm. The S- and C-V{sub 2}O{sub 5} NPs showed higher dissolution rates compared to other VO NPs. We orally dosed the five types of VO NPs (70 and 210 μg/mouse, approximately 2 and 6 mg/kg) to mice for 28 days and compared their biodistribution and toxic effects. We found that S-V{sub 2}O{sub 5} and S-V{sub 2}O{sub 3} NPs more accumulated in tissues compared to other three types of VO NPs, and the accumulated level was in order of heart>liver>kidney>spleen. Additionally, tissue levels of redox reaction-related elements and electrolytes (Na{sup +}, K{sup +}, and Ca{sup 2+}) were most clearly altered in the heart of treated mice. Notably, all S- and C-VO NPs decreased the number of WBCs at the higher dose, while total protein and albumin levels were reduced at the higher dose of S-V{sub 2}O{sub 5} and S-V{sub 2}O{sub 3} NPs. Taken together, we conclude that the biodistribution and toxic effects of VO NPs depend on their dissolution rates and size (surface area). Additionally, we suggest that further studies

  15. Identification of a cytochrome P4502E1/Bid/C1q-dependent axis mediating inflammation in adipose tissue after chronic ethanol feeding to mice.

    Science.gov (United States)

    Sebastian, Becky M; Roychowdhury, Sanjoy; Tang, Hui; Hillian, Antoinette D; Feldstein, Ariel E; Stahl, Gregory L; Takahashi, Kazue; Nagy, Laura E

    2011-10-14

    Chronic, heavy alcohol exposure results in inflammation in adipose tissue, insulin resistance, and liver injury. Here we have identified a CYP2E1/Bid/C1q-dependent pathway that is activated in response to chronic ethanol and is required for the development of inflammation in adipose tissue. Ethanol feeding for 25 days to wild-type (C57BL/6J) mice increased expression of multiple markers of adipose tissue inflammation relative to pair-fed controls independent of increased body weight or adipocyte size. Ethanol feeding increased the expression of CYP2E1 in adipocytes, but not stromal vascular cells, in adipose tissue and Cyp2e1(-/-) mice were protected from adipose tissue inflammation in response to ethanol. Ethanol feeding also increased the number of TUNEL-positive nuclei in adipose tissue of wild-type mice but not in Cyp2e1(-/-) or Bid (-/-) mice. Apoptosis contributed to adipose inflammation, as the expression of multiple inflammatory markers was decreased in mice lacking the Bid-dependent apoptotic pathway. The complement protein C1q binds to apoptotic cells, facilitating their clearance and activating complement. Making use of C1q-deficient mice, we found that activation of complement via C1q provided the critical link between CYP2E1/Bid-dependent apoptosis and onset of adipose tissue inflammation in response to chronic ethanol. In summary, chronic ethanol increases CYP2E1 activity in adipose, leading to Bid-mediated apoptosis and activation of complement via C1q, finally resulting in adipose tissue inflammation. Taken together, these data identify a novel mechanism for the development of adipose tissue inflammation that likely contributes to the pathophysiological effects of ethanol.

  16. Dose-response for X-ray induction of myeloid leukaemia in male CBA/H mice

    Energy Technology Data Exchange (ETDEWEB)

    Mole, R H; Papworth, D G; Corp, M J [Medical Research Council, Harwell (UK). Radiobiological Research Unit

    1983-02-01

    The form of the dose-response for induction of malignant diseases in vivo by ionizing radiation is not yet established in spite of its scientific interest and its practical importance. Considerably extended observations have confirmed that the dose-response for acute myeloid leukaemia induced in male CBA/H mice by X-ray exposure is highly curvilinear. The dose-response was well fitted by the expression aD/sup 2/esup(-..gamma..D) (D = dose) in agreement with induction at the cellular level in proportion to D/sup 2/ over the whole dose range 0.25-6.0 Gy. The factor esup(-..gamma..D) accounts for the inescapable concomitant inactivating action of the inducing irradiation. The quantitative aspects of induction of myeloid leukaemia by ionizing radiation are unlike the induction of genetic mutation or cell inactivation and suggest that interaction of two adjoining cells is an essential element in radiation leukaemogenesis.

  17. Dose-rate effects and chronological changes of chromosome aberration rates in spleen cells from mice that are chronically exposed to gamma-ray at low dose rates

    International Nuclear Information System (INIS)

    Tanaka, Kimio; Kohda, Atsushi; Ichinohe, Kazuaki; Matsumoto, Tsuneya; Oghiso, Yoichi

    2006-01-01

    Dose-rate effects have not been examined in the low dose-rate regions of less than 60-600 mGy/h. Mice were chronically exposed to gamma-ray at 20 mGy/day (approximately 1 mGy/h) up to 700 days and at 1 mGy/day (approximately 0.05 mGy/h) for 500 days under SPF conditions. Chronological changes of chromosome aberration rates in spleen cells were observed along with accumulated doses at both low dose-rates. Unstable aberrations increased in a biphasic manner within 0-2 Gy and 4-14 Gy in 20 mGy/day irradiation. They slightly increased up to 0.5 Gy in 1 mGy/day irradiation. Chromosome aberration rates at 20 mGy/day and 1 mGy/day were compared at the same total doses of 0.5 Gy and 0.25 Gy. They were 2.0 vs. 0.53, and 1.0 vs. 0.47 respectively. Thus, dose-rate effects were observed in these low dose-rate regions. (author)

  18. Tg.rasH2 Mice and not CByB6F1 Mice Should Be Used for 28-Day Dose Range Finding Studies Prior to 26-Week Tg.rasH2 Carcinogenicity Studies.

    Science.gov (United States)

    Paranjpe, Madhav G; Belich, Jessica; Vidmar, Tom J; Elbekai, Reem H; McKeon, Marie; Brown, Caren

    Our recent retrospective analysis of data, collected from 29 Tg.rasH2 mouse carcinogenicity studies, determined how successful the strategy of choosing the high dose for the 26-week studies was based on the estimated maximum tolerated dose (EMTD) derived from earlier 28-day dose range finding (DRF) studies conducted in CByB6F1 mice. Our analysis demonstrated that the high doses applied at EMTD in the 26-week Tg.rasH2 studies failed to detect carcinogenic effects. To investigate why the dose selection process failed in the 26-week carcinogenicity studies, the initial body weights, terminal body weights, body weight gains, food consumption, and mortality from the first 4 weeks of 26-week studies with Tg.rasH2 mice were compared with 28-day DRF studies conducted with CByB6F1 mice. Both the 26-week and the earlier respective 28-day studies were conducted with the exact same vehicle, test article, and similar dose levels. The analysis of our results further emphasizes that the EMTD and subsequent lower doses, determined on the basis of the 28-day studies in CByB6F1 mice, may not be an accurate strategy for selecting appropriate dose levels for the 26-week carcinogenicity studies in Tg.rasH2 mice. Based on the analysis presented in this article, we propose that the Tg.rasH2 mice and not the CByB6F1 mice should be used in future DRF studies. The Tg.rasH2 mice demonstrate more toxicity than the CByB6F1 mice, possibly because of their smaller size compared to CByB6F1 mice. Also, the Tg.rasH2 males appear to be more sensitive than the female Tg.rasH2 mice.

  19. Muscle physiology changes induced by every other day feeding and endurance exercise in mice: effects on physical performance.

    Directory of Open Access Journals (Sweden)

    Elizabeth Rodríguez-Bies

    Full Text Available Every other day feeding (EOD and exercise induce changes in cell metabolism. The aim of the present work was to know if both EOD and exercise produce similar effects on physical capacity, studying their physiological, biochemical and metabolic effects on muscle. Male OF-1 mice were fed either ad libitum (AL or under EOD. After 18 weeks under EOD, animals were also trained by using a treadmill for another 6 weeks and then analyzed for physical activity. Both, EOD and endurance exercise increased the resistance of animals to extenuating activity and improved motor coordination. Among the groups that showed the highest performance, AL and EOD trained animals, ALT and EODT respectively, only the EODT group was able to increase glucose and triglycerides levels in plasma after extenuating exercise. No high effects on mitochondrial respiratory chain activities or protein levels neither on coenzyme Q levels were found in gastrocnemius muscle. However, exercise and EOD did increase β-oxidation activity in this muscle accompanied by increased CD36 levels in animals fed under EOD and by changes in shape and localization of mitochondria in muscle fibers. Furthermore, EOD and training decreased muscle damage after strenuous exercise. EOD also reduced the levels of lipid peroxidation in muscle. Our results indicate that EOD improves muscle performance and resistance by increasing lipid catabolism in muscle mitochondria at the same time that prevents lipid peroxidation and muscle damage.

  20. Optimizing the dosing schedule of l-asparaginase improves its anti-tumor activity in breast tumor-bearing mice

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    Shoya Shiromizu

    2018-04-01

    Full Text Available Proliferation of acute lymphoblastic leukemic cells is nutritionally dependent on the external supply of asparagine. l-asparaginase, an enzyme hydrolyzing l-asparagine in blood, is used for treatment of acute lymphoblastic leukemic and other related blood cancers. Although previous studies demonstrated that l-asparaginase suppresses the proliferation of cultured solid tumor cells, it remains unclear whether this enzyme prevents the growth of solid tumors in vivo. In this study, we demonstrated the importance of optimizing dosing schedules for the anti-tumor activity of l-asparaginase in 4T1 breast tumor-bearing mice. Cultures of several types of murine solid tumor cells were dependent on the external supply of asparagine. Among them, we selected murine 4T1 breast cancer cells and implanted them into BALB/c female mice kept under standardized light/dark cycle conditions. The growth of 4T1 tumor cells implanted in mice was significantly suppressed by intravenous administration of l-asparaginase during the light phase, whereas its administration during the dark phase failed to show significant anti-tumor activity. Decreases in plasma asparagine levels due to the administration of l-asparaginase were closely related to the dosing time-dependency of its anti-tumor effects. These results suggest that the anti-tumor efficacy of l-asparaginase in breast tumor-bearing mice is improved by optimizing the dosing schedule. Keywords: l-asparaginase, Asparagine, Solid tumor, Chrono-pharmacotherapy

  1. Dosing-time contributes to chronotoxicity of clofarabine in mice via means other than pharmacokinetics

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    Jia-Jie Luan

    2016-05-01

    Full Text Available To evaluate the time- and dose-dependent toxicity of clofarabine in mice and to further define the chronotherapy strategy of it in leukemia, we compared the mortality rates, LD50s, biochemical parameters, histological changes and organ indexes of mice treated with clofarabine at various doses and time points. Plasma clofarabine levels and pharmacokinetic parameters were monitored continuously for up to 8 hours after the single intravenous administration of 20 mg/kg at 12:00 noon and 12:00 midnight by high performance liquid chromatography (HPLC-UV method. Clofarabine toxicity in all groups fluctuated in accordance with circadian rhythms in vivo. The toxicity of clofarabine in mice in the rest phase was more severe than the active one, indicated by more severe liver damage, immunodepression, higher mortality rate, and lower LD50. No significant pharmacokinetic parameter changes were observed between the night and daytime treatment groups. These findings suggest the dosing-time dependent toxicity of clofarabine synchronizes with the circadian rhythm of mice, which might provide new therapeutic strategies in further clinical application.

  2. Macroarray analysis of gene expression in hematopoietic tissues from mice continuously irradiated by low dose-rate ionizing radiation

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    Saitou, Mikio; Nakamura, Shingo; Shirata, Katsutoshi; Yanai, Takanori; Izumi, Jun; Sugihara, Takashi; Tanaka, Satoshi; Tanaka, Kimio; Otsu, Hiroshi; Sato, Fumiaki [Inst. for Environmental Sciences, Rokkasho, Aomori (Japan)

    2002-07-01

    We found that the number of hematopoietic progenitor cells in bone marrow and spleen from 4 - 8 Gy-irradiated mice decreased about 50%, in spite of no change in the number of peripheral blood cells. To evaluate the effects of chronic irradiation by low dose-rate ionizing radiation on the gene expression in mice hematopoietic cells from bone marrow and spleen, the RNA expressions of more than 500 genes such as cytokine genes and oncogenes were measured on the membranes by the RNA macroarray analysis method at accumulated doses at 4.7 and 8 Gy in specific-pathogen-free (SPF) C3H/HeN female mice irradiated by {sup 137}Cs {gamma}-rays with the dose rate of 20 mGy/day. The RNA macroarray analysis in spleens from 8 Gy-irradiated mice showed that the expressions in 16 genes including noggin were more than 1.5 times larger than that of control, while those in 64 genes including shh (sonic hedgehog) and BMP-4 (bone morphogenesis protein 4) were more than 1.5 times smaller than that of control. (author)

  3. Optimizing the dosing schedule of l-asparaginase improves its anti-tumor activity in breast tumor-bearing mice.

    Science.gov (United States)

    Shiromizu, Shoya; Kusunose, Naoki; Matsunaga, Naoya; Koyanagi, Satoru; Ohdo, Shigehiro

    2018-04-01

    Proliferation of acute lymphoblastic leukemic cells is nutritionally dependent on the external supply of asparagine. l-asparaginase, an enzyme hydrolyzing l-asparagine in blood, is used for treatment of acute lymphoblastic leukemic and other related blood cancers. Although previous studies demonstrated that l-asparaginase suppresses the proliferation of cultured solid tumor cells, it remains unclear whether this enzyme prevents the growth of solid tumors in vivo. In this study, we demonstrated the importance of optimizing dosing schedules for the anti-tumor activity of l-asparaginase in 4T1 breast tumor-bearing mice. Cultures of several types of murine solid tumor cells were dependent on the external supply of asparagine. Among them, we selected murine 4T1 breast cancer cells and implanted them into BALB/c female mice kept under standardized light/dark cycle conditions. The growth of 4T1 tumor cells implanted in mice was significantly suppressed by intravenous administration of l-asparaginase during the light phase, whereas its administration during the dark phase failed to show significant anti-tumor activity. Decreases in plasma asparagine levels due to the administration of l-asparaginase were closely related to the dosing time-dependency of its anti-tumor effects. These results suggest that the anti-tumor efficacy of l-asparaginase in breast tumor-bearing mice is improved by optimizing the dosing schedule. Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  4. In vivo99mTc-HYNIC-annexin V imaging of early tumor apoptosis in mice after single dose irradiation

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    He Yong-bo

    2009-10-01

    Full Text Available Abstract Background Apoptosis is a major mode of hematological tumor death after radiation. Early detection of apoptosis may be beneficial for cancer adaptive treatment. 99mTc-HYNIC-annexinV has been reported as a promising agent for in vivo apoptosis imaging. The purpose of this study is to evaluate the feasibility of in vivo99mTc-HYNIC-annexinV imaging of radiation- induced apoptosis, and to investigate its correlation with radiosensitivity. Methods Ten days after inoculation of tumor cells in the right upper limbs, the mice were randomly divided into two groups. The imaging group (4 mice each level, 4 dose levels was injected with 4-8 MBq 99mTc-HYNIC-annexinV 24 hours after irradiation and imaged 1 hr post-injection, and the mice were sacrificed immediately after imaging for biodistribution analysis of annexin V. The observation group (4 mice each level, 2 dose levels was only observed for tumor regression post-radiation. The number of apoptotic cells in a tumor was estimated with TUNEL assay. Results The 99mTc-HYNIC-annexin V uptake in E14 lymphoma significantly increased as the radiation dose escalated from 0 to 8 Gy, and significantly correlated with the number of TUNEL-positive cells (r = 0.892, P Conclusion 99mTc-HYNIC-annexinV in vivo imaging is a feasible method to detect early radiation-induced apoptosis in different tumors, and might be predictive for radiation sensitivity.

  5. Insulin signaling displayed a differential tissue-specific response to low-dose dihydrotestosterone in female mice.

    Science.gov (United States)

    Andrisse, Stanley; Billings, Katelyn; Xue, Ping; Wu, Sheng

    2018-04-01

    Hyperandrogenemia and hyperinsulinemia are believed to play prominent roles in polycystic ovarian syndrome (PCOS). We explored the effects of low-dose dihydrotestosterone (DHT), a model of PCOS, on insulin signaling in metabolic and reproductive tissues in a female mouse model. Insulin resistance in the energy storage tissues is associated with type 2 diabetes. Insulin signaling in the ovaries and pituitary either directly or indirectly stimulates androgen production. Energy storage and reproductive tissues were isolated and molecular assays were performed. Livers and white adipose tissue (WAT) from DHT mice displayed lower mRNA and protein expression of insulin signaling intermediates. However, ovaries and pituitaries of DHT mice exhibited higher expression levels of insulin signaling genes/proteins. Insulin-stimulated p-AKT levels were blunted in the livers and WAT of the DHT mice but increased or remained the same in the ovaries and pituitaries compared with controls. Glucose uptake decreased in liver and WAT but was unchanged in pituitary and ovary of DHT mice. Plasma membrane GLUTs were decreased in liver and WAT but increased in ovary and pituitary of DHT mice. Skeletal muscle insulin-signaling genes were not lowered in DHT mice compared with control. DHT mice did not display skeletal muscle insulin resistance. Insulin-stimulated glucose transport increased in skeletal muscles of DHT mice compared with controls. DHT mice were hyperinsulinemic. However, the differential mRNA and protein expression pattern was independent of hyperinsulinemia in cultured hepatocytes and pituitary cells. These findings demonstrate a differential effect of DHT on the insulin-signaling pathway in energy storage vs. reproductive tissues independent of hyperinsulinemia.

  6. Pre- and postnatal exposure to low dose glufosinate ammonium induces autism-like phenotypes in mice.

    Science.gov (United States)

    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.

  7. Perinatal exposure to low dose glufosinate ammonium induces autism-like phenotypes in mice.

    Directory of Open Access Journals (Sweden)

    Anthony eLaugeray

    2014-11-01

    Full Text Available 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 normalized 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 perinatal 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.

  8. Single Oral Dose Toxicity Test of Blue Honeysuckle Concentrate in Mice

    Science.gov (United States)

    Park, Sang-In; Choi, Seung-Hoon; Song, Chang-Hyun; Park, Soo-Jin; Shin, Yong-Kook; Han, Chang-Hyun; Lee, Young Joon; Ku, Sae-Kwang

    2015-01-01

    The objective of this study was to obtain single oral dose toxicity information for concentrated and lyophilized powder of blue honeysuckle (Lonicera caerulea L., Caprifoliaceae; BHcL) in female and male ICR mice to aid in the process of developing natural origin medicinal ingredients or foods following proximate analysis and phytochemical profile measurement. The proximate analysis revealed that BHcL had an energy value of 3.80 kcal/g and contained 0.93 g/g of carbohydrate, 0.41 g/g of sugar, 0.02 g/g of protein, and 0.20 mg/g of sodium. BHcL did not contain lipids, including saturated lipids, trans fats, or cholesterols. Further, BHcL contained 4.54% of betaine, 210.63 mg/g of total phenols, 159.30 mg/g of total flavonoids, and 133.57 mg/g of total anthocyanins. Following administration of a single oral BHcL treatment, there were no treatment-related mortalities, changes in body weight (bw) or organ weight, clinical signs, necropsy or histopathological findings up to 2,000 mg/kg bw, the limited dosage for rodents of both sexes. We concluded that BHcL is a practically non-toxic material in toxicity potency. PMID:25874034

  9. Survival of tumor bearing mice by sequencing of low dose rate (LDR) neutron and photon radiation

    International Nuclear Information System (INIS)

    Onomura, C.I.; Feola, J.M.; Maruyama, Y.

    1984-01-01

    Cf-252 neutron radiation (NT) has been shown to be effective therapy for bulky, hypoxic human tumor and to produce consistent rapid clearance and 5 year cures. NT has been found to be more or less effective depending upon the schedule in which it is used and upon mixing with photon radiation. In an effort to study this scheduling and photon effect, LSA tumor was irradiated in vivo in a hypoxic, advanced state, in different schedules in combination of NT with Co-60 photons. The LSA lymphoma of C57BL/ym mice represents an accurate system to assess dose-response of tumor cells in vivo. Mean survival time was used as endpoint. A high RBE for LDR Cf-252 NT was observed with a RBE(n) of -- 5.0. The effect was not greatly sensitive to sequence in which photons were used. Comparison studies were also tested relative to LDR Cs-137 photon radiation. The results support the high efficacy of LDR NT for destruction of hypoxic tumor in vivo

  10. Effect of low dose radiation on the odontogenesis of mice foetus

    International Nuclear Information System (INIS)

    Osman, M.; Al-Achkar, W.

    1998-09-01

    Mice foetuses were irradiated in utero by gamma rays (0,2, 4,6 Gy) at 10, 12, 14, 16, 18 days of gestation. Histological study was carried out on the first premandibular tooth after 2,4,6,8 days of irradiation, to investigate the effect of irradiation on different steps of tooth development. It appeared that the irradiation induced a delay in the tooth development depending on the time of irradiation and period of gestation. The 2 Gy irradiation effect was small. The 4 Gy dose induced a delay of the cytodifferentiation of the odontoblasts and the ameloblasts. These effects were associated with a morphological retardation in the coronal and the tooth root. More pronounced effects after 6 Gy irradiation for all aspects of the odontogenesis were observed. It caused a strong decrease in the tooth development of the anlages (irradiation of day 12 of the gestation), blocked the morphogenesis (irradiation of day 14), and delayed the cytodifferentiation of the odontoblasts and the amelobasts (irradiation of day 16). Whereas the irradiation at the day 18 had no effects on the functional differentiation of the odontoblasts, but a delay in the functional differentiation of the ameloblasts was observed. Our results show, in our experimental conditions, that irradiation effect the processes prior to the cytodifferentiation of the ameloblasts and the odontoblasts and there are no effects to be observed on the cyto and functional differentiation of these two blasts when their cells achieved its final differentiation. (author)

  11. Time-effect relationship of immunological adaptive response induced by low dose X-irradiation in mice

    International Nuclear Information System (INIS)

    Zhao Yong; Gong Shouliang; Liu Shuzheng

    1995-01-01

    Kunming mice irradiated with whole-body X-rays were used to observe time-effect relationship of immunological adaptive response induced by ionizing radiation. The results showed that pre-irradiation dose of 75 mGy X-rays with the intervals of 6-48 h between pre-irradiation and challenge irradiation could induce immunological adaptive response in the spontaneous proliferation of thymocytes and the responses of splenocytes to Con A and LPS in mice at 18-24 h after challenge irradiation with 1.5-2.0 Gy X-rays

  12. Inhibitory effects of prior low-dose X-ray irradiation on carbon tetrachloride-induced hepatopathy in acatalasemic mice

    International Nuclear Information System (INIS)

    Yamaoka, Kiyonori; Kataoka, Takahiro; Taguchi, Takehito; Wang, Da-Hong; Mori, Shuji; Hanamoto, Katsumi; Kira, Shohei; Nomura, Takaharu

    2004-01-01

    The catalase activities in blood and organs of the acatalasemic (C3H/AnLCs b Cs b ) mouse of C3H strain are lower than those of the normal (C3H/AnLCs a Cs a ) mouse. We examined the effects of prior low-dose (0.5 Gy) X-ray irradiation, which reduced the oxidative damage under carbon tetrachloride-induced hepatopathy in the acatalasemic or normal mice. The acatalasemic mice showed a significantly lower catalase activity and a significantly higher glutathione peroxidase activity compared with those in the normal mice. Moreover, low-dose irradiation increased the catalase activity in the acatalasemic mouse liver to a level similar to that of the normal mouse liver. Pathological examinations and analyses of blood glutamic oxaloacetic and glutamic pyruvic transaminase activity and lipid peroxide levels showed that carbon tetrachloride induced hepatopathy was inhibited by low-dose irradiation. These findings may indicate that the free radical reaction induced by the lack of catalase and the administration of carbon tetrachloride is more properly neutralized by high glutathione peroxidase activity and low-dose irradiation in the acatalasemic mouse liver. (author)

  13. The Effects of Different Doses of Curcuma longa Aqueous Extract on Memory Retention and Retrieval in Male Mice

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    2016-12-01

    Full Text Available Background and Objectives: Curcumin belongs to ginger family, which is used as food and drug from ancient times. Different studies have shown beneficial effects of curcumin on peptic ulcer, rheumatoid arthritis, asthma, and various types of cancer. In this study, the effect of different doses of Curcuma longa aqueous extract on memory retention and retrieval of mice, was investigated using passive avoidance apparatus. Methods: Mice were divided into 6 groups of 8 each for memory retention test and 6 groups of 8 each for memory retrieval test {experimental groups receiving the extract intraperitoneally at doses of 100, 200, 400, 800mg/kg, blank group, and control group}. In memory retention test, the curcumin extract was administered immediately after electric shock, while in the memory retrieval test, it was administered 24 h after receiving electric shock. To compare the complete stepping in the experiment days, One-way ANOVA and post-test LSD were used. The level of significance was considered p<0.05. Results: In this study, curcuma longa aqueous extract significantly increased memory retention and retrieval on the 4th day compared to blank and control groups. The best response for memory retention was obtained at the dose of 100mg/kg and for memory retrieval at the dose of 200mg/kg. Conclusion: According to the results of this study, it seems that Curcuma longa aqueous extract improves memory retention and retrieval in healthy mice.  

  14. Influence of dose, dose rate, and radiation quality on radiation carcinogenesis and life shortening in RFM and BALB/C mice

    International Nuclear Information System (INIS)

    Ullrich, R.L.; Storer, J.B.

    1978-01-01

    The effects produced by 137 Cs gamma rays delivered at a high (45 rads/min) or intermediate (8.2 rads/day) dose rate and the effect of fission neutrons at a high (25 rads/min) and low (1 rad/day) rate in a population of nearly 30,000 RFM and 11,000 BALB/c mice have been studied. Gamma ray doses ranged from 10 to 400 rads with the RFM's and from 50-400 rads with the BALB/c's, while neutron doses ranged from 5 to 200 rads with both strains. The present paper will present an overview of these data and the general findings while subsequent publications will present detailed analyses of each aspect. A variety of neoplasms were sensitive to induction after radiation exposure, including tumors of both reticular tissue origin (leukemia, lymphoma, etc.) and solid tumors. For the RFM, thymic lymphomas were the dominant reticular tissue neoplasm while the majority of solid tumors were either lung adenomas or fit into the broad category of endocrine related tumors, including ovarian, pituitary, harderian, and uterine tumors. The BALB/c was much less sensitive to induction of reticular tissue neoplasms. The tumors that were most sensitive to induction included malignant lung carcinomas, mammary adenocarcinomas and ovarian tumors. In general for both life shortening and tumor induction after gamma ray exposures, when the low to intermediate dose range was sufficiently defined, linearity could be rejected and a dose squared or linear-dose squared relationship adequately fit the data. For neutron exposures, on the other hand, linear relationships were the general finding. The RBE for neutrons varied with tumor type and total dose level. For gamma ray irradiation, the intermediate dose rate resulted in a decreased effectiveness in all cases, while for neutron exposures the dose rate relationships were more complex

  15. High-fat feeding impairs nutrient sensing and gut brain integration in the caudomedial nucleus of the solitary tract in mice.

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    Althea R Cavanaugh

    Full Text Available Hyperphagic obesity is characterized in part by a specific increase in meal size that contributes to increased daily energy intake, but the mechanisms underlying impaired activity of meal size regulatory circuits, particularly those converging at the caudomedial nucleus of the solitary tract in the hindbrain (cmNTS, remain poorly understood. In this paper, we assessed the consequences of high-fat (HF feeding and diet-induced obesity (DIO on cmNTS nutrient sensing and metabolic integration in the control of meal size. Mice maintained on a standard chow diet, low-fat (LF diet or HF diet for 2 weeks or 6 months were implanted with a bilateral brain cannula targeting the cmNTS. Feeding behavior was assessed using behavioral chambers and meal-pattern analysis following cmNTS L-leucine injections alone or together with ip CCK. Molecular mechanisms implicated in the feeding responses were assessed using western blot, immunofluorescence and pharmacological inhibition of the amino acid sensing mTORC1 pathway (mammalian target of rapamycin complex 1. We found that HF feeding blunts the anorectic consequences of cmNTS L-leucine administration. Increased baseline activity of the L-leucine sensor P70 S6 kinase 1 and impaired L-leucine-induced activation of this pathway in the cmNTS of HF-fed mice indicate that HF feeding is associated with an impairment in cmNTS mTOR nutritional and hormonal sensing. Interestingly, the acute orexigenic effect of the mTORC1 inhibitor rapamycin was preserved in HF-fed mice, supporting the assertion that HF-induced increase in baseline cmNTS mTORC1 activity underlies the defect in L-leucine sensing. Last, the synergistic feeding-suppressive effect of CCK and cmNTS L-leucine was abrogated in DIO mice. These results indicate that HF feeding leads to an impairment in cmNTS nutrient sensing and metabolic integration in the regulation of meal size.

  16. Dose response relationship for unstable-type chromosome aberration rate of spleen cells from mice continuously exposed to low-dose-rate gamma-rays

    International Nuclear Information System (INIS)

    Tanaka, Kimio; Khoda, Atsushi; Ichinohe, Kazuaki; Oghiso, Yoichi

    2007-01-01

    It has been reported that people who are chronically exposed to radiation such as nuclear facility workers and medical radiologists have slightly higher incidences of chromosome aberrations than non-exposed people. However, chronological changes of chromosome aberration rates related to accumulated doses and dose-rates for low dose-rate radiation exposures have not been well studied. Precise analyses of human populations are quite limited because confounding factors influence the results. For this reason, animal experiments are important for analyses. Mice were continuously exposed to gamma-rays at 400 mGy/22 hr/day for 10 days, 20 mGy/22 hr/day for about 400 days, and 1 mGy/22 hr/day for about 615 days under SPF conditions. Chronological changes of unstable-type chromosome aberration rates of spleen cells were observed along with accumulated doses at the middle dose rate and the two low-dose rates by conventional Giemsa-staining method. Aberrations such as dicentric chromosome, ring chromosome and fragment increased in a two-phase manner within 0-1.2 Gy and 2-8 Gy at 20 mGy/22 hr/day. They slightly increased up to 0.5 Gy at 1 mGy/22 hr/day. Aberration rates for 1, 2, 8 Gy at the 20 mGy/22 hr/day and for 0.5 Gy at 1 mGy/22 hr/day were 5.1, 9.6, 13.9 and 2.2 times higher than those of age-matched, non-irradiated control mice, respectively. Chromosome aberration rates at 400 mGy/22 hr/day were 2.7 times higher than that of 20 mGy/22 hr/day for the same total dose of 1.2 Gy. The results that unstable-type chromosome aberrations increased with accumulated dose of the low-dose rate radiation will be important to establish biological dosimetry for people who are chronically exposed to radiation. (author)

  17. Effects of prenatal exposure to low dose beta radiation from tritiated water on postnatal growth and neurobehavior of mice

    International Nuclear Information System (INIS)

    Gao Weimin; Zhou Xiangyan

    1998-01-01

    Pregnant adult C57BL/6J mice were randomly assigned to 4 groups and 3 of them were irradiated with beta-rays from tritiated water (HTO) by a single intraperitoneal injection on the 12.5 th day of gestation. Their offsprings received cumulative dose of 0.036, 0.071 and 0.213 Gy, respectively. Offspring of mice were observed for postnatal growth (body weight), the appearance of four physiologic makers (eye opening, pinna detachment, testes decent, vaginal opening), the age of acquisition of two reflexes (cloff avoidance, air righting) and sensuous functions (auditory startle, pain threshold), movement and coordination functions and activity (pivoting, foot splay, continuous corridor activity), and learning and memory (electric avoidance reflex in Y-maze, conditioning reflex). It was found that results for the parameters in 0.036 or 0.071 Gy group were differed significantly from those for the controls, and for most parameters, a dose dependent effect was found

  18. Production of humoral factors that stimulate spleen colony-forming units in mice irradiated with moderate doses of X rays

    International Nuclear Information System (INIS)

    Grande, T.; Gonzalez, J.; Tejero, C.; Maganto, G.; Bueren, J.A.

    1990-01-01

    The production of humoral factors that stimulate spleen colony-forming units (CFU-S) has been studied in irradiated mice using an in vivo diffusion chamber assay. The experiments show that a significant release of factors that stimulate CFU-S takes place in the first few days after irradiation with moderate doses of 1.5 or 5 Gy. In contrast, the release of significant amounts of these humoral factors was not seen in animals irradiated with either low (0.75 Gy) or high (10 Gy) doses of X rays. The correlation observed between the production of factors that stimulate the CFU-S and the hemopoietic regeneration kinetics of the irradiated mice suggests that these factors represent part of the physiological regulators controlling the proliferation of CFU-S

  19. Early and rapid development of insulin resistance, islet dysfunction and glucose intolerance after high-fat feeding in mice overexpressing phosphodiesterase 3B

    DEFF Research Database (Denmark)

    Walz, Helena A; Härndahl, Linda; Wierup, Nils

    2006-01-01

    Inadequate islet adaptation to insulin resistance leads to glucose intolerance and type 2 diabetes. Here we investigate whether beta-cell cAMP is crucial for islet adaptation and prevention of glucose intolerance in mice. Mice with a beta-cell-specific, 2-fold overexpression of the c......AMP-degrading enzyme phosphodiesterase 3B (RIP-PDE3B/2 mice) were metabolically challenged with a high-fat diet. We found that RIP-PDE3B/2 mice early and rapidly develop glucose intolerance and insulin resistance, as compared with wild-type littermates, after 2 months of high-fat feeding. This was evident from...... did not reveal reduced insulin sensitivity in these tissues. Significant steatosis was noted in livers from high-fat-fed wild-type and RIP-PDE3B/2 mice and liver triacyl-glycerol content was 3-fold higher than in wild-type mice fed a control diet. Histochemical analysis revealed severe islet...

  20. Low dose irradiation does not stimulate in vivo primary antibody response in specific-pathogen-free mice

    International Nuclear Information System (INIS)

    Kamisaku, H.; Sado, T.; Muto, M.; Pongpiachan, P.; Magnemi, U.

    1991-01-01

    Recent studies from other laboratories indicated that exposure of mice to low dose radiation resulted in the enhancement of primary anti-SRBC PFC response in mice. We have repeated these experiments using four strains of mice that are known to differ in radiosensitivity of immune response potential in vivo. In one study mice were exposed to 2.5-25 cGy of X-rays. Nine hours later they were injected with SRBC and the number of PFCs per spleen was assessed individually at 4.5 days. The results indicated no evidence for the enhancement of PFC response at all exposure levels examined. In another study, groups of C57BL/6J mice were immunized with SRBC and exposed to 0, 150, or 300 cGy of X-rays 2 days later. Numbers of direct as well as indirect PFCs per spleen were then assessed individually at frequent intervals thereafter. The results indicated that exposure of mice to 150 cGy resulted in a significant increase in the number of indirect PFCs assessed at day 11 after SRBC injection, or 9 days after radiation exposure. Dose-response analysis of radiation-induced enhancement of indirect PFC response by this protocol indicated that only after exposure to 150 and 300 cGy for C57BL/6 and C3H/He strain, respectively, a significant enhancement of indirect PFC response was demonstrated. Flow cytometric analysis of spleen cells from these animals indicated that CD4+/CD+ cell ratios increased rapidly during the first three days after radiation exposure, followed by a rapid decline, suggesting that relative proportion of helper/inducer as compared to cytotoxic/suppressor T cell subset changed rapidly in favor of the former shortly after radiation exposure and possibly contributed to the observed enhancement of indirect PFC response. (author)

  1. Feeding blueberry diets to young rats dose-dependently inhibits bone resorption through suppression of RANKL in stromal cells.

    Directory of Open Access Journals (Sweden)

    Jian Zhang

    Full Text Available Previous studies have demonstrated that weanling rats fed AIN-93G semi-purified diets supplemented with 10% whole blueberry (BB powder for two weeks beginning on postnatal day 21 (PND21 significantly increased bone formation at PND35. However, the minimal level of dietary BB needed to produce these effects is, as yet, unknown. The current study examined the effects of three different levels of BB diet supplementation (1, 3, and 5% for 35 days beginning on PND25 on bone quality, and osteoclastic bone resorption in female rats. Peripheral quantitative CT scan (pQCT of tibia, demonstrated that bone mineral density (BMD and content (BMC were dose-dependently increased in BB-fed rats compared to controls (P<0.05. Significantly increased bone mass after feeding 5% BB extracts was also observed in a TEN (total enteral nutrition rat model in which daily caloric and food intake was precisely controlled. Expression of RANKL (receptor activator of nuclear factor-κB ligand a protein essential for osteoclast formation was dose-dependently decreased in the femur of BB animals. In addition, expression of PPARγ (peroxisome proliferator-activated receptor γ which regulates bone marrow adipogenesis was suppressed in BB diet rats compared to non-BB diet controls. Finally, a set of in vitro cell cultures revealed that the inhibitory effect of BB diet rat serum on RANKL expression was more profound in mesenchymal stromal cells compared to its effect on mature osteoblasts, pre-adipocytes and osteocytes. These results suggest that inhibition of bone resorption may contribute to increased bone mass during early development after BB consumption.

  2. Mutant Huntingtin Gene-Dose Impacts on Aggregate Deposition, DARPP32 Expression and Neuroinflammation in HdhQ150 Mice

    Science.gov (United States)

    Young, Douglas; Mayer, Franziska; Vidotto, Nella; Schweizer, Tatjana; Berth, Ramon; Abramowski, Dorothee; Shimshek, Derya R.; van der Putten, P. Herman; Schmid, Peter

    2013-01-01

    Huntington's disease (HD) is an autosomal dominant, progressive and fatal neurological disorder caused by an expansion of CAG repeats in exon-1 of the huntingtin gene. The encoded poly-glutamine stretch renders mutant huntingtin prone to aggregation. HdhQ150 mice genocopy a pathogenic repeat (∼150 CAGs) in the endogenous mouse huntingtin gene and model predominantly pre-manifest HD. Treating early is likely important to prevent or delay HD, and HdhQ150 mice may be useful to assess therapeutic strategies targeting pre-manifest HD. This requires appropriate markers and here we demonstrate, that pre-symptomatic HdhQ150 mice show several dramatic mutant huntingtin gene-dose dependent pathological changes including: (i) an increase of neuronal intra-nuclear inclusions (NIIs) in brain, (ii) an increase of extra-nuclear aggregates in dentate gyrus, (iii) a decrease of DARPP32 protein and (iv) an increase in glial markers of neuroinflammation, which curiously did not correlate with local neuronal mutant huntingtin inclusion-burden. HdhQ150 mice developed NIIs also in all retinal neuron cell-types, demonstrating that retinal NIIs are not specific to human exon-1 R6 HD mouse models. Taken together, the striking and robust mutant huntingtin gene-dose related changes in aggregate-load, DARPP32 levels and glial activation markers should greatly facilitate future testing of therapeutic strategies in the HdhQ150 HD mouse model. PMID:24086450

  3. Influence of Vehicles Used for Oral Dosing of Test Molecules on the Progression of Mycobacterium tuberculosis Infection in Mice

    OpenAIRE

    Singh, Shubhra; Dwivedi, Richa; Chaturvedi, Vinita

    2014-01-01

    Preclinical evaluation of drug-like molecules requires their oral administration to experimental animals using suitable vehicles. We studied the effect of oral dosing with corn oil, carboxymethyl cellulose, dimethyl sulfoxide, and polysorbate-80 on the progression of Mycobacterium tuberculosis infection in mice. Infection was monitored by physical (survival time and body weight) and bacteriological (viable counts in lungs) parameters. Compared with water, corn oil significantly improved both ...

  4. [Changes and significance of peripheral blood platelet count in tumor shrinkage induced by a low dose of CTX in T739 mice].

    Science.gov (United States)

    Li, Mo-lin; Jia, Yu-jie; Jiang, Miao-na; Shu, Xiao-hong; Li, Chuan-gang

    2008-06-01

    To establish a mouse model for BTT739 tumor-bearing mice cured by a low dose of cyclophosphamide (CTX). And then to observe the dynamic changes and significance of peripheral blood counts especially blood platelet count during tumor shrinkage induced by a low dose of CTX in T739 mice. Mouse bladder carcinoma tissues were inoculated subcutaneously into T739 mice. Seven days later, different doses of CTX or the same volume of NS were administered intraperitoneally to treat these tumor-bearing T739 mice. Tumor sizes were observed and recorded subsequently to find out the minimal dose of CTX that could cure most of these tumor-bearing mice. Then another 12 tumor-bearing mice were randomly divided into 15 mg/kg CTX treatment group and control group. Blood samples were obtained from orbital venous sinus on different times after CTX treatment. Complete blood counts were performed and the relationship between peripheral blood platelet counts and tumor shrinkage was analyzed. Within 2 weeks after CTX treatment, the speed of tumor shrinkage had a positive relationship with the dose of CTX used; but the survival rate of the tumor-bearing mice had a negative relationship with the dose of CTX used in 2 months after CTX treatment. 15 mg/kg CTX could cure most of the tumor bearing mice, while it had no remarkably inhibitive effects on peripheral blood cells. The perpherial platelet count increased to (1483.4+/-184.4)x10(9)/L in mice 6 h after CTX treatment. There was significant difference compared with that in mice of control group (1086.6+/-81.0)x10(9)/L (P0.05). CTX 15 mg/kg could cure most of bladder tumor-bearing T739 mice. The transient increase of the peripheral platelet count in 6 h after CTX treatment may relate to the antitumor effects of CTX.

  5. Liver-specific Aquaporin 11 knockout mice show rapid vacuolization of the rough endoplasmic reticulum in periportal hepatocytes after amino acid feeding

    DEFF Research Database (Denmark)

    Rojek, Aleksandra; Füchtbauer, Ernst-Martin; Füchtbauer, Annette C.

    2013-01-01

    -specific Aqp11 KO mice, allowing us to study the role of AQP11 protein in liver of mice with normal kidney function. The unchallenged liver-specific Aqp11 KO mice have normal longevity, their livers appeared normal, and the plasma biochemistries revealed only a minor defect in lipid handling. Fasting......Aquaporin 11 (AQP11) is a protein channel expressed intracellularly in multiple organs, yet its physiological function is unclear. Aqp11 knockout (KO) mice die early due to malfunction of the kidney, a result of hydropic degeneration of proximal tubule cells. Here we report the generation of liver...... protein or larger doses of various amino acids. The fasting/refeeding challenge is associated with increased expression of markers of ER stress Grp78 and GADD153 and decreased glutathione levels, suggesting that ER stress may play role in the development of vacuoles in the AQP11-deficient hepatocytes. NMR...

  6. [Study of genome instability using DNA fingerprinting of the offspring of male mice subjected to chronic low dose gamma irradiation].

    Science.gov (United States)

    Bezlepkin, V G; Vasil'eva, G V; Lomaeva, M G; Sirota, N P; Gaziev, A I

    2000-01-01

    By a polymerase chain reaction with an arbitrary primer (AP-PCR), the possibility of transmission of genome instability to somatic cells of the offspring (F1 generation) from male parents of mice exposed to chronic low-level gamma-radiation was studied. Male BALB/c mice 15 days after exposure to 10-50 cGy were mated with unirradiated females. Biopsies were taken from tale tips of two month-old offspring mice and DNA was isolated. The primer in the AP-PCR was a 20-mer oligonucleotide flanking the microsatellite locus Atp1b2 on chromosome 11 of the mouse. A comparative analysis of individual fingerprints of AP-PCR products on DNA-templates from the offspring of irradiated and unirradiated male mice revealed an increased variability of microsatellite-associated sequences in the genome of the offspring of the males exposed to 25 and 50 cGy. The DNA-fingerprints of the offspring of male mice exposed to chronic irradiation with the doses 10 and 25 cGy 15 days before fertilization (at the post-meiotic stage of spermatogenesis) showed an increased frequency of "non-parent bands". The results of the study point to the possibility of transmission to the offspring somatic cells of changes increasing genome instability from male parents exposed to chronic low-level radiation prior to fertilization.

  7. Tumor induction in mice after local irradiation with single doses of either carbon-ion beams or gamma rays.

    Science.gov (United States)

    Ando, Koichi; Koike, Sachiko; Ohmachi, Yasushi; Ando, Yutaka; Kobashi, Gen

    2014-12-01

    To determine the dose-dependent relative biological effectiveness (RBE) for tumor prevalence in mice receiving single localized doses to their right leg of either carbon ions (15, 45 or 75 keV/μm) or 137Cs gamma rays. A total of 1647 female C3H mice were irradiated to their hind legs with a localized dose of either reference gamma rays or 15, 45 or 75 keV/μm carbon-ion beams. Irradiated mice were evaluated for tumors twice a month during their three-year life span, and the dimensions of any tumors found were measured with a caliper. The tumor induction frequency was calculated by Kaplan-Meier analysis. The incidence of tumors from 50 Gy of 45 keV/μm carbon ions was marginally higher than those from 50 Gy of gamma rays. However, 60 Gy of 15 keV/μm carbon ions induced significantly fewer tumors than did gamma rays. RBE values of 0.87 + 0.12, 1.29 + 0.08 or 2.06 + 0.39 for lifetime tumorigenesis were calculated for 15, 45 or 75 keV/μm carbon-ion beams, respectively. Fibrosarcoma predominated, with no Linear Energy Transfer (LET)-dependent differences in the tumor histology. Experiments measuring the late effect of leg skin shrinkage suggested that the carcinogenic damage of 15 keV/μm carbon ions would be less than that of gamma rays. We conclude that patients receiving radiation doses to their normal tissues would face less risk of secondary tumor induction by carbon ions of intermediate LET values compared to equivalent doses of photons.

  8. Toxicity of titanium dioxide nanoparticles: Effect of dose and time on biochemical disturbance, oxidative stress and genotoxicity in mice.

    Science.gov (United States)

    Rizk, Maha Z; Ali, Sanaa A; Hamed, Manal A; El-Rigal, Nagy Saba; Aly, Hanan F; Salah, Heba H

    2017-06-01

    The toxic impact of titanium dioxide nanoparticles (TiO 2 NPs) on human health is of prime importance owing to their wide uses in many commercial industries. In the present study, the effect of different doses and exposure time durations of TiO 2 NPs (21nm) inducing oxidative stress, biochemical disturbance, histological alteration and cytogenetic aberration in mice liver and bone marrow was investigated. Different doses of (TiO 2 NPs) (50, 250 and 500mg/kg body weight) were each daily intrapertioneally injected to mice for 7, 14 and 45days. Aspartate and alanine aminotransferases (AST &ALT), gamma glutamyl transpeptidase (GGT), total protein, total antioxidant capacity (TAC), malondialdehyde (MDA), glutathione (GSH), catalase (CAT) and nitric oxide (NO) levels were measured. The work was extended to evaluate the liver histopathological pattern and the chromosomal aberration in mice spinal cord bone marrow. The results revealed severe TiO 2 NPs toxicity in a dose and time dependent manner with positive correlation (r=0.98) for most investigated biochemical parameters. The same observation was noticed for the histological analysis. In case of cytogenetic study, chromosomal aberrations were demonstrated after injection of TiO 2 NPs with 500mg/kg b. wt. for 45days. In conclusion, the selected biochemical parameters and the liver architectures were influenced with dose and time of TiO 2 NPs toxicity, while the genetic disturbance started at the high dose of exposure and for long duration. Further studies are needed to fulfil the effect of TiO 2 NPs on pharmaceutical and nutritional applications. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  9. Genetic injury in hybrid male mice exposed to low doses of 60CO γ-rays or fission neutrons. 1

    International Nuclear Information System (INIS)

    Grahn, D.; Carnes, B.A.; Farrington, B.H.; Lee, C.H.

    1984-01-01

    Young adult male B6CF 1 mice were exposed to single whole body doses of fission neutrons or 60 Co γ rays. Postspermatogonial dominant lethal injury, incidence of reciprocal chromosome translocations induced in spermatogonia, incidence of abnormal epididymal sperm 4-6 weeks after exposure, and testis weight loss 3-6 weeks after exposure were all measured. Significant effects were seen at 1 and 2.5 rad of neutrons consistent with extrapolation from higher doses, with the exception of dominant lethal mutations, which occurred in significant excess of expectation. Dose-response functions were linear or linear-quadratic, depending upon end point, radiation quality, and dose range. For translocation frequencies, the D 2 term was negative for neutron and positive for γ-ray irradiations. RBE values varied with dose and end point. For testis weight loss and abnormal sperm over the full dose range, the RBEs were between 5 and 6. They were between 7 and 9 at lower doses (< 10 rad) for translocations. RBEs for postimplantation and total dominant lethal rates were 5-6 above 10 rad and 10-14 below 10 rad. The RBEs for preimplant losses were between 15 and 25 above 10 rad and possibly higher below 10 rad, although the data are statistically 'noisy'. (Auth.)

  10. Toxicology and carcinogenesis studies of p,p'-dichlorophenyl sulfone (CAS No. 80-07-9) in F344/N rats and B6C3F1 mice (feed studies).

    Science.gov (United States)

    2001-09-01

    p,pN-Dichlorodiphenyl sulfone is used as a starting material in the production of polysulfones and polyethersulfones and as a component in reactive dyes in the textile industry; it is also a by-product of pesticide production. p,pN-Dichlorodiphenyl sulfone was nominated for study by the National Cancer Institute because of its history of high production and use, the prospect of increased production and use, and the absence of adequate toxicity testing. Male and female F344/N rats and B6C3F1 mice were exposed top,pN-dichlorodiphenyl sulfone (greater than 99% pure)in feed for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium,cultured Chinese hamster ovary cells, and mouse bone marrow. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 30, 100, 300, 1,000, or 3,000 ppm p,pN-dichlorodiphenyl sulfone (equivalent to average daily doses of approximately 2, 6, 19, 65, or 200 mgp,pN-dichlorodiphenyl sulfone/kg body weight) for 14 weeks. All rats survived until the end of the study. Mean body weights of groups exposed to 300 ppm or greater were significantly less than those of the controls. Liver weights of groups exposed to 100 ppm or greater and kidney weights of 1,000 and 3,000 ppm male rats were significantly greater than those of the controls. Centrilobular hepatocyte hypertrophy of the liver was observed in most male rats exposed to 100 ppm or greater and in all female rats exposed to 300 ppm or greater, and the severities were increased in 300 ppm males and 1,000 and 3,000 ppm males and females. The incidences of nephropathy in 1,000 and 3,000 ppm female rats were significantly increased. Dose-related increases in severity of nephropathy were observed in male rats. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were fed diets containing 0, 30, 100, 300, 1,000, or 3,000 ppm p,pN-dichlorodiphenyl sulfone (equivalent to average daily doses of approximately 3.5, 15, 50

  11. Effect of source and dose of probiotics and exogenous fibrolytic enzymes (EFE) on intake, feed efficiency, and growth of male buffalo (Bubalus bubalis) calves.

    Science.gov (United States)

    Malik, Raman; Bandla, Srinivas

    2010-08-01

    Probiotics of Lactobacillus acidophilus, Saccharomyces cerevisiae, and Aspergillus niger and three commercial exogenous fibrolytic enzymes (EFE) were tested in vitro to select best source and optimum dose followed by in vivo studies on male buffalo calves. Bacterial (P calves with concentrate supplement (CS). Calves were randomly divided into three groups either without probiotics and EFE (CG) or with probiotics (EG(1)) or probiotics combined with EFE (EG(2)) on wheat straw diet. Organic matter, neutral detergent fiber, and acid detergent fiber digestibility was improved significantly. Average daily weight gain (ADG) and feed efficiency were significantly higher (P feed efficiency was 2.6% or 1.6% more (P calves.

  12. Real-time, in vivo measurement of radiation dose during radioimmunotherapy in mice using a miniature MOSFET dosimeter probe

    International Nuclear Information System (INIS)

    Gladstone, D.J.; Chin, L.M.

    1995-01-01

    This report presents the first real-time measurement of absorbed radiation dose during radioimmunotherapy in mice. Dose rate and total dose at the center of the tumor were measured after administration of 90 Y-labeled antibodies using a miniature metal oxide semiconductor field-effect transistor radiation dosimeter probe which was inserted into the center of the tumor volume. Continuous real-time measurements were made for as long as 23 h after injection of the radiolabeled antibodies. Comparison of the real-time dose-rate measurements with estimates based on the MIRD formalism indicates good agreement. The real-time measurements are further compared to measurements made in a second experiment in which groups of mice were sacrificed at individual times after injection of the same radiolabeled antibodies. The real-time measurements agree well with the measurements in excised tumors. The real-time measurements have greater time resolution and are much more efficient than traditional uptake measurements. 17 refs., 2 figs

  13. Whole body exposure of mice to secondhand smoke induces dose-dependent and persistent promutagenic DNA adducts in the lung

    International Nuclear Information System (INIS)

    Kim, Sang-In; Arlt, Volker M.; Yoon, Jae-In; Cole, Kathleen J.; Pfeifer, Gerd P.; Phillips, David H.; Besaratinia, Ahmad

    2011-01-01

    Secondhand smoke (SHS) exposure is a known risk factor for lung cancer in lifelong nonsmokers. However, the underlying mechanism of action of SHS in lung carcinogenesis remains elusive. We have investigated, using the 32 P-postlabeling assay, the genotoxic potential of SHS in vivo by determining the formation and kinetics of repair of DNA adducts in the lungs of mice exposed whole body to SHS for 2 or 4 months (5 h/day, 5 days/week), and an ensuing one-month recovery period. We demonstrate that exposure of mice to SHS elicits a significant genotoxic response as reflected by the elevation of DNA adduct levels in the lungs of SHS-exposed animals. The increases in DNA adduct levels in the lungs of SHS-exposed mice are dose-dependent as they are related to the intensity and duration of SHS exposure. After one month of recovery in clean air, the levels of lung DNA adducts in the mice exposed for 4 months remain significantly higher than those in the mice exposed for 2 months (P < 0.0005), levels in both groups being significantly elevated relative to controls (P < 0.00001). Our experimental findings accord with the epidemiological data showing that exposure to smoke-derived carcinogens is a risk factor for lung cancer; not only does the magnitude of risk depend upon carcinogen dose, but it also becomes more irreversible with prolonged exposure. The confirmation of epidemiologic data by our experimental findings is of significance because it strengthens the case for the etiologic involvement of SHS in nonsmokers' lung cancer. Identifying the etiologic factors involved in the pathogenesis of lung cancer can help define future strategies for prevention, early detection, and treatment of this highly lethal malignancy.

  14. Stimulation effects of low dose-rate irradiation on pancreatic antioxidant activity in type II diabetes model mice

    International Nuclear Information System (INIS)

    Nomura, Takaharu; Sakai, Kazuo

    2005-01-01

    The effects of low dose-rate gamma irradiation on the type II diabetes mellitus were investigated in BKS.Cg-+Lepr db /+Lepr db /Jcl (DB mice). Ten-week-old female DB mice (5 mice in each group) were irradiated with gamma ray at 0.35, 0.70, or 1.2 mGy/hr. During the course of the 12 weeks the glucose level slightly increased with little difference between the irradiated and the non-irradiated groups. The plasma insulin concentration decreased within the first 4 weeks in all groups. The level was kept low in the non-irradiated mice; while the insulin level in the irradiated groups showed a tendency to increase. In the 0.70 mGy/hr group the increase was statistically significant after 12 weeks of irradiation. Total activity of SOD, one of antioxidative enzymes, decreased both in non-irradiated and irradiated groups; however the decrease was less in the irradiated groups, especially 0.70 mGy/hr group. In the 0.70 mGy/hr group Mn-SOD activity, one of the components of total SOD activity, increased after 12-week irradiation. A pathological examination of the pancreas revealed that damage to β cells responsible for the secretion of insulin was much less in the 0.70 mGy/hr group compared to that in the non-irradiated group. These results indicated that the low dose-rate irradiation increase the antioxidative capacity in the pancreas to protect β cells from oxidative damage, and the to increase the insulin level. This mechanism would lead the mice to the recovery from the disease and the prolongation of the life span as is demonstrated in our previous report. (author)

  15. Protection of lethally irradiated mice with allogeneic fetal liver cells: influence of irradiation dose on immunologic reconstitution

    International Nuclear Information System (INIS)

    Tulunay, O.; Good, R.A.; Yunis, E.J.

    1975-01-01

    After lethal irradiation long-lived, immunologically vigorous C3Hf mice were produced by treatment with syngeneic fetal liver cells or syngeneic newborn or adult spleen cells. Treatment of lethally irradiated mice with syngeneic or allogeneic newborn thymus cells or allogeneic newborn or adult spleen cells regularly led to fatal secondary disease or graft-versus-host reactions. Treatment of the lethally irradiated mice with fetal liver cells regularly yielded long-lived, immunologically vigorous chimeras. The introduction of the fetal liver cells into the irradiated mice appeared to be followed by development of immunological tolerance of the donor cells. The findings suggest that T-cells at an early stage of differentiation are more susceptible to tolerance induction than are T-lymphocytes at later stages of differentiation. These investigations turned up a perplexing paradox which suggests that high doses of irradiation may injure the thymic stroma, rendering it less capable of supporting certain T-cell populations in the peripheral lymphoid tissue. Alternatively, the higher and not the lower dose of irradiation may have eliminated a host cell not readily derived from fetal liver precursors which represents an important helper cell in certain cell-mediated immune functions, e.g., graft-versus-host reactions, but which is not important in others, e.g., allograft rejections. The higher dose of lethal irradiation did not permit development or maintenance of a population of spleen cells that could initiate graft-versus-host reactions but did permit the development of a population of donor cells capable of achieving vigorous allograft rejection

  16. Effects of a prolonged irradiation with low dose-rate ionizing radiation on the hemopoiesis of mice

    Energy Technology Data Exchange (ETDEWEB)

    Yanai, Takanori; Shirata, Katsutoshi; Saitou, Mikio; Tanaka, Satoshi; Onodera, Jun' ichi; Izumi, Jun; Otsu, Hiroshi; Sato, Fumiaki [Inst. for Environmental Sciences, Rokkasho, Aomori (Japan); Kanaiwa-Kudo, Syouko

    2000-07-01

    SPF C3H/HeN female mice were irradiated with {sup 137}Cs {gamma}-rays at doses of 1-8 Gy at the dose rate of 20 mGy/22 h/day. After irradiation, the numbers of CFU-S and CFU-GM in the bone marrow were determined. Number of peripheral blood cells was also counted. The day 12-CFU-S, which is in the earliest stage of differentiation, decreased as the dose increased. Decreases in the numbers of day 7-CFU-S and CFU-GM were also observed. Regardless of the severe decrease in the number of hemopoietic stem cells, no remarkable changes were observed in the number of peripheral blood cells, indicating an enhanced differentiation of the precursor cells. (author)

  17. Comparison of feed energy costs of maintenance, lean deposition, and fat deposition in three lines of mice selected for heat loss.

    Science.gov (United States)

    Eggert, D L; Nielsen, M K

    2006-02-01

    Three replications of mouse selection populations for high heat loss (MH), low heat loss (ML), and a nonselected control (MC) were used to estimate the feed energy costs of maintenance and gain and to test whether selection had changed these costs. At 21 and 49 d of age, mice were weighed and subjected to dual x-ray densitometry measurement for prediction of body composition. At 21 d, mice were randomly assigned to an ad libitum, an 80% of ad libitum, or a 60% of ad libitum feeding group for 28-d collection of individual feed intake. Data were analyzed using 3 approaches. The first approach was an attempt to partition energy intake between costs for maintenance, fat deposition, and lean deposition for each replicate, sex, and line by multiple regression of feed intake on the sum of daily metabolic weight (kg(0.75)), fat gain, and lean gain. Approach II was a less restrictive attempt to partition energy intake between costs for maintenance and total gain for each replicate, sex, and line by multiple regression of feed intake on the sum of daily metabolic weight and total gain. Approach III used multiple regression on the entire data set with pooled regressions on fat and lean gains, and subclass regressions for maintenance. Contrasts were conducted to test the effect of selection (MH - ML) and asymmetry of selection [(MH + ML)/2 - MC] for the various energy costs. In approach I, there were no differences between lines for costs of maintenance, fat deposition, or protein deposition, but we question our ability to estimate these accurately. In approach II, selection changed both cost of maintenance (P = 0.03) and gain (P = 0.05); MH mice had greater per unit costs than ML mice for both. Asymmetry of the selection response was found in approach II for the cost of maintenance (P = 0.06). In approach III, the effect of selection (P maintenance cost, but asymmetry of selection (P > 0.17) was not evident. Sex effects were found for the cost of fat deposition (P = 0.02) in

  18. Increased apoptotic potential and dose-enhancing effect of gold nanoparticles in combination with single-dose clinical electron beams on tumor-bearing mice

    International Nuclear Information System (INIS)

    Chang Mengya; Chen Yuhung; Chang Chihjui; Chen Helen H-W; Wu Chaoliang; Shiau Aili

    2008-01-01

    High atomic number material, such as gold, may be used in conjunction with radiation to provide dose enhancement in tumors. In the current study, we investigated the dose-enhancing effect and apoptotic potential of gold nanoparticles in combination with single-dose clinical electron beams on B16F10 melanoma tumor-bearing mice. We revealed that the accumulation of gold nanoparticles was detected inside B16F10 culture cells after 18 h of incubation, and moreover, the gold nanoparticles were shown to be colocalized with endoplasmic reticulum and Golgi apparatus in cells. Furthermore, gold nanoparticles radiosensitized melanoma cells in the colony formation assay (P=0.02). Using a B16F10 tumor-bearing mouse model, we further demonstrated that gold nanoparticles in conjunction with ionizing radiation significantly retarded tumor growth and prolonged survival compared to the radiation alone controls (P<0.05). Importantly, an increase of apoptotic signals was detected inside tumors in the combined treatment group (P<0.05). Knowing that radiation-induced apoptosis has been considered a determinant of tumor responses to radiation therapy, and the length of tumor regrowth delay correlated with the extent of apoptosis after single-dose radiotherapy, these results may suggest the clinical potential of gold nanoparticles in improving the outcome of melanoma radiotherapy. (author)

  19. Metabolic alterations due to caloric restriction and every other day feeding in normal and growth hormone receptor knockout mice.

    Science.gov (United States)

    Westbrook, Reyhan; Bonkowski, Michael S; Arum, Oge; Strader, April D; Bartke, Andrzej

    2014-01-01

    Mutations causing decreased somatotrophic signaling are known to increase insulin sensitivity and extend life span in mammals. Caloric restriction and every other day (EOD) dietary regimens are associated with similar improvements to insulin signaling and longevity in normal mice; however, these interventions fail to increase insulin sensitivity or life span in growth hormone receptor knockout (GHRKO) mice. To investigate the interactions of the GHRKO mutation with caloric restriction and EOD dietary interventions, we measured changes in the metabolic parameters oxygen consumption (VO2) and respiratory quotient produced by either long-term caloric restriction or EOD in male GHRKO and normal mice. GHRKO mice had increased VO2, which was unaltered by diet. In normal mice, EOD diet caused a significant reduction in VO2 compared with ad libitum (AL) mice during fed and fasted conditions. In normal mice, caloric restriction increased both the range of VO2 and the difference in minimum VO2 between fed and fasted states, whereas EOD diet caused a relatively static VO2 pattern under fed and fasted states. No diet significantly altered the range of VO2 of GHRKO mice under fed conditions. This provides further evidence that longevity-conferring diets cause major metabolic changes in normal mice, but not in GHRKO mice.

  20. Effects of prolonged irradiation by low dose-rate ionizing radiation on the gene expression of hemopoietic factors of mice

    Energy Technology Data Exchange (ETDEWEB)

    Shirata, Katsutoshi; Saitou, Mikio; Yanai, Takanori; Sato, Fumiaki [Institute for Environmental Science, Rokkasho, Aomori (Japan)

    2000-07-01

    To evaluate the effect of prolonged low-dose irradiation on the gene expression of hemopoietic factors in tissues, gene expression was analyzed in the spleen as a hemopoietic tissue that is well known to be one of the most sensitive tissues to irradiation. SPF C3H/HeN female mice (Clea Japan Inc.) were irradiated under SPF conditions with {sup 137}Cs {gamma}-rays at doses of 2, 4, 6, and 8 Gy and a dose rate of 20 mGy/day. Non-irradiated mice of the same age were maintained as controls. At the end of the period of irradiation, both groups of mice were sacrificed and dissected to extract total RNA from their tissues. Reverse transcriptase-polymerase chain reaction (RT-PCR) and the Northern hybridization were employed to detect gene expression. RT-PCT showed no marked changes in the gene expression of GM-CSF. IL-6 gene expression was shown to tend to be enhanced by prolonged low-dose irradiation. The results of Northern hybridization showed that IL-6 mRNA was expressed slightly in both groups, and it was too weak to compare the difference in mRNA expression level between the irradiated group and the controls. No mRNA expression of GM-CSF was detected by Northern hybridization. Based on these results, it was concluded that the gene expression levels of IL-6 and GM-CSF were inadequate to detect the chemiluminescence signals without amplification. It was therefore concluded that improvement of detection sensitivity and larger RNA samples would be necessary for further analysis of the gene expression of hemopoietic factors. (K.H.)

  1. Influence of Exposure to Fractionated Dose of Gamma Radiation and Antioxidants Supplementation to Mice on program cell death induction

    International Nuclear Information System (INIS)

    Hanafi, A.

    2010-01-01

    The previous studies reported that the tumor suppressor protein (P53) is not functioning correctly in most human cancers, and that it plays a crucial role in the prevention of tumor development. This study was designed to evaluate if exposure to fractionated dose of gamma radiation impair function of P53 by the administration of antioxidants. Group of control mice was used. Another groups treated with 3 mg/mouse/day of Antox drug which contains the three main antioxidant vitamins (A, C, and E) together with trace element selenium for 15 days. Another group subjected to 1 Gy of gamma radiation 5 times every other day either alone or combined with the Antox drug supplementation. Hepatic and renal functions were evaluated. Antioxidant markers (MDA and GSH) levels, histopathological changes and P53 expression were recorded in liver and kidney tissues. Animals treated with Antox showed some increase in liver transaminases, non significant changes in total protein and albumin levels, a non significant change in kidney function profiles, a non significant increase in MDA and a significant increase in GSH levels in liver and kidney tissues. However, the exposure of mice to fractionated dose of gamma radiation led to a significant increase in kidney function profiles, AST and ALT activity, a significant decrease in total protein and albumin level, a significant increase in MDA levels and a significant decrease in GSH levels in liver and kidney were observed. Exposure of experimental animals post treatment with Antox drug to fractionated dose of gamma radiation revealed a significant amelioration in liver and kidney function profiles, a highly significant decrease in MDA levels and a significant increase in GSH level in comparison with irradiated group. Histopathological changes in liver and kidney recorded the same alterations observed with the biochemical parameters. P53 expression negatively expressed in normal liver and kidney tissues. However, the exposure of mice to

  2. Cellular and humoral immuno-stimulatory effects of diagnostic doses of X-rays in BALB/c mice

    International Nuclear Information System (INIS)

    Mortazavi, S.M.J.; Jafar-Zadeh, A.; Khosravi, M.H.; Mehdipour, L.A.; Behnejad, B.B.

    2006-01-01

    Objective: The immunosuppressive effects of high doses of ionizing radiation have long been known, while researchers know less about the effects of low dose radiation on the immune system. Recently, in human and experimental animal models it has been reported that low dose radiation may have immuno-stimulatory effects. The aim of this study was to evaluate the effects of low doses of diagnostic doses of X-rays on cell mediated and humoral immune responses in a Balb/c animal model. Materials and Methods: Using a conventional Villa radiography machine, three groups of male Balb/c mice were exposed one, two and three times to 30 mGy of X-rays. The measured surface dose was equal to the dose of a single view lateral lumbar radiography. Two to four hours after irradiation, the delayed type hypersensitivity (DTH) and humoral responses to sheep red blood cell (SRBC) were measured and compared to the responses of sham and control groups. Results: The mean titer of anti-SRBC antibodies in two-times irradiated (74.66± 26.12 ) and three-times irradiated (128 ± 70.1) groups were significantly higher than those of non-irradiated (26.66 ± 8.26) or sham irradiated (28.8 ± 20.86) group (p<0.001). However, no significant differences were observed between the mean titer of anti-SRBC antibodies in one-time irradiated (22.4 ± 8.76) and either non-irradiated or sham irradiated groups. Similarly, comparing DTH responses showed that the differences between either two-times irradiated (12.2 ± 3.9 ) or three times-irradiated (6.9 ± 3.7) and non-irradiated (4 ± 0.2) or sham irradiated (4.3 ± 3) groups was statistically significant (p<0.001). Conclusion: Theses results show that two-times and three-times irradiated mice demonstrate significant stimulatory effects on both DTH and antibody responses. However, one-time irradiated animals did not exhibit any bio- positive effect on DTH and humoral responses. Moreover, no statistically significant difference was observed between the DTH

  3. Specific dose-dependent damage of Lieberkuehn crypts promoted by large doses of type 2 ribosome-inactivating protein nigrin b intravenous injection to mice

    International Nuclear Information System (INIS)

    Gayoso, M.J.; Munoz, R.; Arias, Y.; Villar, R.; Rojo, M.A.; Jimenez, P.; Ferreras, J.M.; Aranguez, I.; Girbes, T.

    2005-01-01

    Nigrin b is a non-toxic type 2 ribosome-inactivating protein as active as ricin at ribosomal level but 10 5 and 5 x 10 3 times less toxic for animal cell cultures and mice, respectively, than ricin. The purpose of the present study was to analyze the effects of intravenous injection of large amounts of nigrin b to the mouse. Injection through the tail vein of 16 mg/kg body weight killed all mice studied before 2 days. Analysis of several major tissues by light microscopy did not reveal gross nigrin b-promoted changes, except in the intestines which appeared highly damaged. As a consequence of the injury, the villi and crypt structures of the small intestine disappeared, leading to profuse bleeding and death. In contrast, intravenous injection of 5 mg/kg body weight was not lethal to mice but did trigger reversible toxic effects. In both cases, lethal and sub-lethal doses, the target of nigrin b appeared to be the highly proliferating stem cells of the intestinal crypts, which had undergone apoptotic changes. In contrast to nigrin b, the injection of 3 μg/kg of ricin kills all mice in 5 days but does not trigger apoptosis in the crypts. Therefore, the effect seen with sub-lethal nigrin b concentrations seems to be specific. Nigrin b killed COLO 320 human colon adenocarcinoma cells with an IC 50 of 3.1 x 10 -8 M and the effect was parallel to the extent of DNA fragmentation of these cells. Accordingly, despite the low general toxicity exerted by nigrin b as compared with ricin, intravenous injection of large amounts of nigrin b is able to kill mouse intestinal stem cells without threatening the lives of the animals, thereby opening a door for its use for the targeting of intestinal stem cells

  4. Suppressor of cytokine signaling 2 (SOCS2) deletion protects against multiple low dose streptozotocin-induced type 1 diabetes in adult male mice

    DEFF Research Database (Denmark)

    Alkharusi, Amira; Mirecki-Garrido, Mercedes; Ma, Zuheng

    2016-01-01

    Background: Diabetes type 1 is characterized by the failure of beta cells to produce insulin. Suppressor of cytokine signaling (SOCS) proteins are important regulators of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. Previous studies have shown that GH can...... prevent the development of type I diabetes in mice and that SOCS2 deficiency mimics a state of increased GH sensitivity. Methodology: The elevated sensitivity of SOCS2-/- mice to GH and possibly to PRL was the rationale to analyze the effects of multiple low dose streptozotocin (MLDSTZ)-induced diabetes...... in SOCS2-/- mice. Results: We show that 6-month-old SOCS2-/- mice, but not 2-month-old mice, were less sensitive to MLDSTZ-induced diabetes, compared to controls. MLDSTZ treatment induced glucose intolerance in both SOCS2+/+ and SOCS2-/- mice, as shown by glucose tolerance tests, with SOCS2+/+ mice...

  5. Long term low dose rate irradiation causes recovery from type II diabetes and suppression of aging in type II diabetes-prone mice

    International Nuclear Information System (INIS)

    Namura, T.; Oda, T.

    2003-01-01

    The effects of low dose rate gamma irradiation on model C57BL/KsJ-db/db mice with Type II diabetes mellitus was investigated. These mice develop Type II diabetes by 10 weeks of age, due to obesity, and are characterized by hyperinsulinemia. A group of 12 female 10-week old mice were irradiated at 0.65 mGy/hr in the low dose rate irradiation facility in the Low Dose Radiation Research Center. The urine glucose levels of all of the mice were strongly positive at the beginning of the irradiation. In the irradiated group, a decrease in the glucose level was observed in three mice, one in the 35th week, another in the 52nd week and the third in the 80th week. No recovery from the diabetes was observed in the 12 mice of non-irradiated control group. There was no systematic change of body weight or consumption of food and drinking water between the irradiated group and the non-irradiated group or between the recovered mice and the non-recovered mice. Survival was better in the irradiated group. The surviving fraction at the age of 90 weeks was 75 % in the irradiated group but only 40 % in the non-irradiated. A marked difference was also observed in the appearance of the coat hair, skin and tail. The irradiated group was in much better condition. Mortality was delayed and the healthy appearance was prolonged in the irradiated mice by about 20-30 weeks compared with the control mice. These results suggest that the low dose irradiation modified the condition of the diabetic mice, leading not only to recovery from diabetes, but also to suppression of the aging process

  6. Short communication: Experimental toxocarosis in Chinese Kun Ming mice: Dose-dependent larval distribution and modulation of immune responses.

    Science.gov (United States)

    Ma, Guangxu; Tan, Yancai; Hu, Ling; Luo, Yongfang; Zhu, Honghong; Zhou, Rongqiong

    2015-12-01

    Toxocarosis is an important parasitic zoonosis which is mainly caused by the infective larvae of Toxocara canis. To identify whether there are correlations among the infectious dose, the larval migrans and immune modulation in inbred Chinese Kun Ming (KM) mice, experimental infections were carried out with a range of dosages of 100, 500, 1000, 2000, and 3000 embryonated eggs (EE). Pathogenic reactions were observed in terms of physical and central nervous symptoms. Distributions of T. canis larvae in liver, lung, kidney, heart and brain organs were respectively detected by scanning tissue sections. Moreover, quantitative real-time PCR was employed to identify the variations of Th2 immune response. The results showed that high inocula resulted in advanced larval emergences and arrested migrations in liver, lung, kidney and brain. However, no larvae were found in any of the histological sections of heart tissues. Higher levels of interleukin (IL)-4, IL-5, and IL-10 were detected along with the increasing inoculation doses, but the heaviest inoculum (3000 EE in this study) resulted in the sharp reduction of these ILs. Although no neurological symptoms or mortalities were noticed, these results indicated dose-dependent distribution patterns and immune regulations of T. canis larvae infection in KM mice. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Radioprotective influence on mice DNA of biopolymer complexes from tinder Fomes Fomentarius under ionizing radiation in small doses

    Directory of Open Access Journals (Sweden)

    O. F. Seniuk

    2014-03-01

    Full Text Available The effects of similar doses of the values of common external irradiation (0,19 Gy/4hours and 0,24 Gy/6 months at single-strand DNA breaks and the level of the hydrogen bonds in this molecule in different cell types (lymphocytes, hepatocytes and splenocytes linear mice CC57W/mv are discussed. Mice were exposed to γ-fields produced by “hot” particles of emergency 4-th Chernobyl Unit containing the same radionuclides in the proportions. The possibility of leveling the radiation effects using complex biopolymers from Fomes fomentarius was shown. The ability of melanin-glucan complex to directly counteract the fragmentation of DNA in a model system with lambda phage this macromolecule oxidation products of benzidine and neutralize mutagenic effect in Salmonella typhimurium strains in the classical Ames test was studied.

  8. Radioprotective influence on mice DNA of biopolymer complexes from tinder Fomes Fomentarius under ionizing radiation in small doses

    International Nuclear Information System (INIS)

    Senyuk, O.F.; Koval'ov, O.V.; Palamar, L.A.; Krul', M.Yi.; Gorovij, L.F.

    2014-01-01

    The effects of similar doses of the values of common external irradiation (0,19 Gy/4 hours and 0,24 Gy/6 months) at single-strand DNA breaks and the level of the hydrogen bonds in this molecule in different cell types (lymphocytes, hepatocytes and splenocytes) linear mice CC57W/mv are discussed. Mice were exposed to γ-fields produced by h ot - particles of emergency 4-th Chernobyl Unit containing the same radionuclides in the proportions. The possibility of leveling the radiation effects using complex biopolymers from Fomes Fomentarius was shown. The ability of melanin-glucan complex to directly counteract the fragmentation of DNA in a model system with lambda phage this macromolecule oxidation products of benzidine and neutralize mutagenic effect in Salmonella typhimurium strains in the classical Ames test was studied

  9. Hypothalamic gliosis associated with high-fat diet feeding is reversible in mice: a combined immunohistochemical and magnetic resonance imaging study.

    Science.gov (United States)

    Berkseth, Kathryn E; Guyenet, Stephan J; Melhorn, Susan J; Lee, Donghoon; Thaler, Joshua P; Schur, Ellen A; Schwartz, Michael W

    2014-08-01

    Gliosis, the activation of astrocyte and microglial cell populations, is a hallmark of central nervous system injury and is detectable using either immunohistochemistry or in vivo magnetic resonance imaging (MRI). Obesity in rodents and humans is associated with gliosis of the arcuate nucleus, a key hypothalamic region for the regulation of energy homeostasis and adiposity, but whether this response is permanent or reversible is unknown. Here we combine terminal immunohistochemistry analysis with serial, noninvasive MRI to characterize the progression and reversibility of hypothalamic gliosis in high-fat diet (HFD)-fed mice. The effects of HFD feeding for 16 weeks to increase body weight and adiposity relative to chow were nearly normalized after the return to chow feeding for an additional 4 weeks in the diet-reversal group. Mice maintained on the HFD for the full 20-week study period experienced continued weight gain associated with the expected increases of astrocyte and microglial activation in the arcuate nucleus, but these changes were not observed in the diet-reversal group. The proopiomelanocortin neuron number did not differ between groups. Although MRI demonstrated a positive correlation between body weight, adiposity, and the gliosis-associated T2 signal in the mediobasal hypothalamus, it did not detect the reversal of gliosis among the HFD-fed mice after the return to chow diet. We conclude that hypothalamic gliosis associated with 16-week HFD feeding is largely reversible in rodents, consistent with the reversal of the HFD-induced obesity phenotype, and extend published evidence regarding the utility of MRI as a tool for studying obesity-associated hypothalamic gliosis in vivo.

  10. Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses

    Science.gov (United States)

    Saal, Frederick S. vom; Timms, Barry G.; Montano, Monica M.; Palanza, Paola; Thayer, Kristina A.; Nagel, Susan C.; Dhar, Minati D.; Ganjam, V. K.; Parmigiani, Stefano; Welshons, Wade V.

    1997-01-01

    On the basis of results of studies using high doses of estrogens, exposure to estrogen during fetal life is known to inhibit prostate development. However, it is recognized in endocrinology that low concentrations of a hormone can stimulate a tissue, while high concentrations can have the opposite effect. We report here that a 50% increase in free-serum estradiol in male mouse fetuses (released by a maternal Silastic estradiol implant) induced a 40% increase in the number of developing prostatic glands during fetal life; subsequently, in adulthood, the number of prostatic androgen receptors per cell was permanently increased by 2-fold, and the prostate was enlarged by 30% (due to hyperplasia) relative to untreated males. However, as the free serum estradiol concentration in male fetuses was increased from 2- to 8-fold, adult prostate weight decreased relative to males exposed to the 50% increase in estradiol. As a model for fetal exposure to man-made estrogens, pregnant mice were fed diethylstilbestrol (DES) from gestation days 11 to 17. Relative to controls, DES doses of 0.02, 0.2, and 2.0 ng per g of body weight per day increased adult prostate weight, whereas a 200-ng-per-g dose decreased adult prostate weight in male offspring. Our findings suggest that a small increase in estrogen may modulate the action of androgen in regulating prostate differentiation, resulting in a permanent increase in prostatic androgen receptors and prostate size. For both estradiol and DES, prostate weight first increased then decreased with dose, resulting in an inverted-U dose-response relationship. PMID:9050904

  11. Dose Optimization of Calcusol™ and Calcium Oxalate Monohydrate (COM on Primary Renal Epithelial Cells Cultures of Mice ( Mus musculus

    Directory of Open Access Journals (Sweden)

    Ahmad Soni

    2014-05-01

    Full Text Available Kidney stones are one of the urologic diseases that have plagued mankind for centuries. The main constituents of stones in the kidney are calcium oxalate monohydrate (COM crystals. Nowadays, there are varieties of drugs and treatments that can be made to minimize the grievances due to kidney stone disease. The treatment can be done either by using chemicals or traditional medicine. Calcusol™ is one of the popular herbal products that have been used by Indonesian people in curing the kidney stone disease. The main constituent that was contained in Calcusol™ is an extract of the tempuyung leaves (Sonchus arvensis L., which is expected could cure the kidney stone disease. This study used primary cultured renal epithelial cells of mice to determine the optimal dose of Calcusol™ and the optimal dose of COM. The primary Kidney epithelial cell were treated with Calcusol™ and COM at various doses. The analysis of the cell death either by necrosis or apoptosis pathways was analyzed by flow cytometric analysis. The results that were obtained is the percentage of cell death that is then analyzed by using a complete randomized design (CRD One Way Anova. Based on the results that were obtained, it is known that the optimal dose of Calcusol™ in vitro were ranging from 75 ppm to 100 ppm, whereas the optimal dose of COM suggested for 500 ppm.

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

    Energy Technology Data Exchange (ETDEWEB)

    Anthérieu, Sébastien; Le Guillou, Dounia; Coulouarn, Cédric; Begriche, Karima [INSERM, U991, Université de Rennes 1, 35000 Rennes (France); Trak-Smayra, Viviane [Pathology Department, Saint-Joseph University, Beirut (Lebanon); Martinais, Sophie [INSERM, U991, Université de Rennes 1, 35000 Rennes (France); Porceddu, Mathieu [Mitologics SAS, Hôpital Robert Debré, 48 Boulevard Sérurier, 75019 Paris (France); Robin, Marie-Anne [INSERM, U991, Université de Rennes 1, 35000 Rennes (France); Fromenty, Bernard, E-mail: bernard.fromenty@inserm.fr [INSERM, U991, Université de Rennes 1, 35000 Rennes (France)

    2014-04-01

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

  13. Stereological estimation of ovarian volume and number of follicles in low dose of Vitex agnus castus treated mice

    OpenAIRE

    HAMIDIAN, Gholamreza; YAHYAVI, Fariba

    2014-01-01

    Vitex agnus castus (VAC) has been proven to have a wide range of biological activities. It is commonly used in the treatment of menstrual disorders resulting from corpus luteum deficiency, including premenstrual symptoms and spasmodic dysmenorrheal, for certain menopausal conditions, and for insufficient lactation. The aim of this study was to investigate the effects of low dose of VAC essential oil on ovarian volume and oocyte number in mice by stereological technique. In this study 10 young...

  14. Effect of low dose radiation on Th1 and Th2 of thymocytes and splenocytes in mice

    International Nuclear Information System (INIS)

    Bai Ou; Liu Shuzheng; Mu Ying

    1998-01-01

    Objective: To elucidate the possible mechanism of activation of helper T cells after low dose radiation (LDR) exposure, the influence of whole-body irradiation (WBI) with 75 mGy X-rays on Th1 and Th2 was studied. Methods: Mice were irradiated at a dose rate of 12.5 mGy/min, and IFN-γ and IL-6 mRNA levels of the myocytes and splenocytes were analyzed by dot blot and Northern blot hybridization. Results: It was found that IFN-γ and IL-6 mRNA significantly increased after WBI with 75 mGy X-rays. Conclusion: The gene induction of cytokine profile after LDR indicates that activation of both Th1 and Th2 subtypes may be involved in the stimulation of immune functions by LDR

  15. Stimulating effect of low dose radiation expression of G-CSF receptors in bone marrow cells in mice

    International Nuclear Information System (INIS)

    Zhang Honglai; Liu Shuzheng; Zhang Ming

    1993-01-01

    The expression of G-CSF receptors in bone marrow cells (BMC) was studied by using 125 I labelled G-CSF ( 1 '2 5 I-G-CSF). The results showed that the reaction equilibrium of 125 I-G-CSF bound to BMC at 37 degree C was reached in 60 minutes, the maximum binding (Bmax) to 3 x 10 6 BMC being 15.1 pmol, the dissociation constant (Kd) being 78.6 pmol, and the estimated number of G-CSF receptors per cell being about 3100. The number of G-CSF receptors in BMC in mice 48 hours after whole body exposure to doses of 50, 75 and 100 mGy X-rays increased significantly to 161%, 169% and 342% of controls, respectively. The results suggested that the expression of G-CSF receptors in BMC was enhanced markedly following low dose radiation, which would lead to stimulation of BMC proliferation

  16. Effect of low dose of vinclozolin on reproductive tract development and sperm parameters in CD1 outbred mice.

    Science.gov (United States)

    Elzeinova, Fatima; Novakova, Vendula; Buckiova, Daniela; Kubatova, Alena; Peknicova, Jana

    2008-01-01

    The effect of a low dose of vinclozolin within the development of the reproductive tract during gestation (VIN-GD 15-22) and puberty (VIN-PND 23-44) in CD1 mice was tested. We found a decrease in the anogenital distance, prostate weight and pathology of testes in both experimental groups. Sperm counts decreased to 46% (VIN-GD) and to 81% (VIN-PND), and also the acrosomal state (evaluated by antiacrosomal antibody) decreased in both groups to 89% in comparison to the control group (100%). Sperm head abnormalities increased by approximately 18% and 13%, respectively. In this connection, the expression of some genes was changed (arosome-related gene (Acr), apoptosis related genes (p53, p21)). In conclusion, a low dose of vinclozolin affected the reproductive tract, sperm parameters and expression of selected genes in both experimental groups.

  17. Effects of different doses of glucose and insulin on morphine state-dependent memory of passive avoidance in mice.

    Science.gov (United States)

    Jafari, M R; Zarrindast, M R; Djahanguiri, B

    2004-10-01

    Behavioral effects of morphine, including its effect on memory, have been demonstrated to be influenced by glucose pretreatment. The measurement of step-down latency in passive avoidance has been used to study memory in laboratory animals. The pre-training injection of 5 mg/kg morphine impaired memory, which was restored when 24 h later the same dose of the drug was administered. To investigate the effects of glucose and insulin alone or in combination with morphine, on pre-test day, on memory recall in mice. The effects of different doses of glucose (50, 100, and 200 mg/kg, IP) and insulin (5, 10, and 20 IU/kg, IP) alone or in combination with morphine, have been studied in mice. The blood glucose level and locomotor activity of the animals were also measured. Although the administration of glucose alone showed no effect on morphine-induced memory impairment, its co-administration with morphine resulted in a significant and dose-dependent memory enhancement compared with the effects of morphine administration alone. Like glucose, the administration of different doses of insulin alone produced no change in the memory, but when the drug was co-administered with morphine, it significantly reduced morphine-induced memory retrieval. The effect of insulin was the opposite of glucose. None of the animals subjected to insulin treatment showed convulsions. Glucose is suggested to increase, on the test day, the morphine-induced memory enhancement by three different mechanisms: cholinergic or opioidergic modulations, or regulation of the ATP-dependent potassium channels.

  18. Aspartame and the hippocampus: Revealing a bi-directional, dose/time-dependent behavioural and morphological shift in mice.

    Science.gov (United States)

    Onaolapo, Adejoke Y; Onaolapo, Olakunle J; Nwoha, Polycarp U

    2017-03-01

    Changes, in behaviour, oxidative markers of stress and hippocampal morphology were evaluated following aspartame administration. Mice, (20-22g each) were given vehicle (10ml/kg) or aspartame (20, 40, 80 and 160mg/kg) daily for 28days. They were tested in the Y-maze, radial-arm maze and elevated plus-maze (EPM) after the first and last dose of vehicle or aspartame; and then sacrificed. Hippocampal slices were analysed for aspartic acid, nitric oxide (NO) and superoxide dismutase (SOD); and processed for general histology and neuritic plaques. Glial fibrillary-acid protein (GFAP) expression and neuron-specific enolase (NSE) activities were determined. Radial-arm maze scores increased significantly after acute administration at 80 and 160mg/kg. Repeated administration at 20 and 40mg/kg (Y-maze) and at 40mg/kg (radial-arm maze) was also associated with increased scores, however, performance decreased at higher doses. EPM tests revealed anxiogenic responses following both acute and repeated administration. Significant increase in SOD and NO activities were observed at 40, 80 and 160mg/kg. Neuron counts reduced at higher doses of aspartame. At 40, 80 and 160mg/kg, fewer GFAP-reactive astrocytes were observed in the cornus ammonis, but increased GFAP-reactivity was observed in the dentate gyrus subgranular zone. NSE-positive neurons were readily identifiable within the dentate gyrus at the lower doses of aspartame; but at 160mg/kg, there was marked neuron loss and reduction in NSE-positive neurons. Oral aspartame significantly altered behaviour, anti-oxidant status and morphology of the hippocampus in mice; also, it may probably trigger hippocampal adult neurogenesis. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. A lower dose threshold for the in vivo protective adaptive response to radiation. Tumorigenesis in chronically exposed normal and Trp53 heterozygous C57BL/6 mice

    International Nuclear Information System (INIS)

    Mitchel, R.E.J.; Burchart, P.; Wyatt, H.

    2008-01-01

    Low doses of ionizing radiation to cells and animals may induce adaptive responses that reduce the risk of cancer. However, there are upper dose thresholds above which these protective adaptive responses do not occur. We have now tested the hypothesis that there are similar lower dose thresholds that must be exceeded in order to induce protective effects in vivo. We examined the effects of low dose/low dose rate fractionated exposures on cancer formation in Trp53 normal or cancer-prone Trp53 heterozygous female C57BL/6 mice. Beginning at 6 weeks of age, mice were exposed 5 days/week to single daily doses (0.33 mGy, 0.7 mGy/h) totaling 48, 97 or 146 mGy over 30, 60 or 90 weeks. The exposures for shorter times (up to 60 weeks) appeared to be below the level necessary to induce overall protective adaptive responses in Trp53 normal mice, and detrimental effects (shortened lifespan, increased frequency) evident for only specific tumor types (B- and T-cell lymphomas), were produced. Only when the exposures were continued for 90 weeks did the dose become sufficient to induce protective adaptive responses, balancing the detrimental effects for these specific cancers, and reducing the risk level back to that of the unexposed animals. Detrimental effects were not seen for other tumor types, and a protective effect was seen for sarcomas after 60 weeks of exposure, which was then lost when the exposure continued for 90 weeks. As previously shown for the upper dose threshold for protection by low doses, the lower dose boundary between protection and harm was influenced by Trp53 functionality. Neither protection nor harm was observed in exposed Trp53 heterozygous mice, indicating that reduced Trp53 function raises the lower dose/dose rate threshold for both detrimental and protective tumorigenic effects. (author)

  20. Prenatal and lactational exposure to low-doses of bisphenol A alters adult mice behavior.

    Science.gov (United States)

    Nakamura, Keiko; Itoh, Kyoko; Dai, Hongmei; Han, Longzhe; Wang, Xiaohang; Kato, Shingo; Sugimoto, Tohru; Fushiki, Shinji

    2012-01-01

    Bisphenol A (BPA) is an endocrine-disrupting chemical, widely used in dentistry and various industries. We previously reported that BPA affected murine neocortical development by accelerating neuronal differentiation/migration, resulting in abnormal neocortical architecture as well as aberrant thalamocortical connections in the brains of adult mice. The aim of this study was to investigate whether prenatal and lactational BPA exposure affected behavior in adult mice. Pregnant mice were injected subcutaneously with 20μg/kg of BPA daily from embryonic day 0 (E0) until postnatal day 21 (P21). Control animals received a vehicle alone. Behavioral tests (n=15-20) were conducted at postnatal 3weeks (P3W) and P10-15W. After an open-field test, an elevated plus maze and Morris water maze tests were performed. The total distance in the elevated plus maze test at P3W and in the open-field test at P10W was significantly decreased in the BPA-exposed group, compared with the control group. Significant sex differences were observed in the time spent in the central area in the open-field test at P3W and in the total distance in the elevated plus maze test at P11W. These results indicated that prenatal and lactational BPA exposure disturbed the murine behavior in the postnatal development period and the adult mice. Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  1. High-saturated fat-sucrose feeding affects lactation energetics in control mice and mice selectively bred for high wheel-running behavior

    NARCIS (Netherlands)

    Guidotti, Stefano; Jonas, Izabella; Schubert, Kristin A.; Garland, Theodore; Meijer, Harro A. J.; Scheurink, Anton J. W.; van Dijk, Gertjan

    2013-01-01

    Feeding a diet high in fat and sucrose (HFS) during pregnancy and lactation is known to increase susceptibility to develop metabolic derangements later in life. A trait for increased behavioral activity may oppose these effects, since this would drain energy from milk produced to be made available

  2. Effect of repeated small-dose γ-ray irradiation on atopic dermatitis in NC/Nga mice

    International Nuclear Information System (INIS)

    Fang, Su-Ping; Muto, Yasuko; Tago, Fumitoshi; Simura, Noriko; Kojima, Shuji

    2006-01-01

    We previously showed that several small-dose 0.5 Gy whole-body γ-ray irradiation inhibits tumor growth in mice via elevation of the interferon (IFN)-γ/interleukin 4 (IL-4) ratio concomitantly with a decrease in the percentage of B cells. Here, we examined whether repeated small-dose (0.5 Gy, 10 times) γ-ray irradiation influences atopic dermatitis in an NC/Nga mouse model. It was found that repeated γ-ray irradiation increased total IgE in comparison with the disease-control group. Levels of IL-4 and IL-5 were increased versus the disease-control group, while IFN-γ was slightly decreased, resulting in a further decrease of the IFN-γ/IL-4 ratio compared with the disease-control group. These results indicate that repeated small-dose γ-ray irradiation may exacerbate atopic dermatitis. This may be because the irradiation induces not helper T lymphocyte 1 (Th1), but Th2 polarization in this atopic mouse model, i.e., the effects of small-dose irradiation may be different in conditions involving immune hypersensitivity and impaired immunity. (author)

  3. Effect of antimicrobial therapy on the gastrointestinal bacterial flora, infection and mortality in mice exposed to different doses of irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Brook, I.; Ledney, G.D. (Armed Forces Radiobiology Research Inst., Bethesda, MD (United States))

    1994-01-01

    The effect of antimicrobial therapy on gut flora, sepsis, and mortality was investigated in C[sub 3]H/HeN female mice irradiated with 7.0, 8.0 or 8.5 Gy or [sup 60]Co. The antimicrobial agents tested were metronidazole, penicillin, imipenem, gentamicin and ofloxacin. In control mice, the greatest reduction of lactose fermenting organisms (1.7-2.8 logs) occurred on day 8 after irradiation and were related directly to radiation doses. After day 8 lactose fermenting organism levels increased and the increases were associated with mortality due to Enterobacteriaceae sepsis. Irradiation reduced the populations of strict anaerobic bacteria in control mice by 2-8 logs, and these remained at low levels. Treatment with either metronidazole or penicillin resulted in greater reductions of strict anaerobic bacteria than occurred in the controls and induced earlier and greater increases in lactose fermenting organisms and associated mortality. Therapies with either gentamicin or ofloxacin resulted in lesser reductions of strict anaerobic bacteria (1.1-2.2 logs) than occurred in controls, and caused greater decreases in lactose fermenting organisms and mortality. The changes in the bacterial flora and mortality following imipenem treatment were similar to controls. These data demonstrate that in animals exposed to irradiation, antimicrobial agents effective against strict anaerobic bacteria can be deleterious, but antimicrobial agents effective against lactose fermenting organsims may be beneficial. (Author).

  4. Effect of antimicrobial therapy on the gastrointestinal bacterial flora, infection and mortality in mice exposed to different doses of irradiation

    International Nuclear Information System (INIS)

    Brook, I.; Ledney, G.D.

    1994-01-01

    The effect of antimicrobial therapy on gut flora, sepsis, and mortality was investigated in C 3 H/HeN female mice irradiated with 7.0, 8.0 or 8.5 Gy or 60 Co. The antimicrobial agents tested were metronidazole, penicillin, imipenem, gentamicin and ofloxacin. In control mice, the greatest reduction of lactose fermenting organisms (1.7-2.8 logs) occurred on day 8 after irradiation and were related directly to radiation doses. After day 8 lactose fermenting organism levels increased and the increases were associated with mortality due to Enterobacteriaceae sepsis. Irradiation reduced the populations of strict anaerobic bacteria in control mice by 2-8 logs, and these remained at low levels. Treatment with either metronidazole or penicillin resulted in greater reductions of strict anaerobic bacteria than occurred in the controls and induced earlier and greater increases in lactose fermenting organisms and associated mortality. Therapies with either gentamicin or ofloxacin resulted in lesser reductions of strict anaerobic bacteria (1.1-2.2 logs) than occurred in controls, and caused greater decreases in lactose fermenting organisms and mortality. The changes in the bacterial flora and mortality following imipenem treatment were similar to controls. These data demonstrate that in animals exposed to irradiation, antimicrobial agents effective against strict anaerobic bacteria can be deleterious, but antimicrobial agents effective against lactose fermenting organsims may be beneficial. (Author)

  5. Examination of gene expression in mice exposed to low dose radiation using affymetrix cDNA microarrays

    Energy Technology Data Exchange (ETDEWEB)

    Morris, D.; Knox, D.; Lavoie, J.; Lemon, J.; Boreham, D. [McMaster Univ., Hamilton, Ontario (Canada)

    2005-07-01

    'Full text:' Gamma radiation acts via the indirect effect to damage cells by producing reactive oxygen species (ROS). These ROS are capable damaging macromolecules and, altering signal pathways and gene transcription. Cells have evolved enzymes and mechanisms to scavenge ROS and repair oxidative damage. Microarrays allow the survey of the gene transcription activity of thousands of genes simultaneously. Messenger RNA is extracted from cells, hybridized with the complementary DNA (cDNA) of a microarray chip, and examined with a chip reader. Affymetrix microarray chips have been produced by the CSCHAH in Winnipeg containing 26000 murine genes. Groups of female mice have been exposed to low dose whole body chronic gamma radiation exposures of 0,50,100, and 120 mGy, corresponding to 15,30,60, and 75 weeks, respectively. MRNA from mice brain tissue has been extracted, isolated, converted to cDNA and labeled. Gene expression in each irradiated mouse was compared to the pooled expression of the control mice. Analysis of gene expression levels are performed with microarray analytical software, Array Pro by Media Cybernetics, and powerful statistical software, BRB microarray tools. Differences in gene expressions, focusing on genes for cytokines, DNA repair mechanisms, immuno-modulators, apoptosis pathways, and enzymatic anti-oxidant systems, are being examined and will be reported. (author)

  6. Molecular characterization of non-thymic lymphomas in mice exposed to continuous low-dose-rate g-ray irradiation

    International Nuclear Information System (INIS)

    Takabatake, T.; Fujikawa, K.; Nakamura, S.; Tanaka, S.; Tanaka, I.; Tanaka-Braga III, I.; Sunaga, Y.; Ichinoche, K.; Sato, F.; Tanaka, K.; Matsumoto, T.

    2004-01-01

    To investigate the effects of continuous low-dose-rate irradiation on life span and neoplasm incidence, SPE B6C3 F1 mice were irradiated with 137Cs-ray at dose-rates of 20, 1 and 0.05 mGy/day with accumulated doses equivalent to 8000, 40 and 20 mGy, respectively. Examination of a total of 3,000 irradiated and 1,000 non-irradiated control mice showed that the life spans of the both sexes irradiated at 20 mGy/day, respectively. Examination of a total of 3,000 irradiated and 1,000 non-irradiated control mice showed that the life spans of the both sexes irradiated at 20 mGy/day were significantly shorter than that of the non-irradiated group. No significant difference in the cause of death and mortality rates was found between the groups. However, non-thymic lymphomas, the most common lethal neoplasm, showed a tendency to develop at an earlier age in mice irradiated with 20 mGy/day, regardless of sex. to obtain clues on the molecular mechanisms underlying the earlier development of non-thymic lymphomas in 20 mGy/day irradiated group, detailed molecular characterizations of non-thymic lymphomas with respect to B-cell or T-cell origin was done by detecting rearrangements in immunoglobulin heavy gene and in T-cell receptor b-and g chain genes by Southem hybridization method. to determine whether the early development of non-thymic lymphomas in 20 mGy/day irradiated group is associated wi the any recurrent chromosomal imbalance such as deletions and amplifications, the genome-wide scanning is also currently in progress by both LOH and array CGH methods. Present data obtained by LOH method show that deletions in parts of chromosomes 11 and 12 were more frequent than in chromosomes 2, 4 and 14 in both the non-irradiated control and 20 mGy/day irradiated groups. this work is supported by grants from Aomori Prefecture, Japan. (Author)

  7. Comparative study on hematopoietic damage of mice caused by high-dose of gamma-ray irradiation

    International Nuclear Information System (INIS)

    Wu Hongying; Wang Yueying; Li Deguan; Wang Xiaochun; Zhang Heng; Lu Lu; Chang Jianhui; Du Liqing; Wang Yan; Men Aimin

    2010-01-01

    Objective: To study the effect of high-dose of gamma-ray irradiation on hematopoiesis injury and recovery of IRM-2 and C57BL/6 J mouse. Methods: The experiment was designed to study the effects of radiation (4 Gy) on spleen index, CFU-S and DNA damage on the 9 th day of IRM-2 and ICR mice and the effects of radiation (6 Gy) on WBC change and its absolute value on the 45 th days of IRM-2 and C57BL/6 J mice. Results: The IRM-2 mouse spleen index, CFU-S and DNA were higher than ICR mouse on the 9 th days, and there were significant difference in CFU-S and DNA (P<0.01). The IRM-2 mouse WBC, RMC, HGB and HCT were higher than C57BL/6 J mouse on the 45 th days, and there were significant difference (P<0.01). Conclusion: IRM-2 mouse hematopoiesis resumes quicker than C57BL/6 J and ICR do after high-dose of gamma-ray irradiation. (authors)

  8. Watermelon (Citrullus lanatus (Thunb.) Matsum. and Nakai) juice modulates oxidative damage induced by low dose X-ray in mice.

    Science.gov (United States)

    Mohammad, Mohd Khairul Amran; Mohamed, Muhamad Idham; Zakaria, Ainul Mardhiyah; Abdul Razak, Hairil Rashmizal; Saad, Wan Mazlina Md

    2014-01-01

    Watermelon is a natural product that contains high level of antioxidants and may prevent oxidative damage in tissues due to free radical generation following an exposure to ionizing radiation. The present study aimed to investigate the radioprotective effects of watermelon (Citrullus lanatus (Thunb.) Matsum. and Nakai) juice against oxidative damage induced by low dose X-ray exposure in mice. Twelve adult male ICR mice were randomly divided into two groups consisting of radiation (Rx) and supplementation (Tx) groups. Rx received filtered tap water, while Tx was supplemented with 50% (v/v) watermelon juice for 28 days ad libitum prior to total body irradiation by 100 μGy X-ray on day 29. Brain, lung, and liver tissues were assessed for the levels of malondialdehyde (MDA), apurinic/apyrimidinic (AP) sites, glutathione (GSH), and superoxide dismutase (SOD) inhibition activities. Results showed significant reduction of MDA levels and AP sites formation of Tx compared to Rx (P watermelon juice restore the intracellular antioxidant activities by significantly increased SOD inhibition activities and GSH levels compared to Rx. These findings may postulate that supplementation of 50% watermelon (Citrullus lanatus (Thunb.) Matsum. and Nakai) juice could modulate oxidative damage induced by low dose X-ray exposure.

  9. Effects of dietary fat energy restriction and fish oil feeding on hepatic metabolic abnormalities and insulin resistance in KK mice with high-fat diet-induced obesity.

    Science.gov (United States)

    Arai, Takeshi; Kim, Hyoun-ju; Hirako, Satoshi; Nakasatomi, Maki; Chiba, Hiroshige; Matsumoto, Akiyo

    2013-01-01

    We investigated the effects of dietary fat energy restriction and fish oil intake on glucose and lipid metabolism in female KK mice with high-fat (HF) diet-induced obesity. Mice were fed a lard/safflower oil (LSO50) diet consisting of 50 energy% (en%) lard/safflower oil as the fat source for 12 weeks. Then, the mice were fed various fat energy restriction (25 en% fat) diets - LSO, FO2.5, FO12.5 or FO25 - containing 0, 2.5, 12.5, or 25 en% fish oil, respectively, for 9 weeks. Conversion from a HF diet to each fat energy restriction diet significantly decreased final body weights and visceral and subcutaneous fat mass in all fat energy restriction groups, regardless of fish oil contents. Hepatic triglyceride and cholesterol levels markedly decreased in the FO12.5 and FO25 groups, but not in the LSO group. Although plasma insulin levels did not differ among groups, the blood glucose areas under the curve in the oral glucose tolerance test were significantly lower in the FO12.5 and FO25 groups. Real-time polymerase chain reaction analysis showed fatty acid synthase mRNA levels significantly decreased in the FO25 group, and stearoyl-CoA desaturase 1 mRNA levels markedly decreased in the FO12.5 and FO25 groups. These results demonstrate that body weight gains were suppressed by dietary fat energy restriction even in KK mice with HF diet-induced obesity. We also suggested that the combination of fat energy restriction and fish oil feeding decreased fat droplets and ameliorated hepatic hypertrophy and insulin resistance with suppression of de novo lipogenesis in these mice. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. High-fat feeding in cardiomyocyte-restricted PPARdelta knockout mice leads to cardiac overexpression of lipid metabolic genes but fails to rescue cardiac phenotypes.

    Science.gov (United States)

    Li, Yuquan; Cheng, Lihong; Qin, Qianhong; Liu, Jian; Lo, Woo-kuen; Brako, Lowrence A; Yang, Qinglin

    2009-10-01

    Peroxisome proliferator-activated receptor delta (PPARdelta) is an essential determinant of basal myocardial fatty acid oxidation (FAO) and bioenergetics. We wished to determine whether increased lipid loading affects the PPARdelta deficient heart in transcriptional regulation of FAO and in the development of cardiac pathology. Cardiomyocyte-restricted PPARdelta knockout (CR-PPARdelta(-/-)) and control (alpha-MyHC-Cre) mice were subjected to 48 h of fasting and to a long-term maintenance on a (28 weeks) high-fat diet (HFD). The expression of key FAO proteins in heart was examined. Serum lipid profiles, cardiac pathology, and changes of various transduction signaling pathways were also examined. Mice subjected to fasting exhibited upregulated transcript expression of FAO genes in the CR-PPARdelta(-/-) hearts. Moreover, long-term HFD in CR-PPARdelta(-/-) mice induced a strikingly greater transcriptional response. After HFD, genes encoding key FAO enzymes were expressed remarkably more in CR-PPARdelta(-/-) hearts than in those of control mice. Despite the marked rise of FAO gene expression, corresponding protein expression remained low in the CR-PPARdelta(-/-) heart, accompanied by abnormalities in sarcomere structures and mitochondria that were similar to those of CR-PPARdelta(-/-) hearts with regular chow feeding. The CR-PPARdelta(-/-) mice displayed increased expression of PPARgamma co-activator-1alpha (PGC-1alpha) and PPARalpha in the heart with deactivated Akt and p42/44 MAPK signaling in response to HFD. We conclude that PPARdelta is an essential determinant of myocardial FAO. Increased lipid intake activates cardiac expression of FAO genes via PPARalpha/PGC-1alpha pathway, albeit it is not sufficient to improve cardiac pathology due to PPARdelta deficiency.

  11. Radiation sources providing increased UVA/UVB ratios induce photoprotection dependent on the UVA dose in hairless mice.

    Science.gov (United States)

    Reeve, Vivienne E; Domanski, Diane; Slater, Michael

    2006-01-01

    In studies involving mice in which doses of UVA (320-400 nm) and UVB (290-320 nm) radiation were administered alone or combined sequentially, we observed a protective effect of UVA against UVB-induced erythema/edema and systemic suppression of contact hypersensitivity. The UVA immunoprotection was mediated by the induction of the stress enzyme heme oxygenase-1 (HO-1) in the skin, protection of the cutaneous Th1 cytokines interferon-gamma (IFN-gamma) and IL-12 and inhibition of the UVB-induced expression of the Th2 cytokine IL-10. In this study, we seek evidence for an immunological waveband interaction when UVA and UVB are administered concurrently to hairless mice as occurs during sunlight exposure in humans. A series of spectra providing varying ratios of UVA/UVB were developed, with the UVA ratio increased to approximately 3.5 times the UVA component in solar simulated UV (SSUV). We report that progressively increasing the UVA component of the radiation while maintaining a constant UVB dose resulted in a reduction of both the erythema/edema reaction and the degree of systemic immunosuppression, as measured as contact hypersensitivity. The UVA-enhanced immunoprotection was abrogated in mice treated with a specific HO enzyme inhibitor. UVA-enhanced radiation also upregulated the expression of cutaneous IFN-gamma and IL-12 and inhibited expression of both IL-6 and IL-10, compared with the activity of SSUV. The results were consistent with the previously characterized mechanisms of photoprotection by the UVA waveband alone and suggest that the UVA component of solar UV may have beneficial properties for humans.

  12. 70-Day Supraphysiologic Dose of the Power-Enhancing Drug Oxymetholone: the Effects on Oogenesis in NMRI Mice

    Directory of Open Access Journals (Sweden)

    M Azarniya

    2012-05-01

    Full Text Available

    Background and objectives

    Oxymetholone is an orally-administered active anabolic-androgenic steroid. This drug was synthesized in 1959. It is a 17α-methylated, 5α-saturated compound. It is used for the treatment of a variety of diseases including anemia, growth delay in children, myocardial damage in heart failure and treatment of HIV associated wasting. This is one of the drugs used in high doses by the doping athletes because of its anabolic effects and its influence on muscular mass. In this study, the effect of oxymetholone in supraphysiologic doses was evaluated on oogenesis in NMRI mice.

    Methods

    In our experiments, 12 mg/kg/day oxymetholone was injected intraperitoneally to 4- and 6-week old mice for 70 days.

    Results

    The results demonstrated a significant difference between treatment and control groups after both 35 and 70 days of treatment. This drug led to significant decrease in the number of corpus lutea, decrease in the number of atretic follicles, decrease in the weight and diameter of ovaries, decrease in the diameter of granulosa layer, increase in number of primordial follicles, decrease in number of primary follicles, decrease in number of growing follicles, decrease in the number of graafian follicles, and decrease in the progesterone level. Additionally, disordered formation of granulosa layers and growing of oocytes in antra, anomaly of the ovular medulla and formation of two oocytes in one folliculus were observed in some mice.

    Conclusion

    The results show that oxymetholone decreases the ovarian growth and the rate of ovulation.

  13. 70-Day Supraphysiologic Dose of the Power-Enhancing Drug Oxymetholone: the Effects on Oogenesis in NMRI Mice

    Directory of Open Access Journals (Sweden)

    M. Azarniya

    2007-04-01

    Full Text Available Background and objectivesOxymetholone is an orally-administered active anabolic-androgenic steroid. This drug was synthesized in 1959. It is a 17α-methylated, 5α-saturated compound. It is used for the treatment of a variety of diseases including anemia, growth delay in children, myocardial damage in heart failure and treatment of HIV associated wasting. This is one of the drugs used in high doses by the doping athletes because of its anabolic effects and its influence on muscular mass. In this study, the effect of oxymetholone in supraphysiologic doses was evaluated on oogenesis in NMRI mice.MethodsIn our experiments, 12 mg/kg/day oxymetholone was injected intraperitoneally to 4- and 6-week old mice for 70 days. ResultsThe results demonstrated a significant difference between treatment and control groups after both 35 and 70 days of treatment. This drug led to significant decrease in the number of corpus lutea, decrease in the number of atretic follicles, decrease in the weight and diameter of ovaries, decrease in the diameter of granulosa layer, increase in number of primordial follicles, decrease in number of primary follicles, decrease in number of growing follicles, decrease in the number of graafian follicles, and decrease in the progesterone level. Additionally, disordered formation of granulosa layers and growing of oocytes in antra, anomaly of the ovular medulla and formation of two oocytes in one folliculus were observed in some mice.ConclusionThe results show that oxymetholone decreases the ovarian growth and the rate of ovulation. Keywords: Oxymetholone; Anabolic Steroid; Oogenesis; Androgens

  14. Effect of extended exposure to low-dose radiation on autoimmune diseases of immunologically suppressed MRL/MpTn-gld/gld mice

    International Nuclear Information System (INIS)

    Ootsuyama, Akira; Okazaki, Ryuji; Norimura, Toshiyuki

    2003-01-01

    The purpose of this paper is to analyze the relationship between alterations of splenic T-cell subpopulations and the amelioration of autoimmune diseases of MRL/MpTn-gld/gld mice (MRL/gld mice) after extended exposure to low-dose radiation. After the onset of disease, 4-month-old MRL/gld mice were exposed to doses of 0.05, 0.2, and 0.5 Gy/day for 4 weeks (5 days/week), for total doses of 1, 4, and 10 Gy, respectively. The MRL/gld mice that were irradiated with 0.2 and 0.5 Gy/day showed an obvious decrease in the proportion of splenic CD4 - CD8 - T cells and remission of their autoimmune diseases. After the last irradiation, apoptotic cells were found in the white pulp of the spleen of the MRL/gld mice irradiated with 0.2 Gy/day, but not in the MRL/MpJ-+/+ mice (MRL/wild mice), which experienced a similar treatment. Before the onset of disease, 3-month-old MRL/gld mice subjected to 0.2 Gy/day showed a decrease in the proportion of splenic CD4 - CD8 - T cells and less remission of their autoimmune diseases than the 4-month-old mice. These results suggest that the accumulated CD4 - CD8 - T cells are more sensitive to radiation than other T cell subpopulations, and that decreasing CD4 - CD8 - T cells with extended exposure to low-dose radiation leads to the amelioration of autoimmune disease. (author)

  15. Effect of single lithium doses on haemopoiesis regeneration after radiation exposure in mice

    International Nuclear Information System (INIS)

    Krajewski, K.

    1988-01-01

    The reported experiment failed to demonstrate any effect of single doses of lithium carbonate on haemopoiesis regeneration in experimental haematological syndrome of acute radiation sickness. The effects of gamma radiation on blood formation are shown. 3 figs., 6 refs. (author)

  16. Corticotropin-releasing factor overexpression in mice abrogates sex differences in body weight, visceral fat, and food intake response to a fast and alters levels of feeding regulatory hormones.

    Science.gov (United States)

    Wang, Lixin; Goebel-Stengel, Miriam; Yuan, Pu-Qing; Stengel, Andreas; Taché, Yvette

    2017-01-01

    Corticotropin-releasing factor overexpressing (CRF-OE) male mice showed an inhibited feeding response to a fast, and lower plasma acyl ghrelin and Fos expression in the arcuate nucleus compared to wild-type (WT) mice. We investigated whether hormones and hypothalamic feeding signals are impaired in CRF-OE mice and the influence of sex. Male and female CRF-OE mice and WT littermates (4-6 months old) fed ad libitum or overnight fasted were assessed for body, adrenal glands and perigonadal fat weights, food intake, plasma hormones, blood glucose, and mRNA hypothalamic signals. Under fed conditions, compared to WT, CRF-OE mice have increased adrenal glands and perigonadal fat weight, plasma corticosterone, leptin and insulin, and hypothalamic leptin receptor and decreased plasma acyl ghrelin. Compared to male, female WT mice have lower body and perigonadal fat and plasma leptin but higher adrenal glands weights. CRF-OE mice lost these sex differences except for the adrenals. Male CRF-OE and WT mice did not differ in hypothalamic expression of neuropeptide Y (NPY) and proopiomelanocortin (POMC), while female CRF-OE compared to female WT and male CRF-OE had higher NPY mRNA levels. After fasting, female WT mice lost more body weight and ate more food than male WT, while CRF-OE mice had reduced body weight loss and inhibited food intake without sex difference. In male WT mice, fasting reduced plasma insulin and leptin and increased acyl ghrelin and corticosterone while female WT showed only a rise in corticosterone. In CRF-OE mice, fasting reduced insulin while leptin, acyl ghrelin and corticosterone were unchanged with no sex difference. Fasting blood glucose was higher in CRF-OE with female > male. In WT mice, fasting increased hypothalamic NPY expression in both sexes and decreased POMC only in males, while in CRF-OE mice, NPY did not change, and POMC decreased in males and increased in females. These data indicate that CRF-OE mice have abnormal basal and fasting

  17. Immediate and Delayed Drug Therapy Effects on Low Dose Sarin Exposed Mice Myocardial Performance

    Science.gov (United States)

    2011-03-01

    studied using electrocardiography ( EKG ) and histological/immunochemical techniques (staining with hematoxylin/eosin and brain natriuretic peptide, BNP...size and BNP levels than controls (p = 0.001). EKGs showed T-wave anomalies. These results are indicators of cardiac insult. The second treatment...mice include being able to only take short time interval readings and the development of movement artifacts in the recordings. To prevent issues

  18. Timed feeding of mice modulates light-entrained circadian rhythms of reticulated platelet abundance and plasma thrombopoietin and affects gene expression in megakaryocytes.

    Science.gov (United States)

    Hartley, Paul S; Sheward, John; Scholefield, Emma; French, Karen; Horn, Jacqueline M; Holmes, Megan C; Harmar, Anthony J

    2009-07-01

    Circadian (c. 24 h) rhythms of physiology are entrained to either the environmental light-dark cycle or the timing of food intake. In the current work the hypothesis that rhythms of platelet turnover in mammals are circadian and entrained by food intake was explored in mice. Mice were entrained to 12 h light-dark cycles and given either ad libitum (AL) or restricted access (RF) to food during the light phase. Blood and megakaryocytes were then collected from mice every 4 h for 24 h. It was found that total and reticulated platelet numbers, plasma thrombopoietin (TPO) concentration and the mean size of mature megakaryocytes were circadian but not entrained by food intake. In contrast, a circadian rhythm in the expression of Arnt1 in megakaryocytes was entrained by food. Although not circadian, the expression in megakaryocytes of Nfe2, Gata1, Itga2b and Tubb1 expression was downregulated by RF, whereas Ccnd1 was not significantly affected by the feeding protocol. It is concluded that circadian rhythms of total platelet number, reticulated platelet number and plasma TPO concentration are entrained by the light-dark cycle rather than the timing of food intake. These findings imply that circadian clock gene expression regulates platelet turnover in mammals.

  19. Bisphenol A (BPA) aggravates multiple low-dose streptozotocin-induced Type 1 diabetes in C57BL/6 mice.

    Science.gov (United States)

    Cetkovic-Cvrlje, Marina; Thinamany, Sinduja; Bruner, Kylie A

    2017-12-01

    Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disorder characterized by destruction of insulin-producing pancreatic β-cells. Whereas epidemiological data implicate environmental factors in the increasing incidence of T1D, their identity remains unknown. Though exposure to bisphenol A (BPA) has been associated with several disorders, no epidemiologic evidence has linked BPA exposure and T1D. The goal of this study was to elucidate diabetogenic potentials of BPA and underlying mechanisms in the context of T-cell immunity, in a multiple low-dose streptozotocin (MLDSTZ)-induced autoimmune mouse T1D model. C57BL/6 mice were orally exposed to 1 or 10 mg BPA/L starting at 4 wk of age; diabetes was induced at 9 wk of age with STZ. T-cell composition, function, and insulitis levels were studied at Days 11 and 50 during diabetes development (i.e. post-first STZ injection). Results showed both BPA doses increased diabetes incidence and affected T-cell immunity. However, mechanisms of diabetogenic action appeared divergent based on dose. Low-dose BPA fits a profile of an agent that exhibits pro-diabetogenic effects via T-cell immunomodulation in the early stages of disease development, i.e. decreases in splenic T-cell subpopulations [especially CD4 + T-cells] along with a trend in elevation of splenic T-cell formation of pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-6). In contrast, high-dose BPA did not affect T-cell populations and led to decreased levels of IFN-γ and TNF-α. Both treatments did not affect insulitis levels at the disease early stage, but aggravated it later on. By the study end, besides decreasing T-cell proliferative capacity, low-dose BPA did not affect other T-cell-related parameters, including cytokine secretion, comparable to the effects of high-dose BPA. In conclusion, this study confirmed BPA as a potential diabetogenic compound with immunomodulatory mechanisms of action - in the context of T-cell immunity - that seemed to be dose

  20. Radiosensitizing activity and pharmacokinetics of multiple dose administered KU-2285 in peripheral nerve tissue in mice

    International Nuclear Information System (INIS)

    Iwai, Hiroyuki; Matsuno, Etsuko; Sasai, Keisuke; Abe, Mitsuyuki; Shibamoto, Yuta

    1994-01-01

    In a clinical trial in which a 2-nitroimidazole radiosensitizer was administered repeatedly, the dose-limiting toxicity was found to be peripheral neuropathy. In the present study, the in vivo radiosensitizing activity of KU-2285 in combination with radiation dose fractionation, and the pharmacokinetics of cumulative dosing of KU-2285 in the peripheral nerves were examined. The ability of three nitroimidazoles, misonidazole (MISO), etanidazole (SR-2508) and KU-2285, to sensitize SCCVII tumors to radiation treatment has been compared for drug doses in the range 0-200 mg/kg. Single radiation doses or two different fractionation schedules (6 Gy/fractions x three fractions/48 h or 5 Gy/fractions x five fractions/48 h) were used; the tumor cell survival was determined using an in vivo/in vitro colony assay. The pharmacokinetics in the sciatic nerves were undertaken, when KU-2285 or etanidazole were injected at a dose of 200 mg/kg intravenously one, two, three, or four times at 2-h intervals. At less than 100 mg/kg, KU-2285 sensitized SCCVII tumors more than MISO and SR-2508 by fractionated irradiation. Evaluation of pharmacokinetics in the peripheral nerves showed that the apparent biological half-life of SR-2508 increased with the increases in the number of administrations, whereas that of KU-2285 became shorter. Since most clinical radiotherapy is given in small multiple fractions, KU-2285 appears to be a hypoxic cell radiosensitizer that could be useful in such regimens, and that poses no risk of chronic peripheral neurotoxicity. 12 refs., 5 figs., 1 tab

  1. Effects of prenatal exposure to low-dose β radiation from tritiated water on the neutrobehavior of mice

    International Nuclear Information System (INIS)

    Wang Bing; Zhou Xiangyan.

    1995-01-01

    Pregnant adult C57BL/6J mice, randomly assigned to 1 of 4 groups, 3 of them were irradiated with β-rays from tritiated water (HTO) by a single intraperitoneal injection on the 12.5th day of gestation. Their offspring received cumulative doses of 0, 5, 10 or 30 cGy in utero. Male pups were trained and examined using a set of behavioral tests that included avoidance acquisition and avoidance maintenance, open field test, hole-board dipping, a water maze, and a food labyrinth. Results were found for most parameters in the 10 and 30 cGy groups that differed significantly from results for the controls, indicating that the behavioral teratogenic effect of prenatal exposure to chronic β-ray radiation from HTO may be greater than the same dose of acute X- or γ-irradiation and that 10 cGy may be the lowest detectable dose level at which behavioral changes is detectable under the conditions used in this experiment. (author) 56 refs

  2. Effects of prenatal exposure to low-dose {beta} radiation from tritiated water on the neutrobehavior of mice

    Energy Technology Data Exchange (ETDEWEB)

    Wang Bing [Tokyo Univ. (Japan). Faculty of Science; Zhou Xiangyan

    1995-06-01

    Pregnant adult C57BL/6J mice, randomly assigned to 1 of 4 groups, 3 of them were irradiated with {beta}-rays from tritiated water (HTO) by a single intraperitoneal injection on the 12.5th day of gestation. Their offspring received cumulative doses of 0, 5, 10 or 30 cGy in utero. Male pups were trained and examined using a set of behavioral tests that included avoidance acquisition and avoidance maintenance, open field test, hole-board dipping, a water maze, and a food labyrinth. Results were found for most parameters in the 10 and 30 cGy groups that differed significantly from results for the controls, indicating that the behavioral teratogenic effect of prenatal exposure to chronic {beta}-ray radiation from HTO may be greater than the same dose of acute X- or {gamma}-irradiation and that 10 cGy may be the lowest detectable dose level at which behavioral changes is detectable under the conditions used in this experiment. (author) 56 refs.

  3. Effect of single-dose x irradiation on the growth curves of a human malignant melanoma transplanted into nude mice

    International Nuclear Information System (INIS)

    Spang-Thomsen, M.; Visfeldt, J.; Nielsen, A.

    1981-01-01

    A human malignant melanoma transplanted into nude mice was exposed to single-dose x irradiation. Experimental growth data described mathematically according to a transformed Gompertz function were used to determine the effect of irradiation on growth delay, growth rate, and tumor shrinkage. The radiation-induced changes in the histology of the tumors were also described. The results showed that irradiation induced a dose-dependent growth delay; this parameter was therefore found suitable for the assessment of relative therapeutic effect. The treatment also induced a dose-dependent reduction in growth rate during regrowth. As a result of this effect on growth rate, extrapolation of tumor shrinkage to the time of treatment became directly misleading as a measure of the effect of the treatment. From this it can be deduced that in therapeutic studies where treatment induces nonparallel posttherapeutic growth curves, growth delay for various tumors and therapies cannot be compared directly. The transformed Gompertz function proved to be extremely well suited for evaluating these conditions

  4. Cyclosporine promotes the induction of thymic lymphomas in C57BL/6 mice initiated by a single dose of γ-radiation

    International Nuclear Information System (INIS)

    Yabu, Koji; Warty, V.S.; Gorelik, E.; Shinozuka, Hisashi

    1991-01-01

    We previously demonstrated that a single dose of γ-radiation (350 rads) was able to induce thymic lymphomas in C57BL mice when followed by promoting treatment with oral cyclosporine (CsA), a non-genotoxic immunosuppressant. We have now tested the efficacy of various doses of γ-radiation as an initiator of CsA promotion of the induction of thymic lymphomas in male C57BL mice. The effects of oral CsA on the splenic natural killer (NK) cell activity of non-irradiated and irradiated (400 rads, 1X) mice were tested by the standard 51 Cr release assays against YAC-1 cells. The cumulative incidence of thymic lymphomas induced by a single dose of γ-radiation at 100, 200, 400 and 600 rads were 10, 25, 63 and 75% respectively, after 42 weeks of CsA promotion. The splenic NK cell activity in non-irradiated mice given CsA for 4 weeks was twice as high as that in the control mice. CsA inhibited poly I:C-induced augmentation of the splenic NK cell activity. In mice given a single dose (400 rads) of γ-radiation and CsA for 4 weeks, a similar but reduced enhancement of the splenic NK cell activity as seen in non-irradiated mice was observed. These results indicate that the efficacy of CsA promotion in the induction of thymic lymphomas is dependent on the initiating doses of γ-radiation, and that CsA enhances host splenic NK cell activity during the early stage of tumor promotion. (author)

  5. Fluoxetine treatment induces dose dependent alterations in depression associated behavior and neural plasticity in female mice

    OpenAIRE

    Hodes, Georgia E.; Hill-Smith, Tiffany E.; Lucki, Irwin

    2010-01-01

    Antidepressant induced increases in neurogenesis and neurotrophin mobilization in rodents and primates are proposed to be necessary for behavioral efficacy. The current study examines the relationship between the effects of fluoxetine treatment on behavior, cell proliferation and the neurotrophin BDNF in females. Female MRL/MpJ mice were treated acutely (5 and 10 mg/kg) or chronically (2.5, 5 and 10 mg/kg b.i.d.) with fluoxetine and tested in the tail suspension test (TST) and or novelty indu...

  6. Influence of different dose irradiation on genetic effect in mice somatic and germ cells

    International Nuclear Information System (INIS)

    Kostrova, L.N.; Molofej, V.P.; Mosseh, I.B.

    2007-01-01

    Comparison of clastogenic effects of different radiation doses in somatic and germ cells of one the same animals has been studied. Correlation analysis allows to extrapolate genetic effects from somatic cells to germ ones. This can be useful for human model elaboration. (authors)

  7. SODIUM BICARBONATE FACILITATES LOW-DOSE ORAL TOLERANCE TO PEANUT IN MICE

    Science.gov (United States)

    Rationale: Oral tolerance specifically inhibits production of allergic IgE antibody and is therefore a potential method for suppressing food allergy. We have previously demonstrated that a single oral dose of one mg is sufficient to induce oral tolerance to egg white but not pean...

  8. Effect of extended exposure of low-dose radiation on autoimmune diseases of immunologically depressed MRL/MpJ-gld/gld mice

    International Nuclear Information System (INIS)

    Ootsuyama, A.; Okazaki, R.; Norimura, T.

    2000-01-01

    We analyzed alterations of splenic T cell subpopulations and amelioration of autoimmune disease of MRL/MpJ-gld/gld mice (MRL/gld mice) after the extended exposure to low-dose radiation (LDR). Four-month old MRL/gld mice were exposed to 0.05, 0.2 and 0.5 Gy/day for 4 weeks (5 days/week) with a total dose of 1, 4 and 10 Gy, respectively. The mice irradiated with 0.2 and 0.5 Gy/day showed an obvious decrease in the proportions of splenic CD4 - CD8 - T cells and remission of their autoimmune disease. In the mice irradiated with 0.2 Gy/day, apoptotic cells were found in the white pulp of the spleen after the last irradiation, but not in that of the treated MRL/MpJ-+/+ mice (MRL/wild type mice). It seems that the accumulated CD4 - CD8 - T cells are more sensitive to radiation than other T cell subpopulations and prone to apoptosis, and efficient elimination of abnormal CD4 - CD8 - T cells by radiation-induced apoptosis may lead to the amelioration of autoimmune disease. (author)

  9. GLUT2 in pancreatic islets: crucial target molecule in diabetes induced with multiple low doses of streptozotocin in mice.

    Science.gov (United States)

    Wang, Z; Gleichmann, H

    1998-01-01

    In mice, diabetes can be induced by multiple low doses of streptozotocin (MLD-STZ), i.e., 40 mg/kg body wt on each of 5 consecutive days. In this model, diabetes develops only when STZ induces both beta-cell toxicity and T-cell-dependent immune reactions. The target molecule(s) of MLD-STZ-induced beta-cell toxicity are not known, however. In this study, we report that GLUT2 is a target molecule for MLD-STZ toxicity. Ex vivo, a gradual decrement of both GLUT2 protein and mRNA expression was found in pancreatic islets isolated from MLD-STZ-treated C57BL/6 male mice, whereas mRNA expression of beta-actin, glucokinase, and proinsulin remained unaffected. Significant reduction of both GLUT2 protein and mRNA expression was first noted 1 day after the third STZ injection, clearly preceding the onset of hyperglycemia. The extent of reduction increased with the number of STZ injections administered and increased over time, after the last, i.e., fifth, STZ injection. The STZ-induced reduction of GLUT2 protein and mRNA was not due to an essential loss of beta-cells, because ex vivo, not only the total RNA yield and protein content in isolated islets, but also proinsulin mRNA expression, failed to differ significantly in the differently treated groups. Furthermore, islets isolated from MLD-STZ-treated donors responded to the nonglucose secretagogue arginine in a pattern similar to that of solvent-treated donors. Interestingly, the MLD-STZ-induced reduction of both GLUT2 protein and mRNA was prevented by preinjecting mice with 5-thio-D-glucose before each STZ injection. Apparently, GLUT2 is a crucial target molecule of MLD-STZ toxicity, and this toxicity seems to precede the immune reactions against beta-cells.

  10. Protective effect of Ocimum sanctum L after high-dose {sup 131}Iodine exposure in mice: an in vivo study

    Energy Technology Data Exchange (ETDEWEB)

    Bhartiya, Uma S; Raut, Yogita S; Joseph, Lebana J [Laboratory Nuclear Medicine Section, Radiochemistry and Isotope Group, Bhabha Atomic Research Centre, Tata Memorial Hospital Annexe, Parel, Mumbai (India); Rao, Badanidiyoor S [Radiological Physics and Advisory Division, Bhabha Atomic Research Centre, Mumbai (India)

    2006-08-15

    Radioprotective effect of aqueous extract of Ocimum sanctum (40 mg/kg body weight, for 15 days) in mice exposed to high-doses (3.7 MBq) of oral {sup 131}Iodine was investigated by studying the organ weights, lipid peroxidation and antioxidant defense enzymes in various target organs like liver, kidneys, salivary glands and stomach at 24 hr after exposure in adult Swiss mice. The mean weight of the salivary glands showed significant increase after {sup 131}Iodine administration. {sup 131}Iodine exposure significantly increased lipid peroxidation in kidneys and salivary glands in comparison to control animals. Pretreatment with O. sanctum in radioiodine exposed group showed significant reduction in lipid peroxidation in both kidneys and salivary glands. In liver, reduced glutathione (GSH) levels showed significant reduction after radioiodine exposure while pretreatment with O. sanctum exhibited less depletion in GSH level even after {sup 131}Iodine exposure. However, no such changes were observed in stomach. The results indicate the possibility of using aqueous extract of O. sanctum for ameliorating {sup 131}lodine induced damage to the salivary glands. (author)

  11. Dose response evaluation of gene expression profiles in the skin of K6/ODC mice exposed to sodium arsenite

    International Nuclear Information System (INIS)

    Ahlborn, Gene J.; Nelson, Gail M.; Ward, William O.; Knapp, Geremy; Allen, James W.; Ouyang Ming; Roop, Barbara C.; Chen Yan; O'Brien, Thomas; Kitchin, Kirk T.; Delker, Don A.

    2008-01-01

    Chronic drinking water exposure to inorganic arsenic and its metabolites increases tumor frequency in the skin of K6/ODC transgenic mice. To identify potential biomarkers and modes of action for this skin tumorigenicity, we characterized gene expression profiles from analysis of K6/ODC mice administered 0, 0.05, 0.25, 1.0 and 10 ppm sodium arsenite in their drinking water for 4 weeks. Following exposure, total RNA was isolated from mouse skin and processed to biotin-labeled cRNA for microarray analyses. Skin gene expression was analyzed with Affymetrix Mouse Genome 430A 2.0 GeneChips (registered) , and pathway analysis was conducted with DAVID (NIH), Ingenuity (registered) Systems and MetaCore's GeneGo. Differential expression of several key genes was verified through qPCR. Only the highest dose (10 ppm) resulted in significantly altered KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, including MAPK, regulation of actin cytoskeleton, Wnt, Jak-Stat, Tight junction, Toll-like, phosphatidylinositol and insulin signaling pathways. Approximately 20 genes exhibited a dose response, including several genes known to be associated with carcinogenesis or tumor progression including cyclin D1, CLIC4, Ephrin A1, STAT3 and DNA methyltransferase 3a. Although transcription changes in all identified genes have not previously been linked to arsenic carcinogenesis, their association with carcinogenesis in other systems suggests that these genes may play a role in the early stages of arsenic-induced skin carcinogenesis and can be considered potential biomarkers

  12. The study of hemopoietic cells. Effect of prolonged irradiation by low dose rate radiation on the hemopoiesis in the spleen of mice

    Energy Technology Data Exchange (ETDEWEB)

    Shirata, Katsutoshi; Yanai, Takanori; Yamada, Yutaka; Saitou, Mikio; Izumi, Jun; Tanaka, Satoshi; Otsu, Hiroshi; Sato, Fumiaki [Inst. for Environmental Sciences, Dept. of Radiobiology, Rokkasho, Aomori (Japan)

    2001-07-01

    For evaluation of effects of prolonged irradiation by low dose-rate ionizing radiation on the hemopoiesis of mice, SPF C3H/HeN female mice were irradiated with {sup 137}Cs {gamma}-rays with doses of 5-8 Gy at the dose rate of 20 mGy/22h-day. After irradiation, the number of hemopoietic cells contained in spleen was determined by the methods of CFU-S and CFU-GM assays, and the number of peripheral blood cells was counted. It was shown that the number of hemopoietic cells (CFU-S colonies and CFU-GM colonies) decreased as dose increased. No remarkable changes in the number of peripheral blood cells, however, were observed. (author)

  13. Effects of low dose radiation on tumor growth and changes of erythrocyte immune function and activity of SOD in tumor-bearing mice

    International Nuclear Information System (INIS)

    Yu Hongsheng; Lu Yanda

    2001-01-01

    Objective: To study the effect of low dose radiation on tumor growth and changes of erythrocyte immune function and activity of SOD in the tumor-bearing mice. Methods: Kunming strain male mice were implanted with S 180 sarcoma cells in the right inguen subcutaneously as an experimental in situ animal model. Six hours before implantation the mice were given 75 mG whole-body X-ray irradiation and tumor-formation rate was counted 5 days late. From then, every two days the tumor volume was measured to draw a tumor growth curve. Fifteen days later, all mice were killed to measure the tumor weight, observe the necrosis area and the tumor-infiltration lymphoreticular cells (TIL) in the tumor pathologically. At the same time, erythrocyte immune function and activity of SOD were tested. Results: (1) The mice pre-exposed to low dose radiation had a lower tumor formation rate than those without a pre-exposed (P < 0.05). (2) The tumor growth slowed down significantly in mice receiving a low does irradiation; The average tumor weight in mice receiving a low dose irradiation was lighter too (P < 0.05). (3) The tumor necrosis areas were larger and TILs were more in the irradiation group than those of the control group. (4) The erythrocyte immune function and activity of SOD in the irradiation group were all higher significantly than those of the control group ( P < 0.05). Conclusion: Low dose radiation could markedly increase anti-tumor ability of the organism and improve the erythrocyte immune function and activity of SOD in red cells, suggesting it could be useful in clinical cancer treatment

  14. Inflammatory Signals shift from adipose to liver during high fat feeding and influence the development of steatohepatitis in mice

    OpenAIRE

    Stanton, Michaela C; Chen, Shu-Cheng; Jackson, James V; Rojas-Triana, Alberto; Kinsley, David; Cui, Long; Fine, Jay S; Greenfeder, Scott; Bober, Loretta A; Jenh, Chung-Her

    2011-01-01

    Abstract Background Obesity and inflammation are highly integrated processes in the pathogenesis of insulin resistance, diabetes, dyslipidemia, and non-alcoholic fatty liver disease. Molecular mechanisms underlying inflammatory events during high fat diet-induced obesity are poorly defined in mouse models of obesity. This work investigated gene activation signals integral to the temporal development of obesity. Methods Gene expression analysis in multiple organs from obese mice was done with ...

  15. Toxicological Assessment of β-(1à6-Glucan (Lasiodiplodan in Mice during a 28-Day Feeding Study by Gavage

    Directory of Open Access Journals (Sweden)

    Janaína A. Túrmina

    2012-12-01

    Full Text Available Studies evaluating the toxicity caused by fungal exopolysaccharides of the β-(1®6-D-glucan type are rare. In this study, the toxicological effects of sub-chronic treatments with lasiodiplodan (β-(1®6-D-glucan from Lasiodiplodia theobromae MMPI were evaluated in mice through the assessment of biochemical, hematological, and histopathological alterations. Thirty-two mice (16 male, 16 female were used in this study divided in two groups; one group received lasiodiplodan (50 mg/kg body weight daily for 28 days via gavage, and another (control group received saline during the same period. Blood samples were collected via cardiac puncture for hematological and biochemical analyses. Liver, heart, kidney, and spleen were collected for histopathological analysis. Statistical analysis was performed through one-way analysis of variance and only p < 0.05 F-values were presented. Significant reduction in blood glucose in the male group (35%; p < 0.01, transaminases activity in both sexes (AST and ALT; ~35%; p < 0.05, and urea (20%; p < 0.01 in the female group was observed with the lasiodiplodan treatment. The results showed that sub-chronic treatments with lasiodiplodan did not generate hematological and histopathological alterations leading to signs of toxicity in healthy mice, independent of gender.

  16. [Pharmacokinetics and relative bioavailability of THC and THC-solid dispersion orally to mice at single dose].

    Science.gov (United States)

    Liao, Li; Hua, Hua; Zhao, Jun-Ning; Luo, Heng; Yang, An-Dong

    2014-03-01

    To establish a fast sensitive, reproducible LC-MS/MS method to study pharmacokinetic properties of THC, and compare relative bioavailability of THC and its solid dispersion in mice. 200 mice were divided randomly into two groups, and administered orally with THC and THC-solid dispersion after fasting (calculate on THC:400 mg x kg(-1)), used HPLC-MS/MS method to determine the THC concentration of each period at the following times: baseline ( predose ), 15, 30, 45 min, 1, 1.5, 2, 3, 4, 6, 24 h after dosing. Calculating the pharmacokinetic parameters according to the C-t curv, and then use the Phoenix WinNonlin software for data analysis. The calibration curves were linear over the range 9.06-972 microg x L(-1) for THC (R2 = 0.999). The limit of detection (LOD) was 0.7 microg x L(-1), respectively. The average extraction recoveries for THC was above 75%, The methodology recoveries were between 79% and 108%. The intra-day and inter-day RSD were less than 13%, the stability test showed that the plasma samples was stable under different conditions (RSD THC and THC-solid dispersion orally to mice shows as fllows: T(max), were 60 and 15 min, AUC(0-t) were 44 500.43 and 57 497.81 mg x L(-1) x min, AUC(0-infinity) were 51 226.00 and 68 031.48 mg x L(-1) x min, MRT(0-infinity) were 596.915 6, 661.747 7 min, CL(z)/F were 0.007 809 and 0.005 88 L x min(-1) x kg(-1). Compared with THC, the MRT and t1/2 of the THC-solid dispersion were all slightly extended, the t(max) was significantly reduced, AUC(0-24 h), AUC(0-infinity) and C(max) were all significantly higher, the relative bioavailability of THC-solid dispersion is 1.34 times of THC. The results of the experiment shows that the precision, accuracy, recovery and applicability were found to be adequate for the pharmacokinetic studies. After oral administration to mice, the relative bioavailability of THC-solid dispersion show significant improvement compared to THC.

  17. Effects of low dose radiation on expressions of ICAM-1 mRNA and protein in kidney of diabetic mice

    International Nuclear Information System (INIS)

    Zhang Chi; Li Xiaokun; Gong Shouliang; Liu Xiaoju; Zhao Xue; Liu Xiaoju; Zhao Xue; Shen Wenjie; Li Cai; Cai Lu

    2010-01-01

    Objective: To study the effects of low dose radiation (LDR) on the expressions of intercellular adhesion molecule-1 (ICAM-1) mRNA and protein in kidney of diabetes mellitus (DM) mice and illuminate that anti-inflammation of LDR is a main mechanism for diabetic therapy. Methods: The healthy and right age C57BL/6J mice were divided into 4 groups including control, DM, LDR and DM/LDR. The mice in DM and DM/LDR groups were injected intraperitoneally with streptozocin (STZ) to set up DM models. The mice in DM/LDR and LDR groups were irradiated with 25 mGy every other day for 4 weeks. The expressions of ICAM-1 mRNA and protein in kidney were detected with RT-PCR and Western blotting 2, 4, 8, 12 and 16 weeks after irradiation. Results: The expressions of ICAM-1 mRNA and protein in kidney had no significant difference among 4 groups before LDR (P>0.05). The expressions of ICAM-1 mRNA and protein 2 weeks after irradiation with LDR were higher than those in the other 3 groups (P<0.05). The expressions of ICAM-1 mRNA and protein in the DM/LDR group 4 weeks after irradiation were also significantly higher than those in non-DM groups (P<0.05), but still significantly lower than those in DM group (P<0.05), and the significant differences were kept to 16 weeks after irradiation. But the expressions of ICAM-1 mRNA and protein in LDR group were significantly higher than those in control group (P<0.05). IHC assay showed that the glomerular and tubular in DM and DM/LDR groups were abnormal and the quantities of the positive staining cells were significantly increased compared with non-DM groups. However the damage of glomerular and tubular in DM/LDR was significantly supressed compared with DM group and the positive staining cells were also decreased. Conclusion: Under the circumstance of DM, LDR can significantly decrease the expressions of ICAM-1 mRNA and protein in mouse kidney to relief the inflammation reaction in kidney; but in normal condition, LDR can improve the immunity and

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

    Science.gov (United States)

    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. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

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

    International Nuclear Information System (INIS)

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

    2016-01-01

    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.

  20. Neurotoxicity of low-dose repeatedly intranasal instillation of nano- and submicron-sized ferric oxide particles in mice

    Energy Technology Data Exchange (ETDEWEB)

    Wang Bing; Feng Weiyue, E-mail: fengwy@mail.ihep.ac.cn; Zhu Motao; Wang Yun; Wang Meng [Chinese Academy of Sciences, Laboratory for Bio-Environmental Effects of Nanomaterials and Nanosafety and Key Laboratory of Nuclear Analytical Techniques, Institute of High Energy Physics (China); Gu Yiqun [Maternity Hospital of Haidian District (China); Ouyang Hong; Wang Huajian; Li Ming; Zhao Yuliang, E-mail: zhaoyuliang@mail.ihep.ac.cn; Chai Zhifang [Chinese Academy of Sciences, Laboratory for Bio-Environmental Effects of Nanomaterials and Nanosafety and Key Laboratory of Nuclear Analytical Techniques, Institute of High Energy Physics (China); Wang Haifang [Peking University, College of Chemistry and Molecular Engineering (China)

    2009-01-15

    Olfactory tract has been demonstrated to be an important portal for inhaled solid nanoparticle transportation into the central nervous system (CNS). We have previously demonstrated that intranasally instilled Fe{sub 2}O{sub 3} nanoparticles could transport into the CNS via olfactory pathway. In this study, we investigated the neurotoxicity and size effect of repeatedly low-dose (130 {mu}g) intranasal exposure of nano- and submicron-sized Fe{sub 2}O{sub 3} particles (21 nm and 280 nm) to mice. The biomarkers of oxidative stress, activity of nitric oxide synthases and release of monoamine neurotransmitter in the brain were studied. Our results showed that significant oxidative stress was induced by the two sizes of Fe{sub 2}O{sub 3} particles. The activities of GSH-Px, Cu,Zn-SOD, and cNOS significantly elevated and the total GSH and GSH/GSSG ratio significantly decreased in the olfactory bulb and hippocampus after the nano- and submicron-sized Fe{sub 2}O{sub 3} particle treatment (p < 0.05). The nano-sized Fe{sub 2}O{sub 3} generally induced greater alteration and more significant dose-effect response than the submicron-sized particle did. Some slight perturbation of monoamine neurotransmitters were found in the hippocampus after exposure to the two sizes of Fe{sub 2}O{sub 3} particle. The TEM image showed that some ultrastructural alterations in nerve cells, including neurodendron degeneration, membranous structure disruption and lysosome increase in the olfactory bulb, slight dilation in the rough endoplasmic reticulum and lysosome increase in the hippocampus were induced by the nano-sized Fe{sub 2}O{sub 3} treatment. In contrast, in the submicron-sized Fe{sub 2}O{sub 3} treated mice, slightly swollen mitochondria and some vacuoles were observed in the olfactory bulb and hippocampus, respectively. These results indicate that intranasal exposure of Fe{sub 2}O{sub 3} nanoparticles could induce more severe oxidative stress and nerve cell damage in the brain than the

  1. Effects of low dose radiation combined with cyclophosphamide on tumor cell apoptosis, cell cycle and proliferation of bone marrow in tumor-bearing mice

    International Nuclear Information System (INIS)

    Yu Hongsheng; Fei Conghe; Shen Fangzhen; Liang Jun

    2004-01-01

    Objective: To study the effect of low dose radiation (LDR) combined with cyclophosphamide on tumor cell apoptosis, cell cycle, and proliferation of bone marrow in mice tumor-bearing mice. Methods: Kunming strain male mice were implanted with S180 sarcoma cells in the left hind leg subcutaneously as an experimental animal model. Five and 8 days after implantation, the mice were given 75 mGy whole-body γ-ray radiation and CTX(300 mg/kg) by intraperitoneal injection 36 hour after LDR. All mice were sacrificed to measure the tumor volume, tumor cell apoptosis, and cell cycle; the proliferation of bone marrow was analyzed by flow cytometry. Results: Tumor growth was significantly slowed down in the treated groups. The apoptosis of tumor cells increased significantly after LDR. The tumor cells were arrested in G 1 phase in CTX and CTX+LDR groups, more significantly in the latter group than in the former group. Concentration of bone marrow cells and proliferation index in CTX + LDR group were higher than those in CTX group, although concentration of bone marrow cells in CTX and CTX+LDR groups were much lower than that in normal mice. Conclusion: Low dose radiation combined with cyclophosphamide causes more significant G 1 -phase arrest than cyclophosphamide alone and enhances anti-tumor effect markedly. At the same time LDR significantly protects hematopoietic function of bone marrow, which is of practical significance as an adjuvant chemotherapy

  2. Measurement of micronuclei and internal dose in mice demonstrates that 3-monochloropropane-1,2-diol (3-MCPD) has no genotoxic potency in vivo.

    Science.gov (United States)

    Aasa, Jenny; Törnqvist, Margareta; Abramsson-Zetterberg, Lilianne

    2017-11-01

    In this study 3-monochloropropane-1,2-diol (3-MCPD), a compound that appears as contaminant in refined cooking oils, has been studied with regard to genotoxicity in vivo (mice) with simultaneous measurement of internal dose using state-of-the-art methodologies. Genotoxicity (chromosomal aberrations) was measured by flow cytometry with dual lasers as the frequency of micronuclei in erythrocytes in peripheral blood from BalbC mice intraperitoneally exposed to 3-MCPD (0, 50, 75, 100, 125 mg/kg). The internal doses of 3-MCPD in the mice were calculated from N-(2,3-dihydroxypropyl)-valine adducts to hemoglobin (Hb), quantified at very low levels by high-resolution mass spectrometry. Convincing evidence for absence of genotoxic potency in correlation to measured internal doses in the mice was demonstrated, despite relatively high administered doses of 3-MCPD. The results are discussed in relation to another food contaminant that is formed as ester in parallel to 3-MCPD esters in oil processing, i.e. glycidol, which has been studied previously by us in a similar experimental setup. Glycidol has been shown to be genotoxic, and in addition to have ca. 1000 times higher rate of adduct formation compared to that observed for 3-MCPD. The conclusion is that at simultaneous exposure to 3-MCPD and glycidol the concern about genotoxicity would be glycidol. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Chronic low-dose UVA irradiation induces local suppression of contact hypersensitivity, Langerhans cell depletion and suppressor cell activation in C3H/HeJ mice

    International Nuclear Information System (INIS)

    Bestak, Rosa; Halliday, G.M.

    1996-01-01

    It has previously been demonstrated that chronic low-dose solar-simulated UV radiation could induce both local and systemic immunosuppression as well as tolerance to a topically applied hapten. In this study, we have used a chronic low-dose UV-irradiation protocol to investigate the effects of UVA on the skin immune system of C3H/HeJ mice. Irradiation with UVA+B significantly suppressed the local and systemic primary contact hypersensitivity (CHS) response to the hapten 2,4,6-trinitrochlorobenzene. Furthermore, UVA+B reduced Langerhans cell (LC) and dendritic epidermal T cell (DETC) densities in chronically UV-irradiated mice. Ultraviolet A irradiation induced local, but not systemic, immunosuppression and reduced LC (32%) but not DETC from the epidermis compared to the shaved control animals. Treatment of mice with both UVA+B and UVA radiation also induced an impaired secondary CHS response, and this tolerance was transferable with spleen cells. (Author)

  4. Intermittent feeding as a factor enhancing hemopoietic stem cell proliferation and spleen colony formation in irradiated mice

    International Nuclear Information System (INIS)

    Kozubik, A.; Pospisil, M.

    1985-01-01

    The influence of metabolic stimulation induced by a 3 weeks' adaption of the animals to intermittent food intake on hemopoietic stem cells was investigated in mice. The methods used included transplantation of bone marrow to lethally irradiated recipients, assay of CFUs number, seeding efficiency, and incorporation of 125 iodode oxyuridine into the DNA of spleen cells. A stimulatory effect of the metabolically influenced hemopoietic environment on the proliferative activity in stem cell compartments and on the recovery of hemopoietic organs was demonstrated. These stimulatory effects were most marked when the bone marrow of metabolically influenced donors was transplanted to similarly influenced recipients. (orig.)

  5. Effects of low dose radiation on differential expression of serum protein in mice

    International Nuclear Information System (INIS)

    Chen Wei; He Ying; Shen Xianrong

    2014-01-01

    The aim is to find out the key proteins related with low dose radiation (Ld) by parametric technology, which provided the theory foundation for LDR protection Two-dimensional electrophoresis (2-DE) was performed on serum protein Differential expression proteins were identified by matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) and database analysis Compared with the control group, 7 altered proteins was definite in terms of apolipoprotein C-Ⅲ, beta-globin parotid secretory protein alpha-2-macroglobulin precursor, mouse transthyretin, C1qc protein and clusterin. Some proteins related with LDR are found. It may provide some new explanations for the mechanism of LDR. (authors)

  6. Low-dose-rate high-let radiation cytogenetic effects on mice in vivo as model of space radiation action on mammalian

    Science.gov (United States)

    Sorokina, Svetlana; Zaichkina, Svetlana; Rozanova, Olga; Aptikaeva, Gella; Romanchenko, Sergei; Smirnova, Helene; Dyukina, Alsu; Peleshko, Vladimir

    At present time little is known concerning the biological effects of low-dose-rate high-LET radiation exposure in space. The currently available experimental data on the biological effect of low doses of chronic radiation with high-LET values, which occur under the conditions of aircraft and space flights, have been primarily obtained in the examinations of pilots and astronauts after flights. Another way of obtaining this kind of evidence is the simulation of irradiation conditions during aircraft and space flights on high-energy accelerators and the conduction of large-scale experiments on animals under these conditions on Earth. In the present work, we investigated the cytogenetic effects of low-dose-rate high-LET radiation in the dose ranges of 0.2-30 cGy (1 cGy/day) and 0.5-16 cGy (0.43 cGy/day) in the radiation field behind the concrete shield of the Serpukhov accelerator of 70 GeV protons that simulates the spectral and component composition of radiation fields formed in the conditions of high-altitude flights on SHK mice in vivo. The dose dependence, adaptive response (AR) and the growth of solid tumor were examined. For induction of AR, two groups of mice were exposed to adapting doses of 0.2-30 cGy and the doses of 0.5-16 cGy of high-LET radiation. For comparison, third group of mice from unirradiated males was chronically irradiated with X-rays at adapting doses of 10 cGy (1 cGy/day). After a day, the mice of all groups were exposed to a challenging dose of 1.5 Gy of X-rays (1 Gy/min). After 28 h, the animals of all groups were killed by the method of cervical dislocation. Bone marrow specimens for calculating micronuclei (MN) in polychromatic erythrocytes (PCE) were prepared by a conventional method with minor modifications. The influence of adapting dose of 16 cGy on the growth of solid tumor of Ehrlich ascite carcinoma was estimated by measuring the size of the tumor at different times after the inoculation of ascitic cells s.c. into the femur. It was

  7. Assessing absorbed dose heterogeneities for organ S-value calculation in mice

    International Nuclear Information System (INIS)

    Mauxion, T.; Villoing, D.; Marcatili, S.; Garcia, M.P.; Poirot, M.; Bardies, M.; Suhard, J.; Barbet, J.

    2015-01-01

    Full text of publication follows. Introduction and aim: S-values calculated according to the MIRD scheme strongly depend on the size of source/target regions and particle ranges (1). Several mean organ S-values were recently calculated for mice in the context of targeted radionuclide therapy and molecular imaging (2). However, the heterogeneity of energy deposition at the sub-organ level is seldom taken into account and the relevance of mean organ S-values is not systematically evaluated. This study aims at assessing spatial variations associated to mean S-values for small animals to estimate energy deposition heterogeneity at the sub-organ or voxel level. Materials and methods: a 29 g-mouse-model generated at high spatial sampling (200*200*200 μm 3 ) from the Moby software was used to calculate S-values for several radionuclides of interest (3). Monte Carlo simulations were performed with GATE (v6.2), in which specific corrections were implemented and validated to improve the accuracy of voxel energy-scoring. Mean S-values and standard deviations were calculated from 3D-voxel-based energy deposition maps for several source/target organ pairs. As the standard deviation associated to the mean S-value in a given target organ includes both spatial and statistical fluctuations, we simulated an increasing number of primary particles (typically from 10 6 to 10 10 ) to estimate the impact of relative statistical/spatial fluctuations for several source/target pairs. A spatial dispersion factor (HS-value for Heterogeneity of S-value) was obtained when the standard deviation converged to a stable value. Results: several HS-values calculated for source organs were significant in case of self-irradiation for all considered radionuclides, but remained very low as compared to values obtained for short and large source/target distances. For example, for 131 I sources located in the thyroid, S(thyroid - thyroid)=1.80*10 -9 Gy.Bq -1 .s -1 and HS(thyroid - thyroid)=3.09*10 -10 Gy

  8. Different effects of high- and low-dose phenobarbital on post-stroke seizure suppression and recovery in immature CD1 mice

    Science.gov (United States)

    Markowitz, Geoffrey J.; Kadam, Shilpa D.; Smith, Dani R.; Johnston, Michael V.; Comi, Anne M.

    2011-01-01

    Neonatal stroke presents with seizures that are usually treated with phenobarbital. We hypothesized that anticonvulsants would attenuate ischemic injury, but that the dose-dependent effects of standard anticonvulsants would impact important age-dependent and injury-dependent consequences. In this study, ischemia induced by unilateral carotid ligation in postnatal day 12 (P12) CD1 mice was immediately followed by an i.p. dose of vehicle, low-dose or high-dose phenobarbital. Severity of acute behavioral seizures was scored. 5-bromo-2’-deoxyuridine (BrdU) was administered from P18-P20, behavioral testing performed, and mice perfused at P40. Atrophy quantification and counts of BrdU/NeuN-labeled cells in the dentate gyrus were performed. Blood phenobarbital concentrations were measured. 30 mg/kg phenobarbital reduced acute seizures and chronic brain injury, and restored normal weight gain and exploratory behavior. By comparison, 60 mg/kg was a less efficacious anticonvulsant, was not neuroprotective, did not restore normal weight gain, and impaired behavioral and cognitive recovery. Hippocampal neurogenesis was not different between treatment groups. These results suggest a protective effect of lower-dose phenobarbital, but a lack of this effect at higher concentrations after stroke in P12 mice. PMID:21481568

  9. Effect of potato plants grown from tubers irradiated with low doses of gamma radiation on feeding and reproductive behaviours of potato tuber moth Phtorimaea Operculella (Lep., Gelechiidae)

    International Nuclear Information System (INIS)

    Saour, G.; Makee, H.; Al-Oudat, M.

    1997-09-01

    The feeding behavior of potato tuber moth Phthorimaea Operculella (Lep., Gelechiidae) larvae reared on leaves and tubers of potato plants, which its seeds had been irradiated with low doses of gamma irradiation (1, 3, 5, 10, Gy) has been studied. Significant differences in the larval developmental time, pupae developmental time, pupae weight, mortality, fecundity and percentage of egg hatch, was observed between insects fed on plants grown from the irradiated seeds and the control. It appears that leaves of potato plants grown from the irradiated seeds, particularly those of 3 Gy, became more favourable for the larvae, whilst the resulted tubers, except tubers of the dose of 10 Gy, which could have repellent properties became more resistant to potato tuber moth. Plant development stage and tubers storage at ambient temperatures condition affect the degree of sensitivity of the larvae. Leaves and tubers of 10 Gy irradiated seeds became more suitable for insect development, indicating that the later dose may inhibit the production of secondary plant metabolites chemical compounds. (author)

  10. The doubling dose of ionizing radiation for drosophilia, mice, and humans

    International Nuclear Information System (INIS)

    Neel, J.V.

    1997-01-01

    It is part of the lore of radiation genetics that Drosophila is much more resistant to the genetic effects of radiation than the mouse. For across-species comparisons and risk setting, an estimate of the mutational doubling dose (DD) for human germ cells (immature oocytes and spermatogonia) was approximately 2 Sv equivalents. Neel and Lewis suggested that the population DD for mouse spermatogonia was approximately 1.3 Sv equivalents, with the rate for immature oocytes even higher, because of the failure to recover mutations in the late litters of radiated females. With the incorporation of cluster mutations into the mouse DD estimate, as discussed by Selby here last year, these mouse DD can only go higher. Given the relative agreement between these two mammals, I have now reviewed all the pertinent Drosophila data, the results of which review will be presented. There are many difficulties to combining the results of the various relevant Drosophila studies, but, to a first approximation, a population DD of approximately 4 Gy emerges. There is, thus, given the uncertainties in such estimates, agreement within a factor of 2 between the three species, with such different life histories. The coincidence, to what extent a simple function of target size, and to what extent the result of an evolutionary adjustment by virtue of which induced mutation rates (i.e., repair inefficiencies) are proportional to generation length rather than absolute time

  11. Toxicology and carcinogenesis studies of acrylamide (CASRN 79-06-1) in F344/N rats and B6C3F1 mice (feed and drinking water studies).

    Science.gov (United States)

    2012-07-01

    diet. The neuronal degenerative changes were accompanied, at times, by atrophy in skeletal muscle of the hind-limb and luminal dilation of the urinary bladder. Degeneration of the germ cells in the testes was observed in six of eight male mice given 3.52 mM acrylamide and seven of seven mice fed 370 mg acrylamide per kg diet. 2 YEAR STUDY IN RATS: Groups of 48 male and 48 female F344/N rats were administered acrylamide in the drinking water ad libitum for 2 years. Concentrations of 0.0875, 0.175, 0.35, and 0.70 mM acrylamide (6.25, 12.5, 25, and 50 ppm acrylamide) resulted in an average daily consumption of approximately 0.33, 0.66, 1.32, and 2.71 mg acrylamide per kg body weight in male F344/N rats and 0.44, 0.88, 1.84, and 4.02 mg acrylamide per kg body weight in female F344/N rats. Acrylamide had no effect upon the survival of male F344/N rats. Female F344/N rats administered 0.175, 0.35, or 0.70 mM acrylamide had decreased survival compared to control female F344/N rats. Acrylamide caused significant dose-related decreasing trends in body weight in F344/N rats. At the end of the 2 year period, male and female F344/N rats administered 0.70 mM acrylamide weighed 86% and 85% of their respective control groups. Feed consumption was generally not affected by acrylamide; water consumption in female F344/N rats was increased at later time points. In male F344/N rats, the incidence of epididymis malignant mesothelioma, combined epididymis or testicular tunica malignant mesothelioma, heart malignant incidences of schwannoma, pancreatic islets adenoma, thyroid gland follicular cell carcinoma, and combined thyroid gland follicular cell adenoma or carcinoma was increased significantly in the 0.70 mM acrylamide group. In female F344/N rats, the incidence of clitoral gland carcinoma was increased significantly in the 0.0875, 0.175, and 0.70 mM acrylamide groups. The incidence of mammary gland fibroadenoma was increased significantly at 0.175, 0.35, and 0.70 mM acrylamide

  12. Dose-Dependent Effect of Intravenous Administration of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Neonatal Stroke Mice

    Science.gov (United States)

    Tanaka, Emi; Ogawa, Yuko; Mukai, Takeo; Sato, Yoshiaki; Hamazaki, Takashi; Nagamura-Inoue, Tokiko; Harada-Shiba, Mariko; Shintaku, Haruo; Tsuji, Masahiro

    2018-01-01

    Neonatal brain injury induced by stroke causes significant disability, including cerebral palsy, and there is no effective therapy for stroke. Recently, mesenchymal stem cells (MSCs) have emerged as a promising tool for stem cell-based therapies. In this study, we examined the safety and efficacy of intravenously administered human umbilical cord-derived MSCs (UC-MSCs) in neonatal stroke mice. Pups underwent permanent middle cerebral artery occlusion at postnatal day 12 (P12), and low-dose (1 × 104) or high-dose (1 × 105) UC-MSCs were administered intravenously 48 h after the insult (P14). To evaluate the effect of the UC-MSC treatment, neurological behavior and cerebral blood flow were measured, and neuroanatomical analysis was performed at P28. To investigate the mechanisms of intravenously injected UC-MSCs, systemic blood flowmetry, in vivo imaging and human brain-derived neurotrophic factor (BDNF) measurements were performed. Functional disability was significantly improved in the high-dose UC-MSC group when compared with the vehicle group, but cerebral blood flow and cerebral hemispheric volume were not restored by UC-MSC therapy. The level of exogenous human BDNF was elevated only in the cerebrospinal fluid of one pup 24 h after UC-MSC injection, and in vivo imaging revealed that most UC-MSCs were trapped in the lungs and disappeared in a week without migration toward the brain or other organs. We found that systemic blood flow was stable over the 10 min after cell administration and that there were no differences in mortality among the groups. Immunohistopathological assessment showed that the percent area of Iba1-positive staining in the peri-infarct cortex was significantly reduced with the high-dose UC-MSC treatment compared with the vehicle treatment. These results suggest that intravenous administration of UC-MSCs is safe for a mouse model of neonatal stroke and improves dysfunction after middle cerebral artery occlusion by modulating

  13. Dose-Dependent Effect of Intravenous Administration of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Neonatal Stroke Mice

    Directory of Open Access Journals (Sweden)

    Emi Tanaka

    2018-03-01

    Full Text Available Neonatal brain injury induced by stroke causes significant disability, including cerebral palsy, and there is no effective therapy for stroke. Recently, mesenchymal stem cells (MSCs have emerged as a promising tool for stem cell-based therapies. In this study, we examined the safety and efficacy of intravenously administered human umbilical cord-derived MSCs (UC-MSCs in neonatal stroke mice. Pups underwent permanent middle cerebral artery occlusion at postnatal day 12 (P12, and low-dose (1 × 104 or high-dose (1 × 105 UC-MSCs were administered intravenously 48 h after the insult (P14. To evaluate the effect of the UC-MSC treatment, neurological behavior and cerebral blood flow were measured, and neuroanatomical analysis was performed at P28. To investigate the mechanisms of intravenously injected UC-MSCs, systemic blood flowmetry, in vivo imaging and human brain-derived neurotrophic factor (BDNF measurements were performed. Functional disability was significantly improved in the high-dose UC-MSC group when compared with the vehicle group, but cerebral blood flow and cerebral hemispheric volume were not restored by UC-MSC therapy. The level of exogenous human BDNF was elevated only in the cerebrospinal fluid of one pup 24 h after UC-MSC injection, and in vivo imaging revealed that most UC-MSCs were trapped in the lungs and disappeared in a week without migration toward the brain or other organs. We found that systemic blood flow was stable over the 10 min after cell administration and that there were no differences in mortality among the groups. Immunohistopathological assessment showed that the percent area of Iba1-positive staining in the peri-infarct cortex was significantly reduced with the high-dose UC-MSC treatment compared with the vehicle treatment. These results suggest that intravenous administration of UC-MSCs is safe for a mouse model of neonatal stroke and improves dysfunction after middle cerebral artery occlusion by

  14. Dose and time effect of CdTe quantum dots on antioxidant capacities of the liver and kidneys in mice

    Directory of Open Access Journals (Sweden)

    Wang J

    2017-09-01

    Full Text Available Jilong Wang,1,2,* Hubo Sun,1,2,* Peijun Meng,1,2 Mengmeng Wang,1,2 Mi Tian,3 Yamin Xiong,1,2 Xueying Zhang,1,2 Peili Huang1,2 1School of Public Health, Capital Medical University, 2Beijing Key Laboratory of Environmental Toxicology, 3Medical Experiment and Test Center, Capital Medical University, Beijing, People’s Republic of China *These authors contributed equally to this work Abstract: Although quantum dot (QD-induced toxicity occurs due to free radicals, generation of oxidative stress mediated by reactive oxygen species (ROS formation is considered an important mechanism. However, free radical mechanisms are essentially difficult to elucidate at the molecular level because most biologically relevant free radicals are highly reactive and short-lived, making them difficult to directly detect, especially in vivo. Antioxidants play an important role in preventing or, in most cases, limiting the damage caused by ROS. Healthy people and animals possess many endogenous antioxidative substances that scavenge free radicals in vivo to maintain the redox balance and genome integrity. The antioxidant capacity of an organism is highly important but seldom studied. In this study, the dose and time effects of CdTe QDs on the antioxidant capacities of the liver and kidneys were investigated in mice using the electron paramagnetic resonance (EPR spin-trapping technique. We found that the liver and kidneys of healthy mice contain specific antioxidant capacities that scavenge ·OH and ·O2-. Furthermore, oxidative stress markers (superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GPx], glutathione [GSH] and malondialdehyde [MDA] were examined. In dose course studies, the free radical scavenging efficiencies of the liver and kidneys were found to gradually decrease with increasing concentration of CdTe QD exposure. The activities and levels of SOD, CAT, GPx and MDA were observed to increase in treated groups, whereas those of GSH were reduced

  15. Low dose of L-glutamic acid attenuated the neurological dysfunctions and excitotoxicity in bilateral common carotid artery occluded mice.

    Science.gov (United States)

    Ramanathan, Muthiah; Abdul, Khadar K; Justin, Antony

    2016-10-01

    Glutamate, an excitatory neurotransmitter in the brain, produces excitotoxicity through its agonistic action on postsynaptic N-methyl-D-aspartate receptor, resulting in neurodegeneration. We hypothesized that the administration of low doses of glutamate in cerebral ischemia could attenuate the excitotoxicity in neurons through its autoreceptor regulatory mechanism, and thereby control neurodegeneration. To test the hypothesis, the effect of L-glutamic acid (L-GA) 400 μmol/l/kg was evaluated in a bilateral common carotid artery occlusion-induced global ischemic mouse model. Memantine was used as a positive control. Global ischemia in mice was induced by occlusion of both the common carotid artery (bilateral common carotid artery occlusion) for 20 min, followed by reperfusion injury. L-GA was infused slowly through the tail vein 30 min before the surgery and every 24 h thereafter until the end of the experiment. The time-dependent change in cerebral blood flow was monitored using a laser Doppler image analyzer. The neurotransmitters glutamate and γ-aminobutyric acid (GABA) and the neurobiochemicals ATP, glutathione, and nitric oxide were measured in the different regions of brain at 0, 24, 48, and 72 h after reperfusion injury. L-GA increased locomotor activity, muscle coordination, and cerebral blood flow in ischemic mice at 72 h after ischemic insult. L-GA reduced glutamate levels in the cortex, striatum, and hippocampus at 72 h, whereas GABA levels were elevated in all three brain regions studied. Further, L-GA elevated glutathione levels and attenuated nitric oxide levels, but failed to restore ATP levels 72 h after ischemia-reperfusion. We conclude that the gradual reduction of glutamate along with elevation of GABA in different brain regions could have contributed toward the neuroprotective effect of L-GA. Hence, a slow infusion of a low dose of L-GA could be beneficial in controlling excitotoxicity-induced neurodegeneration following ischemia.

  16. Dose-effect relationships for fife shortening, tumorigenesis, and systemic injuries in mice irradiated with fission neutron or 60Co gamma radiation

    International Nuclear Information System (INIS)

    Ainsworth, E.J.; Fry, R.J.M.; Williamson, F.S.; Brennan, P.C.; Stearner, S.P.; Yang, V.V.; Crouse, D.A.; Rust, J.H.; Borak, T.B.

    1977-01-01

    The objective of this research is to provide additional data on life shortening, neoplastic and non-neoplastic diseases, and other systematic injuries necessary for the determination of dose-response relationships. The data are used to test existing predictive models and formulate new models which may assist with radiation risk assessment. Late somatic effects of fission neutrons from the JANUS reactor or from cobalt-60 gamma radiation are evaluated in young adult B6CF 1 mice that receive either a range of single doses or protracted doses at low dose rates; the protracted irradiation is administered over a 6-month period. After single doses of gamma radiation the relationship between radiation dose and percent life shortening appears linear whereas after single doses of fission spectrum neutrons a non-linear dose response is observed. These results suggest that estimates of radiation risk for fission spectrum neutrons should take into account the following: the curvilinearity of the neutron dose-response curve for life shortening, and the increased life shortening produced by neutron dose fractionation

  17. Long-term effects of environmentally relevant doses of 2,2',4,4',5,5' hexachlorobiphenyl (PCB153 on neurobehavioural development, health and spontaneous behaviour in maternally exposed mice

    Directory of Open Access Journals (Sweden)

    Heegaard Einar

    2011-01-01

    Full Text Available Abstract Background Polychlorinated biphenyls (PCBs are widespread in the environment, human food and breast milk. Seafood is known to contain nutrients beneficial for the normal development and function of the brain, but also contaminants such as PCBs which are neurotoxic. Exposure to non-coplanar PCBs during brain development can disrupt spontaneous behaviour in mice and lead to hyperactive behaviour. Humans are chronically exposed to the highest relative levels of organochlorines in early childhood during brain development, though usually at doses which do not give clinical symptoms of toxicity. This study aimed to elucidate the developmental and behavioural effects of 2,2',4,4',5,5' hexachlorobiphenyl (PCB153 in mice, mimicking human exposure during gestation and lactation. Methods Environmentally relevant doses of PCB153 were added to the experimental diets. Feed concentrations were approximately 0.5, 6.5, and 1500 μg PCB153/kg feed, representing a realistic and a worst case scenario of frequent consumption of contaminated fish. The study also investigated the effects of maternal nutrition, i.e. a standard rodent diet versus a high inclusion of salmon. Mice pups were examined for physical- and reflex development, sensorimotor function and spontaneous behaviour from five days after birth until weaning. A selection of pups were followed until 16 weeks of age and tested for open field behaviour and the acoustic startle response (ASR with prepulse inhibition (PPI. Blood thyroid hormones and liver enzymes, blood lipids and PCB153 content in fat were examined at 16 weeks. Statistical analyses modelled the three way interactions of diet, PCB exposure and litter size on behaviour, using generalized linear models (GLM and linear mixed effect models (LME. The litter was used as a random variable. Non-parametric tests were used for pair wise comparisons of biochemical analyses. Results Litter size consistently influenced pup development and behaviour

  18. Long-term effects of environmentally relevant doses of 2,2',4,4',5,5' hexachlorobiphenyl (PCB153) on neurobehavioural development, health and spontaneous behaviour in maternally exposed mice.

    Science.gov (United States)

    Haave, Marte; Bernhard, Annette; Jellestad, Finn K; Heegaard, Einar; Brattelid, Trond; Lundebye, Anne-Katrine

    2011-01-13

    Polychlorinated biphenyls (PCBs) are widespread in the environment, human food and breast milk. Seafood is known to contain nutrients beneficial for the normal development and function of the brain, but also contaminants such as PCBs which are neurotoxic. Exposure to non-coplanar PCBs during brain development can disrupt spontaneous behaviour in mice and lead to hyperactive behaviour. Humans are chronically exposed to the highest relative levels of organochlorines in early childhood during brain development, though usually at doses which do not give clinical symptoms of toxicity. This study aimed to elucidate the developmental and behavioural effects of 2,2',4,4',5,5' hexachlorobiphenyl (PCB153) in mice, mimicking human exposure during gestation and lactation. Environmentally relevant doses of PCB153 were added to the experimental diets. Feed concentrations were approximately 0.5, 6.5, and 1500 μg PCB153/kg feed, representing a realistic and a worst case scenario of frequent consumption of contaminated fish. The study also investigated the effects of maternal nutrition, i.e. a standard rodent diet versus a high inclusion of salmon. Mice pups were examined for physical- and reflex development, sensorimotor function and spontaneous behaviour from five days after birth until weaning. A selection of pups were followed until 16 weeks of age and tested for open field behaviour and the acoustic startle response (ASR) with prepulse inhibition (PPI). Blood thyroid hormones and liver enzymes, blood lipids and PCB153 content in fat were examined at 16 weeks. Statistical analyses modelled the three way interactions of diet, PCB exposure and litter size on behaviour, using generalized linear models (GLM) and linear mixed effect models (LME). The litter was used as a random variable. Non-parametric tests were used for pair wise comparisons of biochemical analyses. Litter size consistently influenced pup development and behaviour. Few lasting PCB153 related changes were observed

  19. Pathology of Serially Sacrificed Female B6C3F1 Mice Continuously Exposed to Very Low-Dose-Rate Gamma Rays.

    Science.gov (United States)

    Tanaka, I B; Komura, J; Tanaka, S

    2017-03-01

    We have previously reported on life span shortening as well as increased incidence rates in several neoplasms in B6C3F1 mice that were continuously exposed to 21 mGy/day of gamma rays for 400 days. To clarify whether the life shortening was due to early appearance of neoplasms (shortened latency) or increased promotion/progression, 8-week-old female specific-pathogen-free B6C3F1 mice were gamma-ray irradiated at a low dose rate of 20 mGy/day for 400 days. At 100 days postirradiation, 60-90 mice were sacrificed, and thereafter every 100 days alongside the age-matched nonirradiated controls, for 700 days. Additional groups were allowed to live out their natural life span. Pathological examination was performed on all mice to identify lesions, non-neoplastic and neoplastic, as well as to determine the cause of death. Body weights were significantly increased in irradiated mice from sacrifice days 200-500. Incidence rates for spontaneously occurring non-neoplastic lesions, such as adrenal subcapsular cell hyperplasia, fatty degeneration of the liver, atrophy and tubulostromal hyperplasia of the ovaries, were significantly increased in irradiated mice. Significantly increased incidence rates with no shortening of latency periods were observed in irradiated mice for malignant lymphomas, hepatocellular adenomas/carcinomas, bronchioloalveolar adenomas, harderian gland adenoma/adenocarcinoma. Shortened latencies with significantly increased incidence rates were observed for adrenal subcapsular cell adenomas and ovarian neoplasms (tubulostromal adenoma, granulosa cell tumors) in irradiated mice. Life span shortening in mice exposed to 20 mGy/day was mostly due to malignant lymphomas. Multiple primary neoplasms were significantly increased in mice exposed to 20 mGy/day from sacrifice days 400-700 and in the life span group. Our results confirm that continuous low-dose-rate gamma-ray irradiation of female B6C3F1 mice causes both cancer induction (shortened latency) and

  20. Comparison of three rapamycin dosing schedules in A/J Tsc2+/- mice and improved survival with angiogenesis inhibitor or asparaginase treatment in mice with subcutaneous tuberous sclerosis related tumors

    Directory of Open Access Journals (Sweden)

    Dabora Sandra L

    2010-02-01

    Full Text Available Abstract Background Tuberous Sclerosis Complex (TSC is an autosomal dominant tumor disorder characterized by the growth of hamartomas in various organs including the kidney, brain, skin, lungs, and heart. Rapamycin has been shown to reduce the size of kidney angiomyolipomas associated with TSC; however, tumor regression is incomplete and kidney angiomyolipomas regrow after cessation of treatment. Mouse models of TSC2 related tumors are useful for evaluating new approaches to drug therapy for TSC. Methods In cohorts of Tsc2+/- mice, we compared kidney cystadenoma severity in A/J and C57BL/6 mouse strains at both 9 and 12 months of age. We also investigated age related kidney tumor progression and compared three different rapamycin treatment schedules in cohorts of A/J Tsc2+/- mice. In addition, we used nude mice bearing Tsc2-/- subcutaneous tumors to evaluate the therapeutic utility of sunitinib, bevacizumab, vincristine, and asparaginase. Results TSC related kidney disease severity is 5-10 fold higher in A/J Tsc2+/- mice compared with C57BL/6 Tsc2+/- mice. Similar to kidney angiomyolipomas associated with TSC, the severity of kidney cystadenomas increases with age in A/J Tsc2+/- mice. When rapamycin dosing schedules were compared in A/J Tsc2+/- cohorts, we observed a 66% reduction in kidney tumor burden in mice treated daily for 4 weeks, an 82% reduction in mice treated daily for 4 weeks followed by weekly for 8 weeks, and an 81% reduction in mice treated weekly for 12 weeks. In the Tsc2-/- subcutaneous tumor mouse model, vincristine is not effective, but angiogenesis inhibitors (sunitinib and bevacizumab and asparaginase are effective as single agents. However, these drugs are not as effective as rapamycin in that they increased median survival only by 24-27%, while rapamycin increased median survival by 173%. Conclusions Our results indicate that the A/J Tsc2+/- mouse model is an improved, higher through-put mouse model for future TSC

  1. Cyp1a1(-/-) male mice: protection against high-dose TCDD-induced lethality and wasting syndrome, and resistance to intrahepatocyte lipid accumulation and uroporphyria

    International Nuclear Information System (INIS)

    Uno, Shigeyuki; Dalton, Timothy P.; Sinclair, Peter R.; Gorman, Nadia; Wang, Bin; Smith, Andrew G.; Miller, Marian L.; Shertzer, Howard G.; Nebert, Daniel W.

    2004-01-01

    To study liver toxicity and uroporphyrin (URO) accumulation and urinary excretion, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent ligand for the aryl hydrocarbon receptor (AHR), is often used as the prototype. In this study, we asked the question how important is the role of CYP1A1 in causing TCDD toxicity. Using a single large intraperitoneal dose of TCDD (200 μg/kg) and following the response over an 8-week period, we found this dose: (a) was lethal in less than 4 weeks to Cyp1a1(+/+) males but not to Cyp1a1(-/-) males or to females of either genotype; (b) caused a wasting syndrome in Cyp1a1(+/+) but not Cyp1a1(-/-) mice; (c) resulted in thymic atrophy, regardless of gender or genotype; (d) decreased spleen size and caused leukocytopenia in males but not females of either genotype; (e) caused hepatocyte hypertrophy in Cyp1a1(+/+) more so than in Cyp1a1(-/-) mice; (f) increased intrahepatocyte lipids and total liver fat content in Cyp1a1(+/+) more than Cyp1a1(-/-) males and females; and (g) caused uroporphyria in Cyp1a1(+/+) males much more than Cyp1a1(+/+) females, or in Cyp1a1(-/-) mice. Contrary to Cyp1a2(-/-) knockout mice that exhibited 15 times less accumulation of TCDD in liver than Cyp1a1/1a2(+/+) wild-type mice, Cyp1a1(-/-) mice did not show this altered TCDD distribution - indicating that CYP1A2 but not CYP1A1 is the major hepatic TCDD-binding 'sink'. Our data demonstrate that CYP1A1 contributes to high-dose TCDD-induced toxicity, uroporphyria, and lethality

  2. The small-molecule TNF-α inhibitor, UTL-5g, delays deaths and increases survival rates for mice treated with high doses of cisplatin.

    Science.gov (United States)

    Shaw, Jiajiu; Media, Joseph; Chen, Ben; Valeriote, Fredrick

    2013-09-01

    UTL-5g is a novel small-molecule chemoprotector that lowers hepatotoxicity, nephrotoxicity, and myelotoxicity induced by cisplatin through TNF-α inhibition among other factors. The objective of this study was to investigate whether UTL-5g can reduce the overall acute toxicity of cisplatin and increase cisplatin tolerability in mice. BDF1 female mice were treated individually with UTL-5g (suspended in Ora-Plus) by oral gavage at 60 mg/kg, 30 min before i.p. injection of cisplatin at 10, 15, and 20 mg/kg, respectively, on Day 0. Starting from Day 1, individual mice were again treated daily by the same dose of UTL-5g for 4 consecutive days. Survivals and body weights were monitored. UTL-5g treatment increased the survival rate and delayed the time to death for mice treated with 150 % of the maximum tolerated dose (MTD) of cisplatin (15 mg/kg). Likewise, at 200 % of the MTD of cisplatin (20 mg/kg), treatment of UTL-5g increased the survival rate and delayed the time to death. Treatment of UTL-5g did not have a significant effect on weight loss induced by cisplatin, indicating that body weight may not be a sensitive-enough measure for chemoprotection of UTL-5g against cisplatin. In summary, UTL-5g delayed deaths and increased survival rates of mice treated by high doses of cisplatin, indicating that UTL-5g is capable of reducing the overall acute toxicity of cisplatin and increased cisplatin tolerability in mice; this is in line with the specific chemoprotective effects of UTL-5g previously reported. Further investigation of UTL-5g in combination with cisplatin is warranted.

  3. Novel regulator of acylated ghrelin, CF801, reduces weight gain, rebound feeding after a fast, and adiposity in mice

    Directory of Open Access Journals (Sweden)

    Martin K Wellman

    2015-09-01

    Full Text Available Ghrelin is a 28 amino-acid hormonal peptide that is intimately related to the regulation of food intake and body weight. Once secreted, ghrelin binds to the growth hormone secretagogue receptor-1a (GHSR-1a, the only known receptor for ghrelin and is capable of activating a number of signaling cascades ultimately resulting in an increase in food intake and adiposity. Because ghrelin has been linked to overeating and the development of obesity, a number of pharmacological interventions have been generated in order to interfere with either the activation of ghrelin or interrupting ghrelin signaling as a means to reducing appetite and decrease weight gain. Here we present a novel peptide, CF801, capable of reducing circulating acylated ghrelin levels and subsequent body weight gain and adiposity. To this end, we show that IP administration of CF801 is sufficient to reduce circulating plasma acylated ghrelin levels. Acutely, intraperitoneal injections of CF801 resulted in decreased rebound feeding after an overnight fast. When delivered chronically decreased weight gain and adiposity without affecting caloric intake. CF801, however, did cause a change in diet preference, decreasing preference for a high fat diet and increasing preference for regular chow diet. Given the complexity of ghrelin receptor function, we propose that CF801 along with other compounds that regulate ghrelin secretion may prove to be a beneficial tool in the study of the ghrelin system, and potential targets for ghrelin based obesity treatments without altering the function of ghrelin receptors.

  4. Dose-dependency and reversibility of radiation-induced injury in cardiac explant-derived cells of mice

    Science.gov (United States)

    Luo, Lan; Yan, Chen; Urata, Yoshishige; Hasan, Al Shaimaa; Goto, Shinji; Guo, Chang-Ying; Zhang, Shouhua; Li, Tao-Sheng

    2017-01-01

    We evaluated the dose-dependency and reversibility of radiation-induced injury in cardiac explant-derived cells (CDCs), a mixed cell population grown from heart tissues. Adult C57BL/6 mice were exposed to 0, 10, 50 and 250 mGy γ-rays for 7 days and atrial tissues were collected for experiments 24 hours after last exposure. The number of CDCs was significantly decreased by daily exposure to over 250 mGy. Interestingly, daily exposure to over 50 mGy significantly decreased the c-kit expression and telomerase activity, increased 53BP1 foci in the nuclei of CDCs. However, CD90 expression and growth factors production in CDCs were not significantly changed even after daily exposure to 250 mGy. We further evaluated the reversibility of radiation-induced injury in CDCs at 1 week and 3 weeks after a single exposure to 3 Gy γ-rays. The number and growth factors production of CDCs were soon recovered at 1 week. However, the increased expression of CD90 were retained at 1 week, but recovered at 3 weeks. Moreover, the decreased expression of c-kit, impaired telomerase activity, and increased 53BP1 foci were poorly recovered even at 3 weeks. These data may help us to find the most sensitive and reliable bio-parameter(s) for evaluating radiation-induced injury in CDCs. PMID:28098222

  5. Anti-inflammatory effects of low-dose radiotherapy in an experimental model of systemic inflammation in mice

    International Nuclear Information System (INIS)

    Arenas, Meritxell; Gil, Felix B.A.; Gironella, Meritxell; Hernandez, Victor; Jorcano, Sandra; Biete, Albert; Pique, Josep M.; Panes, Julian

    2006-01-01

    Purpose: The aim of this study was to determine the effects of low-dose radiotherapy (LD-RT) on the inflammatory response and to characterize the potential mechanisms underlying these effects. Methods and Materials: Mice were irradiated with 0.1, 0.3, 0.6 Gy, or sham radiation before lipopolysaccharide (LPS) challenge. Leukocyte-endothelial cell interactions in intestinal venules were assessed using intravital microscopy. Intercellular adhesion molecule-1 (ICAM-1) expression was determined using radiolabeled antibodies 5 h after irradiation. Production of transforming growth factor-β 1 (TGF-β 1 ) was measured by enzyme-linked immunosorbent assay and its in vivo functional relevance by immunoneutralization. Results: Compared with vehicle treated animals, LPS induced a marked increase in leukocyte adhesion (0.13 ± 0.59 vs. 5.89 ± 1.03, p 1 were significantly increased in response to LD-RT in controls and LPS challenged animals. Neutralization of TGF-β 1 partially restored LPS-induced adhesion (4.83 ± 1.41, p 1 production and is not related to modulation of ICAM-1 expression

  6. Brain development in mice after prenatal irradiation: Modes of effect manifestation; dose-response-relationships and the RBE of neutrons

    International Nuclear Information System (INIS)

    Konermann, G.

    1986-01-01

    Postnatal effect manifestation in the CNS after exposures during advanced prenatal stages of development is due to both the prolonged period of neurogenesis and its complexity. Apart from acute proliferative effects, examples of two types of long-term effects in the brains of prenatally exposed mice are represented. Namely, persistent structural damage, and, fluctuating responses during the histochemical and biochemical brain maturation. Structural effects following X-ray exposure are quantified on the basis of data for diameter diminution of the cortical plate, corpus callosum and fimbria hippocampi. The studies include computerized micro-videoanalysis of neuronal branching defects. Continuous extension of exposure levels to doses as low as 0.05 Gy give evidence for the existence of thresholds for these types of structural damage in the vicinity of exposures to 0.1 Gy. The effects following X-ray exposures are partly compared with corresponding effects after neutron exposures. Our studies on postnatal maturation disturbances include proliferative responses, myelin formation, as well as the determination of different biochemical parameters (ATP, myelin-proteins, Na + /K + -balance). From our experimental findings we are able to stress the special significance of neurogenetical long-term effects for risk estimates in man. (orig.)

  7. Functional and histological findings of the islets of Langerhans in mice after fractioned telecobalt irradiations with tumor doses

    International Nuclear Information System (INIS)

    Konermann, G.; Petersen, K.G.; Slanina, J.; Blachnitzky, E.O.; Kraft, C.; Freiburg Univ.

    1979-01-01

    After a local radiation exposure of the pancreas of mice to a total dose of 5000 rd ( 60 Co gamma radiation over five weeks with 5 x 200 rd per week), there is no demonstrable alteration, even at long term, of the glucose tolerance and the insulin secretion of isolated islets of Langerhans in vitro and of the density of a histochemically prepared islet secretion. However, the proinsuline synthesis under glucose loading is reduced by about 40%. A radiogenic reduction of the total insulin content in the islet tissue of 27,6% is accompanied by a diminution of the body weight of 10% and a reduction of the organ weight of pancreas, liver and spleen of 20%, 13% and 47%. In view of these findings and taking into account a cellular death rate in the islet tissue of 21% immediately after the radiotherapy and of 5,8% eight weeks post irradiationem, the authors suppose a compensating secretion by the remaining islet cells which is sufficient under normal conditions. Signs of a tissue degeneration near the vessels are clearer in the exocrine pancreas than in the islet tissue. (orig.) 891 MG/orig. 892 RKD [de

  8. Safety of sucrose esters from Physalis peruviana L. in a 28-day repeated-dose study in mice.

    Science.gov (United States)

    Ocampo, Yanet C; Caro, Daneiva C; Rivera, David E; Franco, Luis A

    2017-06-01

    Although extracts and consumed foods from Physalis species contain sucrose esters from their glandular trichomes, there is no experimental data available on their toxicological effects. As peruvioses A and B isolated from Physalis peruviana L. calyces have proved to be effective anti-inflammatory and immunomodulatory compounds, this work aimed to investigate their sub-acute toxicity study and genotoxicity. For this, CD-1(ICR) mice were treated intraperitoneally with peruvioses at doses of 2.5, 5, and 10mg/kg/day for 28 consecutive days, to simulate therapeutic and over-therapeutic dosage levels. At the end of the treatment, animals were sacrificed and their organs weighted, and blood and tissue samples were collected. Toxicological endpoints included clinical signs; food consumption; body and organ weights; hematological and biochemical parameters; as well as macroscopic and microscopic examination of tissues. The results showed no significant differences between treated animals and control group at macroscopic, histological, molecular, and biochemical levels. In addition, a combination of mammalian erythrocyte micronucleus test, comet assay in peripheral blood cells, and Ames test, did not reveal genotoxic effects induced by peruvioses. Taken together, our data suggests that peruvioses A and B can be safely employed to treat inflammatory diseases. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  9. ß-cell specific overexpression of suppressor of cytokine signalling-3 does not protect against multiple low dose streptozotocin induced type 1 diabetes in mice

    DEFF Research Database (Denmark)

    Börjesson, A; Rønn, S G; Karlsen, A E

    2011-01-01

    We investigated the impact of ß-cell specific overexpression of suppressor of cytokine signalling-3 (SOCS-3) on the development of multiple low dose streptozotocin (MLDSTZ) induced Type 1 diabetes and the possible mechanisms involved. MLDSTZ treatment was administered to RIP-SOCS-3 transgenic......RNA in islet cells and secretion of IL-1Ra into culture medium. MLDSTZ treatment caused gradual hyperglycemia both in the wt mice and in the transgenic mice with the latter tending to be more sensitive. In vitro experiments on wt and transgenic islets did not reveal any differences in sensitivity to damaging...

  10. Pulmonary instillation of low doses of titanium dioxide nanoparticles in mice leads to particle retention and gene expression changes in the absence of inflammation

    DEFF Research Database (Denmark)

    Husain, Mainul; Saber, Anne Thoustrup; Guo, Charles

    2013-01-01

    We investigated gene expression, protein synthesis, and particle retention in mouse lungs following intratracheal instillation of varying doses of nano-sized titanium dioxide (nano-TiO2). Female C57BL/6 mice were exposed to rutile nano-TiO2 via single intratracheal instillations of 18, 54, and 162......μg/mouse. Mice were sampled 1, 3, and 28days post-exposure. The deposition of nano-TiO2 in the lungs was assessed using nanoscale hyperspectral microscopy. Biological responses in the pulmonary system were analyzed using DNA microarrays, pathway-specific real-time RT-PCR (qPCR), gene-specific q...

  11. Candidate Gene Identification of Feed Efficiency and Coat Color Traits in a C57BL/6J × Kunming F2 Mice Population Using Genome-Wide Association Study.

    Science.gov (United States)

    Miao, Yuanxin; Soudy, Fathia; Xu, Zhong; Liao, Mingxing; Zhao, Shuhong; Li, Xinyun

    2017-01-01

    Feed efficiency (FE) is a very important trait in livestock industry. Identification of the candidate genes could be of benefit for the improvement of FE trait. Mouse is used as the model for many studies in mammals. In this study, the candidate genes related to FE and coat color were identified using C57BL/6J (C57) × Kunming (KM) F2 mouse population. GWAS results showed that 61 and 2 SNPs were genome-wise suggestive significantly associated with feed conversion ratio (FCR) and feed intake (FI) traits, respectively. Moreover, the Erbin, Msrb2, Ptf1a, and Fgf10 were considered as the candidate genes of FE. The Lpl was considered as the candidate gene of FI. Further, the coat color trait was studied. KM mice are white and C57 ones are black. The GWAS results showed that the most significant SNP was located at chromosome 7, and the closely linked gene was Tyr. Therefore, our study offered useful target genes related to FE in mice; these genes may play similar roles in FE of livestock. Also, we identified the major gene of coat color in mice, which would be useful for better understanding of natural mutation of the coat color in mice.

  12. Candidate Gene Identification of Feed Efficiency and Coat Color Traits in a C57BL/6J × Kunming F2 Mice Population Using Genome-Wide Association Study

    Directory of Open Access Journals (Sweden)

    Yuanxin Miao

    2017-01-01

    Full Text Available Feed efficiency (FE is a very important trait in livestock industry. Identification of the candidate genes could be of benefit for the improvement of FE trait. Mouse is used as the model for many studies in mammals. In this study, the candidate genes related to FE and coat color were identified using C57BL/6J (C57 × Kunming (KM F2 mouse population. GWAS results showed that 61 and 2 SNPs were genome-wise suggestive significantly associated with feed conversion ratio (FCR and feed intake (FI traits, respectively. Moreover, the Erbin, Msrb2, Ptf1a, and Fgf10 were considered as the candidate genes of FE. The Lpl was considered as the candidate gene of FI. Further, the coat color trait was studied. KM mice are white and C57 ones are black. The GWAS results showed that the most significant SNP was located at chromosome 7, and the closely linked gene was Tyr. Therefore, our study offered useful target genes related to FE in mice; these genes may play similar roles in FE of livestock. Also, we identified the major gene of coat color in mice, which would be useful for better understanding of natural mutation of the coat color in mice.

  13. Pulmonary instillation of low doses of titanium dioxide nanoparticles in mice leads to particle retention and gene expression changes in the absence of inflammation

    International Nuclear Information System (INIS)

    Husain, Mainul; Saber, Anne T.; Guo, Charles; Jacobsen, Nicklas R.; Jensen, Keld A.; Yauk, Carole L.; Williams, Andrew; Vogel, Ulla; Wallin, Hakan; Halappanavar, Sabina

    2013-01-01

    We investigated gene expression, protein synthesis, and particle retention in mouse lungs following intratracheal instillation of varying doses of nano-sized titanium dioxide (nano-TiO 2 ). Female C57BL/6 mice were exposed to rutile nano-TiO 2 via single intratracheal instillations of 18, 54, and 162 μg/mouse. Mice were sampled 1, 3, and 28 days post-exposure. The deposition of nano-TiO 2 in the lungs was assessed using nanoscale hyperspectral microscopy. Biological responses in the pulmonary system were analyzed using DNA microarrays, pathway-specific real-time RT-PCR (qPCR), gene-specific qPCR arrays, and tissue protein ELISA. Hyperspectral mapping showed dose-dependent retention of nano-TiO 2 in the lungs up to 28 days post-instillation. DNA microarray analysis revealed approximately 3000 genes that were altered across all treatment groups (± 1.3 fold; p 2 in the absence of inflammation over time may potentially perturb calcium and ion homeostasis, and affect smooth muscle activities. - Highlights: • Pulmonary effects following exposure to low doses of nano-TiO 2 were examined. • Particle retention in lungs was assessed using nanoscale hyperspectral microscopy. • Particles persisted up to 28 days in lungs in all dose groups. • Inflammation was the pathway affected in the high dose group at all time points. • Ion homeostasis and muscle activity pathways were affected in the low dose group

  14. Long-term Treatment with Low-Dose Caffeine Worsens BPSD-Like Profile in 3xTg-AD Mice Model of Alzheimer’s Disease and Affects Mice with Normal Aging

    Directory of Open Access Journals (Sweden)

    Raquel Baeta-Corral

    2018-02-01

    Full Text Available Coffee or caffeine has recently been suggested as prophylaxis for dementia. Although memory problems are hallmarks of Alzheimer’s disease, this dementia is also characterized by neuropsychiatric symptoms called Behavioral and Psychological Symptoms of Dementia (BPSD. The impact of preventive/therapeutic strategies on both cognitive and non-cognitive symptoms can be addressed in the 3xTg-AD mice, since they exhibit cognitive but also BPSD-like profiles. Here, we studied the long-term effects of a low dose of caffeine in male 3xTg-AD mice and as compared to age-matched non-transgenic (NTg counterparts with normal aging. Animals were treated (water or caffeine in drinking water from adulthood (6 months of age until middle-aged (13 months of age, that in 3xTg-AD mice correspond to onset of cognitive impairment and advanced stages, respectively. The low caffeine dosing used (0.3 mg/ml was previously found to give a plasma concentration profile in mice roughly equivalent to that of a human coffee drinker. There were significant effects of caffeine on most behavioral variables, especially those related to neophobia and other anxiety-like behaviors, emotionality, and cognitive flexibility. The 3xTg-AD and NTg mice were differently influenced by caffeine. Overall, the increase of neophobia and other anxiety-related behaviors resulted in an exacerbation of BPSD-like profile in 3xTg-AD mice. Learning and memory, strongly influenced by anxiety in 3xTg-AD mice, got little benefit from caffeine, only shown after a detailed analysis of navigation strategies. The worsened pattern in NTg mice and the use of search strategies in 3xTg-AD mice make both groups more similar. Circadian motor activity showed genotype differences, which were found to be enhanced by caffeine. Selective effects of caffeine on NTg were found in the modulation of behaviors related to emotional profile and risk assessment. Caffeine normalized splenomegaly of 3xTg-AD mice, a physical

  15. Immunological network activation by low-dose rate irradiation. Analysis of cell populations and cell surface molecules in whole body irradiated mice

    International Nuclear Information System (INIS)

    Ina, Yasuhiro; Sakai, Kazuo

    2003-01-01

    The effects of low-dose rate whole body irradiation on biodefense and immunological systems were investigated using female C57BL/6 (B6) mice. These B6 mice were exposed continuously to γ-rays from a 137 Cs source in the long-term low-dose rate irradiation facility at CRIEPI for 0 - 12 weeks at a dose rate of 0.95 mGy/hr. In the bone marrow, thymus, spleen, lymph nodes, and peripheral blood of the irradiated mice, changes in cell populations and cell surface molecules were examined. The cell surface functional molecules (CD3, CD4, CD8, CD19, CD45R/B220, ICAM-1, Fas, NK-1.1, CXCR4, and CCR5), and activation molecules (THAM, CD28, CD40, CD44H, CD70, B7-1, B7-2, OX-40 antigen, CTLA-4, CD30 ligand, and CD40 ligand) were analyzed by flow cytometry. The percentage of CD4 + T cells and cell surface CD8 molecule expressions on the CD8 + T cells increased significantly to 120-130% after 3 weeks of the irradiation, compared to non-irradiated control mice. On the other hand, the percentage of CD45R/B220 + CD40 + B cells, which is one of the immunological markers of inflammation, infection, tumor, and autoimmune disease, decreased significantly to 80-90% between the 3rd to 5th week of irradiation. There was no significant difference in other cell population rates and cell surface molecule expression. Furthermore, abnormal T cells bearing mutated T cell receptors induced by high-dose rate irradiation were not observed throughout this study. These results suggest that low-dose rate irradiation activates the immunological status of the whole body. (author)

  16. Dose-response and histopathological study, with special attention to the hypophysis, of the differential effects of domoic acid on rats and mice.

    Science.gov (United States)

    Vieira, Andrés Crespo; Martínez, J Manuel Cifuentes; Pose, Roberto Bermúdez; Queijo, Álvaro Antelo; Posadas, Nuria Alemañ; López, Luis M Botana

    2015-05-01

    The effects of the neurotoxin domoic acid (DA) in the central nervous system of rodents (essentially rats and mice) after intraperitoneal administration have been profusely studied in the past. These observations have shown that the toxin induces similar symptoms and pathology in both species, but the lethality varies greatly. This article addresses the common and specific histopathological effects in rats and mice and the difference in sensitivity of these species to DA. Various sublethal and lethal doses were employed in mice (from 3 mg/kg to 8 mg/kg) to observe their neurotoxicity by using different histological techniques, and these results were compared with the pathological effects after the administration of LD50 in rats (2.5 mg/kg). Additionally we also detected the presence of this toxin in various tissues by means of immunohistochemistry. Our results showed that rats are more vulnerable than mice to the neurotoxic effects of DA after intraperitoneal inoculation: lethality was extremely high in rats and the toxin produced hippocampal damage in rats surviving the intoxication, while lesions were not observed in DA-inoculated mice. As for similarities between rats and mice, both displayed similar clinical signs and in both the toxin was detected in the hypophysis by immunohistochemistry, a brain region not reported to date as target of the toxin. © 2015 Wiley Periodicals, Inc.

  17. Stimulation of anti-tumor effect by low-dose irradiation. Pt. 2. The prolongation of life span in AKR mice

    International Nuclear Information System (INIS)

    Ishii, Keiichiro; Misonoh, Jun; Hosoi, Yoshio; Ono, Tetsuya; Sakamoto, Kiyohiko.

    1994-01-01

    To elucidate the antileukemic effect of low-dose X-irradiation, we studied the influence of periodical low-dose X-irradiation on survival and tumor incidence of thymus using AKR mice. The findings of the experiments were as follows; (1) The median survival time of control AKR mice was 283±3 days. It of irradiation group of 15 cGy/week and 30cGy was 309±14 days and 316±10 days respectively. The life span was significantly prolonged (p < 0.05 and p < 0.01 respectively by Wilcoxon test) by periodical low-dose X-irradiation in term of breeding. (2) The incidence of thymus tumor which is observed remarkably in control AKR mice was 48.8%. It of irradiation group of 15 cGy/week and 30 cGy/week was 40% and 20% respectively. Inversely, the non-tumor incidence of tymus in control AKR mice was 19.5%. It of irradiation group of 15 cGy/week and 30 cGy/week was 32.5% and 51.4% respectively. The thymic tumor incidence was significantly decreased (p < 0.01 by chi-square test) in irradiation group of 30 cGy/week. (3) The incidence of thymic lymphoma as a death cause in control AKR mice was 80.4%. It of irradiation group of 15 cGy/week and 30cGy/week was 67.5% and 48.6% respectively. The incidence of thymic lymphoma was significantly decreased (p < 0.05 by chi-square test) in irradiation group of 30 cGy/week. (author)

  18. Effect of low-intensity low-dose rate irradiation on the incidence and the development of spontaneous leukosis in AKR mice

    International Nuclear Information System (INIS)

    Burlakova, E.B.; Erokhin, V.N.

    2001-01-01

    Development of spontaneous leukosis in AKR mice is accelerated by irradiation with low doses of 1.2-2.4 cGy and low dose rate 0.06 cGy/day. The leukoses incidence rate increases. Deaths of the animals from leukosis occurs earlier, shortening the average and maximum life-spans of the animals. The dynamics of changes in the mass of organs of the immune systems (thymus and spleen) shows extrema. The moment of reaching the extremum correlates with the maximum rate of animals' deaths [ru

  19. Histological and histoenzymatic studies on the cellular immunoreaction in Ehrlich tumor-bearing C3H/He mice exposed to various doses of local irradiation

    International Nuclear Information System (INIS)

    Imanaka, Kazufumi; Gose, Kyuhei; Ogawa, Yasuhiro; Imajo, Yoshinari; Kimura, Shuji; Itoh, Hiroshi.

    1982-01-01

    To examine the relationship between the degree of stromal reaction and the dose of irradiation applied locally to the tumor tissue, Ehrlich tumor was transplanted into the right thighs of C3H/He mice, which were subsequently irradiated with a single dose of 1,000, 2,000, 3,000 or 4,000 rad. The mice were killed 1, 3, 5, 7, 10 or 14 days after irradiation, and the resected tumor tissues were examined histologically and enzymohistochemically. The number of peripheral lymphocytes was also counted. The higher the dose of irradiation, the smaller the number of peripheral lymphocytes was observed. Lymphocytic infiltration around the tumor tissue was most intensive about 7 days after irradiation of any dose. The most intensive lymphocytic reaction was observed in the group exposed to 3,000 rad at 7 day after irradiation. Enzymohistochemical study revealed that the infiltrating lymphocytes were mostly T-lymphocytes. These results suggest that there is an optimal dose that produces the most effective cellular immune response against topical tumor cells. (author)

  20. Age and sex dependence in tumorigenesis in mice by continuous low-dose-rate gamma-ray whole-body irradiation

    International Nuclear Information System (INIS)

    Otsu, Hiroshi; Kobayashi, Shigeru; Furuse, Takeshi; Noda, Yuko; Shiragai, Akihiro; Sato, Fumiaki.

    1992-01-01

    We investigated the dependency of sex and age in mice in the induction of neoplasms by gamma-rays from cesium-137 at a low dose rate of 0.375Gy/22h/day. Thymic lymphomas occurred significantly at the same incidence in both sexes, and more frequently when younger mice were exposed to radiation. Strain C57BL/6J mice were divided into 8 groups, which were whole-body irradiated with a total dose of 39Gy for 105 days each. The exposure was begun at 28 days of age (male:AM1, female:AF1), and then stepwise increasing the starting age by 105 days, i.e., from 133 days (AM2 and AF2), from 238 days (AM3 and AF3), and from 343 days (AM4 and AF4), respectively. Unirradiated mice served as control (UM and UF). The incidence of thymic lymphomas was about 60 % in AM1, AM2, AF1 and AF2, 40 % in AM3 and AF3 and 20 % in AF4 and AF4, demonstrating no sex dependency, but a distinct age dependency, for lymphomogenesis. It was proven that mice showed a tendency to become less susceptible to radiation induced thymic lymphoma with increasing age. Concomitantly, life-shortening also was caused, and the greater the degree of life-shortening was, the younger the mice were the start of exposure. Life-shortening was attributed to thymic lymphoma, and hemorrhage and infectious diseases due to the depletion of bone marrow cells. (author)

  1. Proinflammatory Stimulation of Toll-Like Receptor 9 with High Dose CpG ODN 1826 Impairs Endothelial Regeneration and Promotes Atherosclerosis in Mice.

    Directory of Open Access Journals (Sweden)

    Alexander O Krogmann

    Full Text Available Toll-like receptors (TLR of the innate immune system have been closely linked with the development of atherosclerotic lesions. TLR9 is activated by unmethylated CpG motifs within ssDNA, but also by CpG motifs in nucleic acids released during vascular apoptosis and necrosis. The role of TLR9 in vascular disease remains controversial and we sought to investigate the effects of a proinflammatory TLR9 stimulation in mice.TLR9-stimulation with high dose CpG ODN at concentrations between 6.25 nM to 30 nM induced a significant proinflammatory cytokine response in mice. This was associated with impaired reendothelialization upon acute denudation of the carotid and increased numbers of circulating endothelial microparticles, as a marker for amplified endothelial damage. Chronic TLR9 agonism in apolipoprotein E-deficient (ApoE-/- mice fed a cholesterol-rich diet increased aortic production of reactive oxygen species, the number of circulating endothelial microparticles, circulating sca-1/flk-1 positive cells, and most importantly augmented atherosclerotic plaque formation when compared to vehicle treated animals. Importantly, high concentrations of CpG ODN are required for these proatherogenic effects.Systemic stimulation of TLR9 with high dose CpG ODN impaired reendothelialization upon acute vascular injury and increased atherosclerotic plaque development in ApoE-/- mice. Further studies are necessary to fully decipher the contradictory finding of TLR9 agonism in vascular biology.

  2. Multilineage hematopoietic recovery with concomitant antitumor effects using low dose Interleukin-12 in myelosuppressed tumor-bearing mice

    Directory of Open Access Journals (Sweden)

    Miller Joseph D

    2008-05-01

    Full Text Available Abstract Background Interleukin-12 (IL-12 is a cytokine well known for its role in immunity. A lesser known function of IL-12 is its role in hematopoiesis. The promising data obtained in the preclinical models of antitumor immunotherapy raised hope that IL-12 could be a powerful therapeutic agent against cancer. However, excessive clinical toxicity, largely due to repeat dose regimens, and modest clinical response observed in the clinical trials have pointed to the necessity to design protocols that minimize toxicity without affecting the anti-tumor effect of IL-12. We have focused on the lesser known role of IL-12 in hematopoiesis and hypothesized that an important clinical role for IL-12 in cancer may be as an adjuvant hematological cancer therapy. In this putative clinical function, IL-12 is utilized for the prevention of cancer therapy-related cytopenias, while providing concomitant anti-tumor responses over and above responses observed with the primary therapy alone. This putative clinical function of IL-12 focuses on the dual role of IL-12 in hematopoiesis and immunity. Methods We assessed the ability of IL-12 to facilitate hematopoietic recovery from radiation (625 rad and chemotherapy (cyclophosphamide in two tumor-bearing murine models, namely the EL4 lymphoma and the Lewis lung cancer models. Antitumor effects and changes in bone marrow cellularity were also assessed. Results We show herein that carefully designed protocols, in mice, utilizing IL-12 as an adjuvant to radiation or chemotherapy yield facile and consistent, multilineage hematopoietic recovery from cancer therapy-induced cytopenias, as compared to vehicle and the clinically-utilized cytokine granulocyte colony-stimulating factor (G-CSF (positive control, while still providing concomitant antitumor responses over and above the effects of the primary therapy alone. Moreover, our protocol design utilizes single, low doses of IL-12 that did not yield any apparent toxicity

  3. A Low Dose of Dietary Quercetin Fails to Protect against the Development of an Obese Phenotype in Mice.

    Directory of Open Access Journals (Sweden)

    Reilly T Enos

    Full Text Available The purpose of this study was to examine the effect of a 40% high-fat diet (HFD supplemented with a dietary attainable level of quercetin (0.02% on body composition, adipose tissue (AT inflammation, Non-Alcoholic Fatty-Liver Disease (NAFLD, and metabolic outcomes. Diets were administered for 16 weeks to C57BL/6J mice (n = 10/group beginning at 4 weeks of age. Body composition and fasting blood glucose, insulin, and total cholesterol concentrations were examined intermittently. AT and liver mRNA expression (RT-PCR of inflammatory mediators (F4/80, CD206 (AT only, CD11c (AT only TLR-2 (AT only, TLR-4 (AT only, MCP-1, TNF-α, IL-6 (AT only, and IL-10 (AT only were measured along with activation of NFκB-p65, and JNK (western blot. Hepatic lipid accumulation, gene expression (RT-PCR of hepatic metabolic markers (ACAC1, SREBP-1, PPAR-γ, protein content of Endoplasmic Reticulum (ER Stress markers (BiP, phosphorylated and total EIF2α, phosphorylated and total IRE1α, CHOP, and hepatic oxidative capacity were assessed (western blot. Quercetin administration had no effect at mitigating increases in visceral AT, AT inflammation, hepatic steatosis, ER Stress, decrements in hepatic oxidative capacity, or the development of insulin resistance and hypercholesterolemia. In conclusion, 0.02% quercetin supplementation is not an effective therapy for attenuating HFD-induced obesity development. It is likely that a higher dose of quercetin supplementation is needed to elicit favorable outcomes in obesity.

  4. Genome-wide screen of DNA methylation changes induced by low dose X-ray radiation in mice.

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    Jingzi Wang

    Full Text Available Epigenetic mechanisms play a key role in non-targeted effects of radiation. The purpose of this study was to investigate global hypomethylation and promoter hypermethylation of particular genes induced by low dose radiation (LDR. Thirty male BALB/c mice were divided into 3 groups: control, acutely exposed (0.5 Gy X-rays, and chronic exposure for 10 days (0.05Gy/d×10d. High-performance liquid chromatography (HPLC and MeDIP-quantitative polymerase chain reaction (qPCR were used to study methylation profiles. DNMT1 and MBD2 expression was determined by qPCR and western blot assays. Methylation and expression of Rad23b and Ddit3 were determined by bisulfate sequencing primers (BSP and qPCR, respectively. The results show that LDR induced genomic hypomethylation in blood 2 h postirraditaion, but was not retained at 1-month. DNMT1 and MBD2 were downregulated in a tissue-specific manner but did not persist. Specific hypermethylation was observed for 811 regions in the group receiving chronic exposure, which covered almost all key biological processes as indicated by GO and KEGG pathway analysis. Eight hypermethylated genes (Rad23b, Tdg, Ccnd1, Ddit3, Llgl1, Rasl11a, Tbx2, Scl6a15 were verified by MeDIP-qPCR. Among them, Rad23b and Ddit3 gene displayed tissue-specific methylation and downregulation, which persisted for 1-month postirradiation. Thus, LDR induced global hypomethylation and tissue-specific promoter hypermethylation of particular genes. Promoter hypermethylation, rather than global hypomethylation, was relatively stable. Dysregulation of methylation might be correlated with down-regulation of DNMT1 and MBD2, but much better understanding the molecular mechanisms involved in this process will require further study.

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

    Science.gov (United States)

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

    2016-11-01

    Radiation therapy is a major cause of long-term complications observed in survivors of pediatric brain tumors. However, the effects of low-doses of ionizing radiation (IR) to the brain are less studied. On the other hand, tobacco is one of the most heavily abused drugs in the world. Tobacco is not only a health concern for adults. It has also shown to exert deleterious effects on fetuses, newborns, children and adolescents. Exposure to nicotine (Nic) from smoking may potentiate the toxic effects induced by IR on brain development. In this study, we evaluated in mice the cognitive effects of concomitant exposure to low doses of internal radiation ( 137 Cs) and Nic during neonatal brain development. On postnatal day 10 (PND10), two groups of C57BL/6J mice were subcutaneously exposed to 137-Cesium ( 137 Cs) (4000 and 8000 Bq/kg) and/or Nic (100 μg/ml). At the age of two months, neurobehavior of mice was assessed. Results showed that exposure to IR-alone or in combination with Nic-increased the anxiety-like of the animals without changing the activity levels. Moreover, exposure to IR impaired learning and spatial memory. However, Nic administration was able to reverse this effect, but only at the low dose of 137 Cs. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Hormesis of specific IgG antibody to rabies virus in serum of mice irradiated with low dose γ-rays

    International Nuclear Information System (INIS)

    Liu Qingjie; Chen Deqing

    1998-01-01

    Objective: To explore the effect of low dose ionizing radiation on specific antibody in mouse serum. Methods: Kunming strain male mice, weighing 18-22 g, aged 6-8 weeks, were immunized intraperitoneally with rabies vaccine after exposure to cobalt-60 γ-rays. The specific IgG antibody against rabies virus in mouse serum was measured. Results: (1) The serum levels of specific IgG in mice irradiated with 5-30 cGy γ-rays were significantly elevated in comparison with those in control mice (P<0.01), the optimum stimulating dose being 10 cGy. (2) Exposure to 10 cGy caused significant enhancement and earlier emergence of the peak level of specific IgG in serum. (3) The hormesis of specific IgG to rabies virus induced by 10 cGy γ-rays could last one week at least. Conclusion: Low dose ionizing radiation can enhance the level of specific antibody in mouse serum, and this effect can last for one week at least

  7. Action of 50 R X-ray doses on the breeding function of C3H strain mice - effect of splitting the dose, action of repeated irradiations on successive generations

    International Nuclear Information System (INIS)

    Alix, D.

    1965-01-01

    X-rays exposure effect was studied on C3H strain mice, at the standpoint of the effects produced on breeding function. The method used with this purpose was the following: single doses 20 - 30 - 40 and 50 R/dose, fractional doses: 50 R/total dose, divided in 2 - 5 - 10 or 25 irradiations distributed in one month duration. The offsprings were irradiated at the same doses than the parents, consanguinity being maintained. Statistical treatment of results was carried out, that led at the following conclusions: 1) Couples receiving single exposure of 50 R or two exposures of 25 R at one month interval give comparable results. Fractional doses do not involve the slightest diminution of X-rays effect. 2) 30 R exposure brings about a decrease in fertility, with an increase in abortions. Fertility of 20 R irradiated couples remains below controls. 3) After ten times 5 R and twenty-five 2 R, the number of abortions is the largest. Ovarian function is particularly sensitive to X-rays; one may think that twenty-five 2 R give injuries conditioning non-viability of conception products, smaller doses should produce mutations and yield births of altered genotype individuals. (author) [fr

  8. Effects of low dose radiation on tumor apoptosis, cell cycle progression and changes of apoptosis-related protein bcl-2 in tumor-bearing mice

    International Nuclear Information System (INIS)

    Yu Hongsheng; Fei Conghe; Shen Fangzhen; Liang Jun

    2003-01-01

    Objective: To study the effect of low dose radiation (LDR) on tumor apoptosis, cell cycle progression and changes of apoptosis-related protein bcl-2 in tumor-bearing mice. Methods: Kunming stain male mice were implanted with S180 sarcoma cells in the left inguen subcutaneously as an in situ experimental animal model. Seven days after implantation, the mice were given 75 mGy whole-body γ-irradiation. At 24 and 48 h after irradiation, all mice were sacrificed to measure the tumor volume, and tumor cell apoptosis, cell cycle progression were analyzed by flow cytometry. The expression of apoptosis-related protein bcl-2 and the apoptotic rate of tumor cells were observed by immunohistochemistry and electron microscopy. Results: Tumor growth was significantly slowed down after LDR (P 1 phase and the expression of bcl-2 protein decreased at 24 h. Apoptotic rate of tumor cells increased significantly at 48 h after LDR. Conclusion: LDR could cause a G 1 -phase arrest and increase the apoptosis of tumor cells through the low level of apoptosis-related protein bcl-2 in the tumor-bearing mice. The organized immune function and anti-tumor ability are markedly increased after LDR. The study provides practical evidence of clinical application to cancer treatment

  9. HDL and CER-001 Inverse-Dose Dependent Inhibition of Atherosclerotic Plaque Formation in apoE-/- Mice: Evidence of ABCA1 Down-Regulation.

    Science.gov (United States)

    Tardy, Claudine; Goffinet, Marine; Boubekeur, Nadia; Cholez, Guy; Ackermann, Rose; Sy, Gavin; Keyserling, Constance; Lalwani, Narendra; Paolini, John F; Dasseux, Jean-Louis; Barbaras, Ronald; Baron, Rudi

    2015-01-01

    CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression in vitro and in vivo in the presence of CER-001 and native HDL (HDL3). CER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL. A strong down-regulation of the ATP-binding cassette A1 (ABCA1) transporter mRNA (- 50%) as well as the ABCA1 membrane protein expression (- 50%) was observed at higher doses of CER-001 and HDL3 compared to non-lipidated apoA-I. In vivo, in an apoE-/- mouse "flow cessation model," in which the left carotid artery was ligatured to induce local inflammation, the inhibition of atherosclerotic plaque burden progression in response to a dose-range of every-other-day CER-001 or HDL in the presence of a high-fat diet for two weeks was assessed. We observed a U-shaped dose-response curve: inhibition of the plaque total cholesterol content increased with increasing doses of CER-001 or HDL3 up to a maximum inhibition (- 51%) at 5 mg/kg; however, as the dose was increased above this threshold, a progressively less pronounced inhibition of progression was observed, reaching a complete absence of inhibition of progression at doses of 20 mg/kg and over. ABCA1 protein expression in the same atherosclerotic plaque was decreased by-45% and-68% at 50 mg/kg for CER-001 and HDL respectively. Conversely, a-12% and 0% decrease in ABCA1 protein expression was observed at the 5 mg/kg dose for CER-001 and HDL respectively. These data demonstrate that high doses of HDL and CER-001 are less effective at slowing progression of atherosclerotic plaque in apoE-/- mice compared to lower doses, following a U-shaped dose-response curve. A potential mechanism for this phenomenon is supported by the observation that high doses of HDL and CER-001 induce a rapid and

  10. Radiation-induced changes in breathing frequency and lung histology of C57BL/6J mice are time- and dose-dependent

    Energy Technology Data Exchange (ETDEWEB)

    Eldh, T.; Heinzelmann, F.; Velalakan, A. [Univ. Hospital of Tuebingen (Germany). Dept. of Radiation Oncology; Budach, W. [Duesseldorf Univ. (Germany). Dept. of Radiation Oncology; Belka, C. [Univ. Hospital of Tuebingen (Germany). Dept. of Radiation Oncology; Muenchen Univ. (Germany). Dept. of Radiation Oncology; Jendrossek, V. [Univ. Hospital of Tuebingen (Germany). Dept. of Radiation Oncology; Duisburg-Essen Univ., Essen (DE). Inst. of Cell Biology (Cancer Research)

    2012-03-15

    Pneumonitis and fibrosis constitute serious adverse effects of radiotherapy in the thoracic region. In this study, time-course and dose-dependence of clinically relevant parameters of radiation-induced lung injury in C57BL/6J mice were analyzed. A well-characterized disease model is necessary for the analysis of the cellular and molecular mechanisms using genetically modified mice. C57BL/6J mice received single dose right hemithorax irradiation with 12.5 or 22.5 Gy. Body weight and breathing frequency were recorded as parameters for health impairment. Lung tissue was collected over 24 weeks for histological analysis. Hemithorax irradiation with 12.5 or 22.5 Gy induced biphasic breathing impairment with the first increase between days 7 and 70. Although breathing impairment was more pronounced in the 22.5 Gy group, it was accompanied in both dose groups by pneumonitis-associated histological changes. A second rise in breathing frequency ratios became visible starting on day 70 with a steady increase until day 210. Again, breathing was more strongly affected in the 22.5 Gy group. However, breathing impairment coincided only in the 22.5 Gy group with a significant increase in collagen deposition in the lung tissue by day 210. Tissue inflammation and fibrosis were observed in the irradiated and the shielded lungs, pointing toward involvement of systemic effects. Hemithorax irradiation induces time-dependent pneumonitis and fibrosis in C57BL/6J mice. While hemithorax irradiation with 12.5 Gy is sufficient to induce lung inflammation, it is below the threshold for collagen deposition and fibrosis development by day 210.

  11. The environmental chemical tributyltin chloride (TBT) shows both estrogenic and adipogenic activities in mice which might depend on the exposure dose

    International Nuclear Information System (INIS)

    Penza, M.; Jeremic, M.; Marrazzo, E.; Maggi, A.; Ciana, P.; Rando, G.; Grigolato, P.G.; Di Lorenzo, D.

    2011-01-01

    Exposure during early development to chemicals with hormonal action may be associated with weight gain during adulthood because of altered body homeostasis. It is known that organotins affect adipose mass when exposure occurs during fetal development, although no knowledge of effects are available for exposures after birth. Here we show that the environmental organotin tributyltin chloride (TBT) exerts adipogenic action when peripubertal and sexually mature mice are exposed to the chemical. The duration and extent of these effects depend on the sex and on the dose of the compound, and the effects are relevant at doses close to the estimated human intake (0.5 μg/kg). At higher doses (50-500 μg/kg), TBT also activated estrogen receptors (ERs) in adipose cells in vitro and in vivo, based on results from acute and longitudinal studies in ERE/luciferase reporter mice. In 3T3-L1 cells (which have no ERs), transiently transfected with the ERE-dependent reporter plus or minus ERα or ERβ, TBT (in a dose range of 1-100 nM) directly targets each ER subtype in a receptor-specific manner through a direct mechanism mediated by ERα in undifferentiated preadipocytic cells and by ERβ in differentiating adipocytes. The ER antagonist ICI-182,780 inhibits this effect. In summary, the results of this work suggest that TBT is adipogenic at all ages and in both sexes and that it might be an ER activator in fat cells. These findings might help to resolve the apparent paradox of an adipogenic chemical being also an estrogen receptor activator by showing that the two apparently opposite actions are separated by the different doses to which the organism is exposed. - Research highlights: → The environmental organotin tributyltin chloride shows dose-dependent estrogenic and adipogenic activities in mice. → The duration and extent of these effects depend on the sex and the dose of the compound. → The estrogenic and adipogenic effects of TBT occur at doses closed to the estimated

  12. Add-On Aliskiren Elicits Stronger Renoprotection Than High-Dose Valsartan in Type 2 Diabetic KKAy Mice That Do Not Respond to Low-Dose Valsartan

    Science.gov (United States)

    Lei, Bai; Nakano, Daisuke; Fan, Yu-Yan; Kitada, Kento; Hitomi, Hirofumi; Kobori, Hiroyuki; Mori, Hirohito; Masaki, Tsutomu; Nishiyama, Akira

    2012-01-01

    We hypothesized that aliskiren provides renoprotection in diabetic animals that did not receive sufficient renoprotection by AT1-receptor antagonist treatment. Type 2 diabetic KKAy mice were treated with group 1: vehicle or group 2: valsartan (15 mg/kg per day) from 12 to 16 weeks of age. The mice were subsequently divided into 4 groups and treated with the following combinations of drugs for another 6 weeks: 1: group 1 kept receiving vehicle, 2: group 2 continuously received 15 mg/kg per day of valsartan (Val-Val15), 3: group 2 received 50 mg/kg per day of valsartan (Val-Val50), 4: group 2 continuously received 15 mg/kg per day of valsartan with 25 mg/kg per day of aliskiren (Val-Val+Ali). Aliskiren exerted significant anti-albuminuric effects, whereas valsartan failed to ameliorate the albuminuria in the first four weeks. Surprisingly, the increasing dosage of valsartan in the Val-Val50 group showed non-significant tendencies to attenuate the albuminuria compared with vehicle infusion. Val-Val+Ali significantly suppressed the development of albuminuria and podocyte injury. Val-Val50 and Val-Val+Ali showed similar suppression of angiotensin II contents in the kidney of KKAy mice. In conclusion, the anti-albuminuric effect that was observed in the type 2 diabetic mice showing no anti-albuminuric effect by valsartan can be attributed to the add-on aliskiren. PMID:22673148

  13. Impact of UVR Exposure Pattern on Squamous Cell Carcinoma-A Dose-Delivery and Dose-Response Study in Pigmented Hairless Mice

    DEFF Research Database (Denmark)

    Lerche, Catharina M; Togsverd-Bo, Katrine; Philipsen, Peter A

    2017-01-01

    Cumulative lifetime ultraviolet radiation (UVR) is an important factor in the development of squamous cell carcinoma. This study examines the impact of UVR exposure pattern on tumor development. Hairless C3.Cg/TifBomTac immunocompetent pigmented mice (n = 351) were irradiated with 12 standard...

  14. The effect of low doses on the metabolism of thymidine in bone marrow cells of NMRI mice; an in vivo - in vitro study using labeled nucleic acid precursors

    International Nuclear Information System (INIS)

    Lindberg, C.

    1984-12-01

    Low-dose whole-body exposure of mice to less than 0.01 Gy causes a temporary inhibition of incorporation of thymidine into DNA of bone-marrow cells in vitro. This inhibition has its maximum at 4 hours after irradiation. The low-dose effect is due to the temporary inhibition of cellular thymidine kinase. This decrease in thymidine kinase activity involves only 35% of the entire cellular enzyme activity and, analogous to the depression of thymidine incorporation into the cells, is only seen in the presence of a physiological concentration of NaHCO 3 . The inhibition of TdR-kinase at very low doses should not be viewed as an expression of cell damage but might be part of a cellular protection mechanism different from known repair systems. (orig.) [de

  15. Intravenous administration of high-dose Paclitaxel reduces gut-associated lymphoid tissue cell number and respiratory immunoglobulin A concentrations in mice.

    Science.gov (United States)

    Moriya, Tomoyuki; Fukatsu, Kazuhiko; Noguchi, Midori; Okamoto, Koichi; Murakoshi, Satoshi; Saitoh, Daizoh; Miyazaki, Masaru; Hase, Kazuo; Yamamoto, Junji

    2014-02-01

    Chemotherapy remains a mainstay of treatment for cancer patients. However, anti-cancer drugs frequently cause a wide range of side effects, including leukopenia and gastrointestinal toxicity. These adverse effects can lead to treatment delays or necessitate temporary dose reductions. Although chemotherapy-related changes in gut morphology have been demonstrated, the influences of chemotherapeutic regimens on gut immunity are understood poorly. This study aimed to examine whether the anti-cancer drug paclitaxel (PTX) impairs gut immunity in mice. Male ICR mice were randomized into three groups: Control, low-dose PTX (low PTX; 2 mg/kg), or high-dose PTX (high PTX; 4 mg/kg). A single intravenous dose was given. On day seven after the injection, lymphocytes from Peyer patches (PP), intraepithelial (IE) spaces, and the lamina propria (LP) were counted and analyzed by flow cytometry (CD4(+), CD8(+), αβTCR(+), γδTCR(+), B220(+)). Immunoglobulin A (IgA) concentrations were measured in small intestinal and respiratory tract washings. Total, CD4(+) and γδTCR(+) lymphocyte numbers in PPs were significantly lower in the high PTX than in the control group. The CD4(+) lymphocyte numbers in the IE spaces were significantly lower in both PTX groups than in the control group. Respiratory tract IgA concentrations were lower in the high PTX than in the control group. The present data suggest high-dose PTX impairs mucosal immunity, possibly rendering patients more vulnerable to infection. Careful dose selection and new therapies may be important for maintaining mucosal immunity during PTX chemotherapy.

  16. Pulmonary instillation of low doses of titanium dioxide nanoparticles in mice leads to particle retention and gene expression changes in the absence of inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Husain, Mainul, E-mail: mainul.husain@hc-sc.gc.ca [Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario K1A 0K9 (Canada); Saber, Anne T., E-mail: ats@nrcwe.dk [The Danish NanoSafety Centre, National Research Centre for the Working Environment, Copenhagen DK-2100 (Denmark); Guo, Charles, E-mail: charles.guo@hc-sc.gc.ca [Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario K1A 0K9 (Canada); Jacobsen, Nicklas R., E-mail: nrj@nrcwe.dk [The Danish NanoSafety Centre, National Research Centre for the Working Environment, Copenhagen DK-2100 (Denmark); Jensen, Keld A., E-mail: kaj@nrcwe.dk [The Danish NanoSafety Centre, National Research Centre for the Working Environment, Copenhagen DK-2100 (Denmark); Yauk, Carole L., E-mail: carole.yauk@hc-sc.gc.ca [Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario K1A 0K9 (Canada); Williams, Andrew, E-mail: andrew.williams@hc-sc.gc.ca [The Danish NanoSafety Centre, National Research Centre for the Working Environment, Copenhagen DK-2100 (Denmark); Vogel, Ulla, E-mail: ubv@nrcwe.dk [The Danish NanoSafety Centre, National Research Centre for the Working Environment, Copenhagen DK-2100 (Denmark); Department of Micro- and Nanotechnology, Technical University of Denmark, Kgs. Lyngby DK-2800 (Denmark); Wallin, Hakan, E-mail: hwa@nrcwe.dk [The Danish NanoSafety Centre, National Research Centre for the Working Environment, Copenhagen DK-2100 (Denmark); Institute of Public Health, University of Copenhagen, Copenhagen DK-1014 (Denmark); Halappanavar, Sabina, E-mail: sabina.halappanavar@hc-sc.gc.ca [Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario K1A 0K9 (Canada)

    2013-06-15

    We investigated gene expression, protein synthesis, and particle retention in mouse lungs following intratracheal instillation of varying doses of nano-sized titanium dioxide (nano-TiO{sub 2}). Female C57BL/6 mice were exposed to rutile nano-TiO{sub 2} via single intratracheal instillations of 18, 54, and 162 μg/mouse. Mice were sampled 1, 3, and 28 days post-exposure. The deposition of nano-TiO{sub 2} in the lungs was assessed using nanoscale hyperspectral microscopy. Biological responses in the pulmonary system were analyzed using DNA microarrays, pathway-specific real-time RT-PCR (qPCR), gene-specific qPCR arrays, and tissue protein ELISA. Hyperspectral mapping showed dose-dependent retention of nano-TiO{sub 2} in the lungs up to 28 days post-instillation. DNA microarray analysis revealed approximately 3000 genes that were altered across all treatment groups (± 1.3 fold; p < 0.1). Several inflammatory mediators changed in a dose- and time-dependent manner at both the mRNA and protein level. Although no influx of neutrophils was detected at the low dose, changes in the expression of several genes and proteins associated with inflammation were observed. Resolving inflammation at the medium dose, and lack of neutrophil influx in the lung fluid at the low dose, were associated with down-regulation of genes involved in ion homeostasis and muscle regulation. Our gene expression results imply that retention of nano-TiO{sub 2} in the absence of inflammation over time may potentially perturb calcium and ion homeostasis, and affect smooth muscle activities. - Highlights: • Pulmonary effects following exposure to low doses of nano-TiO{sub 2} were examined. • Particle retention in lungs was assessed using nanoscale hyperspectral microscopy. • Particles persisted up to 28 days in lungs in all dose groups. • Inflammation was the pathway affected in the high dose group at all time points. • Ion homeostasis and muscle activity pathways were affected in the low dose

  17. Comparison of the dose-response relationship of radiation-induced apoptosis in the hippocampal dentate gyrus and intestinal crypt of adult mice

    International Nuclear Information System (INIS)

    Kim, J. S.; Yang, M.; Kim, J.; Lee, D.; Kim, J. C.; Shin, T.; Kim, S. H.; Moon, C.

    2012-01-01

    The present study compared the dose-response curves for the frequency of apoptosis in mouse hippocampal dentate gyrus (DG) and intestinal crypt using whole-body gamma irradiation. The incidence of gamma-ray-induced apoptosis was measured using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end-labelling (TUNEL) method. TUNEL-positive apoptotic nuclei in the DG and intestinal crypt were increased in a dose-dependent pattern (0-2 Gy). The dose-response curves were linear-quadratic, with a significant relationship between the appearance of apoptosis and irradiation dose. The slopes of the dose-response curves in the DG were much steeper (∼5-6-fold) than those in the intestinal crypt within the range of 0-1 Gy exposure. Hippocampal DG might be a more effective and sensitive evaluation structure than the intestinal crypt to estimate the degree of radiation exposure in damaged organs of adult mice exposed to low irradiation dose. copy; The Author 2011. Published by Oxford Univ. Press. All rights reserved. (authors)

  18. Regeneration of pancreatic non-β endocrine cells in adult mice following a single diabetes-inducing dose of streptozotocin.

    Directory of Open Access Journals (Sweden)

    Yanqing Zhang

    Full Text Available The non-β endocrine cells in pancreatic islets play an essential counterpart and regulatory role to the insulin-producing β-cells in the regulation of blood-glucose homeostasis. While significant progress has been made towards the understanding of β-cell regeneration in adults, very little is known about the regeneration of the non-β endocrine cells such as glucagon-producing α-cells and somatostatin producing δ-cells. Previous studies have noted the increase of α-cell composition in diabetes patients and in animal models. It is thus our hypothesis that non-β-cells such as α-cells and δ-cells in adults can regenerate, and that the regeneration accelerates in diabetic conditions. To test this hypothesis, we examined islet cell composition in a streptozotocin (STZ-induced diabetes mouse model in detail. Our data showed the number of α-cells in each islet increased following STZ-mediated β-cell destruction, peaked at Day 6, which was about 3 times that of normal islets. In addition, we found δ-cell numbers doubled by Day 6 following STZ treatment. These data suggest α- and δ-cell regeneration occurred rapidly following a single diabetes-inducing dose of STZ in mice. Using in vivo BrdU labeling techniques, we demonstrated α- and δ-cell regeneration involved cell proliferation. Co-staining of the islets with the proliferating cell marker Ki67 showed α- and δ-cells could replicate, suggesting self-duplication played a role in their regeneration. Furthermore, Pdx1(+/Insulin(- cells were detected following STZ treatment, indicating the involvement of endocrine progenitor cells in the regeneration of these non-β cells. This is further confirmed by the detection of Pdx1(+/glucagon(+ cells and Pdx1(+/somatostatin(+ cells following STZ treatment. Taken together, our study demonstrated adult α- and δ-cells could regenerate, and both self-duplication and regeneration from endocrine precursor cells were involved in their regeneration.

  19. Effects of co-treatment with mirtazapine and low doses of risperidone on immobility time in the forced swimming test in mice.

    Science.gov (United States)

    Rogóż, Zofia

    2010-01-01

    The aim of the present study was to examine the effect of mirtazapine (MIR) and risperidone (an atypical antipsychotic drug), given separately or jointly, on immobility time in the forced swimming test in male C57BL/6J mice. Fluoxetine (FLU) was used as a reference drug. MIR (2.5, 5 and 10 mg/kg) and FLU (5 and 10 mg/kg), or risperidone in low doses (0.05 and 0.1 mg/kg) given alone did not change the immobility time of mice in the forced swimming test. Joint administration of MIR (5 and 10 mg/kg) or FLU (10 mg/kg) and risperidone (0.1 mg/kg) produced antidepressant-like activity in the forced swimming test. WAY100636 (a 5-HT(1A) receptor antagonist) inhibited, while yohimbine (an α(2)-adrenergic receptor antagonist) potentiated the antidepressant-like effect induced by co-administration of MIR and risperidone. Active behavior in that test did not reflect an increase in general activity, since combined administration of antidepressants and risperidone failed to enhance the locomotor activity of mice. The obtained results indicate that risperidone applied in a low dose enhances the antidepressant-like activity of MIR and that, among other mechanisms, 5-HT(1A)-, and α(2)-adrenergic receptors may play a role in this effect.

  20. Effect of low-dose irradiation upon T cell subsets involved in the response of primed A/J mice to SaI cells

    International Nuclear Information System (INIS)

    Anderson, R.E.; Williams, W.L.; Tokuda, Sei

    1988-01-01

    A/Jax (A/J) mice primed to Sarcoma I (SaI) exhibit an augmented response in association with low-dose (0.15 Gy) irradiation. This phenomenon is best demonstrated in tumour neutralization (Winn assay) or cell transfer experiments utilizing mice depleted of thymus-derived (T) cells. It is particularly dependent upon the duration of priming and the growth characteristics of the tumour in the primary host. The importance of these two variables appears to relate to their influence upon the cell types responsible for the host response, and includes both an effector and a suppressor component. Radiation-induced inhibition of the suppressor component appears responsible for low-dose augmentation and results in injury to a T cell of the Lyt-1 - 2 + phenotype. In Winn assays employing equal numbers of immune spleen cells and SaI cells, the smallest tumours are associated with Lyt-1-positive (Lyt-1 + 2 - and Lyt-1 + 2 + ) cells and exposure to 0.15 Gy markedly inhibits their anti-SaI activity. Thus, even though the effect is in the opposite direction, both the effector and suppressor components of the anti-SaI response in A/J mice are exceedingly radiosensitive. (author)

  1. Expression of Fas and Bcl-2 and their relationship to apoptosis in spleen lymphocytes of mice irradiated with large dose 60Co γ-rays

    International Nuclear Information System (INIS)

    Gao Linlu; Cui Yufang; Yang Hong; Xia Guowei; Peng Ruiyun; Gao Yabin; Wang Dewen

    2000-01-01

    Objective: To investigate the expressions of Fas and Bcl-2 and their significance in apoptosis of spleen lymphocyte of mice after large dose γ-ray irradiation. Methods: At 3,6,12,24 h, 3, 7, 14 and 28 d after 6-20 Gy γ-ray irradiation mice were sacrificed and their spleens were removed. The expressions of Fas and Bcl-2 oncoprotein were analysed by LSAB immunohistochemical method. Results: The expression of Fas was strongly positive at 6 h after irradiation, especially in 6-12 Gy groups. It become less obvious along with prolongation of time after irradiation and almost disappeared on d 7 after irradiation. The expression of Bcl-2 was nearly negative at 6 h after irradiation, especially in 12-20 Gy groups, and did not recover on d 28 after irradiation. Conclusion: After large dose γ-ray irradiation the expression of Fas in mouse spleen lymphocytes shows a better relationship to lymphocyte apoptosis; in other words, Fas can prompt apoptosis. On the other hand, the action of Bcl-2 is reduced or even disappeared. Both of them play an important role in spleen lymphocyte apoptosis after large dose of γ-irradiation

  2. The use of the mouse chimera assay to detect early embryonic damage from male mice exposed to low-dose radiation

    International Nuclear Information System (INIS)

    Oudiz, D.; Warner, P.; Walsh, K.J.; Wiley, L.

    1990-01-01

    Mouse chimeras are in vitro aggregations of two 4-cell embryos and are used to detect subtle, nonlethal changes, which are expressed as a proliferative disadvantage in exposed embryos. One of the embryos is labeled with a viable dye (FITC) in order to determine the relative cellular contribution of each embryo when the chimera is dissociated 40 hours later. This proliferative disadvantage has been seen at doses which do not produce an effect on cell number when the embryos are cultured singly. Previously, the assay has detected a decrease in cellular proliferation in embryos from male mice exposed to a single dose of x-radiation as low as 0.05 Gy. In the current study, male mice were irradiated with a single dose of 0, 0.001, 0.01, or 0.05 Gy, and then serially mated for the next 8 weeks to unexposed females. Chimeras were constructed from control and treated embryos. Embryos from males treated with 0.05 Gy exhibited a significant decrease in cellular proliferation during weeks 6 and 7 post-irradiation. A similar decrease was seen in the males treated with 0.01 Gy. No reductions were observed from embryos cultured singly in any of the treatment groups

  3. Listeria monocytogenes strains encoding premature stop codons in inlA invade mice and guinea pig fetuses in orally dosed dams

    DEFF Research Database (Denmark)

    Holch, Anne; Ingmer, Hanne; Licht, Tine Rask

    2013-01-01

    potential of a group of food-processing persistent L. monocytogenes strains encoding a premature stop codon in inlA (encoding internalin A) by using two orally dosed models, pregnant mice and pregnant guinea pigs. A food-processing persistent strain of L. monocytogenes invaded placentas (n = 58; 10...... % positive) and fetuses (3 % positive) of pregnant mice (n = 9 animals per strain), similar to a genetically manipulated murinized strain, EGD-e InlAm* (n = 61; 3 and 2 %, respectively). In pregnant guinea pigs (n = 9 animals per bacterial strain), a maternofetal strain (from a human fetal clinical fatal...... case) was isolated from 34 % of placenta samples (n = 50), whereas both food-processing persistent strains were found in 5 % of placenta samples (n = 36 or 37). One of the food-processing persistent strains, N53-1, was found in up to 8 % of guinea pig fetal liver and brain samples, whereas...

  4. The environmental chemical tributyltin chloride (TBT) shows both estrogenic and adipogenic activities in mice which might depend on the exposure dose.

    Science.gov (United States)

    Penza, M; Jeremic, M; Marrazzo, E; Maggi, A; Ciana, P; Rando, G; Grigolato, P G; Di Lorenzo, D

    2011-08-15

    Exposure during early development to chemicals with hormonal action may be associated with weight gain during adulthood because of altered body homeostasis. It is known that organotins affect adipose mass when exposure occurs during fetal development, although no knowledge of effects are available for exposures after birth. Here we show that the environmental organotin tributyltin chloride (TBT) exerts adipogenic action when peripubertal and sexually mature mice are exposed to the chemical. The duration and extent of these effects depend on the sex and on the dose of the compound, and the effects are relevant at doses close to the estimated human intake (0.5μg/kg). At higher doses (50-500μg/kg), TBT also activated estrogen receptors (ERs) in adipose cells in vitro and in vivo, based on results from acute and longitudinal studies in ERE/luciferase reporter mice. In 3T3-L1 cells (which have no ERs), transiently transfected with the ERE-dependent reporter plus or minus ERα or ERβ, TBT (in a dose range of 1-100nM) directly targets each ER subtype in a receptor-specific manner through a direct mechanism mediated by ERα in undifferentiated preadipocytic cells and by ERβ in differentiating adipocytes. The ER antagonist ICI-182,780 inhibits this effect. In summary, the results of this work suggest that TBT is adipogenic at all ages and in both sexes and that it might be an ER activator in fat cells. These findings might help to resolve the apparent paradox of an adipogenic chemical being also an estrogen receptor activator by showing that the two apparently opposite actions are separated by the different doses to which the organism is exposed. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. Differences in micronucleus induction in peripheral blood reticulocytes of mice exposed to N-ethyl-N-nitrosourea at light and dark dosing times.

    Science.gov (United States)

    Itoh, Keiichi; Masumori, Shoji; Nakajima, Madoka; Hayashi, Makoto; Sakakibara, Hiroyuki; Shimoi, Kayoko

    2012-01-01

    Mammals, including human beings, have a circadian clock system to regulate behavioral and physiological processes. In this study, we investigated the effect of dosing time on micronucleus induction in the bone marrow by evaluating the frequencies of micronucleated peripheral reticulocytes (MNRETs) in mice exposed to N-ethyl-N-nitrosourea (ENU) to assess any difference in genotoxic sensitivity to chemicals between light and dark periods (inactive phase for rodents and active phase for rodents). Male C3H/He mice were treated intraperitoneally with ENU (12.5 or 25 mg/kg body weight) at zeitgeber time (ZT) 3 in the light period or ZT15 in the dark period, and then the time courses of the frequencies of the MNRETs were determined. The frequencies of the MNRETs induced by ENU increased time-dependently and peaked at 48 hr after treatment for ZT3 and ZT15, and were obviously higher in the ZT15 treatment group than the ZT3 treatment group. The MNRETs were measured at 48 hr after treatment with ENU (25 mg/kg body weight) at various dosing times (ZT0, 3, 6, 12, 15 and 18). The frequencies of the MNRETs in mice treated at ZT0, 15 and 18 were significantly higher than those in mice treated at ZT3, 6 and 12. These results suggest that genotoxic sensitivity to chemicals in mouse bone marrow is different between light and dark periods maybe due to different biological responses (detoxification, cell cycle, DNA repair, etc.) related to circadian rhythms.

  6. Ionizing radiation and autoimmunity: Induction of autoimmune disease in mice by high dose fractionated total lymphoid irradiation and its prevention by inoculating normal T cells

    International Nuclear Information System (INIS)

    Sakaguchi, N.; Sakaguchi, S.; Miyai, K.

    1992-01-01

    Ionizing radiation can functionally alter the immune system and break self-tolerance. High dose (42.5 Gy), fractionated (2.5 Gy 17 times) total lymphoid irradiation (TLI) on mice caused various organ-specific autoimmune diseases, such as gastritis, thyroiditis, and orchitis, depending on the radiation dosages, the extent of lymphoid irradiation, and the genetic background of the mouse strains. Radiation-induced tissue damage is not the primary cause of the autoimmune disease because irradiation of the target organs alone failed to elicit the autoimmunity and shielding of the organs from irradiation was unable to prevent it. In contrast, irradiation of both the thymus and the peripheral lymphoid organs/tissues was required for efficient induction of autoimmune disease by TLI. TLI eliminated the majority of mature thymocytes and the peripheral T cells for 1 mo, and inoculation of spleen cell, thymocyte, or bone marrow cell suspensions (prepared from syngeneic nonirradiated mice) within 2 wk after TLI effectively prevented the autoimmune development. Depletion of T cells from the inocula abrogated the preventive activity. CD4 + T cells mediated the autoimmune prevention but CD8 + T cells did not. CD4 + T cells also appeared to mediate the TLI-induced autoimmune disease because CD4 + T cells from disease-bearing TLI mice adoptively transferred the autoimmune disease to syngeneic naive mice. Taken together, these results indicate that high dose, fractionated ionizing radiation on the lymphoid organs/tissues can cause autoimmune disease by affecting the T cell immune system, rather than the target self-Ags, presumably by altering T cell-dependent control of self-reactive T cells. 62 refs., 9 figs., 2 tabs

  7. Low-Dose Radiation Activates Akt and Nrf2 in the Kidney of Diabetic Mice: A Potential Mechanism to Prevent Diabetic Nephropathy

    Directory of Open Access Journals (Sweden)

    Xiao Xing

    2012-01-01

    Full Text Available Repetitive exposure of diabetic mice to low-dose radiation (LDR at 25 mGy could significantly attenuate diabetes-induced renal inflammation, oxidative damage, remodeling, and dysfunction, for which, however, the underlying mechanism remained unknown. The present study explored the effects of LDR on the expression and function of Akt and Nrf2 in the kidney of diabetic mice. C57BL/6J mice were used to induce type 1 diabetes with multiple low-dose streptozotocin. Diabetic and age-matched control mice were irradiated with whole body X-rays at either single 25 mGy and 75 mGy or accumulated 75 mGy (25 mGy daily for 3 days and then sacrificed at 1–12 h for examining renal Akt phosphorylation and Nrf2 expression and function. We found that 75 mGy of X-rays can stimulate Akt signaling pathway and upregulate Nrf2 expression and function in diabetic kidneys; single exposure of 25 mGy did not, but three exposures to 25 mGy of X-rays could offer a similar effect as single exposure to 75 mGy on the stimulation of Akt phosphorylation and the upregulation of Nrf2 expression and transcription function. These results suggest that single 75 mGy or multiple 25 mGy of X-rays can stimulate Akt phosphorylation and upregulate Nrf2 expression and function, which may explain the prevention of LDR against the diabetic nephropathy mentioned above.

  8. Differential stimulation of antioxidant defense in various organs of mice after whole body exposure to low-dose gamma radiation

    International Nuclear Information System (INIS)

    Pathak, C.M.; Avti, P.K.; Khanduja, K.L.; Sharma, S.C.

    2007-01-01

    It has been generally considered that any dose of ionizing radiation is detrimental to the living organisms, however low the radiation dose may be. The much relied upon 'Linear-No-Threshold' (LNT) hypothesis dose not have any convincing experimental evidence regarding the damaging effects at very low-doses and low-dose rates. Generally, the deleterious biological effects have been inferred theoretically by extrapolating the known effects of high radiation dose to low-dose range. Recently, it has been reported that the living organisms do not respond to ionizing radiations in a linear manner in the low-dose range 0.01-0.50 Gy and rather restore the homeostasis both in-vivo and in-vitro by normal physiological mechanisms such as, cellular and DNA repair processes, immune reactions, antioxidant defense, adaptive responses, activation of immune functions; stimulation of growth etc. In this study, we have attempted to find: (i) the critical radiation dose range and the post irradiation period during which the antioxidant defense systems in the lungs, liver and kidneys remain stimulated; and (ii) to evaluate the degree to which these defense mechanisms remain stimulated in these organs after whole body exposure of the animal to low-dose radiation

  9. Mimicking the effects of spaceflight on bone: Combined effects of disuse and chronic low-dose rate radiation exposure on bone mass in mice

    Science.gov (United States)

    Yu, Kanglun; Doherty, Alison H.; Genik, Paula C.; Gookin, Sara E.; Roteliuk, Danielle M.; Wojda, Samantha J.; Jiang, Zhi-Sheng; McGee-Lawrence, Meghan E.; Weil, Michael M.; Donahue, Seth W.

    2017-11-01

    During spaceflight, crewmembers are subjected to biomechanical and biological challenges including microgravity and radiation. In the skeleton, spaceflight leads to bone loss, increasing the risk of fracture. Studies utilizing hindlimb suspension (HLS) as a ground-based model of spaceflight often neglect the concomitant effects of radiation exposure, and even when radiation is accounted for, it is often delivered at a high-dose rate over a very short period of time, which does not faithfully mimic spaceflight conditions. This study was designed to investigate the skeletal effects of low-dose rate gamma irradiation (8.5 cGy gamma radiation per day for 20 days, amounting to a total dose of 1.7 Gy) when administered simultaneously to disuse from HLS. The goal was to determine whether continuous, low-dose rate radiation administered during disuse would exacerbate bone loss in a murine HLS model. Four groups of 16 week old female C57BL/6 mice were studied: weight bearing + no radiation (WB+NR), HLS + NR, WB + radiation exposure (WB+RAD), and HLS+RAD. Surprisingly, although HLS led to cortical and trabecular bone loss, concurrent radiation exposure did not exacerbate these effects. Our results raise the possibility that mechanical unloading has larger effects on the bone loss that occurs during spaceflight than low-dose rate radiation.

  10. Neutropenia induced in outbred mice by a simplified low-dose cyclophosphamide regimen: characterization and applicability to diverse experimental models of infectious diseases

    Directory of Open Access Journals (Sweden)

    Zapata Ana X

    2006-03-01

    Full Text Available Abstract Background For its low cost and ease of handling, the mouse remains the preferred experimental animal for preclinical tests. To avoid the interaction of the animal immune system, in vivo antibiotic pharmacodynamic studies often employ cyclophosphamide (CPM to induce neutropenia. Although high doses (350–450 mg/kg are still used and their effects on mouse leukocytes have been described, a lower dose (250 mg/kg is widely preferred today, but the characteristics and applicability of this approach in outbred mice have not been determined. Methods Fifteen female ICR mice were injected intraperitoneally with 150 and 100 mg/kg of CPM on days 1 and 4, respectively. Blood samples (~160 μL were drawn from the retro-orbital sinus of each mouse on days 1, 4, 5, 6, 7 and 11. Leukocytes were counted manually and the number of granulocytes was based on microscopic examination of Wright-stained smears. The impact of neutropenia induced by this method was then determined with a variety of pathogens in three different murine models of human infections: pneumonia (Klebsiella pneumoniae, Streptococcus pneumoniae, Staphylococcus aureus, meningoencephalitis (S. pneumoniae, and the thigh model (S. aureus, Escherichia coli, Bacteroides fragilis. Results The basal count of leukocytes was within the normal range for outbred mice. On day 4, there was an 84% reduction in total white blood cells, and by day 5 the leukopenia reached its nadir (370 ± 84 cells/mm3. Profound neutropenia (≤10 neutrophils/mm3 was demonstrated at day 4 and persisted through days 5 and 6. Lymphocytes and monocytes had a 92% and 96% decline between days 1 and 5, respectively. Leukocytes recovered completely by day 11. Mice immunosupressed under this protocol displayed clinical and microbiological patterns of progressive and lethal infectious diseases after inoculation in different organs with diverse human pathogens. Conclusion A CPM total dose of 250 mg/kg is sufficient to induce

  11. Acute Oral Toxicity of Tetrodotoxin in Mice: Determination of Lethal Dose 50 (LD50 and No Observed Adverse Effect Level (NOAEL

    Directory of Open Access Journals (Sweden)

    Paula Abal

    2017-02-01

    Full Text Available Tetrodotoxin (TTX is starting to appear in molluscs from the European waters and is a hazard to seafood consumers. This toxin blocks sodium channels resulting in neuromuscular paralysis and even death. As a part of the risk assessment process leading to a safe seafood level for TTX, oral toxicity data are required. In this study, a 4-level Up and Down Procedure was designed in order to determine for the first time the oral lethal dose 50 (LD50 and the No Observed Adverse Effect Level (NOAEL in mice by using an accurate well-characterized TTX standard.

  12. Genistein protects against biomarkers of delayed lung sequelae in mice surviving high-dose total body irradiation

    International Nuclear Information System (INIS)

    Day, R.M.; Barshishat-Kupper, M.; Mog, S.R.; Mccart, E.A.; Prasanna, P.G.S.; Landauer, M.R.; Davis, T.A.

    2008-01-01

    The effects of genistein on 30-day survival and delayed lung injury were examined in C57BL/6J female mice. A single subcutaneous injection of vehicle (PEG-400) or genistein (200 mg/kg) was administered 24 h before total body irradiation (7.75 Gy 60 Co, 0.6 Gy/min). Experimental groups were: No treatment+Sham (NC), Vehicle+Sham (VC), Genistein+Sham (GC), Radiation only (NR), Vehicle+Radiation (VR), Genistein+Radiation (GR). Thirty-day survivals after 7.75 Gy were: NR 23%, VR 53%, and GR 92%, indicating significant protection from acute radiation injury by genistein. Genistein also mitigated radiation-induced weight loss on days 13-28 postirradiation. First generation lung fibroblasts were analyzed for micronuclei 24 h postirradiation. Fibroblasts from the lungs of GR-treated mice had significantly reduced micronuclei compared with NR mice. Collagen deposition was examined by histochemical staining. At 90 days postirradiation one half of the untreated and vehicle irradiated mice had focal distributions of small collagen-rich plaques in the lungs, whereas all of the genistein-treated animals had morphologically normal lungs. Radiation reduced the expression of COX-2, transforming growth factor-β receptor (TGFβR) I and II at 90 days after irradiation. Genistein prevented the reduction in TGFβRI. However, by 180 days postirradiation, these proteins normalized in all groups. These results demonstrate that genistein protects against acute radiation-induced mortality in female mice and that GR-treated mice have reduced lung damage compared to NR or VR. These data suggest that genistein is protective against a range of radiation injuries. (author)

  13. Genistein Protects Against Biomarkers of Delayed Lung Sequelae in Mice Surviving High-Dose Total Body Irradiation

    Science.gov (United States)

    DAY, Regina M.; BARSHISHAT-KUPPER, Michal; MOG, Steven R.; MCCART, Elizabeth A.; PRASANNA, P. G. S.; DAVIS, Thomas A.; LANDAUER, Michael R.

    2008-01-01

    The effects of genistein on 30-day survival and delayed lung injury were examined in C57BL/6J female mice. A single subcutaneous injection of vehicle (PEG-400) or genistein (200 mg/kg) was administered 24 h before total body irradiation (7.75 Gy 60Co, 0.6 Gy/min). Experimental groups were: No treatment + Sham (NC), Vehicle + Sham (VC), Genistein + Sham (GC), Radiation only (NR), Vehicle + Radiation (VR), Genistein + Radiation (GR). Thirty-day survivals after 7.75 Gy were: NR 23%, VR 53%, and GR 92%, indicating significant protection from acute radiation injury by genistein. Genistein also mitigated radiation-induced weight loss on days 13–28 postirradiation. First generation lung fibroblasts were analyzed for micronuclei 24 h postirradiation. Fibroblasts from the lungs of GR-treated mice had significantly reduced micronuclei compared with NR mice. Collagen deposition was examined by histochemical staining. At 90 days postirradiation one half of the untreated and vehicle irradiated mice had focal distributions of small collagen-rich plaques in the lungs, whereas all of the genistein-treated animals had morphologically normal lungs. Radiation reduced the expression of COX-2, transforming growth factor-β receptor (TGFβR) I and II at 90 days after irradiation. Genistein prevented the reduction in TGFβRI. However, by 180 days postirradiation, these proteins normalized in all groups. These results demonstrate that genistein protects against acute radiation-induced mortality in female mice and that GR-treated mice have reduced lung damage compared to NR or VR. These data suggest that genistein is protective against a range of radiation injuries. PMID:18434686

  14. Comparative hazard identification by a single dose lung exposure of zinc oxide and silver nanomaterials in mice

    DEFF Research Database (Denmark)

    Gosens, Ilse; Kermanizadeh, Ali; Jacobsen, Nicklas Raun

    2015-01-01

    , or by systemic inflammation. A decrease in glutathione levels was demonstrated in the liver following exposure to high doses of all three nanomaterials irrespective of any noticeable inflammatory or cytotoxic effects in the lung. By applying benchmark dose (BMD) modeling statistics to compare potencies...

  15. Clinical Dosing Regimen of Selinexor Maintains Normal Immune Homeostasis and T-cell Effector Function in Mice: Implications for Combination with Immunotherapy.

    Science.gov (United States)

    Tyler, Paul M; Servos, Mariah M; de Vries, Romy C; Klebanov, Boris; Kashyap, Trinayan; Sacham, Sharon; Landesman, Yosef; Dougan, Michael; Dougan, Stephanie K

    2017-03-01

    Selinexor (KPT-330) is a first-in-class nuclear transport inhibitor currently in clinical trials as an anticancer agent. To determine how selinexor might affect antitumor immunity, we analyzed immune homeostasis in mice treated with selinexor and found disruptions in T-cell development, a progressive loss of CD8 T cells, and increases in inflammatory monocytes. Antibody production in response to immunization was mostly normal. Precursor populations in bone marrow and thymus were unaffected by selinexor, suggesting that normal immune homeostasis could recover. We found that a high dose of selinexor given once per week preserved nearly normal immune functioning, whereas a lower dose given 3 times per week did not restore immune homeostasis. Both naïve and effector CD8 T cells cultured in vitro showed impaired activation in the presence of selinexor. These experiments suggest that nuclear exportins are required for T-cell development and function. We determined the minimum concentration of selinexor required to block T-cell activation and showed that T-cell-inhibitory effects of selinexor occur at levels above 100 nmol/L, corresponding to the first 24 hours post-oral dosing. In a model of implantable melanoma, selinexor treatment at 10 mg/kg with a 4-day drug holiday led to intratumoral IFNγ + , granzyme B + cytotoxic CD8 T cells that were comparable with vehicle-treated mice. Overall, selinexor treatment leads to transient inhibition of T-cell activation, but clinically relevant once and twice weekly dosing schedules that incorporate sufficient drug holidays allow for normal CD8 T-cell functioning and development of antitumor immunity. Mol Cancer Ther; 16(3); 428-39. ©2017 AACR See related article by Farren et al., p. 417 . ©2017 American Association for Cancer Research.

  16. Clinical dosing regimen of selinexor maintains normal immune homeostasis and T cell effector function in mice: implications for combination with immunotherapy

    Science.gov (United States)

    Tyler, Paul M.; Servos, Mariah M.; de Vries, Romy C.; Klebanov, Boris; Kashyap, Trinayan; Sacham, Sharon; Landesman, Yosef; Dougan, Michael; Dougan, Stephanie K.

    2017-01-01

    Selinexor (KPT-330) is a first in class nuclear transport inhibitor currently in clinical trials as an anti-cancer agent. To determine how selinexor might impact anti-tumor immunity, we analyzed immune homeostasis in mice treated with selinexor and found disruptions in T cell development, a progressive loss of CD8 T cells and increases in inflammatory monocytes. Antibody production in response to immunization was mostly normal. Precursor populations in bone marrow and thymus were unaffected by selinexor, suggesting that normal immune homeostasis could recover. We found that a high dose of selinexor given once per week preserved nearly normal immune functioning, whereas a lower dose given 3 times per week did not restore immune homeostasis. Both naïve and effector CD8 T cells cultured in vitro showed impaired activation in the presence of selinexor. These experiments suggest that nuclear exportins are required for T cell development and function. We determined the minimum concentration of selinexor required to block T cell activation, and showed that T cell inhibitory effects of selinexor occur at levels above 100nM, corresponding to the first 24 hours post-oral dosing. In a model of implantable melanoma, selinexor treatment at 10 mg/kg with a 5 day drug holiday led to intratumoral IFNγ+, granzyme B+ cytotoxic CD8 T cells that were comparable to vehicle treated mice. Overall, selinexor treatment leads to transient inhibition of T cell activation but clinically relevant once and twice weekly dosing schedules that incorporate sufficient drug holidays allow for normal CD8 T cell functioning and development of anti-tumor immunity. PMID:28148714

  17. Analgesia induced by repeated exposure to low dose X-rays in mice, and involvement of the accessory olfactory system in modulation of the radiation effects

    International Nuclear Information System (INIS)

    Miyachi, Yukihisa; Yamada, Takeshi

    1997-01-01

    The effects of low-dose X-rays on mouse nociceptive behavior were examined using a formalin injected test which rated the amount of time the animals spent licking the injected hind-paw. Male ICR White Swiss mice showed a marked suppression of licking behavior after repeated low-dose X-irradiation (5 cGy/day, 6 consecutive days). The most profound effect was observed on the day 30 after irradiation. The decline of licking behavior, however, was not observed at all following olfactory bulbectomy or vomeronasal tract cut. The analgesic effects could be observed in writhing animals administered acetic-acid intraperitoneally. Moreover, analgesia was totally blocked by the administration of N-nitro-L-arginine, a nitric oxide synthase inhibitor, to accessory olfactory bulbs prior to the exposure. The present results indicate that the olfactory system plays an important role in modulation of radiation-induced analgesia, and a possible involvement of nitric oxide in the formation of recognition memory subjected to repeated X-rays. Relatively higher doses (5 cGy x 9 days, 5 cGy x 12 days), however, did not induce such effects, namely, the decline of nociceptive response was limited to the animals irradiated with the smaller dose. (author)

  18. No indications of an enhanced UV-light-induced unscheduled DNA synthesis in splenocytes of mice following a low-dose irradiation in vivo or in vitro

    International Nuclear Information System (INIS)

    Wojcik, A.; Seemayer, C.A.; Mueller, W.U.; Streffer, C.

    1995-01-01

    One of the open questions regarding the adaptive response to ionizing radiation is whether it can be induced in G 0 lymphocytes. In the majority of experiments in which an adaptive response in G 0 lymphocytes was observed, the adapting dose was applied in vivo. In order to investigate whether there is some in vivo component of adaptive response, mouse splenocytes of the C57BL/6 strain were irradiated with 0.1 Gy x-rays either in vivo or in vitro, and their UV-light-induced unscheduled DNA synthesis (UDS) levels were determined autoradiographically. An augmented UV-light-induced UDS following an adapting dose applied in vivo has previously been described by several authors in splenocytes of C57BL/6 mice, indicating that the adapting dose enhanced the DNA repair capacity of lymphocytes. In the present investigation, however, no evidence of an adaptive response could be seen regardless of whether the adapting dose was given in vivo or in vitro. Those results present a further indication for the fact that the adaptive response to ionizing radiation is not always inducible, even in lymphocytes of an inbred mouse strain in which its existence has been reported before. (orig.)

  19. NOAEL-dose of a neonicotinoid pesticide, clothianidin, acutely induce anxiety-related behavior with human-audible vocalizations in male mice in a novel environment.

    Science.gov (United States)

    Hirano, Tetsushi; Yanai, Shogo; Takada, Tadashi; Yoneda, Naoki; Omotehara, Takuya; Kubota, Naoto; Minami, Kiichi; Yamamoto, Anzu; Mantani, Youhei; Yokoyama, Toshifumi; Kitagawa, Hiroshi; Hoshi, Nobuhiko

    2018-01-05

    Neonicotinoids are novel systemic pesticides acting as agonists on the nicotinic acetylcholine receptors (nAChRs) of insects. Experimental studies have revealed that neonicotinoids pose potential risks for the nervous systems of non-target species, but the brain regions responsible for their behavioral effects remain incompletely understood. This study aimed to assess the neurobehavioral effects of clothianidin (CTD), a later neonicotinoid developed in 2001 and widely used worldwide, and to explore the target regions of neonicotinoids in the mammalian brain. A single-administration of 5 or 50mg/kg CTD to male C57BL/6N mice at or below the no-observed-adverse-effect level (NOAEL) induced an acute increase in anxiety during the elevated plus-maze test. In addition, mice in the CTD-administered group spontaneously emitted human-audible vocalizations (4-16kHz), which are behavioral signs of aversive emotions, and showed increased numbers of c-fos immunoreactive cells in the paraventricular thalamic nucleus and dentate gyrus of the hippocampus. In conclusion, mice exposed to NOAEL-dose CTD would be rendered vulnerable to a novel environment via the activation of thalamic and hippocampal regions related to stress responses. These findings should provide critical insight into the neurobehavioral effects of neonicotinoids on mammals. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Protective Effects of Hydrogen against Low-Dose Long-Term Radiation-Induced Damage to the Behavioral Performances, Hematopoietic System, Genital System, and Splenic Lymphocytes in Mice

    Directory of Open Access Journals (Sweden)

    Jiaming Guo

    2016-01-01

    Full Text Available Molecular hydrogen (H2 has been previously reported playing an important role in ameliorating damage caused by acute radiation. In this study, we investigated the effects of H2 on the alterations induced by low-dose long-term radiation (LDLTR. All the mice in hydrogen-treated or radiation-only groups received 0.1 Gy, 0.5 Gy, 1.0 Gy, and 2.0 Gy whole-body gamma radiation, respectively. After the last time of radiation exposure, all the mice were employed for the determination of the body mass (BM observation, forced swim test (FST, the open field test (OFT, the chromosome aberration (CA, the peripheral blood cells parameters analysis, the sperm abnormality (SA, the lymphocyte transformation test (LTT, and the histopathological studies. And significant differences between the treatment group and the radiation-only groups were observed, showing that H2 could diminish the detriment induced by LDLTR and suggesting the protective efficacy of H2 in multiple systems in mice against LDLTR.

  1. T cell potentiation in normal and autoimmune-prone mice after extended exposure to low doses of ionizing radiation and/or caloric restriction

    Energy Technology Data Exchange (ETDEWEB)

    James, S.J.; Makinodan, T.

    1988-01-01

    In order to better understand the apparent physiologic up-regulation in response to low levels of potentially lethal insults, murine T lymphocytes were analysed for functional and phenotypic alterations after exposure to 0.005 Gy/day, 0.01 Gy/day and 0.04 Gy/day in groups of ad-libitum-fed and calorie-restricted mice. Studies were conducted in two strains of mice: long-lived and immunologically normal C57B1/6 +/+ and congenic short-lived immunologically depressed C57B1/6 1pr/1pr. Whole-body exposure to 0.01 Gy/day and 0.04 Gy/day for an extended period of 20 days was associated with an increase in splenic proliferative response and shifts in proportions of T cell subpopulations in the thymus and spleen of both strains. Caloric restriction independently altered functional activity and T cell subpopulations in the same direction as low dose rates of ionizing radiation. Although dose-response augmentation in proliferative activity was similar in the strains, observed alterations in thymic and splenic T cell subpopulations were clearly different, suggesting different mechanisms were responsible for immune enhancement in each strain.

  2. Dose-response effects of systemic anandamide administration in mice sequentially submitted to the open field and elevated plus-maze tests.

    Science.gov (United States)

    Ribeiro, A; Ferraz-de-Paula, V; Pinheiro, M L; Palermo-Neto, J

    2009-06-01

    The endocannabinoid system is involved in the control of many physiological functions, including the control of emotional states. In rodents, previous exposure to an open field increases the anxiety-like behavior in the elevated plus-maze. Anxiolytic-like effects of pharmacological compounds that increase endocannabinoid levels have been well documented. However, these effects are more evident in animals with high anxiety levels. Several studies have described characteristic inverted U-shaped dose-response effects of drugs that modulate the endocannabinoid levels. However, there are no studies showing the effects of different doses of exogenous anandamide, an endocannabinoid, in animal models of anxiety. Thus, in the present study, we determined the dose-response effects of exogenous anandamide at doses of 0.01, 0.1, and 1.0 mg/kg in C57BL/6 mice (N = 10/group) sequentially submitted to the open field and elevated plus-maze. Anandamide was diluted in 0.9% saline, ethyl alcohol, Emulphor (18:1:1) and administered ip (0.1 mL/10 g body weight); control animals received the same volume of anandamide vehicle. Anandamide at the dose of 0.1 mg/kg (but not of 0.01 or 1 mg/kg) increased (P open field, as well as the exploration of the open arms of the elevated plus-maze. Thus, exogenous anandamide, like pharmacological compounds that increase endocannabinoid levels, promoted a characteristic inverted U-shaped dose-response effect in animal models of anxiety. Furthermore, anandamide (0.1 mg/kg) induced an anxiolytic-like effect in the elevated plus-maze (P open field test.

  3. Increased cost of motor activity and heat transfer between non-shivering thermogenesis, motor activity and thermic effect of feeding in mice housed at room temperature – Implications in pre-clinical studies.

    Directory of Open Access Journals (Sweden)

    Patrick Christian Even

    2016-10-01

    Full Text Available The components of energy expenditure, total metabolic rate (TMR, resting metabolic rate (RMR, thermogenic response to feeding (TEF, activity and cost of activity were measured in fed and fasted mice housed at 22°C and 30° C. Mice housed at 22°C had more than 2 times larger TMR and RMR. Mice at 22°C were less active when fasted but more active when fed. Cost of activity was nearly doubled in the fasted and in the fed state. Analysis of the short-term relation between TMR, RMR and bouts of activity showed that, at 22°C, the bouts of activity induced a decrease in the intensity of RMR that reflected the reduced need for thermal regulation induced by the heat released from muscular contraction. This phenomenon induced a considerable underestimation of TEF and prevented its reliable measurement when mice were housed at 22°C. Correlation between TMR and activity measured across time in individual mice was very strong at both 22°C and 30°C, but the correlation measured across mice was much weaker at 30°C and no longer significant at 22°C. We suspect that this phenomenon was due to the fact that RMR is a much more reliable predictor of TMR than activity. RMR is more variable at 22°C than at 30°C because of heat-transfers between thermal regulation and heat released by other discontinuous processes such as activity and TEF. Therefore more noise is introduced into the correlations performed across multiple mice between TMR and activity at 22°C. On the other hand it should be kept in mind that the doubling of TMR and RMR at 22°C is fueled by an increased non-shivering thermogenesis that can obviously modify how the mouse responds to pharmacological and nutritional challenges. Taken together these results suggest that in pre-clinical studies, mice should be housed in conditions where thermal regulation is limited as is generally the case in humans. However, the increased sensitivity of mice to small changes in ambient temperature can also be

  4. Lack of effect on the chromosomal non-disjunction in aged female mice after low dose x-irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Strausmanis, R; Hendrikson, I B; Holmberg, M; Roennbaeck, C [Research Inst. of National Defence, Sundbyberg (Sweden). Dept. 4

    1978-02-01

    Karyotypes were determined in 1064 embryos of aged C57/BL mothers. The virgin female mice were irradiated with 0, 4, 8 or 16 R of X-rays, respectively, and placed with young untreated males 5 days after irradiation. 10.5-days old embryos were recovered from the uterus. Aneuploid embryos classified as alive (heart beats observed at the dissection) were 1 monosomic in the control group (496 embryos) and 2 trisomics in the irradiated group (568 embryos). The number of aneuploid embryos classified as dead was 4 trisomic cases in the control group and 3 trisomics in the irradiated group. The data indicate that trisomic embryos are not uncommon in the mouse but are eliminated in post-implantation death. In contrast to the results of Yamamoto et al. the present data do not demonstrate an increased frequency of chromosome abnormalities in embryos of aged mice X-irradiated before mating as compared to non-irradiated ones.

  5. Lack of effect on the chromosomal non-disjunction in aged female mice after low dose x-irradiation

    International Nuclear Information System (INIS)

    Strausmanis, R.; Hendrikson, I.-B.; Holmberg, M.; Roennbaeck, C.

    1978-01-01

    Karyotypes were determined in 1064 embryos of aged C57/BL mothers. The virgin female mice were irradiated with 0, 4, 8 or 16 R of X-rays, respectively, and placed with young untreated males 5 days after irradiation. 10.5-days old embryos were recovered from the uterus. Aneuploid embryos classified as alive (heart beats observed at the dissection) were 1 monosomic in the control group (496 embryos) and 2 trisomics in the irradiated group (568 embryos). The number of aneuploid embryos classified as dead was 4 trisomic cases in the control group and 3 trisomics in the irradiated group. The data indicate that trisomic embryos are not uncommon in the mouse but are eliminated in post-implantation death. In contrast to the results of Yamamoto et al. the present data do not demonstrate an increased frequency of chromosome abnormalities in embryos of aged mice X-irradiated before mating as compared to non-irradiated ones

  6. Effects of High Fat Feeding and Diabetes on Regression of Atherosclerosis Induced by Low-Density Lipoprotein Receptor Gene Therapy in LDL Receptor-Deficient Mice.

    Directory of Open Access Journals (Sweden)

    Florian Willecke

    Full Text Available We tested whether a high fat diet (HFD containing the inflammatory dietary fatty acid palmitate or insulin deficient diabetes altered the remodeling of atherosclerotic plaques in LDL receptor knockout (Ldlr-/- mice. Cholesterol reduction was achieved by using a helper-dependent adenovirus (HDAd carrying the gene for the low-density lipoprotein receptor (Ldlr; HDAd-LDLR. After injection of the HDAd-LDLR, mice consuming either HFD, which led to insulin resistance but not hyperglycemia, or low fat diet (LFD, showed regression compared to baseline. However there was no difference between the two groups in terms of atherosclerotic lesion size, or CD68+ cell and lipid content. Because of the lack of effects of these two diets, we then tested whether viral-mediated cholesterol reduction would lead to defective regression in mice with greater hyperglycemia. In both normoglycemic and streptozotocin (STZ-treated hyperglycemic mice, HDAd-LDLR significantly reduced plasma cholesterol levels, decreased atherosclerotic lesion size, reduced macrophage area and lipid content, and increased collagen content of plaque in the aortic sinus. However, reductions in anti-inflammatory and ER stress-related genes were less pronounced in STZ-diabetic mice compared to non-diabetic mice. In conclusion, HDAd-mediated Ldlr gene therapy is an effective and simple method to induce atherosclerosis regression in Ldlr-/- mice in different metabolic states.

  7. A CpG oligonucleotide can protect mice from a low aerosol challenge dose of Burkholderia mallei.

    Science.gov (United States)

    Waag, David M; McCluskie, Michael J; Zhang, Ningli; Krieg, Arthur M

    2006-03-01

    Treatment with an oligodeoxynucleotide (ODN) containing CPG motifs (CpG ODN 7909) was found to protect BALB/c mice from lung infection or death after aerosol challenge with Burkholderia mallei. Protection was associated with enhanced levels of gamma interferon (IFN-gamma)-inducible protein 10, interleukin-12 (IL-12), IFN-gamma, and IL-6. Preexposure therapy with CpG ODNs may protect victims of a biological attack from glanders.

  8. Chronic Dosing with Membrane Sealant Poloxamer 188 NF Improves Respiratory Dysfunction in Dystrophic Mdx and Mdx/Utrophin-/- Mice.

    Directory of Open Access Journals (Sweden)

    Bruce E Markham

    Full Text Available Poloxamer 188 NF (national formulary (NF grade of P-188 improves cardiac muscle function in the mdx mouse and golden retriever muscular dystrophy models. However in vivo effects on skeletal muscle have not been reported. We postulated that P-188 NF might protect diaphragm muscle membranes from contraction-induced injury in mdx and mdx/utrophin-/- (dko muscular dystrophy models. In the first study 7-month old mdx mice were treated for 22 weeks with subcutaneous (s.c. injections of saline or P-188 NF at 3 mg/Kg. In the second, dkos were treated with saline or P-188 NF (1 mg/Kg for 8 weeks beginning at age 3 weeks. Prednisone was the positive control in both studies. Respiratory function was monitored using unrestrained whole body plethysmography. P-188 NF treatment affected several respiratory parameters including tidal volume/BW and minute volume/BW in mdx mice. In the more severe dko model, P-188 NF (1 mg/Kg significantly slowed the decline in multiple respiratory parameters compared with saline-treated dko mice. Prednisone's effects were similar to those seen with P-188 NF. Diaphragms from P-188 NF or prednisone treated mdx and dko mice showed signs of muscle fiber protection including less centralized nuclei, less variation in fiber size, greater fiber density, and exhibited a decreased amount of collagen deposition. P-188 NF at 3 mg/Kg s.c. also improved parameters of systolic and diastolic function in mdx mouse hearts. These results suggest that P-188 NF may be useful in treating respiratory and cardiac dysfunction, the leading causes of death in Duchenne muscular dystrophy patients.

  9. A single dose of trichloroethylene given during development does not substantially alter markers of neuroinflammation in brains of adult mice.

    Science.gov (United States)

    Meadows, Jacqueline R; Parker, Chevonne; Gilbert, Kathleen M; Blossom, Sarah J; DeWitt, Jamie C

    2017-12-01

    Trichloroethylene (TCE) is a widespread environmental contaminant associated with developmental immunotoxicity and neurotoxicity. Previous studies have shown that MRL +/+ mice exposed to TCE from gestation through early-life demonstrate robust increases in inflammatory markers in peripheral CD4 + T-cells, as well as glutathione depletion and increased oxidative stress in cerebellum-associated with alterations in behavior. Since increased oxidative stress is associated with neuroinflammation, we hypothesized that neuroinflammatory markers could be altered relative to unexposed mice. MRL +/+ mice were given 0.5 mg/ml of TCE in vehicle or vehicle (water with 1% Alkamuls EL-620) from conception through early adulthood via drinking water to dams and then directly to post-weaning offspring. Animals were euthanized at 49 days of age and levels of pro- and anti-inflammatory cytokines, density of T-cell staining, and micro-glial morphology were evaluated in brains to begin to ascertain a neuroinflammatory profile. Levels of IL-6 were decreased in female animals and while not statistically significant, and levels of IL-10 were higher in brains of exposed male and female animals. Supportive of this observation, although not statistically significant, the number of ameboid microglia was higher in exposed relative to unexposed animals. This overall profile suggests the emergence of an anti-inflammatory/neuroprotective phenotype in exposed animals, possibly as a compensatory response to neuroinflammation that is known to be induced by developmental exposure to TCE.

  10. Sex- and dose-dependent effects of calcium ion irradiation on behavioral performance of B6D2F1 mice during contextual fear conditioning training

    Science.gov (United States)

    Raber, Jacob; Weber, Sydney J.; Kronenberg, Amy; Turker, Mitchell S.

    2016-06-01

    The space radiation environment includes energetic charged particles that may impact behavioral and cognitive performance. The relationship between the dose and the ionization density of the various types of charged particles (expressed as linear energy transfer or LET), and cognitive performance is complex. In our earlier work, whole body exposure to 28Si ions (263 MeV/n, LET = 78keV / μ m ; 1.6 Gy) affected contextual fear memory in C57BL/6J × DBA2/J F1 (B6D2F1) mice three months following irradiation but this was not the case following exposure to 48Ti ions (1 GeV/n, LET = 107keV / μ m ; 0.2 or 0.4 Gy). As an increased understanding of the impact of charged particle exposures is critical for assessment of risk to the CNS of astronauts during and following missions, in this study we used 40Ca ion beams (942 MeV/n, LET = 90keV / μm) to determine the behavioral and cognitive effects for the LET region between that of Si ions and Ti ions. 40Ca ion exposure reduced baseline activity in a novel environment in a dose-dependent manner, which suggests reduced motivation to explore and/or a diminished level of curiosity in a novel environment. In addition, exposure to 40Ca ions had sex-dependent effects on response to shock. 40Ca ion irradiation reduced the response to shock in female, but not male, mice. In contrast, 40Ca ion irradiation did not affect fear learning, memory, or extinction of fear memory for either gender at the doses employed in this study. Thus 40Ca ion irradiation affected behavioral, but not cognitive, performance. The effects of 40Ca ion irradiation on behavioral performance are relevant, as a combination of novelty and aversive environmental stimuli is pertinent to conditions experienced by astronauts during and following space missions.

  11. Combinatorial effects of administration of immunostimulatory compounds in feed and follow-up administration of triple-dose SLICE® (emamectin benzoate) on Atlantic salmon, Salmo salar L., infection with Lepeophtheirus salmonis.

    Science.gov (United States)

    Poley, J; Purcell, S L; Igboeli, O O; Donkin, A; Wotton, H; Fast, M D

    2013-03-01

    Several immunostimulatory feed additives have shown the ability to induce protective responses in Atlantic salmon to infection with Lepeophtheirus salmonis. However, even the most encouraging results rarely surpass a 50% protective index in the host. That fact coupled with the well-documented limitations of single-therapy strategies in the effective management of parasitic infections generally make it imperative to identify therapies that can be combined in an integrated pest management approach for sea lice. With this in mind, we hypothesized that immunostimulatory feeds could enhance the protection provided by SLICE® emamectin benzoate (EMB). To test this hypothesis, Atlantic salmon were fed one of two different immunostimulatory feeds (CpG ODN or Aquate®) for c. 7 weeks, challenged with L. salmonis copepodids early within that immunostimulatory feed period and then placed on a triple-dose (150 μg kg(-1) ) feed of SLICE® for 1 week following the completion of the immunostimulatory feeding period. CpG ODN (2 mg kg(-1) ) and the commercial yeast extract (Aquate® 0.2%) inclusion in feeds were able to successfully induce inflammatory gene expression (interleukin-1β) in the head kidneys of infected fish at 13 and 26 days post-exposure (DPE), and 13 DPE, respectively. Lice burdens were lower on fish fed CpG ODN (18%) or Aquate® (19%) diets; however, due to variability, these were not statistically significant over time. Despite no statistically significant reductions in lice numbers, by 33 DPE fish on immunostimulatory feeds had significantly reduced cortisol levels when compared to infected fish on control diet. Cortisol levels in fish receiving an immunostimulatory diet were no different from initial baseline levels prior to infection, whereas the levels in control diet fish were significantly elevated from all other time points. Despite the positive effects on infection of fish fed immunostimulatory feeds, no synergism was observed with follow-up treatment

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

    Science.gov (United States)

    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

    2016-09-01

    Although the chlorinated flame retardant Dechlorane (Dec) 602 has been detected in food, human blood, and breast milk, there is limited information on potential health effects, including possible immunotoxicity. We determined the immunotoxic potential of Dec 602 in mice by examining the expression of phenotypic markers on thymocyte and splenic lymphocyte subsets, Th1/Th2 transcription factors, and the production of cytokines and antibodies. Adult male C57BL/6 mice were orally exposed to environmentally relevant doses of Dec 602 (1 and 10 μg/kg body weight per day) for 7 consecutive days. Thymocyte and splenic CD4 and CD8 subsets and splenocyte apoptosis were examined by flow cytometric analysis. Cytokine expression was measured at both the mRNA and the protein levels. Levels of the transcription factors Th1 (T-bet and STAT1) and Th2 (GATA3) were determined using quantitative real-time polymerase chain reaction (qPCR). Serum levels of immunoglobulins IgG1, IgG2a, IgG2b and IgE were measured by enzyme-linked immunosorbent assay (ELISA). Splenic CD4+ and CD8+ T cell subsets were decreased compared with vehicle controls, and apoptosis was significantly increased in splenic CD4+ T cells. Expression (mRNA and protein) of Th2 cytokines [interleukin (IL)-4, IL-10, and IL-13] increased, and that of Th1 cytokines [IL-2, interferon (IFN)-γ and tumor necrosis factor (TNF)-α] decreased. The Th2 transcriptional factor GATA3 increased, whereas the Th1 transcriptional factors T-bet and STAT1 decreased. As additional indicators of the Th2-Th1 imbalance, production of IgG1 was significantly increased, whereas IgG2a was reduced. To our knowledge, we are the first to report evidence of the effects of Dec 602 on immune function in mice, with findings indicating that Dec 602 exposure favored Th2 responses and reduced Th1 function. Feng Y, Tian J, Xie HQ, She J, Xu SL, Xu T, Tian W, Fu H, Li S, Tao W, Wang L, Chen Y, Zhang S, Zhang W, Guo TL, Zhao B. 2016. Effects of acute low-dose

  13. CXCL12 expression in hematopoietic tissues of mice exposed to sublethal dose of ionizing radiation in the presence od iNOS inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Perez Vieira, Daniel [Instituto de Pesquisas Energeticas e Nucleares (IPEN), Sao Paulo, SP (Brazil). Lab. de Biologia Molecular; Hermida, Felipe Pessoa de Melo; Andrade Junior, Heitor Franco de [Instituto de Medicina Tropical de Sao Paulo, SP (Brazil). Lab. de Protozoologia

    2005-07-01

    Full text of publication follows: We study the production of CXCL12, a stem cell homing chemokine, in spleen and bone marrow of mice exposed at LD50% of {gamma}-radiation, w/wo a iNOS blocker, aminoguanidine, to test if inflammatory nitric oxide is involved in necrotic processes of stem cell death after ionizing radiation exposure. Groups of 10 male 6-week old C57Bl/6j mice were killed at specific time points after a 8Gy dose irradiation ({sup 60}Co source; 4,22kGy/h dose rate) and spleen and bone marrow samples were immersed and stored in TriZOL for total mRNA extraction. RT-PCR assays were performed to determine the production of CXCL12 as compared to murine {beta}-actin at days 2nd, 5th, 7th, 9th and 15th days after radiation in a semiquantitative way. PCR was performed after cDNA synthesis using Oligo-dT primers and specific primers for CXCL12 and {beta}-actin. Artificial optical density was determined in silver-stained PAGE resolved specific amplification products of CXCL12, using amplification of murine {beta}-actin as standard, and measurements obtained by the Image J freeware. CXCL12 production in spleen samples reached its maximum at 5th day after radiation exposure in animals not treated with aminoguanidine, but this peak was extended to at 7th day in treated animals. Non treated animals presented a decrease of CXCL12 expression up to 15th day of experiment, and aminoguanidine treated animals showed sustained increase of expression levels between 9th and 15th days. In bone marrow samples, the main difference among the two different experimental groups was a maintenance of CXCL12 mRNA expression between 7th and 9th days, persisting until the end of the experiment. Our data demonstrates that the effect of aminoguanidine appears to sustain the CXCL12 mRNA synthesis in hematopoietic tissues of irradiated mice, providing some evidences that the axis iNOS -NO - inflammation must be involved in stem cell death, aside to the direct radiation effect, suggesting

  14. Prenatal and early postnatal NOAEL-dose clothianidin exposure leads to a reduction of germ cells in juvenile male mice.

    Science.gov (United States)

    Yanai, Shogo; Hirano, Tetsushi; Omotehara, Takuya; Takada, Tadashi; Yoneda, Naoki; Kubota, Naoto; Yamamoto, Anzu; Mantani, Youhei; Yokoyama, Toshifumi; Kitagawa, Hiroshi; Hoshi, Nobuhiko

    2017-07-07

    Neonicotinoids are pesticides used worldwide. They bind to insect nicotinic acetylcholine receptors (nAChRs) with high affinity. We previously reported that clothianidin (CTD), one of the latest neonicotinoids, reduced antioxidant expression and induced germ cell death in the adult testis of vertebrates. Here, we investigated the male reproductive toxicity of prenatal and early postnatal exposure to CTD, because it is likely that developmental exposure more severely affects the testis compared to adults due to the absence of the blood-testis barrier. Pregnant C57BL/6 mice were given water gel blended with CTD (0, 10 or 50 mg/kg/day; no-observed-adverse-effect-level [NOAEL for mice]: 47.2 mg/kg/day) between gestational day 1 and 14 days post-partum. We then examined the testes of male offspring at postnatal day 14. The testis weights and the numbers of germ cells per seminiferous tubule were decreased in the CTD-50 group, and abnormal tubules containing no germ cells appeared. Nevertheless, the apoptotic cell number and proliferative activity were not significantly different between the control and CTD-exposed groups. There were no significant differences in the androgen-related parameters, such as the Leydig cell volume per testis, the Sertoli cell number and the tubule diameter. The present study is the first demonstration that in utero and lactational exposures to CTD at around the NOAEL for mice reduce the germ cell number, but our findings suggest that these exposures do not affect steroidogenesis in Leydig cells during prenatal or early postnatal life.

  15. Effect of Linezolid on the 50% Lethal Dose and 50% Protective Dose in Treatment of Infections by Gram-Negative Pathogens in Naive and Immunosuppressed Mice and on the Efficacy of Ciprofloxacin in an Acute Murine Model of Septicemia

    Science.gov (United States)

    Marra, Andrea; Lamb, Lucinda; Medina, Ivette; George, David; Gibson, Glenn; Hardink, Joel; Rugg, Jady; Van Deusen, Jeffrey

    2012-01-01

    Murine models of infection were used to study the effect of linezolid on the virulence of Gram-negative bacteria and to assess potential pharmacodynamic interactions with ciprofloxacin in the treatment of these infections, prompted by observations from a recent clinical trial. Naive and immunosuppressed mice were challenged with Klebsiella pneumoniae 53A1109, K. pneumoniae GC6658, and Pseudomonas aeruginosa UC12120 in acute sepsis and pulmonary infection models, using different serial dilutions of these pathogens (groups of 8 animals each). Linezolid (100 mg/kg/dose) was administered orally at 0.5 and 4.0 h postchallenge in the sepsis model and at 4 h postchallenge followed by 2 days of twice-daily treatment in the pulmonary model. Further, ciprofloxacin alone and in combination with oral linezolid was investigated in the sepsis model. Survival was assessed for 4 and 10 days postchallenge in the systemic and respiratory models, respectively. The data were fitted to a nonlinear regression analysis to determine 50% lethal doses (LD50s) and 50% protective doses (PD50s). A clinically relevant, high-dose regimen of linezolid had no significant effect on LD50 in these models. This lack of effect was independent of immune status. A combination of oral ciprofloxacin with linezolid yielded lower PD50s than oral ciprofloxacin alone (ciprofloxacin in combination, 8.4 to 32.7 mg/kg; oral ciprofloxacin, 39.4 to 88.3 mg/kg). Linezolid did not improve the efficacy of subcutaneous ciprofloxacin (ciprofloxacin in combination, 2.0 to 2.4 mg/kg; subcutaneous ciprofloxacin, 2.0 to 2.8 mg/kg). In conclusion, linezolid does not seem to potentiate infections caused by Gram-negative pathogens or to interact antagonistically with ciprofloxacin. PMID:22710118

  16. Dose-dependent induction of transforming growth factor β (TGF-β) in the lung tissue of fibrosis-prone mice after thoracic irradiation

    International Nuclear Information System (INIS)

    Ruebe, Claudia E.; Uthe, Daniela; Schmid, Kurt W.; Richter, Klaus D.; Wessel, Jan; Schuck, Andreas; Willich, Norman; Ruebe, Christian

    2000-01-01

    Purpose: The lung is the major dose-limiting organ for radiotherapy of cancer in the thoracic region. The pathogenesis of radiation-induced lung injury at the molecular level is still unclear. Immediate cellular damage after irradiation is supposed to result in cytokine-mediated multicellular interactions with induction and progression of fibrotic tissue reactions. The purpose of this investigation was to evaluate the acute and long-term effects of radiation on the gene expression of transforming growth factor beta (TGF-β) in a model of lung injury using fibrosis-sensitive C57BL/6 mice. Methods and Materials: The thoraces of C57BL/6 mice were irradiated with 6 and 12 Gy, respectively. Treated and sham-irradiated control mice were sacrificed at times corresponding to the latent period (1, 3, 6, 12, 24, 48, 72 hours and 1 week postirradiation), the pneumonic phase (2, 4, 8, and 16 weeks postirradiation), and the beginning of the fibrotic phase (24 weeks postirradiation). The lung tissue from three different mice per dosage and time point was analyzed by a combination of polymerase chain reaction (PCR), immunohistochemistry, and light microscopy. The mRNA expression of TGF-β was quantified by competitive reverse transcriptase/polymerase chain reaction (RT-PCR); the cellular origin of the TGF-β protein was identified by immunohistochemical staining (alkaline phosphatase-anti-alkaline phosphatase [APAAP]). The cytokine expression on mRNA and protein level was correlated with the histopathological alterations. Results: Following thoracic irradiation with a single dose of 12 Gy, radiation-induced TGF-β release in lung tissue was appreciable already within the first hours (1, 3, and 6 hours postirradiation) and reached a significant increase after 12 hours; subsequently (48 hours, 72 hours, and 1 week postirradiation) the TGF-β expression declined to basal levels. At the beginning of the pneumonic phase, irradiation-mediated stimulation of TGF-β release reached

  17. Indications of an adaptive response in C57bl mice pre-exposed in vivo to low doses of ionizing radiation

    International Nuclear Information System (INIS)

    Wojcik, A.; Tuschl, H.

    1989-08-01

    C57bl/6 mice were whole body irradiated with 50 mGy/day ('adapting dose') on four consecutive days and their spleens removed on the 1 st , 3 rd , 7 th , 12 th , 19 th , and 26 th day after the last irradiation. In vitro UV-light-induced UDS and MMC-induced SCEs were scored in lymphocytes, UV-light and MMC being the 'challenging agents' yielding higher UDS values and lower frequencies of induced SCEs than in cells of nonadapted animals. On day 12 this effect could only be seen in half, on day 19 and 26 in none of the performed experiments. The results support those published by Tuschl and Liu in showing that it is possible to induce the adaptive response in vivo. 1 fig., 4 tabs., 26 refs. (Authors)

  18. The stimulatory effect of single-dose pre-irradiation administration of indomethacin and diclofenac on haemopoietic recovery in the spleen of gamma-irradiated mice

    International Nuclear Information System (INIS)

    Kozubik, A.; Pospisil, M.; Netikova, J.

    1989-01-01

    The aim of the work was to examine the effect of the single-dose pre-irradiation administration of non-steroid anti-inflammatory drugs, i.e. indomethacin (0.15 mg/mouse) and diclofenac (0.6 mg/mouse) on the recovery of haemopoiesis in the spleen of whole-body irradiated male mice (CBA x C57BL/10)F 1 . It was shown that the administation of these substances 1-24 h prior to sublethal irradiation stimulates the recovery of the proliferation activity of the spleen and the formation of endogenous spleen colonies. These results can be explained as the inhibitory effect of the substances administered on biosynthesis of prostaglandins. (author)

  19. Relationship between chromosomal aberration of bone marrow cells and dosage of irradiation after 46Sc internal pollution and external low dose X-irradiation in mice

    International Nuclear Information System (INIS)

    Li Guofu; Li Zhang; Wu Yin

    1989-01-01

    The relationship between chromosomal aberration of bone marrow cells and dosage in mice 24 h after 46 Sc internal pollution combined with external low dose whole body X-irradiation was quantiatively studied. The results showed that the relationship between chromosomal aberration and dosage was expressed in a linear regression equation. The chromosomal aberration rate was lower in the combined exposure than that of the sum of internal and external exposures, but higher than that of either the internal or external exposure singly. The relationship between chromosomal aberration and time was expressed in the following three phase exponential function: Y(t) = 2.9078 exp 0.27668t + 2.9371 exp -0.0778t + 2.3786 -0.01788t . By means of fit test, there was no significant difference between the determined and the theoretical values. The 90% theoretical values got from all the equations distributed over the determined values

  20. Cerebral edema induced in mice by a convulsive dose of soman. Evaluation through diffusion-weighted magnetic resonance imaging and histology

    International Nuclear Information System (INIS)

    Testylier, Guy; Lahrech, Hana; Montigon, Olivier; Foquin, Annie; Delacour, Claire; Bernabe, Denis; Segebarth, Christoph; Dorandeu, Frederic; Carpentier, Pierre

    2007-01-01

    Purpose: In the present study, diffusion-weighted magnetic resonance imaging (DW-MRI) and histology were used to assess cerebral edema and lesions in mice intoxicated by a convulsive dose of soman, an organophosphate compound acting as an irreversible cholinesterase inhibitor. Methods: Three hours and 24 h after the intoxication with soman (172 μg/kg), the mice were anesthetized with an isoflurane/N 2 O mixture and their brain examined with DW-MRI. After the imaging sessions, the mice were sacrificed for histological analysis of their brain. Results: A decrease in the apparent diffusion coefficient (ADC) was detected as soon as 3 h after the intoxication and was found strongly enhanced at 24 h. A correlation was obtained between the ADC change and the severity of the overall brain damage (edema and cellular degeneration): the more severe the damage, the stronger the ADC drop. Anesthesia was shown to interrupt soman-induced seizures and to attenuate edema and cell change in certain sensitive brain areas. Finally, brain water content was assessed using the traditional dry/wet weight method. A significant increase of brain water was observed following the intoxication. Conclusions: The ADC decrease observed in the present study suggests that brain edema in soman poisoning is mainly intracellular and cytotoxic. Since entry of water into Brain was also evidenced, this type of edema is certainly mixed with others (vasogenic, hydrostatic, osmotic). The present study confirms the potential of DW-MRI as a non-invasive tool for monitoring the acute neuropathological consequences (edema and neurodegeneration) of soman-induced seizures

  1. Regulatory Forum Opinion Piece*: Retrospective Evaluation of Doses in the 26-week Tg.rasH2 Mice Carcinogenicity Studies: Recommendation to Eliminate High Doses at Maximum Tolerated Dose in Future Studies. A Response to the Counterpoints.

    Science.gov (United States)

    Paranjpe, Madhav G; Denton, Melissa D; Vidmar, Tom J; Elbekai, Reem H

    2016-01-01

    We recently conducted a retrospective analysis of data collected from 29 Tg.rasH2 carcinogenicity studies conducted at our facility to determine how successful was the strategy of choosing the high dose of the 26-week studies based on an estimated maximum tolerated dose (MTD). As a result of our publication, 2 counterviews were expressed. Both counterviews illustrate very valid points in their interpretation of our data. In this article, we would like to highlight clarifications based on several points and issues they have raised in their papers, namely, the dose-level selection, determining if MTD was exceeded in 26-week studies, and a discussion on the number of dose groups to be used in the studies. © The Author(s) 2015.

  2. Dose estimation in B16 tumour bearing mice for future irradiation in the thermal column of the TRIGA reactor after B/Gd/LDL adduct infusion

    Energy Technology Data Exchange (ETDEWEB)

    Protti, N., E-mail: nicoletta.protti@pv.infn.it [University of Pavia, Department of Nuclear and Theoretical Physics, via Bassi 6, 27100 Pavia (Italy)] [National Institute of Nuclear Physics (INFN) Section of Pavia, via Bassi 6, 27100 Pavia (Italy); Ballarini, F.; Bortolussi, S. [University of Pavia, Department of Nuclear and Theoretical Physics, via Bassi 6, 27100 Pavia (Italy)] [National Institute of Nuclear Physics (INFN) Section of Pavia, via Bassi 6, 27100 Pavia (Italy); Bruschi, P. [University of Pavia, Department of Nuclear and Theoretical Physics, via Bassi 6, 27100 Pavia (Italy); Stella, S. [University of Pavia, Department of Nuclear and Theoretical Physics, via Bassi 6, 27100 Pavia (Italy)] [National Institute of Nuclear Physics (INFN) Section of Pavia, via Bassi 6, 27100 Pavia (Italy); Geninatti, S.; Alberti, D.; Aime, S. [University of Torino, Chemistry Department, via Nizza 52, 10126 Torino (Italy); Altieri, S. [University of Pavia, Department of Nuclear and Theoretical Physics, via Bassi 6, 27100 Pavia (Italy)] [National Institute of Nuclear Physics (INFN) Section of Pavia, via Bassi 6, 27100 Pavia (Italy)

    2011-12-15

    To test the efficacy of a new {sup 10}B-vector compound, the B/Gd/LDL adduct synthesised at Torino University, in vivo irradiations of murine tumours are in progress at the TRIGA Mark II reactor of the Pavia University. A localised B16 melanoma tumour is generated in C57BL/6 mice and subsequently infused with the adduct. During the irradiation, the mouse will be put in a shield to protect the whole body except the tumour in the back-neck area. To optimise the treatment set-up, MCNP simulations were performed. A very simplified mouse model was built using MCNP geometry capabilities, as well as the geometry of the shield made of 99% {sup 10}B enriched boric acid. A hole in the shield is foreseen in correspondence of the back-neck region. Many configurations of the shield were tested in terms of neutron flux, dose distribution and mean induced activity in the tumour region and in the radiosensitive organs of the mouse. In the final set-up, up to five mice can be treated simultaneously in the reactor thermal column and the neutron fluence in the tumour region for 10 min of irradiation is of about 5 Multiplication-Sign 10{sup 12} cm{sup -2}.

  3. Effects of marrow grafting on preleukemia cells and thymic nurse cells in C57BL/Ka mice after a leukemogenic split-dose irradiation

    International Nuclear Information System (INIS)

    Defresne, M.P.; Greimers, R.; Lenaerts, P.; Boniver, J.

    1986-01-01

    A split-dose regimen of whole-body irradiation (4 X 175 rad at weekly intervals) induced thymic lymphomas in C57BL/Ka mice after a latent period of 3-9 months. Meanwhile, preleukemia cells arose in the thymus and bone marrow and persisted until the onset of lymphomas. Simultaneously, thymic lymphopoiesis was impaired; thymocyte numbers were subnormal and thymic nurse cells disappeared in a progressive but irreversible fashion. The depletion of these lymphoepithelial complexes, which are normally involved in the early steps of thymic lymphopoiesis, was related to altered prothymocyte activity in bone marrow and to damaged thymic microenvironment, perhaps as a consequence of the presence of preleukemia cells. The grafting of normal bone marrow cells after irradiation prevented the development of lymphomas. However, marrow reconstitution did not inhibit the induction of preleukemia cells. They disappeared from the thymus during the second part of the latent period. At the same time, thymic lymphopoiesis was restored; thymocytes and nurse cell numbers returned to normal as a consequence of the proliferation of grafted marrow-derived cells within the thymus. The results thus demonstrated an intimate relationship between preleukemia cells and an alteration of thymic lymphopoiesis, which particularly involved the nurse cell microenvironment. Some preleukemia cells in marrow-reconstituted, irradiated mice derived from the unirradiated marrow inoculate. Thus these cells acquired neoplastic potential through a factor present in the irradiated tissues. The nature of this indirect mechanism was briefly discussed

  4. Toxicogenomic analysis of the particle dose- and size-response relationship of silica particles-induced toxicity in mice

    International Nuclear Information System (INIS)

    Lu Xiaoyan; Jin Tingting; Jin Yachao; Wu Leihong; Hu Bin; Tian Yu; Fan Xiaohui

    2013-01-01

    This study investigated the relationship between particle size and toxicity of silica particles (SP) with diameters of 30, 70, and 300 nm, which is essential to the safe design and application of SP. Data obtained from histopathological examinations suggested that SP of these sizes can all induce acute inflammation in the liver. In vivo imaging showed that intravenously administrated SP are mainly present in the liver, spleen and intestinal tract. Interestingly, in gene expression analysis, the cellular response pathways activated in the liver are predominantly conserved independently of particle dose when the same size SP are administered or are conserved independently of particle size, surface area and particle number when nano- or submicro-sized SP are administered at their toxic doses. Meanwhile, integrated analysis of transcriptomics, previous metabonomics and conventional toxicological results support the view that SP can result in inflammatory and oxidative stress, generate mitochondrial dysfunction, and eventually cause hepatocyte necrosis by neutrophil-mediated liver injury. (paper)

  5. Effect of low dose of Vitex agnus castus on volume and surface area of oocyte in mice

    OpenAIRE

    HAMIDIAN, Gholamreza; YAHYAVI, Fariba

    2014-01-01

    Vitex agnus-castus L. (VAC) is a deciduous shrub that is native to Mediterranean, Europe and Central Asia. VAC extract has been used traditionally in the treatment of menstrual disorders (amenorrhoea, dysmenorrhoea), premenstrual syndrome (PMS), corpus luteum insufficiency, uterine bleeding, fibroid cysts, infertility, acne, menopause, disrupted lactation and hyperprolactinaemia. This study was aimed to evaluate the effects of low dose of VAC essential oil on volume and surface area of oocyte...

  6. Feeding Tubes

    Science.gov (United States)

    ... feeding therapies have been exhausted. Please review product brand and method of placement carefully with your physician ... Total Parenteral Nutrition. Resources: Oley Foundation Feeding Tube Awareness Foundation Children’s Medical Nutrition Alliance APFED’s Educational Webinar ...

  7. Ultradian feeding in mice not only affects the peripheral clock in the liver, but also the master clock in the brain

    NARCIS (Netherlands)

    Sen, Satish; Raingard, Hélène; Dumont, Stéphanie; Kalsbeek, A.; Vuillez, Patrick; Challet, Etienne

    2017-01-01

    Restricted feeding during the resting period causes pronounced shifts in a number of peripheral clocks, but not the central clock in the suprachiasmatic nucleus (SCN). By contrast, daily caloric restriction impacts also the light-entrained SCN clock, as indicated by shifted oscillations of clock

  8. Exercise training in transgenic mice is associated with attenuation of early breast cancer growth in a dose-dependent manner.

    Directory of Open Access Journals (Sweden)

    Jorming Goh

    Full Text Available Epidemiological research suggests that regular physical activity confers beneficial effects that mediate an anti-tumor response and may reduce cancer recurrence. It is unclear what amount of physical activity is necessary to exert such a protective effect and what mechanisms are involved. We investigated the effects of voluntary wheel running on tumor progression and cytokine gene expression in the transgenic polyoma middle T oncoprotein (PyMT mouse model of invasive breast cancer. Runners showed significantly reduced tumor sizes compared with non-runners after 3 weeks of running (p ≤ 0.01, and the greater the running distance the smaller the tumor size (Pearson's r = -0.61, p ≤ 0.04, R(2 = 0.38. Mice running greater than 150 km per week had a significantly attenuated tumor size compared with non-runners (p ≤ 0.05. Adipose tissue mass was inversely correlated with tumor size in runners (Pearson's r = -0.77, p = 0.014 but not non-runners. Gene expression of CCL22, a cytokine associated with recruitment of immunosuppressive T regulatory cells, was decreased in tumors of runners compared to non-runners (p ≤ 0.005. No differences in tumor burden or metastatic burden were observed between runners and non-runners after ten weeks of running when the study was completed. We conclude that voluntary wheel running in PyMT mice correlates with an attenuation in tumor progression early during the course of invasive breast cancer. This effect is absent in the later stages of overwhelming tumor burden even though cytokine signaling for immunosuppressive regulatory T cells was down regulated. These observations suggest that the initiation of moderate exercise training for adjunctive therapeutic benefit early in the course of invasive breast cancer should be considered for further investigation.

  9. Safety and toxicology assessment of chicken breast for high-dose irradiation

    International Nuclear Information System (INIS)

    Zhu Jiating; Feng Min; Yan Jianmin; Yang Ping; Wang Dening; Gao Meixu; Ha Yiming; Liu Chunquan

    2011-01-01

    Feeding wholesomeness tests of irradiated chicken breast were studied by using acute oral toxicology, Ames, micronucleus of born marrow cell, sperm shape abnormality in mice and 30 d feeding test. The LD 50 of all the rats and mice were more than 10 g/kg · BW, which means that the pet foods belonged to actually non-toxic grade; ames test, and the tests of micronucleus of born marrow cell, sampan shape abnormality in mice were all negative results; 30 d feeding test in rats demonstrated that it had no distinctive effects on routine blood, body weight and biochemical index. It is concluded that pet foods irradiated up to 25 kGy high dose were no safety and toxicology problems. (authors)

  10. High-dose recombinant apolipoprotein A-I(milano) mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophage content in apolipoprotein e-deficient mice. Potential implications for acute plaque stabilization.

    Science.gov (United States)

    Shah, P K; Yano, J; Reyes, O; Chyu, K Y; Kaul, S; Bisgaier, C L; Drake, S; Cercek, B

    2001-06-26

    Repeated doses of recombinant apolipoprotein A-I(Milano) phospholipid complex (apoA-I(m)) reduce atherosclerosis and favorably change plaque composition in rabbits and mice. In this study, we tested whether a single high dose of recombinant apoA-I(m) could rapidly mobilize tissue cholesterol and reduce plaque lipid and macrophage content in apoE-deficient mice. High cholesterol-fed, 26-week-old apoE-deficient mice received a single intravenous injection of saline (n=16), 1080 mg/kg dipalmitoylphosphatidylcholine (DPPC; n=14), or 400 mg/kg of recombinant apoA-I(m) complexed with DPPC (1:2.7 weight ratio; n=18). Blood was sampled before and 1 and 48 hours after injection, and aortic root plaques were evaluated for lipid content and macrophage content after oil-red O and immunostaining, respectively. One hour after injection, the plasma cholesterol efflux-promoting capacity was nearly 2-fold higher in recombinant apoA-I(m)-treated mice compared with saline and DPPC-treated mice (P<0.01). Compared with baseline values, serum free cholesterol, an index of tissue cholesterol mobilization, increased 1.6-fold by 1 hour after recombinant apoA-I(m) injection, and it remained significantly elevated at 48 hours (P<0.01). Mice receiving recombinant apoA-I(m) had 40% to 50% lower lipid content (P<0.01) and 29% to 36% lower macrophage content (P<0.05) in their plaques compared with the saline- and DPPC-treated mice, respectively. A single high dose of recombinant apoA-I(m) rapidly mobilizes tissue cholesterol and reduces plaque lipid and macrophage content in apoE-deficient mice. These findings suggest that this strategy could rapidly change plaque composition toward a more stable phenotype.

  11. Evaluation of changes in serum chemistry in association with feed withdrawal or high dose oral gavage with Dextran Sodium Sulfate (DSS) induced gut leakage in broiler chickens

    Science.gov (United States)

    Dextran sodium sulfate (DSS) has been shown to be effective at inducing enteric inflammation in broiler chickens, resulting in increased leakage of orally administered fluorescein isothiocyanate dextran to circulation. In a previous study, two doses of DSS (0.45g/dose) administered as oral gavage re...

  12. Feeding mice with diets containing mercury-contaminated fish flesh from French Guiana: a model for the mercurial intoxication of the Wayana Amerindians

    Directory of Open Access Journals (Sweden)

    Rossignol Rodrigue

    2008-10-01

    Full Text Available Abstract Background In 2005, 84% of Wayana Amerindians living in the upper marshes of the Maroni River in French Guiana presented a hair mercury concentration exceeding the limit set up by the World Health Organization (10 μg/g. To determine whether this mercurial contamination was harmful, mice have been fed diets prepared by incorporation of mercury-polluted fish from French Guiana. Methods Four diets containing 0, 0.1, 1, and 7.5% fish flesh, representing 0, 5, 62, and 520 ng methylmercury per g, respectively, were given to four groups of mice for a month. The lowest fish regimen led to a mercurial contamination pressure of 1 ng mercury per day per g of body weight, which is precisely that affecting the Wayana Amerindians. Results The expression of several genes was modified with mercury intoxication in liver, kidneys, and hippocampus, even at the lowest tested fish regimen. A net genetic response could be observed for mercury concentrations accumulated within tissues as weak as 0.15 ppm in the liver, 1.4 ppm in the kidneys, and 0.4 ppm in the hippocampus. This last value is in the range of the mercury concentrations found in the brains of chronically exposed patients in the Minamata region or in brains from heavy fish consumers. Mitochondrial respiratory rates showed a 35–40% decrease in respiration for the three contaminated mice groups. In the muscles of mice fed the lightest fish-containing diet, cytochrome c oxidase activity was decreased to 45% of that of the control muscles. When mice behavior was assessed in a cross maze, those fed the lowest and mid-level fish-containing diets developed higher anxiety state behaviors compared to mice fed with control diet. Conclusion We conclude that a vegetarian diet containing as little as 0.1% of mercury-contaminated fish is able to trigger in mice, after only one month of exposure, disorders presenting all the hallmarks of mercurial contamination.

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

    DEFF Research Database (Denmark)

    Kyjovska, Zdenka O.; Jacobsen, Nicklas R.; Saber, Anne T.

    2015-01-01

    of 0.67, 2, 6, and 162 mu g 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...... 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. (c) 2014 The Authors...

  14. Celecoxib Enhances the Efficacy of Low-Dose Antibiotic Treatment against Polymicrobial Sepsis in Mice and Clinical Isolates of ESKAPE Pathogens.

    Science.gov (United States)

    Annamanedi, Madhavi; Varma, Gajapati Y N; Anuradha, K; Kalle, Arunasree M

    2017-01-01

    Treatment of multidrug resistant bacterial infections has been a great challenge globally. Previous studies including our study have highlighted the use of celecoxib, a non-steroidal anti-inflammatory drug in combination with antibiotic has decreased the minimal inhibitory concentration to limit Staphylococcus aureus infection. However, the efficacy of this combinatorial treatment against various pathogenic bacteria is not determined. Therefore, we have evaluated the potential use of celecoxib in combination with low doses of antibiotic in limiting Gram-positive and Gram-negative bacteria in vivo in murine polymicrobial sepsis developed by cecum ligation and puncture (CLP) method and against clinically isolated human ESKAPE pathogens ( Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa , and Enterobacter species). The in vivo results clearly demonstrated a significant reduction in the bacterial load in different organs and in the inflammatory markers such as COX-2 and NF-κB via activation of SIRT1 in mice treated with imipenem, a choice of antibiotic for polymicrobial sepsis treatment. Combinatorial treatment of ampicillin and celecoxib was effective on clinical isolates of ESKAPE pathogens, 45% of tested clinical isolates showed more than 50% reduction in the colony forming units when compared to ampicillin alone. In conclusion, this non-traditional treatment strategy might be effective in clinic to reduce the dose of antibiotic to treat drug-resistant bacterial infections.

  15. Synergistic induction of tumors in NMRI mice by combined fetal X-irradiation with low doses and ethylnitrosourea administered to juvenile offspring

    Energy Technology Data Exchange (ETDEWEB)

    Schmahl, W.

    1988-08-01

    Mice were X-irradiated on day 15 of gestation with 0.2, 0.4, 0.8 or 1.6 Gy. Offspring were reared by their mothers and divided into two subgroups at an age of 21 days, one subgroup receiving a single dose (45 mg/kg) of ethylnitrosourea (ENU). All animals were kept ultimately until 22 months to register the long-term tumor pattern. The carcinogenic effects of ENU alone were also studied in two separate experiments. Prenatal X-irradiation with 1.6 Gy mostly abolished the carcinogenic late effects of ENU, with the exception of an almost constant leucosis incidence and an unchanged lung tumor frequency. Lowering the prenatal X-ray dose to 0.8 Gy resulted in a significantly increased rate of liver tumors and ovary tumors. Synergistic effects on various tissues were observed after both 0.4- and 0.2-Gy fetal X-irradiation treatment in combination with postnatal application of ENU. These effects mainly involved a significant increase in the frequency of leucosis and of tumors of the liver, intestine, uterus and ovaries. The greater-than-additive effect in the case of these tumors suggests that low-level prenatal X-irradiation leads to a lasting sensitivity of some tissues towards a subsequent carcinogenic stimulus.

  16. Mice long-term high-fat diet feeding recapitulates human cardiovascular alterations: an animal model to study the early phases of diabetic cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Sebastián D Calligaris

    Full Text Available BACKGROUND/AIM: Hypercaloric diet ingestion and sedentary lifestyle result in obesity. Metabolic syndrome is a cluster of clinical features secondary to obesity, considered as a pre-diabetic condition and recognized as an independent risk factor for cardiovascular diseases. To better understand the relationship between obesity, metabolic syndrome and cardiovascular disease as well as for the development of novel therapeutic strategies, animal models that reproduce the etiology, course and outcomes of these pathologies are required. The aim of this work was to characterize the long-term effects of high-fat diet-induced obesity on the mice cardiovascular system, in order to make available a new animal model for diabetic cardiomyopathy. METHODS/RESULTS: Male C57BL/6 mice were fed with a standardized high-fat diet (obese or regular diet (normal for 16 months. Metabolic syndrome was evaluated testing plasma glucose, triglycerides, cholesterol, insulin, and glucose tolerance. Arterial pressure was measured using a sphygmomanometer (non invasive method and by hemodynamic parameters (invasive method. Cardiac anatomy was described based on echocardiography and histological studies. Cardiac function was assessed by cardiac catheterization under a stress test. Cardiac remodelling and metabolic biomarkers were assessed by RT-qPCR and immunoblotting. As of month eight, the obese mice were overweight, hyperglycaemic, insulin resistant, hyperinsulinemic and hypercholesterolemic. At month 16, they also presented normal arterial pressure but altered vascular reactivity (vasoconstriction, and cardiac contractility reserve reduction, heart mass increase, cardiomyocyte hypertrophy, cardiac fibrosis, and heart metabolic compensations. By contrast, the normal mice remained healthy throughout the study. CONCLUSIONS: Mice fed with a high-fat diet for prolonged time recapitulates the etiology, course and outcomes of the early phases of human diabetic cardiomyopathy.

  17. Transcriptional changes associated with reduced spontaneous liver tumor incidence in mice chronically exposed to high dose arsenic

    International Nuclear Information System (INIS)

    Nelson, Gail M.; Ahlborn, Gene J.; Allen, James W.; Ren, Hongzu; Corton, J. Christopher; Waalkes, Michael P.; Kitchin, Kirk T.; Diwan, Bhalchandra A.; Knapp, Geremy; Delker, Don A.

    2009-01-01

    Exposure of male C3H mice in utero (from gestational days 8-18) to 85 ppm sodium arsenite via the dams' drinking water has previously been shown to increase liver tumor incidence by 2 years of age. However, in our companion study (Ahlborn et al., 2009), continuous exposure to 85 ppm sodium arsenic (from gestational day 8 to postnatal day 365) did not result in increased tumor incidence, but rather in a significant reduction (0% tumor incidence). The purpose of the present study was to examine the gene expression responses that may lead to the apparent protective effect of continuous arsenic exposure. Genes in many functional categories including cellular growth and proliferation, gene expression, cell death, oxidative stress, protein ubiquitination, and mitochondrial dysfunction were altered by continuous arsenic treatment. Many of these genes are known to be involved in liver cancer. One such gene associated with rodent hepatocarcinogenesis, Scd1, encodes stearoyl-CoA desaturase and was down-regulated by continuous arsenic treatment. An overlap between the genes in our study affected by continuous arsenic exposure and those from the literature affected by long-term caloric restriction suggests that reduction in the spontaneous tumor incidence under both conditions may involve similar gene pathways such as fatty acid metabolism, apoptosis, and stress response.

  18. Evaluation of the radioprotective effect of turmeric extract and vitamin E in mice exposed to therapeutic dose of radioiodine

    International Nuclear Information System (INIS)

    Bhartiya, Uma S.; Raut, Yogita S.; Joseph, Lebana J.; Hawaldar, Rohini W.; Rao, Badanidiyoor S.

    2008-01-01

    The aim of this study was to evaluate the radioprotective effect of turmeric extract (40 mg/kg body weight) and vitamin E (α - tocopherol acetate, 400 IU/kg body weight) supplementation on lipid peroxidation, reduced glutathione and antioxidant defense enzymes in various organs like liver, kidney and salivary glands at 24 h in adult Swiss mice. 131 Iodine exposure significantly increased lipid peroxidation in kidney and salivary glands in comparison to control animals. Pre supplementation with turmeric extract for 15 days showed significant lowering of lipid peroxidation in kidney. On the other hand vitamin E pre supplementation showed marked reduction in lipid peroxidation in salivary glands. Reduced glutathione levels decreased significantly in liver after radiation exposure. However, pre supplementation with turmeric extract and vitamin E did not improve glutathione levels in liver. In conclusion we have observed differential radioprotective effect of turmeric extract and vitamin E in kidney and salivary glands. However, Vitamin E seems to offer better radioprotection for salivary glands which is known to be the major site of cellular destruction after radioiodine therapy in patients. (author)

  19. Changes in hemopoiesis of mice during chronic irradiation with a dose rate of 957 mGy/day

    International Nuclear Information System (INIS)

    Mackova, N.; Marko, L.; Horak, J.

    1982-01-01

    Quantitative and qualitative changes in the blood producing organs and in the peripheral blood of mice were evaluated. The animals have been continually irradiated for 42 days with a daily dosage of 957 mGy. Until the 7th day of irradiation a significant diminution of the cellularity of the bone marrow and of the cellularity as well as the mass of the spleen could be observed. After the 14th day of irradiation a temporary stabilization of the cell number in the bone marrow could be found until the 28th day, after that time there was a moderately strong decrease. The cellularity and the mass of the spleen increased temporarily until the 28th day of irradiation owing to the increase of erythropoiesis and myelopoiesis from 20% to 50%. The most significant changes in the peripheral blood could be observed in agranulocytes as a kind of sudden and permanent decrease. The diminution of the granulocyte and reticulocyte numbers proceeded somewhat more slowly, with a temporarily increasing tendency on the 28th day of irradiation. The erythrocyte numbers as well as the hematocrit and hemoglobin values decreased continually beginning from the 7th day of irradiation until the death of the animals. (author)

  20. Assessment of the Toxicity of Sub-chronic Low and High Doses of the Bio-insecticide Spinosad on the Liver, Kidney and the Cerebellum in Male Albino Mice

    Directory of Open Access Journals (Sweden)

    Sabry A El-Naggar

    2017-06-01

    Full Text Available ABSTRACT Spinosad (SPD is a highly selective insect control product. However, it was reported that SPD has toxicity toward other non-target organisms. This study was conducted to address the toxic effect of two sub-chronic low and high doses; 35 and 350 mg/kg SPD on some biochemical, histological and immunohistochemical parameters of the liver, kidney and cerebellum. Thirty-six male Swiss mice were divided into three groups of 12 mice each; first group (G1 served as a control, second group (G2 received a low sub-chronic dose of SPD that is equal to 35 mg/kg, and third group (G3 received a high sub-chronic dose of SPD that is equal to 350 mg/kg. The results showed that mice which were received 350 mg/kg SPD showed a significant decrease in the body weight and a significant increase in their relative kidney and spleen weights. They also showed a significant increase in alanine aminotransferase (ALT, triglycerides and urea levels. Histopathological examination showed cytoplasmic degeneration and cell necrosis in the liver and kidney. Immunohistochemical examination showed that cerebellum illustrated several neurodegenerative changes and a down-regulation of synaptophysin-Syp. In conclusion, exposure to a high dose of SPD that is equal to 350 mg/kg could cause a marked toxicity on the liver, kidney and cerebellum in male albino mice.

  1. Effect of cadmium doses on chickens. 3. Long term influence of cadmium on feed consumption weight gain, egg performance and egg shell quality of laying hens

    Energy Technology Data Exchange (ETDEWEB)

    Suelz, M; Hardebeck, H; Krampitz, G

    1974-01-01

    In long-lasting experiments the application of Cd resulted in a decreased state of health (nephritis) of hens. Feed consumption, weight gain and egg production were reduced. Egg shell quality was not changed under practical Cd-concentrations. Studies of the ultrastructure of egg shells of animals fed with Cd did not yield any hints of damages. The protein-profiles of egg shells revealed an additional component under Cd-application. 17 references, 2 figures, 2 tables.

  2. Dose-response feeding study of short chain chlorinated paraffins (SCCPs) in laying hens: effects on laying performance and tissue distribution, accumulation and elimination kinetics.

    Science.gov (United States)

    Ueberschär, Karl-Heinz; Dänicke, Sven; Matthes, Siegfried

    2007-02-01

    Technical short chain chlorinated paraffins (C10-C13 with 60% chlorine) were fed to 93 laying hens from 24 to 32 weeks of age in increasing concentrations of up to 100 mg/kg feed. No significant influence on health, relative organ weights or performance (laying intensity, egg weight, feed consumption) was noted. The chlorinated paraffin content of the tissues was linearly related to the concentration of short chain paraffins of the feed. The highest concentrations were found in abdominal fat, egg yolk and fatty tissues. Breast muscle, egg albumen and bile fluid contained minimal or no residues. Less than 1% of the chlorinated paraffins ingested were incorporated into the body (without head, feet, gut and feathers), whereas about 1.5% were eliminated with the egg yolk and 30% were excreted with urine and faeces. A six-week kinetic depuration study revealed a biphasic elimination with half-lifes of 4-40 min (liver, kidneys, legs, fat, blood) for the initial rapid phase, and 15-30 days (blood, fat, liver, yolk, kidneys, legs) for the terminal slow phase.

  3. The effects of intraperitoneal administration of the GABA(B) receptor agonist baclofen on food intake in CFLP and C57BL/6 mice.

    Science.gov (United States)

    Ebenezer, Ivor S; Prabhaker, Monika

    2007-08-13

    The effects of the GABA(B) receptor agonist baclofen were investigated on food intake in non-deprived CFLP and C57BL/6 mice. In Experiment 1, baclofen (1-8 mg /kg) administered i.p. to CFLP mice, produced a dose-related increase in food intake. The 4 and 8 mg/kg doses produced significant increases in cumulative feeding when measure 120 min after administration (at least P GABA(B) agonist baclofen produces an increase in food consumption in two different strains of mice and extend previous observations made in rat to another rodent species.

  4. Toxicology study of senna (CAS No. 8013-11-4) in C57BL/6NTAC Mice and toxicology and carcinogenesis study of senna in genetically modified C3B6.129F1/Tac-Trp53tm1Brd haploinsufficient mice (Feed Studies).

    Science.gov (United States)

    2012-04-01

    Senna is used as a stimulant laxative in the management of constipation resulting from opioid use or when treatment with bulking or osmotic agents has failed. Increased use of senna was expected due to the removal of the stimulant laxatives danthron and phenolphthalein from the market. Senna was nominated for study by the Center for Drug Evaluation and Research, United States Food and Drug Administration (FDA) due to the wide use of laxative preparations, positive genotoxicity in vitro for some senna components or metabolites, and unknown carcinogenic potential. Because a 2-year rat study was ongoing by the manufacturer, the FDA requested that the NTP conduct a senna study in the p53(+/-) mouse. In this study, the potential for carcinogenic effects of senna was studied in the C3B6.129F1/Tac-Trp53tm1Brd N12 haploinsufficient (heterozygous F1 p53(+/-)) mouse model as an ongoing goal of the NTP to develop and test model systems for toxicology and carcinogenesis studies, especially those that can provide mechanistic information relative to understanding an agents mode of action. C57BL/6NTac mice were exposed to senna in feed for 5 weeks; heterozygous F1 p53(+/-) mice were exposed to senna in feed for 40 weeks. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes.

  5. Investigations on the influence of aminopropyl-aminoethyl-phosphorothioic acid on the radio-iron utilization after a whole-body irradiation of mice in the sublethal dose range

    International Nuclear Information System (INIS)

    Moenig, H.; Seiter, I.; Kofler, E.

    1975-01-01

    The effectiveness of the thiophosphate compound WR 2721 was investigated with regard to the radiosensitivity of X-irradiated female mice in the sublethal dose range of 50 to 150 R using the radioiron test ( 59 Fe). An increase of the radioresistance with regard to the radioiron uptake in young erythrocyte populations was obtained only beyond radiation doses of 75 R. In lower dose ranges the animals treated with thiophoshate became even more radiosensitive. At dose values of 100 R and 150 R dose reduction factors (DRF) of 1.3 and 1.5 respectively were obtained. These factors are considerably smaller than the DRF-values found for the survival rate at LDsub(50/30). A possible mechanism for this result may be due to the different dephosphorylation rate of the thiophosphate in various tissues, as described in literature. (orig.) [de

  6. Age-dependent effect of every-other-day feeding and aerobic exercise in ubiquinone levels and related antioxidant activities in mice muscle.

    Science.gov (United States)

    Rodríguez-Bies, Elizabeth; Navas, Plácido; López-Lluch, Guillermo

    2015-01-01

    Aging affects many biochemical, cellular, and physiological processes in the organisms. Accumulation of damage based on oxidized macromolecules is found in many age-associated diseases. Coenzyme Q (Q) is one of the main molecules involved in metabolic and antioxidant activities in cells. Q-dependent antioxidant activities are importantly involved on the protection of cell membranes against oxidation. Many studies indicate that Q decay in most of the organs during aging. In our study, no changes in Q levels were found in old animals in comparison with young animals. On the other hand, the interventions, caloric restriction based on every-other-day feeding procedure, and physical exercise were able to increase Q levels in muscle, but only in old and not in young animals. Probably, this effect prevented the increase in lipid peroxidation found in aged animals and also protein carbonylation. Further, Q-dependent antioxidant activities such as NADH-cytochrome b5 reductase and NAD(P)H-quinone oxidoreductase 1 are also modulated by both exercise and every other day feeding. Taken together, we demonstrate that exercise and dietary restriction as every-other-day procedure can regulate endogenous synthesized Q levels and Q-dependent antioxidant activities in muscle, preventing oxidative damage in aged muscle. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  7. Methylation changes in muscle and liver tissues of male and female mice exposed to acute and chronic low-dose X-ray-irradiation

    International Nuclear Information System (INIS)

    Kovalchuk, Olga; Burke, Paula; Besplug, Jill; Slovack, Mark; Filkowski, Jody; Pogribny, Igor

    2004-01-01

    The biological and genetic effects of chronic low-dose radiation (LDR) exposure and its relationship to carcinogenesis have received a lot of attention in the recent years. For example, radiation-induced genome instability, which is thought to be a precursor of tumorogenesis, was shown to have a transgenerational nature. This indicates a possible involvement of epigenetic mechanisms in LDR-induced genome instability. Genomic DNA methylation is one of the most important epigenetic mechanisms. Existing data on radiation effects on DNA methylation patterns is limited, and no one has specifically studied the effects of the LDR. We report the first study of the effects of whole-body LDR exposure on global genome methylation in muscle and liver tissues of male and female mice. In parallel, we evaluated changes in promoter methylation and expression of the tumor suppressor gene p16 INKa and DNA repair gene O 6 -methylguanine-DNA methyltransferase (MGMT). We observed different patterns of radiation-induced global genome DNA methylation in the liver and muscle of exposed males and females. We also found sex and tissue-specific differences in p16 INKa promoter methylation upon LDR exposure. In male liver tissue, p16 INKa promoter methylation was more pronounced than in female tissue. In contrast, no significant radiation-induced changes in p16 INKa promoter methylation were noted in the muscle tissue of exposed males and females. Radiation also did not significantly affect methylation status of MGMT promoter. We also observed substantial sex differences in acute and chronic radiation-induced expression of p16 INKa and MGMT genes. Another important outcome of our study was the fact that chronic low-dose radiation exposure proved to be a more potent inducer of epigenetic effects than the acute exposure. This supports previous findings that chronic exposure leads to greater genome destabilization than acute exposure

  8. Bacillus thuringiensis Cry5B protein is highly efficacious as a single-dose therapy against an intestinal roundworm infection in mice.

    Directory of Open Access Journals (Sweden)

    Yan Hu

    2010-03-01

    Full Text Available Intestinal parasitic nematode diseases are one of the great diseases of our time. Intestinal roundworm parasites, including hookworms, whipworms, and Ascaris, infect well over 1 billion people and cause significant morbidity, especially in children and pregnant women. To date, there is only one drug, albendazole, with adequate efficacy against these parasites to be used in mass drug administration, although tribendimidine may emerge as a second. Given the hundreds of millions of people to be treated, the threat of parasite resistance, and the inadequacy of current treatments, new anthelmintics are urgently needed. Bacillus thuringiensis (Bt crystal (Cry proteins are the most common used biologically produced insecticides in the world and are considered non-toxic to vertebrates.Here we study the ability of a nematicidal Cry protein, Cry5B, to effect a cure in mice of a chronic roundworm infection caused by the natural intestinal parasite, Heligmosomoides bakeri (formerly polygyrus. We show that Cry5B produced from either of two Bt strains can act as an anthelmintic in vivo when administered as a single dose, achieving a approximately 98% reduction in parasite egg production and approximately 70% reduction in worm burdens when delivered per os at approximately 700 nmoles/kg (90-100 mg/kg. Furthermore, our data, combined with the findings of others, suggest that the relative efficacy of Cry5B is either comparable or superior to current anthelmintics. We also demonstrate that Cry5B is likely to be degraded quite rapidly in the stomach, suggesting that the actual dose reaching the parasites is very small.This study indicates that Bt Cry proteins such as Cry5B have excellent anthelmintic properties in vivo and that proper formulation of the protein is likely to reveal a superior anthelmintic.

  9. Early-life lead exposure results in dose- and sex-specific effects on weight and epigenetic gene regulation in weanling mice

    Science.gov (United States)

    Faulk, Christopher; Barks, Amanda; Liu, Kevin; Goodrich, Jaclyn M; Dolinoy, Dana C

    2013-01-01

    Aims Epidemiological and animal data suggest that the development of adult chronic conditions is influenced by early-life exposure-induced changes to the epigenome. This study investigates the effects of perinatal lead (Pb) exposure on DNA methylation and bodyweight in weanling mice. Materials & methods Viable yellow agouti (Avy) mouse dams were exposed to 0, 2.1, 16 and 32 ppm Pb acetate before conception through weaning. Epigenetic effects were evaluated by scoring coat color of Avy/a offspring and quantitative bisulfite sequencing of two retrotransposon-driven (Avy and CDK5 activator-binding protein intracisternal A particle element) and two imprinted (Igf2 and Igf2r) loci in tail DNA. Results Maternal blood Pb levels were below the limit of detection in controls, and 4.1, 25.1 and 32.1 μg/dl for each dose, respectively. Pb exposure was associated with a trend of increased wean bodyweight in males (p = 0.03) and altered coat color in Avy/a offspring. DNA methylation at Avy and the CDK5 activator-binding protein intracisternal A-particle element was significantly different from controls following a cubic trend (p = 0.04; p = 0.01), with male-specific effects at the Avy locus. Imprinted genes did not shift in methylation across exposures. Conclusion Dose- and sex-specific responses in bodyweight and DNA methylation indicate that Pb acts on the epigenome in a locus-specific fashion, dependent on the genomic feature hosting the CpG site of interest, and that sex is a factor in epigenetic response. PMID:24059796

  10. Chronic Intake of Commercial Sweeteners Induces Changes in Feeding Behavior and Signaling Pathways Related to the Control of Appetite in BALB/c Mice.

    Science.gov (United States)

    Barrios-Correa, Alberto A; Estrada, José A; Martel, Caroline; Olivier, Martin; López-Santiago, Rubén; Contreras, Irazú

    2018-01-01

    Nonnutritive sweetener use is a common practice worldwide. Although considered safe for human consumption, accumulating evidence suggests these compounds may affect metabolic homeostasis; however, there is no consensus on the role of frequent sweetener intake in appetite and weight loss. We sought to determine whether frequent intake of commercial sweeteners induces changes in the JAK2/STAT3 signaling pathway in the brain of mice, as it is involved in the regulation of appetite and body composition. We supplemented adult BALB/c mice with sucrose, steviol glycosides (SG), or sucralose, daily, for 6 weeks. After supplementation, we evaluated body composition and expression of total and phosphorylated JAK2, STAT3, and Akt, as well as SOCS3 and ObRb, in brain tissue. Our results show that frequent intake of commercial SG decreases energy intake, adiposity, and weight gain in male animals, while increasing the expression of pJAK2 and pSTAT3 in the brain, whereas sucralose increases weight gain and pJAK2 expression in females. Our results suggest that chronic intake of commercial sweeteners elicits changes in signaling pathways that have been related to the control of appetite and energy balance in vivo , which may have relevant consequences for the nutritional state and long term health of the organism.

  11. Sequence-dependent toxicity and small bowel mucosal injury in neonatal mice treated with low doses of 5-azacytidine and X-irradiation at the late organogenesis stage

    International Nuclear Information System (INIS)

    Schmahl, W.

    1983-01-01

    A combined treatment of pregnant mice on day 12 of gestation with both azacytidine and X-irradiation in low doses induces sequence-dependent histological effects. These effects, in turn, induce different symptomatic signs if evaluated either prenatally or neonatally. In the azacytidine treatment/X-irradiation sequence the malformations of the fetal forebrain are predominant. Consequently, these dams show a high incidence in the stillbirth rate. Conversely, the X-irradiation/azacytidine treatment schedule leads only to a mild brain hypoplasia, and does not cause an increased stillbirth rate. In these offspring, however, a severe impairment of small bowel epithelial proliferation capacity was found. This is linked to an outstanding neonatal mortality within 48 h after birth. The pathogenesis of these sequence-dependent effects can be attributed to a selective vulnerability of cells in different stages of the generation cycle. This comprises a high degree of cytolethality affecting the S/G 2 -stage cells in azacytidine/X-irradiation treatment and the G 1 /S-stage cells in the reverse combinations (Schmahl 1979). The present observations show the validity of a teratological assay in providing a detailed analysis of the cell kinetic responses after combined noxious influences. (orig.)

  12. Low doses of 17α-ethinyl estradiol alter the maternal brain and induce stereotypies in CD-1 mice exposed during pregnancy and lactation.

    Science.gov (United States)

    Catanese, Mary C; Vandenberg, Laura N

    2017-10-01

    Maternal care is critical for the survival, development and long-term success of offspring. Despite our current understanding of the role of endogenous estrogen in both maternal behavior and the maternal brain, the potential effects of exogenous estrogens on these endpoints remain poorly understood. Here, pregnant CD-1 mice were exposed to low doses of 17α-ethinyl estradiol (EE2), commonly used as a positive control in studies of other xenoestrogens, from day 9 of pregnancy until weaning. Using traditional maternal behavior assays, we document no significant changes in maternal behavior throughout the lactational period. However, EE2 induced increases in repetitive tail retrieval, which may indicate a stereotypy or obsessive compulsive (OCD)-like behavior. We also observed a significant reduction in tyrosine hydroxylase (TH) immunoreactivity in the ventral tegmental area (VTA), a region important for maternal motivation. These results suggest that pregnant adult females are not immune to the effects of this compound. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. The effect of chronic low-dose UVB radiation on Langerhans cells, sunburn cells, urocanic acid isomers, contact hypersensitivity and serum immunoglobulins in mice

    International Nuclear Information System (INIS)

    El-Ghorr, A.A.; Norval, M.; Lappin, M.B.

    1995-01-01

    C3H mice were irradiated three times a week for up to 6 weeks with either 500 J/m 2 or 1000 J/m 2 broadband UVB (270-350 nm) or 3000 J/m 2 narrowband UVB (311-312 nm; TL01 source). Each dose was suberythemal to the mouse strain used. The number of Langerhans cells (LC) in the epidermis was reduced by over 50% after 2 weeks of irradiation with the UVB source and by 20% following TL01 irradiation. Continued irradiation for up to 6 weeks resulted in no further decrease in LC numbers in the case of the UVB source but a steady decline to 40% in the case of the TL01 source. Sunburn cells were detected following irradiation with both sources but the numbers were very low in comparison with acute exposure. Ultraviolet-B exposure resulted in doubling of the thickness of the epidermis throughout the 6 weeks of irradiation while TL01 exposure did not alter epidermal thickness. Conversion of trans- to cis-urocanic acid (UCA) was observed with both UVB and TL01 sources. The percentage of cis-UCA started to return to normal after 4 weeks of TL01 exposure despite continued irradiation. As observed following a single exposure, the contact hypersensitivity (CH) response was significantly reduced following 6 weeks of UVB irradiation but was unaffected by TL01 exposure, indicating no correlation between cis-UCA levels and CH response. (author)

  14. Systemic response of Korean dark-striped field mice, Apodenmus agrarius coreae after high-dose- rate γ-irradiation: Organ weights, hemato-chemistry, apoptosis of splenocytes and sperm

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Kwang Hee; Choi, Hoon; Joo, Hyun Jin; Kim, Hee Sun [Radiation Health Research Institute, KHNP, Gyeongju (Korea, Republic of); Keum, Dong Kwon [Nuclear Environment Research Division, Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2014-11-15

    Since the territory of the radio-contaminated area is in homeogenous in radiation level and spectrum, investigation of the genetical mutation process in the natural animal populations inhabiting the radioontaminated areas will be provide a realistic picture of genetic effects for radiation exposure. However, little is known about the basic data such as systemic responses after ionizing radiation exposures in wild small rodents. Taking into account different radio-sensitivity of dark-striped field mice (A. a. coreae, THOMAS), the objective of the study is focus on investigate the level of systemic responses, included organ weights, hemato-chemistry and apoptosis in splenocytes and sperm of caudal epididymis after high-dose-rate irradiation especially as a potential biological dosimeter in radio-ecology. Figure 1 summarizes the results of the apoptotic events in spleen (data not shown at here) and in sperm of caudal epididymis at 24hrs after a single high-dose-rate γ-irradiation. The results of apoptosis in spleen and sperm caused by exposure to different doses of γ-irradiation are displayed. The data show that the field striped mice after irradiated with more than high dose of 0.5 Gy induces an significantly increased apoptosis. Results also shown that for exposure to 0.5 Gy, the apoptosis of both organs ware decreased compared to those of other γ-irradiated mice.

  15. Effect of time interval between the second Improvest® dose and slaughter and corn dried distillers grains with solubles feeding strategies on carcass composition, primal cutout, and pork quality of immunologically castrated pigs.

    Science.gov (United States)

    Harris, E K; Mellencamp, M A; Johnston, L J; Cox, R B; Shurson, G C

    2017-05-01

    Effects of dried distillers grains with solubles (DDGS) feeding strategies on carcass composition, primal cutout, and lean quality of immunologically castrated (IC; n=863) pigs were evaluated, and consisted of: 1) corn-soybean meal (CS) diet (PCon); 2) CS+40% DDGS (NCon); 3) CS+40, 30, 20, or 10% DDGS fed in phases 1 to 4, respectively (SD); or 4) CS+40% DDGS fed in phase 1 to 3 and CS in phase 4 (WD). All pigs received the first dose of Improvest® at 11weeks. of age, and the second dose was administered at either 9, 7, or 5weeks. before slaughter at 24weeks. of age. The SD and WD improved carcass dressing percentage and resulted in intermediate primal cut yields and pork loin quality compared with pigs fed PCon and NCon. Increasing the time interval between second dose of Improvest® and slaughter increased adipose tissue accretion but did not affect lean quality of pork. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. WE-FG-BRA-10: Radiodosimetry of a Novel Alpha Particle Therapy Targeted to Uveal Melanoma: Absorbed Dose to Organs in Mice

    Energy Technology Data Exchange (ETDEWEB)

    Tichacek, Christopher J.; Tafreshi, Narges K.; Budzevich, Mikalai M.; Ruiz, Epifanio [Small Animal Imaging Core, Tampa, FL (United States); Wadas, Thaddeus J. [Wake Forest School of Medicine, Departments of Radiology and Cancer Biology, Winston-Salem, NC (United States); McLaughlin, Mark L. [Department of Chemistry, Tampa, FL (United States); H. Lee Moffitt Cancer Center & Research Institute (United States); Modulation Therapeutics, Inc., Tampa, FL (United States); Moros, Eduardo G.; Morse, David L.

    2016-06-15

    Purpose: The melanocortin-1 receptor (MC1R) is expressed in 94% of uveal melanomas and is described as an ideal target for this untreatable disease. MC1RL is a high affinity MC1R specific peptidomimetic ligand that can serve as a scaffold for therapeutic conjugates such as alpha particle emitting isotopes. The purpose of this study was to assess normal tissue distribution and risk as a result of using the DOTA chelator conjugated to MC1RL to deliver {sup 225}Ac: MC1RL-DOTA-{sup 225}Ac. Methods: 17 non-tumor bearing BALB/c mice were intravenously injected with the novel MC1RL-DOTA-{sup 225}Ac radiopharmaceutical with an average initial administered activity of 2.5 µCi. After the injection, three groups of animals (6, 6, and 5 per group) were euthanized at 24, 48, and 96 hour time points. A total of 11 organs of interest were harvested at each time point including kidneys and liver. Since the emitted alpha particles from {sup 225}Ac and its daughter products are not easy to detect directly, the isomeric gamma spectra were measured instead in the tissue samples using a modified Atomlab™ Gamma Counter (Biodex Medical Systems, Inc) and converted using factors for gamma ray abundance per alpha decay. Dosimetry was performed using measured radioactivity distribution in organs and the generalized internal dosimetry schema of MIRD pamphlet #21. Results: Our calculations have shown that the maximum absorbed dose was delivered to the liver with a total of 47 cGy per 96 hour period. The average dose per kidney was calculated to be 21 cGy. Heart, brain, lung, spleen, skin doses ranged from 0.01 to 1 cGy over the same time period. All animals gained weight over the 110 day decay period and no organ damage was observed by pathology. Conclusion: Based on our results, the risk of using the MC1RL-DOTA-{sup 225}Ac compound is relatively small in terms of deterministic radiation effects. Funding Support: NIH/NCI P50CA168536-03 Skin SPORE; NIH/NCI Phase I SBIR Contract #HHSN

  17. Enhanced sensitivity to low dose irradiation of ApoE-/- mice mediated by early pro-inflammatory profile and delayed activation of the TGFβ1 cascade involved in fibrogenesis.

    Directory of Open Access Journals (Sweden)

    Virginie Monceau

    Full Text Available AIM: Investigating long-term cardiac effects of low doses of ionizing radiation is highly relevant in the context of interventional cardiology and radiotherapy. Epidemiological data report that low doses of irradiation to the heart can result in significant increase in the cardiovascular mortality by yet unknown mechanisms. In addition co-morbidity factor such as hypertension or/and atherosclerosis can enhance cardiac complications. Therefore, we explored the mechanisms that lead to long-term cardiac remodelling and investigated the interaction of radiation-induced damage to heart and cardiovascular systems with atherosclerosis, using wild-type and ApoE-deficient mice. METHODS AND RESULTS: ApoE-/- and wild-type mice were locally irradiated to the heart at 0, 0.2 and 2 Gy (RX. Twenty, 40 and 60 weeks post-irradiation, echocardiography were performed and hearts were collected for cardiomyocyte isolation, histopathological analysis, study of inflammatory infiltration and fibrosis deposition. Common and strain-specific pathogenic pathways were found. Significant alteration of left ventricular function (eccentric hypertrophy occurred in both strains of mice. Low dose irradiation (0.2 Gy induced premature death in ApoE-/- mice (47% died at 20 weeks. Acute inflammatory infiltrate was observed in scarring areas with accumulation of M1-macrophages and secretion of IL-6. Increased expression of the fibrogenic factors (TGF-β1 and PAI-1 was measured earlier in cardiomyocytes isolated from ApoE-/- than in wt animals. CONCLUSION: The present study shows that cardiac exposure to low dose of ionizing radiation induce significant physiological, histopathological, cellular and molecular alterations in irradiated heart with mild functional impairment. Atherosclerotic predisposition precipitated cardiac damage induced by low doses with an early pro-inflammatory polarization of macrophages.

  18. The therapeutic effect of a preparation extracted from tremella fuciformic berk (TFP) on the hematopoietic residual injury in mice induced by fractionated doses of 60Co γ-ray exposures

    International Nuclear Information System (INIS)

    Lu Shaoping; Yang Fengtong; Xu Chengxiong

    1989-01-01

    Hematopoietic residual injury, which is identified by the permanent defect of the blood forming system, could be induced in mice by repeated sublethal 60 Co γ-ray exposures. The number of hematopoietic stem cells (CFU-S) in mouse femora could be enhanced to a normal or near normal level if the 3 or 5 doses of 4.0 Gy irradiated mice were treated with a preparation extracted from an edible fungus Tremella Fuciformis Berk (TFP) 2 months after the irradiation. The number of endogenous spleen colonies and the spleen weight also increased markedly after the treatment. Because of the similarity found in the changes of hemaopoietic functions between the mice of residual injury and the patients of aplastic anemia, it is suggested that TFP may be useful to the patients of such blood disorder

  19. Ribosomal S6K1 in POMC and AgRP Neurons Regulates Glucose Homeostasis but Not Feeding Behavior in Mice

    Directory of Open Access Journals (Sweden)

    Mark A. Smith

    2015-04-01

    Full Text Available Hypothalamic ribosomal S6K1 has been suggested as a point of convergence for hormonal and nutrient signals in the regulation of feeding behavior, bodyweight, and glucose metabolism. However, the long-term effects of manipulating hypothalamic S6K1 signaling on energy homeostasis and the cellular mechanisms underlying these roles are unclear. We therefore inactivated S6K1 in pro-opiomelanocortin (POMC and agouti-related protein (AgRP neurons, key regulators of energy homeostasis, but in contrast to the current view, we found no evidence that S6K1 regulates food intake and bodyweight. In contrast, S6K1 signaling in POMC neurons regulated hepatic glucose production and peripheral lipid metabolism and modulated neuronal excitability. S6K1 signaling in AgRP neurons regulated skeletal muscle insulin sensitivity and was required for glucose sensing by these neurons. Our findings suggest that S6K1 signaling is not a general integrator of energy homeostasis in the mediobasal hypothalamus but has distinct roles in the regulation of glucose homeostasis by POMC and AgRP neurons.

  20. Ribosomal S6K1 in POMC and AgRP Neurons Regulates Glucose Homeostasis but Not Feeding Behavior in Mice.

    Science.gov (United States)

    Smith, Mark A; Katsouri, Loukia; Irvine, Elaine E; Hankir, Mohammed K; Pedroni, Silvia M A; Voshol, Peter J; Gordon, Matthew W; Choudhury, Agharul I; Woods, Angela; Vidal-Puig, Antonio; Carling, David; Withers, Dominic J

    2015-04-21

    Hypothalamic ribosomal S6K1 has been suggested as a point of convergence for hormonal and nutrient signals in the regulation of feeding behavior, bodyweight, and glucose metabolism. However, the long-term effects of manipulating hypothalamic S6K1 signaling on energy homeostasis and the cellular mechanisms underlying these roles are unclear. We therefore inactivated S6K1 in pro-opiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, key regulators of energy homeostasis, but in contrast to the current view, we found no evidence that S6K1 regulates food intake and bodyweight. In contrast, S6K1 signaling in POMC neurons regulated hepatic glucose production and peripheral lipid metabolism and modulated neuronal excitability. S6K1 signaling in AgRP neuron