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Sample records for 2-knockout mice exposed

  1. Sleep in Kcna2 knockout mice

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    Messing Albee

    2007-10-01

    Full Text Available Abstract Background Shaker codes for a Drosophila voltage-dependent potassium channel. Flies carrying Shaker null or hypomorphic mutations sleep 3–4 h/day instead of 8–14 h/day as their wild-type siblings do. Shaker-like channels are conserved across species but it is unknown whether they affect sleep in mammals. To address this issue, we studied sleep in Kcna2 knockout (KO mice. Kcna2 codes for Kv1.2, the alpha subunit of a Shaker-like voltage-dependent potassium channel with high expression in the mammalian thalamocortical system. Results Continuous (24 h electroencephalograph (EEG, electromyogram (EMG, and video recordings were used to measure sleep and waking in Kcna2 KO, heterozygous (HZ and wild-type (WT pups (P17 and HZ and WT adult mice (P67. Sleep stages were scored visually based on 4-s epochs. EEG power spectra (0–20 Hz were calculated on consecutive 4-s epochs. KO pups die by P28 due to generalized seizures. At P17 seizures are either absent or very rare in KO pups ( Conclusion Kv1.2, a mammalian homologue of Shaker, regulates neuronal excitability and affects NREM sleep.

  2. Subchronic exposure to ethyl tertiary butyl ether resulting in genetic damage in Aldh2 knockout mice.

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    Weng, Zuquan; Suda, Megumi; Ohtani, Katsumi; Mei, Nan; Kawamoto, Toshihiro; Nakajima, Tamie; Wang, Rui-Sheng

    2013-09-15

    Ethyl tertiary butyl ether (ETBE) is biofuel additive recently used in Japan and some other countries. Limited evidence shows that ETBE has low toxicity. Acetaldehyde (AA), however, as one primary metabolite of ETBE, is clearly genotoxic and has been considered to be a potential carcinogen. The aim of this study was to evaluate the effects of ALDH2 gene on ETBE-induced genotoxicity and metabolism of its metabolites after inhalation exposure to ETBE. A group of wild-type (WT) and Aldh2 knockout (KO) C57BL/6 mice were exposed to 500ppm ETBE for 1-6h, and the blood concentrations of ETBE metabolites, including AA, tert-butyl alcohol and 2-methyl-1,2-propanediol, were measured. Another group of mice of WT and KO were exposed to 0, 500, 1750, or 5000ppm ETBE for 6h/day with 5 days per weeks for 13 weeks. Genotoxic effects of ETBE in these mice were measured by the alkaline comet assay, 8-hydroxyguanine DNA-glycosylase modified comet assay and micronucleus test. With short-term exposure to ETBE, the blood concentrations of all the three metabolites in KO mice were significantly higher than the corresponding concentrations of those in WT mice of both sexes. After subchronic exposure to ETBE, there was significant increase in DNA damage in a dose-dependent manner in KO male mice, while only 5000ppm exposure significantly increased DNA damage in male WT mice. Overall, there was a significant sex difference in genetic damage in both genetic types of mice. These results showed that ALDH2 is involved in the detoxification of ETBE and lack of enzyme activity may greatly increase the sensitivity to the genotoxic effects of ETBE, and male mice were more sensitive than females.

  3. Expression of PPARα modifies fatty acid effects on insulin secretion in uncoupling protein-2 knockout mice

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    Chan Catherine B

    2007-03-01

    Full Text Available Abstract Aims/hypothesis In uncoupling protein-2 (UCP2 knockout (KO mice, protection of beta cells from fatty acid exposure is dependent upon transcriptional events mediated by peroxisome proliferator-activated receptor-α (PPARα. Methods PPARα expression was reduced in isolated islets from UCP2KO and wild-type (WT mice with siRNA for PPARα (siPPARα overnight. Some islets were also cultured with oleic or palmitic acid, then glucose stimulated insulin secretion (GSIS was measured. Expression of genes was examined by quantitative RT-PCR or immunoblotting. PPARα activation was assessed by oligonucleotide consensus sequence binding. Results siPPARα treatment reduced PPARα protein expression in KO and WT islets by >85%. In siPPARα-treated UCP2KO islets, PA but not OA treatment significantly decreased the insulin response to 16.5 mM glucose. In WT islets, siPPARα treatment did not modify GSIS in PA and OA exposed groups. In WT islets, PA treatment significantly increased UCP2 mRNA and protein expression. Both PA and OA treatment significantly increased PPARα expression in UCP2KO and WT islets but OA treatment augmented PPARα protein expression only in UCP2KO islets (p Conclusion These data show that the negative effect of saturated fatty acid on GSIS is mediated by PPARα/UCP2. Knockout of UCP2 protects beta-cells from PA exposure. However, in the absence of both UCP2 and PPARα even a short exposure (24 h to PA significantly impairs GSIS.

  4. Altered Expression of EPO Might Underlie Hepatic Hemangiomas in LRRK2 Knockout Mice.

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    Wu, Ben; Xiao, Kaifu; Zhang, Zhuohua; Ma, Long

    2016-01-01

    Parkinson's disease (PD) is a severe neurodegenerative disorder caused by progressive loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. The molecular mechanism of PD pathogenesis is unclear. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common genetic cause of familial and sporadic PD. However, studies on LRRK2 mutant mice revealed no visible dopaminergic neuronal loss in the midbrain. While surveying a LRRK2 knockout mouse strain, we found that old animals developed age-dependent hepatic vascular growths similar to cavernous hemangiomas. In livers of these hemangioma-positive LRRK2 knockout mice, we detected an increased expression of the HIF-2α protein and significant reactivation of the expression of the HIF-2α target gene erythropoietin (EPO), a finding consistent with a role of the HIF-2α pathway in blood vessel vascularization. We also found that the kidney EPO expression was reduced to 20% of the wild-type level in 18-month-old LRRK2 knockout mice. Unexpectedly, this reduction was restored to wild-type levels when the knockout mice were 22 months to 23 months old, implying a feedback mechanism regulating kidney EPO expression. Our findings reveal a novel function of LRRK2 in regulating EPO expression and imply a potentially novel relationship between PD genes and hematopoiesis.

  5. Gliosis after traumatic brain injury in conditional ephrinB2-knockout mice

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    LIU Ling; CHEN Xiao-lin; YANG Jian-kai; REN Ze-guang; WANG Shuo

    2012-01-01

    Background In response to the injury of the central nervous system (CNS),the astrocytes upregulate the expression of glial fibrillary acidic protein (GFAP),which largely contributes to the reactive gliosis after brain injury.The regulatory mechanism of this process is still not clear.In this study,we aimed to compare the ephrin-B2 deficient mice with the wild type ones with regard to gliosis after traumatic brain injury.Methods We generated ephrin-B2 knockout mice specifically in CNS astrocytes.Twelve mice from this gene-knockout strain were randomly selected along with twelve mice from the wild type littermates.In both groups,a modified controlled cortical impact injury model was applied to create a closed traumatic brain injury.Twenty-eight days after the injury,Nissl staining and GFAP immunofluorescence staining were used to compare the brain atrophy and GFAP immunoreactivity between the two groups.All the data were analyzed by t-test for between-group comparison.Results We successfully set up the conditional ephrin-B2 knockout mice strain,which was confirmed by genotyping and ephrin-B2/GFAP double staining.These mice developed normally without apparent abnormality in general appearance.Twenty-eight days following brain injury,histopathology revealed by immunohistochemistry showed different degrees of cerebral injuries in both groups.Compared with wild-type group,the ephrin-B2 knockout group exhibited less brain atrophy ratio for the injured hemispheres (P=0.005) and hippocampus (P=0.027).Also the wild-type group demonstrated greater GFAP immunoreactivity increment within hippocampal regions (P=0.008).Conclusions The establishment of conditional ephrin-B2 knockout mice provides us with a new way to explore the role of ephrin-B2 in astrocytes.Our findings revealed less atrophy and GFAP immunoreactivity in the knockout mice strain after traumatic brain injury,which implied ephrin-B2 could be one of the promoters to upregulate gliosis following brain injury.

  6. CXCR2 knockout mice are protected against DSS-colitis-induced acute kidney injury and inflammation.

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    Ranganathan, Punithavathi; Jayakumar, Calpurnia; Manicassamy, Santhakumar; Ramesh, Ganesan

    2013-11-15

    Organ cross talk exists in many diseases of the human and animal models of human diseases. A recent study demonstrated that inflammatory mediators can cause acute kidney injury and neutrophil infiltration in a mouse model of dextran sodium sulfate (DSS)-colitis. However, the chemokines and their receptors that may mediate distant organ effects in colitis are unknown. We hypothesized that keratinocyte chemoattractant (KC)/IL-8 receptor chemokine (C-X-C motif) ligand 2 (CXCL2) mediates DSS-colitis-induced acute kidney injury. Consistent with our hypothesis, wild-type (WT) mice developed severe colitis with DSS treatment, which was associated with inflammatory cytokine and chemokine expression and neutrophil infiltration in the colon. DSS-colitis in WT was accompanied by acute kidney injury and enhanced expression of inflammatory cytokines in the kidney. However, CXCR2 knockout mice were protected against DSS-colitis as well as acute kidney injury. Moreover, the expression of cytokines and chemokines and neutrophil infiltration was blunted in CXCR2 knockout mice in the colon and kidney. Administration of recombinant KC exacerbated DSS-colitis-induced acute kidney injury. Our results suggest that KC/IL-8 and its receptor CXCR2 are critical and major mediators of organ cross talk in DSS colitis and neutralization of CXCR2 will help to reduce the incidence of acute kidney injury due to ulcerative colitis and Crohn's disease in humans.

  7. Alleviation of high-fat diet-induced fatty liver damage in group IVA phospholipase A2-knockout mice.

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    Ii, Hiromi; Yokoyama, Naoki; Yoshida, Shintaro; Tsutsumi, Kae; Hatakeyama, Shinji; Sato, Takashi; Ishihara, Keiichi; Akiba, Satoshi

    2009-12-01

    Hepatic fat deposition with hepatocellular damage, a feature of non-alcoholic fatty liver disease, is mediated by several putative factors including prostaglandins. In the present study, we examined whether group IVA phospholipase A(2) (IVA-PLA(2)), which catalyzes the first step in prostanoid biosynthesis, is involved in the development of fatty liver, using IVA-PLA(2)-knockout mice. Male wild-type mice on high-fat diets (20% fat and 1.25% cholesterol) developed hepatocellular vacuolation and liver hypertrophy with an increase in the serum levels of liver damage marker aminotransferases when compared with wild-type mice fed normal diets. These high-fat diet-induced alterations were markedly decreased in IVA-PLA(2)-knockout mice. Hepatic triacylglycerol content was lower in IVA-PLA(2)-knockout mice than in wild-type mice under normal dietary conditions. Although high-fat diets increased hepatic triacylglycerol content in both genotypes, the degree was lower in IVA-PLA(2)-knockout mice than in wild-type mice. Under the high-fat dietary conditions, IVA-PLA(2)-knockout mice had lower epididymal fat pad weight and smaller adipocytes than wild-type mice. The serum level of prostaglandin E(2), which has a fat storage effect, was lower in IVA-PLA(2)-knockout mice than in wild-type mice, irrespective of the kind of diet. In both genotypes, high-fat diets increased serum leptin levels equally between the two groups, but did not affect the serum levels of adiponectin, resistin, free fatty acid, triacylglycerol, glucose, or insulin. Our findings suggest that a deficiency of IVA-PLA(2) alleviates fatty liver damage caused by high-fat diets, probably because of the lower generation of IVA-PLA(2) metabolites, such as prostaglandin E(2). IVA-PLA(2) could be a promising therapeutic target for obesity-related diseases including non-alcoholic fatty liver disease.

  8. Hesr2 knockout mice develop aortic valve disease with advancing age.

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    Kokubo, Hiroki; Miyagawa-Tomita, Sachiko; Nakashima, Yasumi; Kume, Tsutomu; Yoshizumi, Masao; Nakanishi, Toshio; Saga, Yumiko

    2013-03-01

    Acquired heart diseases, such as valve disease, are major causes of human morbidity and mortality. However, the pathological mechanisms underlying these diseases are largely unknown. Our aim is to identify the role of the hairy and enhancer of split-related (Hesr)-2 gene in the adult heart. Echocardiography detected heart dysfunctions indicative of aortic valve anomalies, stenosis, and regurgitation, in ≈59% of >12-month-old Hesr2 knockout survivor mice. Morphological and histological analyses revealed thickened semilunar valves with increased fibrotic areas, indicating that sclerotic degeneration of valves is the main cause of aortic valve disease. The expression of osteogenic genes, such as osteopontin and sclerostin, were upregulated in the mutants, and the overexpression of sclerostin in endothelial cells resulted in thickened semilunar valves with increased fibrotic areas, similar to that seen in the Hesr2 knockout mice, suggesting that Hesr2 can regulate osteogenic gene expression in valves. Reduced left ventricular function, which may be caused by increased ventricular interstitial fibrosis, and enlarged myocardial cell size without ventricular wall thickening were found in both aortic valve stenosis/regurgitation-positive (33%) and aortic valve stenosis/regurgitation-negative (38%) subpopulations in 12-month-old survivor mice. Dilated left ventricular internal dimensions were specifically detected in the aortic valve stenosis/regurgitation-positive subpopulation, thus suggesting that the degeneration of cardiomyocytes is influenced by irregular hemodynamics. These data revealed that survivor mice lacking the Hesr2 gene exhibit fibrosis in the aortic valve and ventricle in adulthood, thus suggesting that Hesr2 plays an important role in maintaining the homeostasis of the aortic valve and ventricle.

  9. Metabolism and tissue distribution of sulforaphane in Nrf2 knockout and wild-type mice.

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    Clarke, John D; Hsu, Anna; Williams, David E; Dashwood, Roderick H; Stevens, Jan F; Yamamoto, Masayuki; Ho, Emily

    2011-12-01

    To determine the metabolism and tissue distribution of the dietary chemoprotective agent sulforaphane following oral administration to wild-type and Nrf2 knockout (Nrf2(-/-)) mice. Male and female wild-type and Nrf2(-/-) mice were given sulforaphane (5 or 20 μmoles) by oral gavage; plasma, liver, kidney, small intestine, colon, lung, brain and prostate were collected at 2, 6 and 24 h (h). The five major metabolites of sulforaphane were measured in tissues by high performance liquid chromatography coupled with tandem mass spectrometry. Sulforaphane metabolites were detected in all tissues at 2 and 6 h post gavage, with the highest concentrations in the small intestine, prostate, kidney and lung. A dose-dependent increase in sulforaphane concentrations was observed in all tissues except prostate. At 5 μmole, Nrf2(-/-) genotype had no effect on sulforaphane metabolism. Only Nrf2(-/-) females given 20 μmoles sulforaphane for 6 h exhibited a marked increase in tissue sulforaphane metabolite concentrations. The relative abundance of each metabolite was not strikingly different between genders and genotypes. Sulforaphane is metabolized and reaches target tissues in wild-type and Nrf2(-/-) mice. These data provide further evidence that sulforaphane is bioavailable and may be an effective dietary chemoprevention agent for several tissue sites.

  10. Brain-derived neurotrophic factor signaling is altered in the forebrain of Engrailed-2 knockout mice.

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    Zunino, G; Messina, A; Sgadò, P; Baj, G; Casarosa, S; Bozzi, Y

    2016-06-02

    Engrailed-2 (En2), a homeodomain transcription factor involved in regionalization and patterning of the midbrain and hindbrain regions has been associated to autism spectrum disorders (ASDs). En2 knockout (En2(-/-)) mice show ASD-like features accompanied by a significant loss of GABAergic subpopulations in the hippocampus and neocortex. Brain-derived neurotrophic factor (BDNF) is a crucial factor for the postnatal development of forebrain GABAergic neurons, and altered GABA signaling has been hypothesized to underlie the symptoms of ASD. Here we sought to determine whether interneuron loss in the En2(-/-) forebrain might be related to altered expression of BDNF and its signaling receptors. We first evaluated the expression of different BDNF mRNA isoforms in the neocortex and hippocampus of wild-type (WT) and En2(-/-) mice. Quantitative RT-PCR showed a marked down-regulation of several splicing variants of BDNF mRNA in the neocortex but not hippocampus of adult En2(-/-) mice, as compared to WT controls. Accordingly, levels of mature BDNF protein were lower in the neocortex but not hippocampus of En2(-/-) mice, as compared to WT. Increased levels of phosphorylated TrkB and decreased levels of p75 receptor were also detected in the neocortex of mutant mice. Accordingly, the expression of low density lipoprotein receptor (LDLR) and RhoA, two genes regulated via p75 was significantly altered in forebrain areas of mutant mice. These data indicate that BDNF signaling alterations might be involved in the anatomical changes observed in the En2(-/-) forebrain and suggest a pathogenic role of altered BDNF signaling in this mouse model of ASD.

  11. Lipidomic profiling of tryptophan hydroxylase 2 knockout mice reveals novel lipid biomarkers associated with serotonin deficiency.

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    Weng, Rui; Shen, Sensen; Burton, Casey; Yang, Li; Nie, Honggang; Tian, Yonglu; Bai, Yu; Liu, Huwei

    2016-04-01

    Serotonin is an important neurotransmitter that regulates a wide range of physiological, neuropsychological, and behavioral processes. Consequently, serotonin deficiency is involved in a wide variety of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, schizophrenia, and depression. The pathophysiological mechanisms underlying serotonin deficiency, particularly from a lipidomics perspective, remain poorly understood. This study therefore aimed to identify novel lipid biomarkers associated with serotonin deficiency by lipidomic profiling of tryptophan hydroxylase 2 knockout (Tph2-/-) mice. Using a high-throughput normal-/reversed-phase two-dimensional liquid chromatography-quadrupole time-of-flight mass spectrometry (NP/RP 2D LC-QToF-MS) method, 59 lipid biomarkers encompassing glycerophospholipids (glycerophosphocholines, lysoglycerophosphocholines, glycerophosphoethanolamines, lysoglycerophosphoethanolamines glycerophosphoinositols, and lysoglycerophosphoinositols), sphingolipids (sphingomyelins, ceramides, galactosylceramides, glucosylceramides, and lactosylceramides) and free fatty acids were identified. Systemic oxidative stress in the Tph2-/- mice was significantly elevated, and a corresponding mechanism that relates the lipidomic findings has been proposed. In summary, this work provides preliminary findings that lipid metabolism is implicated in serotonin deficiency.

  12. LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors

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    Hinkle Kelly M

    2012-05-01

    Full Text Available Abstract Mutations in the LRRK2 gene are the most common cause of genetic Parkinson’s disease. Although the mechanisms behind the pathogenic effects of LRRK2 mutations are still not clear, data emerging from in vitro and in vivo models suggests roles in regulating neuronal polarity, neurotransmission, membrane and cytoskeletal dynamics and protein degradation. We created mice lacking exon 41 that encodes the activation hinge of the kinase domain of LRRK2. We have performed a comprehensive analysis of these mice up to 20 months of age, including evaluation of dopamine storage, release, uptake and synthesis, behavioral testing, dendritic spine and proliferation/neurogenesis analysis. Our results show that the dopaminergic system was not functionally comprised in LRRK2 knockout mice. However, LRRK2 knockout mice displayed abnormal exploratory activity in the open-field test. Moreover, LRRK2 knockout mice stayed longer than their wild type littermates on the accelerated rod during rotarod testing. Finally, we confirm that loss of LRRK2 caused degeneration in the kidney, accompanied by a progressive enhancement of autophagic activity and accumulation of autofluorescent material, but without evidence of biphasic changes.

  13. Hepatic Gene Expression Profiling in Nrf2 Knockout Mice after Long-Term High-Fat Diet-Induced Obesity

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    Dionysios V. Chartoumpekis

    2013-01-01

    Full Text Available Introduction. The transcription factor NFE2-related factor 2 (Nrf2 is a central regulator of antioxidant and detoxification gene expression in response to electrophilic or oxidative stress. Nrf2 has recently been shown to cross-talk with metabolic pathways, and its gene deletion protected mice from high-fat-diet-(HFD- induced obesity and insulin resistance. This study aimed to identify potential Nrf2-regulated genes of metabolic interest by comparing gene expression profiles of livers of wild-type (WT versus Nrf2 knockout (Nrf2-KO mice after a long-term HFD. Methods. WT and Nrf2-KO mice were fed an HFD for 180 days; total RNA was prepared from liver and used for microarray analysis and quantitative real-time RT-PCR (qRT-PCR. Results. The microarray analysis identified 601 genes that were differentially expressed between WT and Nrf2-KO mice after long-term HFD. Selected genes, including ones known to be involved in metabolic regulation, were prioritized for verification by qRT-PCR: Cyp7a1 and Fabp5 were significantly overexpressed in Nrf2-KO mice; in contrast, Car, Cyp2b10, Lipocalin 13, Aquaporin 8, Cbr3, Me1, and Nqo1 were significantly underexpressed in Nrf2-KO mice. Conclusion. Transcriptome profiling after HFD-induced obesity confirms that Nrf2 is implicated in liver metabolic gene networks. The specific genes identified here may provide insights into Nrf2-dependent mechanisms of metabolic regulation.

  14. Aldh2 knockout mice were more sensitive to DNA damage in leukocytes due to ethyl tertiary butyl ether exposure.

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    Weng, Zuquan; Suda, Megumi; Ohtani, Katsumi; Mei, Nan; Kawamoto, Toshihiro; Nakajima, Tamie; Wang, Rui-Sheng

    2011-01-01

    To clarify the genotoxicity of ethyl tertiary butyl ether (ETBE), a gasoline additive, male and female C57BL/6 mice of Aldh2+/+ and Aldh2-/- genotypes, aged 8 wk, were exposed to 0, 500, 1,750, or 5,000 ppm ETBE for 6 h/day, 5 d per week for 13 wk. DNA damage in leukocytes was measured by the alkaline comet assay and expressed quantitatively as Tail Intensity (TI). For male mice, TI was significantly higher in all three groups exposed to ETBE than in those without exposure within Aldh2-/- mice, whereas within Aldh2+/+ mice, TI increased only in those exposed to 5,000 ppm of ETBE as compared with mice without exposure. For female mice, a significant increase in TI values was observed in the group exposed to 5,000 ppm of ETBE as compared with those without exposure within Aldh2-/- mice; TI in Aldh2-/- mice exposed to 1,750 and 5,000 ppm was significantly higher than in Aldh2+/+ mice without exposure. TI did not significantly increase in any of the groups exposed to ETBE within female Aldh2+/+ mice. Based on the results we suggest that Aldh2-/- mice are more sensitive to DNA damage caused by ETBE than Aldh2+/+ mice and that males seem more susceptible to this effect than females.

  15. Differential genotoxic effects of subchronic exposure to ethyl tertiary butyl ether in the livers of Aldh2 knockout and wild-type mice.

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    Weng, Zuquan; Suda, Megumi; Ohtani, Katsumi; Mei, Nan; Kawamoto, Toshihiro; Nakajima, Tamie; Wang, Rui-Sheng

    2012-04-01

    Ethyl tertiary butyl ether (ETBE) is used as an additive to gasoline to reduce carbon monoxide emissions in some developed countries. So far, ETBE was not found with positive results in many genotoxic assays. This study is undertaken to investigate the modifying effects of deficiency of aldehyde dehydrogenase 2 (ALDH2) on the toxicity of ETBE in the livers of mice. Eight-week-old wild-type (WT) and Aldh2 knockout (KO) C57BL/6 mice of both sexes were exposed to 0, 500, 1,750, and 5,000 ppm ETBE for 6 h/day with 5 days per weeks for 13 weeks. Histopathology assessments and measurements of genetic effects in the livers were performed. Significantly increased accidences of centrilobular hypertrophy were observed in the livers of WT and KO mice of both sexes in 5,000 ppm group; there was a sex difference in centrilobular hypertrophy between male and female KO mice, with more severe damage in the males. In addition, DNA strand breaks, 8-hydroxyguanine DNA-glycosylase (hOGG1)-modified oxidative base modification, and 8-hydroxydeoxyguanosine as genetic damage endpoints were significantly increased in three exposure groups in KO male mice, while these genotoxic effects were only found in 5,000 ppm group of KO female mice. In WT mice, significant DNA damage was seen in 5,000 ppm group of male mice, but not in females. Thus, sex differences in DNA damage were found not only in KO mice, but also in WT mice. These results suggest that ALDH2 polymorphisms and sex should be taken into considerations in predicting human health effects of ETBE exposure.

  16. Salivary gland hypofunction in tyrosylprotein sulfotransferase-2 knockout mice is due to primary hypothyroidism.

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    Andrew D Westmuckett

    Full Text Available BACKGROUND: Protein-tyrosine sulfation is a post-translational modification of an unknown number of secreted and membrane proteins mediated by two known Golgi tyrosylprotein sulfotransferases (TPST-1 and TPST-2. We reported that Tpst2-/- mice have mild-moderate primary hypothyroidism, whereas Tpst1-/- mice are euthyroid. While using magnetic resonance imaging (MRI to look at the thyroid gland we noticed that the salivary glands in Tpst2-/- mice appeared smaller than in wild type mice. This prompted a detailed analysis to compare salivary gland structure and function in wild type, Tpst1-/-, and Tpst2 -/- mice. METHODOLOGY/PRINCIPAL FINDINGS: Quantitative MRI imaging documented that salivary glands in Tpst2-/- females were (≈ 30% smaller than wild type or Tpst1-/- mice and that the granular convoluted tubules in Tpst2-/- submandibular glands were less prominent and were almost completely devoid of exocrine secretory granules compared to glands from wild type or Tpst1-/- mice. In addition, pilocarpine-induced salivary flow and salivary α-amylase activity in Tpst2-/- mice of both sexes was substantially lower than in wild type and Tpst1-/- mice. Anti-sulfotyrosine Western blots of salivary gland extracts and saliva showed no differences between wild type, Tpst1-/-, and Tpst2-/- mice, suggesting that the salivary gland hypofunction is due to factor(s extrinsic to the salivary glands. Finally, we found that all indicators of hypothyroidism (serum T4, body weight and salivary gland hypofunction (salivary flow, salivary α-amylase activity, histological changes were restored to normal or near normal by thyroid hormone supplementation. CONCLUSIONS/SIGNIFICANCE: Our findings conclusively demonstrate that low body weight and salivary gland hypofunction in Tpst2-/- mice is due solely to primary hypothyroidism.

  17. Common arterial trunk and ventricular non-compaction in Lrp2 knockout mice indicate a crucial role of LRP2 in cardiac development

    NARCIS (Netherlands)

    Baardman, Maria E.; Zwier, Mathijs V.; Wisse, Lambertus J.; Gittenberger-de Groot, Adriana C.; Kerstjens-Frederikse, Wilhelmina S.; Hofstra, Robert M. W.; Jurdzinski, Angelika; Hierck, Beerend P.; Jongbloed, Monique R. M.; Berger, Rolf M. F.; Plosch, Torsten; DeRuiter, Marco C.

    2016-01-01

    Lipoprotein-related receptor protein 2 (LRP2) is important for development of the embryonic neural crest and brain in both mice and humans. Although a role in cardiovascular development can be expected, the hearts of Lrp2 knockout (KO) mice have not yet been investigated. We studied the

  18. Common arterial trunk and ventricular non-compaction in Lrp2 knockout mice indicate a crucial role of LRP2 in cardiac development

    NARCIS (Netherlands)

    T. Baardman (Taco); M.V. Zwier (Mathijs V.); L.J. Wisse (Lambertus); A.C. Gittenberger-De Groot (Adriana); W.S. Kerstjens-Frederikse (Wilhelmina); R.M.W. Hofstra (Robert); A. Jurdzinski (Angelika); B.P. Hierck (Beerend); M.R.M. Jongbloed (Monique); R.M.F. Berger (Rolf); T. Plösch (Torsten); M.C. DeRuiter (Marco)

    2016-01-01

    textabstractLipoprotein-related receptor protein 2 (LRP2) is important for development of the embryonic neural crest and brain in both mice and humans. Although a role in cardiovascular development can be expected, the hearts of Lrp2 knockout (KO) mice have not yet been investigated. We studied the

  19. Common arterial trunk and ventricular non-compaction in Lrp2 knockout mice indicate a crucial role of LRP2 in cardiac development

    NARCIS (Netherlands)

    Baardman, Maria E.; Zwier, Mathijs V.; Wisse, Lambertus J.; Gittenberger-de Groot, Adriana C.; Kerstjens-Frederikse, Wilhelmina S.; Hofstra, Robert M. W.; Jurdzinski, Angelika; Hierck, Beerend P.; Jongbloed, Monique R. M.; Berger, Rolf M. F.; Plosch, Torsten; DeRuiter, Marco C.

    2016-01-01

    Lipoprotein-related receptor protein 2 (LRP2) is important for development of the embryonic neural crest and brain in both mice and humans. Although a role in cardiovascular development can be expected, the hearts of Lrp2 knockout (KO) mice have not yet been investigated. We studied the cardiovascul

  20. Common arterial trunk and ventricular non-compaction in Lrp2 knockout mice indicate a crucial role of LRP2 in cardiac development

    NARCIS (Netherlands)

    T. Baardman (Taco); M.V. Zwier (Mathijs V.); L.J. Wisse (Lambertus); A.C. Gittenberger-De Groot (Adriana); W.S. Kerstjens-Frederikse (Wilhelmina); R.M.W. Hofstra (Robert); A. Jurdzinski (Angelika); B.P. Hierck (Beerend); M.R.M. Jongbloed (Monique); R.M.F. Berger (Rolf); T. Plösch (Torsten); M.C. DeRuiter (Marco)

    2016-01-01

    textabstractLipoprotein-related receptor protein 2 (LRP2) is important for development of the embryonic neural crest and brain in both mice and humans. Although a role in cardiovascular development can be expected, the hearts of Lrp2 knockout (KO) mice have not yet been investigated. We studied the

  1. Virally expressed connexin26 restores gap junction function in the cochlea of conditional Gjb2 knockout mice.

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    Yu, Q; Wang, Y; Chang, Q; Wang, J; Gong, S; Li, H; Lin, X

    2014-01-01

    Mutations in GJB2, which codes for the gap junction (GJ) protein connexin26 (Cx26), are the most common causes of human nonsyndromic hereditary deafness. We inoculated modified adeno-associated viral (AAV) vectors into the scala media of early postnatal conditional Gjb2 knockout mice to drive exogenous Cx26 expression. We found extensive virally expressed Cx26 in cells lining the scala media, and intercellular GJ network was re-established in the organ of Corti of mutant mouse cochlea. Widespread ectopic Cx26 expression neither formed ectopic GJs nor affected normal hearing thresholds in wild-type (WT) mice, suggesting that autonomous cellular mechanisms regulate proper membrane trafficking of exogenously expressed Cx26 and govern the functional manifestation of them. Functional recovery of GJ-mediated coupling among the supporting cells was observed. We found that both cell death in the organ of Corti and degeneration of spiral ganglion neurons in the cochlea of mutant mice were substantially reduced, although auditory brainstem responses did not show significant hearing improvement. This is the first report demonstrating that virally mediated gene therapy restored extensive GJ intercellular network among cochlear non-sensory cells in vivo. Such a treatment performed at early postnatal stages resulted in a partial rescue of disease phenotypes in the cochlea of the mutant mice.

  2. Raman spectroscopy for assessment of bone quality in MMP-2 knockout mice

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    Bi, Xiaohong; Nyman, Jeffry S.; Patil, Chetan A.; Masui, Philip; Lynch, Conor; Mahadevan-Jansen, Anita

    2009-02-01

    Knocking out a gene in mice provide the means to investigate potential regulators of the compositional, structural, and biomechanical properties of bone. Suppressing genes related to matrix turnover (bone remodeling) can have a significant effect on properties related to overall bone quality, which are normally measured using tests such as micro-computed tomography (μ-CT) and three point-bending to determine the structural and mechanical properties, respectively. Although Raman spectroscopy is known to non-destructively characterize biochemical properties of bone such as degree of mineralization and crystallinity, the correlation between these measurements and those of overall bone quality has not yet been systematically investigated. In this study we present a comparison of structural and mechanical properties of bone from mice deficient in matrix metalloproteinase 2 (MMP2) to compositional properties measured with RS. Femora were collected from MMP2+/+ and MMP2-/- mice at 16 weeks of age. Multiple Raman spectra were collected from the mid-diaphysis of intact femora in order to measure the bone's average compositional properties. In addition, μ-CT was used to characterize the structure and bone mineral density (BMD) at the mid-diaphysis, and three-point bending assessed the biomechanical properties of the same bones. Raman derived measurements of mineralization (ratio of Phosphate ν1 to CH2 bending), mineral crystallinity, collagen and mineral contents were significantly lower in the MMP null mice and demonstrated correlation with volumetric BMD, bending strength and modulus. In addition, all these measurements were shown to inversely correlate with post-yield-deflection (p<0.01). These results indicate the potential for RS to qualitatively assess bone quality.

  3. Autism-relevant social abnormalities and cognitive deficits in engrailed-2 knockout mice.

    Directory of Open Access Journals (Sweden)

    Jennifer Brielmaier

    Full Text Available ENGRAILED 2 (En2, a homeobox transcription factor, functions as a patterning gene in the early development and connectivity of rodent hindbrain and cerebellum, and regulates neurogenesis and development of monoaminergic pathways. To further understand the neurobiological functions of En2, we conducted neuroanatomical expression profiling of En2 wildtype mice. RTQPCR assays demonstrated that En2 is expressed in adult brain structures including the somatosensory cortex, hippocampus, striatum, thalamus, hypothalamus and brainstem. Human genetic studies indicate that EN2 is associated with autism. To determine the consequences of En2 mutations on mouse behaviors, including outcomes potentially relevant to autism, we conducted comprehensive phenotyping of social, communication, repetitive, and cognitive behaviors. En2 null mutants exhibited robust deficits in reciprocal social interactions as juveniles and adults, and absence of sociability in adults, replicated in two independent cohorts. Fear conditioning and water maze learning were impaired in En2 null mutants. High immobility in the forced swim test, reduced prepulse inhibition, mild motor coordination impairments and reduced grip strength were detected in En2 null mutants. No genotype differences were found on measures of ultrasonic vocalizations in social contexts, and no stereotyped or repetitive behaviors were observed. Developmental milestones, general health, olfactory abilities, exploratory locomotor activity, anxiety-like behaviors and pain responses did not differ across genotypes, indicating that the behavioral abnormalities detected in En2 null mutants were not attributable to physical or procedural confounds. Our findings provide new insight into the role of En2 in complex behaviors and suggest that disturbances in En2 signaling may contribute to neuropsychiatric disorders marked by social and cognitive deficits, including autism spectrum disorders.

  4. Excitation/inhibition imbalance and impaired synaptic inhibition in hippocampal area CA3 of Mecp2 knockout mice.

    Science.gov (United States)

    Calfa, Gaston; Li, Wei; Rutherford, John M; Pozzo-Miller, Lucas

    2015-02-01

    Rett syndrome (RTT) is a neurodevelopment disorder associated with intellectual disabilities and caused by loss-of-function mutations in the gene encoding the transcriptional regulator Methyl-CpG-binding Protein-2 (MeCP2). Neuronal dysfunction and changes in cortical excitability occur in RTT individuals and Mecp2-deficient mice, including hippocampal network hyperactivity and higher frequency of spontaneous multiunit spikes in the CA3 cell body layer. Here, we describe impaired synaptic inhibition and an excitation/inhibition (E/I) imbalance in area CA3 of acute slices from symptomatic Mecp2 knockout male mice (referred to as Mecp2(-/y) ). The amplitude of TTX-resistant miniature inhibitory postsynaptic currents (mIPSC) was smaller in CA3 pyramidal neurons of Mecp2(-/y) slices than in wildtype controls, while the amplitude of miniature excitatory postsynaptic currents (mEPSC) was significantly larger in Mecp2(-/y) neurons. Consistently, quantitative confocal immunohistochemistry revealed significantly lower intensity of the alpha-1 subunit of GABAA Rs in the CA3 cell body layer of Mecp2(-/y) mice, while GluA1 puncta intensities were significantly higher in the CA3 dendritic layers of Mecp2(-/y) mice. In addition, the input/output (I/O) relationship of evoked IPSCs had a shallower slope in CA3 pyramidal neurons Mecp2(-/y) neurons. Consistent with the absence of neuronal degeneration in RTT and MeCP2-based mouse models, the density of parvalbumin- and somatostatin-expressing interneurons in area CA3 was not affected in Mecp2(-/y) mice. Furthermore, the intrinsic membrane properties of several interneuron subtypes in area CA3 were not affected by Mecp2 loss. However, mEPSCs are smaller and less frequent in CA3 fast-spiking basket cells of Mecp2(-/y) mice, suggesting an impaired glutamatergic drive in this interneuron population. These results demonstrate that a loss-of-function mutation in Mecp2 causes impaired E/I balance onto CA3 pyramidal neurons, leading to a

  5. Apo A1 Mimetic Rescues the Diabetic Phenotype of HO-2 Knockout Mice via an Increase in HO-1 Adiponectin and LKBI Signaling Pathway

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    Jian Cao

    2012-01-01

    Full Text Available Insulin resistance, with adipose tissue dysfunction, is one of the hallmarks of metabolic syndrome. We have reported a metabolic syndrome-like phenotype in heme oxygenase (HO-2 knockout mice, which presented with concurrent HO-1 deficiency and were amenable to rescue by an EET analog. Apo A-I mimetic peptides, such as L-4F, have been shown to induce HO-1 expression and decrease oxidative stress and adiposity. In this study we aimed to characterize alleviatory effects of HO-1 induction (if any on metabolic imbalance observed in HO-2 KO mice. In this regard, HO-2(−/− mice were injected with 2 mg/kg/day L-4F, or vehicle, i.p., for 6 weeks. As before, compared to WT animals, the HO-2 null mice were obese, displayed insulin resistance, and had elevated blood pressure. These changes were accompanied by enhanced tissue (hepatic oxidative stress along with attenuation of HO-1 expression and activity and reduced adiponectin, pAMPK, and LKB1 expression. Treatment with L-4F restored HO-1 expression and activity and increased adiponectin, LKB1, and pAMPK in the HO-2(−/− mice. These alterations resulted in a decrease in blood pressure, insulin resistance, blood glucose, and adiposity. Taken together, our results show that a deficient HO-1 response, in a state with reduced HO-2 basal levels, is accompanied by disruption of metabolic homeostasis which is successfully restored by an HO-1 inducer.

  6. Increased oxidative stress and apoptosis in the hypothalamus of diabetic male mice in the insulin receptor substrate-2 knockout model

    Science.gov (United States)

    Canelles, Sandra; Argente, Jesús; Barrios, Vicente

    2016-01-01

    ABSTRACT Insulin receptor substrate-2-deficient (IRS2−/−) mice are considered a good model to study the development of diabetes because IRS proteins mediate the pleiotropic effects of insulin-like growth factor-I (IGF-I) and insulin on metabolism, mitogenesis and cell survival. The hypothalamus might play a key role in the early onset of diabetes, owing to its involvement in the control of glucose homeostasis and energy balance. Because some inflammatory markers are elevated in the hypothalamus of diabetic IRS2−/− mice, our aim was to analyze whether the diabetes associated with the absence of IRS2 results in hypothalamic injury and to analyze the intracellular mechanisms involved. Only diabetic IRS2−/− mice showed increased cell death and activation of caspase-8 and -3 in the hypothalamus. Regulators of apoptosis such as FADD, Bcl-2, Bcl-xL and p53 were also increased, whereas p-IκB and c-FLIPL were decreased. This was accompanied by increased levels of Nox-4 and catalase, enzymes involved in oxidative stress. In summary, the hypothalamus of diabetic IRS2−/− mice showed an increase in oxidative stress and inflammatory markers that finally resulted in cell death via substantial activation of the extrinsic apoptotic pathway. Conversely, non-diabetic IRS2−/− mice did not show cell death in the hypothalamus, possibly owing to an increase in the levels of circulating IGF-I and in the enhanced hypothalamic IGF-IR phosphorylation that would lead to the stimulation of survival pathways. In conclusion, diabetes in IRS2-deficient male mice is associated with increased oxidative stress and apoptosis in the hypothalamus. PMID:27013528

  7. Impaired phagosomal maturation in neutrophils leads to periodontitis in lysosomal-associated membrane protein-2 knockout mice

    NARCIS (Netherlands)

    Beertsen, W.; Willenborg, M.; Everts, V.; Zirogianni, A.; Podschun, R.; Schröder, B.; Eskelinen, E.L.; Saftig, P.

    2008-01-01

    Inflammatory periodontal diseases constitute one of the most common infections in humans, resulting in the destruction of the supporting structures of the dentition. Circulating neutrophils are an essential component of the human innate immune system. We observed that mice deficient for the major ly

  8. Excitation/Inhibition Imbalance and Impaired Synaptic Inhibition in Hippocampal Area CA3 of Mecp2 Knockout Mice

    OpenAIRE

    Calfa, Gaston; Li, Wei; Rutherford, John M.; Pozzo-Miller, Lucas

    2014-01-01

    Rett syndrome (RTT) is a neurodevelopment disorder associated with intellectual disabilities and caused by loss-of-function mutations in the gene encoding the transcriptional regulator Methyl-CpG-binding Protein-2 (MeCP2). Neuronal dysfunction and changes in cortical excitability occur in RTT individuals and Mecp2-deficient mice, including hippocampal network hyperactivity and higher frequency of spontaneous multi-unit spikes in the CA3 cell body layer. Here, we describe impaired synaptic inh...

  9. Hydrogen Gas Protects Against Intestinal Injury in Wild Type But Not NRF2 Knockout Mice With Severe Sepsis by Regulating HO-1 and HMGB1 Release.

    Science.gov (United States)

    Yu, Yang; Yang, Yongyan; Bian, Yingxue; Li, Yuan; Liu, Lingling; Zhang, Hongtao; Xie, Keliang; Wang, Guolin; Yu, Yonghao

    2017-09-01

    The intestine plays an important role in the pathogenesis of sepsis. Hydrogen gas (H2), which has anti-oxidative, anti-inflammatory, and anti-apoptotic effects, can be effectively used to treat septic mice. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive master switch that regulates the expression of antioxidant and protective enzymes. This study investigated the effects of 2% H2 on intestinal injuries and the underlying mechanisms in a mouse model of severe sepsis. Male Nrf2 knockout mice (Nrf2-KO) and wild-type (WT) mice were randomized into four groups: sham, sham+H2, cecal ligation and puncture (CLP), and CLP+H2. The survival rate was observed and recorded within 7 days, and pro-inflammatory cytokines (TNF-α, IL-6, HMGB1), anti-inflammatory cytokine (IL-10), antioxidant enzymes (superoxide dismutase, and catalase ), and oxidative products (MDA, 8-iso-PGF2α) were detected in the serum and intestine using an enzyme-linked immunosorbent assay. In addition, the protein and mRNA levels of heme oxygenase-1 (HO-1) and high mobility group box 1 (HMGB1) were measured by Western blotting and quantitative PCR, respectively. Immunofluorescence and immunohistochemistry were used to measure HMGB1 and HO-1 release into the intestine, respectively. The results showed that therapy with 2% H2 increased the survival rate, alleviated the injuries caused by oxidative stress and inflammation, reduced HMGB1 levels but increased HO-1 levels in WT septic mice, but not in Nrf2-KO mice. These data demonstrate that 2% H2 inhalation may be a promising therapeutic strategy for intestinal injuries caused by severe sepsis through the regulation of HO-1 and HMGB1 release. In addition, Nrf2 plays a key role in the protective effects of H2 against intestinal damage in this disease.

  10. Common arterial trunk and ventricular non-compaction in Lrp2 knockout mice indicate a crucial role of LRP2 in cardiac development.

    Science.gov (United States)

    Baardman, Maria E; Zwier, Mathijs V; Wisse, Lambertus J; Gittenberger-de Groot, Adriana C; Kerstjens-Frederikse, Wilhelmina S; Hofstra, Robert M W; Jurdzinski, Angelika; Hierck, Beerend P; Jongbloed, Monique R M; Berger, Rolf M F; Plösch, Torsten; DeRuiter, Marco C

    2016-04-01

    Lipoprotein-related receptor protein 2 (LRP2) is important for development of the embryonic neural crest and brain in both mice and humans. Although a role in cardiovascular development can be expected, the hearts ofLrp2knockout (KO) mice have not yet been investigated. We studied the cardiovascular development ofLrp2KO mice between embryonic day 10.5 (E10.5) and E15.5, applying morphometry and immunohistochemistry, using antibodies against Tfap2α (neural crest cells), Nkx2.5 (second heart field), WT1 (epicardium derived cells), tropomyosin (myocardium) and LRP2. TheLrp2KO mice display a range of severe cardiovascular abnormalities, including aortic arch anomalies, common arterial trunk (persistent truncus arteriosus) with coronary artery anomalies, ventricular septal defects, overriding of the tricuspid valve and marked thinning of the ventricular myocardium. Both the neural crest cells and second heart field, which are essential for the lengthening and growth of the right ventricular outflow tract, are abnormally positioned in theLrp2KO. This explains the absence of the aorto-pulmonary septum, which leads to common arterial trunk and ventricular septal defects. Severe blebbing of the epicardial cells covering the ventricles is seen. Epithelial-mesenchymal transition does occur; however, there are fewer WT1-positive epicardium-derived cells in the ventricular wall as compared to normal, coinciding with the myocardial thinning and deep intertrabecular spaces. LRP2 plays a crucial role in cardiovascular development in mice. This corroborates findings of cardiac anomalies in humans withLRP2mutations. Future studies should reveal the underlying signaling mechanisms in which LRP2 is involved during cardiogenesis.

  11. Ins1 Gene Up-Regulated in a β-Cell Line Derived from Ins2 Knockout Mice

    OpenAIRE

    2003-01-01

    The authors have derived a new β-cell line (βIns2−/−lacZ) from Ins2−/− mice that carry the lacZ reporter gene under control of the Ins2 promoter. βIns2−/−lacZ cells stained positively using anti-insulin antibody, expressed β-cell–specific genes encoding the transcription factor PDX-1, glucokinase, and Glut-2, retained glucose-responsiveness for insulin secretion, and expressed the lacZ gene. Analysis of Ins1 expression by reverse transcriptase–polymerase chain reaction (RT-PCR) showed that In...

  12. Islets of Langerhans from prohormone convertase-2 knockout mice show α-cell hyperplasia and tumorigenesis with elevated α-cell neogenesis.

    Science.gov (United States)

    Jones, Huw B; Reens, Jaimini; Brocklehurst, Simon R; Betts, Catherine J; Bickerton, Sue; Bigley, Alison L; Jenkins, Richard P; Whalley, Nicky M; Morgan, Derrick; Smith, David M

    2014-02-01

    Antagonism of the effects of glucagon as an adjunct therapy with other glucose-lowering drugs in the chronic treatment of diabetes has been suggested to aggressively control blood glucose levels. Antagonism of glucagon effects, by targeting glucagon secretion or disabling the glucagon receptor, is associated with α-cell hyperplasia. We evaluated the influence of total glucagon withdrawal on islets of Langerhans using prohormone convertase-2 knockout mice (PC2-ko), in which α-cell hyperplasia is present from a young age and persists throughout life, in order to understand whether or not sustained glucagon deficit would lead to islet tumorigenesis. PC2-ko and wild-type (WT) mice were maintained drug-free, and cohorts of these groups sampled at 3, 12 and 18 months for plasma biochemical and morphological (histological, immunohistochemical, electron microscopical and image analytical) assessments. WT mice showed no islet tumours up to termination of the study, but PC2-ko animals displayed marked changes in islet morphology from α-cell hypertrophy/hyperplasia/atypical hyperplasia, to adenomas and carcinomas, these latter being first encountered at 6-8 months. Islet hyperplasias and tumours primarily consisted of α-cells associated to varying degrees with other islet endocrine cell types. In addition to substantial increases in islet neoplasia, increased α-cell neogenesis associated primarily with pancreatic duct(ule)s was present. We conclude that absolute blockade of the glucagon signal results in tumorigenesis and that the PC2-ko mouse represents a valuable model for investigation of islet tumours and pancreatic ductal neogenesis.

  13. A selective histone deacetylase-6 inhibitor improves BDNF trafficking in hippocampal neurons from Mecp2 knockout mice: implications for Rett syndrome

    Science.gov (United States)

    Xu, Xin; Kozikowski, Alan P.; Pozzo-Miller, Lucas

    2014-01-01

    Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional modulator methyl-CpG-binding protein 2 (MECP2). One of the most prominent gene targets of MeCP2 is brain-derived neurotrophic factor (Bdnf), a potent modulator of activity-dependent synaptic development, function and plasticity. Dysfunctional BDNF signaling has been demonstrated in several pathophysiological mechanisms of RTT disease progression. To evaluate whether the dynamics of BDNF trafficking is affected by Mecp2 deletion, we analyzed movements of BDNF tagged with yellow fluorescent protein (YFP) in cultured hippocampal neurons by time-lapse fluorescence imaging. We found that both anterograde and retrograde vesicular trafficking of BDNF-YFP are significantly impaired in Mecp2 knockout hippocampal neurons. Selective inhibitors of histone deacetylase 6 (HDAC6) show neuroprotective effects in neurodegenerative diseases and stimulate microtubule-dependent vesicular trafficking of BDNF-containing dense core vesicles. Here, we show that the selective HDAC6 inhibitor Tubastatin-A increased the velocity of BDNF-YFP vesicles in Mecp2 knockout neurons in both directions by increasing α–tubulin acetylation. Tubastatin-A also restored activity-dependent BDNF release from Mecp2 knockout neurons to levels comparable to those shown by wildtype neurons. These findings demonstrate that a selective HDAC6 inhibitor is a potential pharmacological strategy to reverse cellular and synaptic impairments in RTT resulting from impaired BDNF signaling. PMID:24639629

  14. A selective histone deacetylase-6 inhibitor improves BDNF trafficking in hippocampal neurons from Mecp2 knockout mice:implications for Rett syndrome

    Directory of Open Access Journals (Sweden)

    Xin eXu

    2014-03-01

    Full Text Available Rett syndrome (RTT is a neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional modulator methyl-CpG-binding protein 2 (MECP2. One of the most prominent gene targets of MeCP2 is brain-derived neurotrophic factor (Bdnf, a potent modulator of activity-dependent synaptic development, function and plasticity. Dysfunctional BDNF signaling has been demonstrated in several pathophysiological mechanisms of RTT disease progression. To evaluate whether the dynamics of BDNF trafficking is affected by Mecp2 deletion, we analyzed movements of BDNF tagged with yellow fluorescent protein (YFP in cultured hippocampal neurons by time-lapse fluorescence imaging. We found that both anterograde and retrograde vesicular trafficking of BDNF-YFP are significantly impaired in Mecp2 knockout hippocampal neurons. Selective inhibitors of histone deacetylase 6 (HDAC6 show neuroprotective effects in neurodegenerative diseases and stimulate microtubule-dependent vesicular trafficking of BDNF-containing dense core vesicles. Here, we show that the selective HDAC6 inhibitor Tubastatin-A increased the velocity of BDNF-YFP vesicles in Mecp2 knockout neurons in both directions by increasing αtubulin acetylation. Tubastatin-A also restored activity-dependent BDNF release from Mecp2 knockout neurons to levels comparable to those shown by wildtype neurons. These findings demonstrate that a selective HDAC6 inhibitor is a potential pharmacological strategy to reverse cellular and synaptic impairments in RTT resulting from impaired BDNF signaling.

  15. MicroRNA profiling in Muc2 knockout mice of colitis-associated cancer model reveals epigenetic alterations during chronic colitis malignant transformation.

    Directory of Open Access Journals (Sweden)

    Yonghua Bao

    Full Text Available Our previous studies have demonstrated that genetic deletion of the Muc2 gene causes colorectal cancers in mice. The current study further showed that at the early stage (3 months the mice exhibited colorectal cancer, including a unique phenotype of rectal prolapsed (rectal severe inflammation and adenocarcinoma. Thus, the age of 3 months might be the key point of the transition from chronic inflammation to cancer. To determine the mechanisms of the malignant transformation, we conducted miRNA array on the colonic epithelial cells from the 3-month Muc2-/- and +/+ mice. MicroRNA profiling showed differential expression of miRNAs (i.e. lower or higher expression enrichments in Muc2-/- mice. 15 of them were validated by quantitative PCR. Based on relevance to cytokine and cancer, 4 miRNAs (miR-138, miR-145, miR-146a, and miR-150 were validate and were found significantly downregulated in human colitis and colorectal cancer tissues. The network of the targets of these miRNAs was characterized, and interestedly, miRNA-associated cytokines were significantly increased in Muc2-/-mice. This is the first to reveal the importance of aberrant expression of miRNAs in dynamically transformation from chronic colitis to colitis-associated cancer. These findings shed light on revealing the mechanisms of chronic colitis malignant transformation.

  16. GABA concentration and GABAergic neuron populations in limbic areas are differentially altered by brain serotonin deficiency in Tph2 knockout mice.

    Science.gov (United States)

    Waider, Jonas; Proft, Florian; Langlhofer, Georg; Asan, Esther; Lesch, Klaus-Peter; Gutknecht, Lise

    2013-02-01

    While tryptophan hydroxylase-2 (Tph2) null mutant (Tph2(-/-)) mice are completely deficient in brain serotonin (5-HT) synthesis, the formation of serotonergic neurons and pathfinding of their projections are not impaired. However, 5-HT deficiency, during development and in the adult, might affect morphological and functional parameters of other neural systems. To assess the influence of 5-HT deficiency on γ-amino butyric acid (GABA) systems, we carried out measurements of GABA concentrations in limbic brain regions of adult male wildtype (wt), heterozygous (Tph2(+/-)) and Tph2(-/-) mice. In addition, unbiased stereological estimation of GABAergic interneuron numbers and density was performed in subregions of amygdala and hippocampus. Amygdala and prefrontal cortex displayed significantly increased and decreased GABA concentrations, respectively, exclusively in Tph2(+/-) mice while no changes were detected between Tph2(-/-) and wt mice. In contrast, in the hippocampus, increased GABA concentrations were found in Tph2(-/-) mice. While total cell density in the anterior basolateral amygdala did not differ between genotypes, the number and density of the GABAergic interneurons were significantly decreased in Tph2(-/-) mice, with the group of parvalbumin (PV)-immunoreactive (ir) interneurons contributing somewhat less to the decrease than that of non-PV-ir GABAergic interneurons. Major morphological changes were also absent in the dorsal hippocampus, and only a trend toward reduced density of PV-ir cells was observed in the CA3 region of Tph2(-/-) mice. Our findings are the first to document that life-long reduction or complete lack of brain 5-HT transmission causes differential changes of GABA systems in limbic regions which are key players in emotional learning and memory processes. The changes likely reflect a combination of developmental alterations and functional adaptations of emotion circuits to balance the lack of 5-HT, and may underlie altered emotional

  17. Continuous fat oxidation in acetyl–CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity

    Science.gov (United States)

    Choi, Cheol Soo; Savage, David B.; Abu-Elheiga, Lutfi; Liu, Zhen-Xiang; Kim, Sheene; Kulkarni, Ameya; Distefano, Alberto; Hwang, Yu-Jin; Reznick, Richard M.; Codella, Roberto; Zhang, Dongyan; Cline, Gary W.; Wakil, Salih J.; Shulman, Gerald I.

    2007-01-01

    Acetyl–CoA carboxylase 2 (ACC)2 is a key regulator of mitochondrial fat oxidation. To examine the impact of ACC2 deletion on whole-body energy metabolism, we measured changes in substrate oxidation and total energy expenditure in Acc2−/− and WT control mice fed either regular or high-fat diets. To determine insulin action in vivo, we also measured whole-body insulin-stimulated liver and muscle glucose metabolism during a hyperinsulinemic–euglycemic clamp in Acc2−/− and WT control mice fed a high-fat diet. Contrary to previous studies that have suggested that increased fat oxidation might result in lower glucose oxidation, both fat and carbohydrate oxidation were simultaneously increased in Acc2−/− mice. This increase in both fat and carbohydrate oxidation resulted in an increase in total energy expenditure, reductions in fat and lean body mass and prevention from diet-induced obesity. Furthermore, Acc2−/− mice were protected from fat-induced peripheral and hepatic insulin resistance. These improvements in insulin-stimulated glucose metabolism were associated with reduced diacylglycerol content in muscle and liver, decreased PKCθ activity in muscle and PKCε activity in liver, and increased insulin-stimulated Akt2 activity in these tissues. Taken together with previous work demonstrating that Acc2−/− mice have a normal lifespan, these data suggest that Acc2 inhibition is a viable therapeutic option for the treatment of obesity and type 2 diabetes. PMID:17923673

  18. Ultrastructural characterization of the mesostriatal dopamine innervation in mice, including two mouse lines of conditional VGLUT2 knockout in dopamine neurons.

    Science.gov (United States)

    Bérubé-Carrière, Noémie; Guay, Ginette; Fortin, Guillaume M; Kullander, Klas; Olson, Lars; Wallén-Mackenzie, Åsa; Trudeau, Louis-Eric; Descarries, Laurent

    2012-02-01

    Despite the increasing use of genetically modified mice to investigate the dopamine (DA) system, little is known about the ultrastructural features of the striatal DA innervation in the mouse. This issue is particularly relevant in view of recent evidence for expression of the vesicular glutamate transporter 2 (VGLUT2) by a subset of mesencephalic DA neurons in mouse as well as rat. We used immuno-electron microscopy to characterize tyrosine hydroxylase (TH)-labeled terminals in the core and shell of nucleus accumbens and the neostriatum of two mouse lines in which the Vglut2 gene was selectively disrupted in DA neurons (cKO), their control littermates, and C57BL/6/J wild-type mice, aged P15 or adult. The three regions were also examined in cKO mice and their controls of both ages after dual TH-VGLUT2 immunolabeling. Irrespective of the region, age and genotype, the TH-immunoreactive varicosities appeared similar in size, vesicular content, percentage with mitochondria, and exceedingly low frequency of synaptic membrane specialization. No dually labeled axon terminals were found at either age in control or in cKO mice. Unless TH and VGLUT2 are segregated in different axon terminals of the same neurons, these results favor the view that the glutamatergic cophenotype of mesencephalic DA neurons is more important during the early development of these neurons than for the establishment of their scarce synaptic connectivity. They also suggest that, in mouse even more than rat, the mesostriatal DA system operates mainly through non-targeted release of DA, diffuse transmission and the maintenance of an ambient DA level.

  19. 雌性Akt2基因缺失小鼠生殖表型研究%Female Akt2 Knockout Mice Reproductive

    Institute of Scientific and Technical Information of China (English)

    张跃辉; 郭文艳; 王娜梅; 吴效科

    2011-01-01

    通过对雌性Akt2 基因敲除纯合子小鼠(Akt2(-/-))及野生型小鼠(Akt2(+/+))基础指标、大体形态学指标、血清糖脂水平和性激素水平等方面的评估,探讨Akt2基因缺失对糖脂代谢和卵巢功能影响.雌性Akt2(+/+)及Akt2(-/-)小鼠各16只,行口服糖耐量(OGTT)实验(2mg/kg),阴道涂片监测动情周期,于动情间期进行动力学实验,将纯合子和野生型小鼠分别随机分为空白组和刺激组2组,刺激组予HMG(人绝经期尿促性激素)(0.5IU/g)刺激2h,空白组予等体积的生理盐水刺激2h,检测各组小鼠体重、体内脂肪重量、血脂、空腹胰岛素水平和生殖激素水平,卵巢常规病理检测各组小鼠卵巢形态学变化.结果发现,同野生型小鼠相比,纯合子小鼠动情周期显着延长(P<0.05),随机血糖、0h血糖、2h血糖、空腹胰岛素水平和HOMA指数均显著升高(P<0.05),而血清甘油三醑(TG)水平则显著降低(P<0.05);性激素检测发现纯合子小鼠血清17羟孕酮(17-OHP)、雌二醇(E2)、△17-OHP、△E2均显着升高.综上,本文认为Akt2基因不仅可以影响机体糖脂代谢,同时也影响卵巢功能,说明胰岛素调节糖代谢的关键信号分子对卵巢生殖功能同样具有重要的调节作用.%If the rat model of diabetes-Akt2 gene knockout mice is homozygous (Akt2 (-/-)) for ovarian function and fertility, then it would be proved that Akt2 gene could affect ovary function and glucose and lipid metabolism. In the experiment, heterozygote (Akt2 (+/-)) of male and female mice is cross-breeding for 60 days, then weanling offspring have been given gene identification in order to select the wild-type (Akt2 (+/+)) and homozygous (Akt2 (-/-)) mice for breeding. As the son of second generation female, subjects are that observe body and fat weight, the estrous cycle, glucose, hormone changes, ovary, and ovary morphological changes. The results show that: (1) homozygous weight and body fat weight of the mice

  20. Skin cancer development in mice exposed chronically to immunosuppressive agents.

    Science.gov (United States)

    Daynes, R A; Harris, C C; Connor, R J; Eichwald, E J

    1979-04-01

    Inbred female C3Hf/HeN, murine mammary tumor virus-negative mice exposed to either UV light or benzo[a]pyrene (BP), were subjected to four different chronic immunosuppressive regimens to determine their effect on skin cancer development. The immunosuppressive agents were cyclophosphamide, methotrexate, cortisone, and heterologous antilymphocyte globulin. Because of an unexpectedly high morbidity and mortality of mice exposed to chronic immunosuppressive measures, the dosages were kept at a level that permitted them to survive but did not prolong allogeneic skin graft survival and lower antibody titers, nor did this level diminish proliferative responses of lymphocytes to mitogens or allogeneic lymphocytes. Nevertheless, the latency periods (time interval between beginning of medication and appearance of skin tumors) of tumors in mice exposed to immunosuppressant measures were significantly shortened in several groups of mice exposed to UV and subjected to cyclophosphamide, cortisone, or antilymphocyte globulin and mice exposed to BP and subjected to cortisone acetate. In 3 groups, spindle cell tumors (fibrosarcomas) shifted to squamous cell carcinomas. A suppressed immune function would not be regarded as the mechanism for the observed responses because immunosuppression was not detected in the experimental mice.

  1. Genetic Analysis of Mice Skin Exposed by Hyper-Gravity

    Science.gov (United States)

    Takahashi, Rika; Terada, Masahiro; Seki, Masaya; Higashibata, Akira; Majima, Hideyuki J.; Ohira, Yoshinobu; Mukai, Chiaki; Ishioka, Noriaki

    2013-02-01

    In the space environment, physiological alterations, such as low bone density, muscle weakness and decreased immunity, are caused by microgravity and cosmic radiation. On the other hand, it is known that the leg muscles are hypertrophy by 2G-gravity. An understanding of the effects on human body from microgravity to hyper-gravity is very important. Recently, the Japan Aerospace Exploration Agency (JAXA) has started a project to detect the changes on gene expression and mineral metabolism caused by microgravity by analyzing the hair of astronauts who stay in the international Space Station (ISS) for a long time. From these results of human hair’s research, the genetic effects of human hair roots by microgravity will become clear. However, it is unclear how the gene expression of hair roots was effected by hypergravity. Therefore, in this experiment, we analyzed the effect on mice skin contained hair roots by comparing microgravity or hypergravity exposed mice. The purpose of this experiment is to evaluate the genetic effects on mice skin by microgravity or 2G-gravity. The samples were taken from mice exposed to space flight (FL) or hypergravity environment (2G) for 3-months, respectively. The extracted and amplified RNA from these mice skin was used to DNA microarray analysis. in this experiment, we analyzed the effect of gravity by using mice skin contained hair roots, which exposed space (FL) and hyper-gravity (2G) for 3 months and each control. By DNA microarray analysis, we found the common 98 genes changed in both FL and 2G. Among these 98 genes, the functions and pathways were identified by Gene Ontology (GO) analysis and Ingenuity Pathways Analysis (IPA) software. Next, we focused the one of the identified pathways and compared the effects on each molecules in this pathways by the different environments, such as FL and 2G. As the results, we could detect some interesting molecules, which might be depended on the gravity levels. In addition, to investigate

  2. Differential cytotoxicity but augmented IFN-γ secretion by NK cells after interaction with monocytes from humans, and those from wild type and myeloid specific COX-2 knockout mice

    Directory of Open Access Journals (Sweden)

    Han-Ching eTseng

    2015-06-01

    Full Text Available The list of genes which augment NK cell function when knocked out in neighboring cells is increasing, and may point to the fundamental function of NK cells targeting cells with diminished capability to differentiate optimally since NK cells are able to target less differentiated cells, and aid in their differentiation. In this paper we aimed at understanding the effect of monocytes from targeted knockout of COX-2 in myeloid cells (Cox-2flox/flox;LysMCre/+ and from control littermates (Cox-2flox/flox;LysM+/+ on ex vivo function of NK cells. Furthermore, we compared the effect of monocytes treated with and without lipopolysaccharide (LPS on NK cells from mice and humans. NK cells purified from Cox-2flox/flox;LysMCre/+ mice had heightened cytotoxic activity when compared to those obtained from control littermates. In addition, NK cells cultured with autologous Cox-2flox/flox;LysMCre/+ monocytes and DCs, mouse embryonic fibroblasts (MEFs from global knock out COX-2, but not with knock out of COX-2 in T cells, had increased cytotoxic function as well as augmented IFN-γ secretion when compared to NK cells from control littermates cultured with monocytes. LPS inhibited NK cell cytotoxicity while increasing IFN-γ secretion when cultured in the presence of monocytes from either Cox-2flox/flox;LysMCre/+ or control littermates. In contrast to mice, NK cells from humans when cultured with monocytes lost cytotoxic function and gained ability to secrete large amounts of IFN-γ, a process which we had previously coined as split anergy. Similar to mice, LPS potentiated the loss of human NK cell cytotoxicity while increasing IFN-γ secretion in the presence of monocytes. Greater loss of cytotoxicity and larger secretion of IFN-γ in NK cells induced by gene knock out cells may be important for the greater need of these cells for differentiation.

  3. Yangjing Capsule Ameliorates Spermatogenesis in Male Mice Exposed to Cyclophosphamide

    Directory of Open Access Journals (Sweden)

    Hongle Zhao

    2015-01-01

    Full Text Available Yangjing capsule (YC, a traditional Chinese compound herbal preparation, has been proven as an effective drug to improve spermatogenesis in clinical practice. However, its pharmacological mechanisms were not fully clarified. This study was designed to investigate the protective effects of YC on spermatogenesis in the mouse model of spermatogenesis dysfunction induced by cyclophosphamide (CP. The administration of YC significantly increased the epididymal index, sperm count, and sperm motility of model mice. Histopathological changes demonstrated that CP caused obvious structural damage to testis, which were reversed by the administration of YC. Results from TUNEL assay showed that treatment with YC dramatically decreased the apoptosis of spermatogenic cell induced by CP. Moreover, YC treatment could inhibit the mRNA and protein expression of Bax to Bcl-2 and also raised expression of AR at both mRNA and protein levels. These data suggest that YC might ameliorate spermatogenesis in male mice exposed to CP through inhibiting the apoptosis of spermatogenic cell and enhancing the actions of testosterone in spermatogenesis.

  4. Melatonin protects uterus and oviduct exposed to nicotine in mice

    Directory of Open Access Journals (Sweden)

    Seyed Saadat Seyedeh Nazanin

    2014-03-01

    Full Text Available Smoking is associated with higher infertility risk. The aim of this study was to evaluate protective effects of melatonin on the uterus and oviduct in mice exposed to nicotine. Adult female mice (n=32 were divided into four groups. Group A: control animals received normal saline, Group B: injected with nicotine 40 μg/kg, Group C: injected with melatonin 10 μg, Group D: injected with nicotine 40 μg/kg and melatonin 10 μg. All animals were treated over 15 days intraperitoneally. On the 16th day, animals in the estrus phase were dissected and their uterus and oviducts were removed. Immunohistochemistry was recruited for studying apoptosis and for detection of estrogen receptor (ER alpha in luminal epithelium of the uterus and oviduct. Enzyme-linked immunosorbent assay was used for serum estradiol level determination. Nicotine in group B decreased estradiol level and ERalpha numbers both in the uterus and oviduct (p<0.05. Co-administration of melatonin-nicotine in Group D ameliorated the histology of the uterus and oviduct, increased ERalpha numbers and reduced apoptosis in the uterus and oviduct compared with the nicotine Group B (p<0.05. This study indicates that nicotine impairs the histology of the uterus and oviduct and co-administration of melatonin-nicotine ameliorates these findings, partly through alteration in ERalpha numbers and reduction of apoptosis

  5. Akt2 knockout mitigates chronic iNOS inhibition-induced cardiomyocyte atrophy and contractile dysfunction despite persistent insulin resistance.

    Science.gov (United States)

    Roe, Nathan D; Ren, Jun

    2011-12-15

    Increased levels of inducible nitric oxide synthase (iNOS) during cardiac stress such as ischemia-reperfusion, sepsis and hypertension may display both beneficial and detrimental roles in cardiac contractile performance. However, the precise role of iNOS in the maintenance of cardiac contractile function remains elusive. This study was designed to determine the impact of chronic iNOS inhibition on cardiac contractile function and the underlying mechanism involved with a special focus on the NO downstream signaling molecule Akt. Male C57 or Akt2 knockout [Akt2(-/-)] mice were injected with the specific iNOS inhibitor 1400W (2 mg/kg/d) or saline for 7 days. Both 1400W and Akt2 knockout dampened glucose and insulin tolerance without additive effects. Treatment of 1400W decreased heart and liver weights as well as cardiomyocyte cross-sectional area in C57 but not Akt2 knockout mice. 1400W but not Akt2 knockout compromised cardiomyocyte mechanical properties including decreased peak shortening and maximal velocity of shortening/relengthening, prolonged relengthening duration, reduced intracellular Ca(2+) release and decay rate, the effects of which were ablated or attenuated by Akt2 knockout. Akt2 knockout but not 1400W increased the levels of intracellular Ca(2+) regulatory proteins including SERCA2a and phospholamban phosphorylation. 1400W reduced the level of anti-apoptotic protein Bcl-2, the effect of which was unaffected by Akt2 knockout. Neither 1400W nor Akt2 knockout significantly affected ER stress, autophagy, the post-insulin receptor signaling Akt, GSK3β and AMPK, as well as the stress signaling IκB, JNK, ERK and p38 with the exception of elevated IκB phosphorylation with jointed effect of 1400W and Akt2 knockout. Taken together, these data indicated that an essential role of iNOS in the maintenance of cardiac morphology and function possibly through an Akt2-dependent mechanism. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  6. Induction of the imbalance of helper T-cell functions in mice exposed to diesel exhaust

    Energy Technology Data Exchange (ETDEWEB)

    Fujimaki, H.; Ushio, H.; Nohara, K. [Environmental Health Sciences Division, National Institute for Environmental Studies, 16-2, Onogawa, Tsukuba, 305 Ibaraki (Japan); Ui, N. [The Jikei University School of Medicine, Minatoku, Tokyo (Japan)

    2001-04-10

    Administration of diesel exhaust particles (DEP) increases antigen-specific IgE production and IgE-secreting cells, and induces Th2-type cytokine profiles in the airway in mice and humans. To determine the early effects of diesel exhaust (DE) inhalation on the cytokine production profile, BALB/c mice were exposed to 0 (controls) and 1.0 mg/m{sup 3} DE inhalation for 4 weeks. Intraperitoneal sensitization with ovalbumin (OVA) was conducted immediately before DE inhalation. Mice were treated with anti-CD4 or anti-CD8 mAb 1 day before and after the sensitization. On day 21, these mice were boosted with OVA and blood; bronchoalveolar lavage (BAL) fluid, and spleens were collected on day 28. In BAL fluid, both TNF{alpha} and IL-10 production in DE-exposed and control mice remained basically the same. IL-6 production in the anti-CD4 treatment group of DE-exposed mice, however, significantly increased compared with that of the controls. In vitro antigen-stimulated interleukin-4 (IL-4) and -10 (IL-10) production in spleen cells of exposed mice were not affected by low-dose DE inhalation. In vitro interferon (IFN)-{gamma} production in the anti-CD4 treated group of exposed mice decreased markedly. Although anti-OVA IgE production in the plasma of sham-treated mice exposed to DE was the same level as for controls, anti-CD4 mAb treatment in DE-exposed mice significantly reduced IgE production compared to controls. In anti-OVA IgG1 production, anti-CD4 or anti-CD8 mAb treatment in DE-exposed groups also significantly reduced. Anti-OVA IgG2a production was reduced by treatment with anti-CD4 mAb, but increased by anti-CD8 mAb treatment in DE-exposed mice. Low dose DE inhalation is thus shown to adversely affect the cytokine and antibody production in mice by altering CD4{sup +} and CD8{sup +} T-cell functions.

  7. RAG1/2 knockout pigs with severe combined immunodeficiency.

    Science.gov (United States)

    Huang, Jiao; Guo, Xiaogang; Fan, Nana; Song, Jun; Zhao, Bentian; Ouyang, Zhen; Liu, Zhaoming; Zhao, Yu; Yan, Quanmei; Yi, Xiaoling; Schambach, Axel; Frampton, Jon; Esteban, Miguel A; Yang, Dongshan; Yang, Huaqiang; Lai, Liangxue

    2014-08-01

    Pigs share many physiological, biochemical, and anatomical similarities with humans and have emerged as valuable large animal models for biomedical research. Considering the advantages in immune system resemblance, suitable size, and longevity for clinical practical and monitoring purpose, SCID pigs bearing dysfunctional RAG could serve as important experimental tools for regenerative medicine, allograft and xenograft transplantation, and reconstitution experiments related to the immune system. In this study, we report the generation and phenotypic characterization of RAG1 and RAG2 knockout pigs using transcription activator-like effector nucleases. Porcine fetal fibroblasts were genetically engineered using transcription activator-like effector nucleases and then used to provide donor nuclei for somatic cell nuclear transfer. We obtained 27 live cloned piglets; among these piglets, 9 were targeted with biallelic mutations in RAG1, 3 were targeted with biallelic mutations in RAG2, and 10 were targeted with a monoallelic mutation in RAG2. Piglets with biallelic mutations in either RAG1 or RAG2 exhibited hypoplasia of immune organs, failed to perform V(D)J rearrangement, and lost mature B and T cells. These immunodeficient RAG1/2 knockout pigs are promising tools for biomedical and translational research.

  8. Hematological changes in mice exposed to biting of the bedbug: Cimex lectularius L. (Hemiptera: Cimicidae).

    Science.gov (United States)

    Abdel-Hamid, Yousrya M; Soliman, Mohamed I

    2010-12-01

    The studies on hematologic changes in humans or animals as a result of bedbug bites are lacking. This study was undertaken to examine changes in the blood picture of mice (Mus musculus) exposed to Cimex lectularius biting. As compared to the check animals, mice exposed to bedbug bites either once or twice within 7 days showed insignificantly higher WBC's (1.6 and 2.8% increase, respectively) and lower HGB content (0.5 and 0.8% decrease, respectively) and significantly higher PLT's (P < 0.01) by 2.2% and 3.0%, respectively. Significantly higher (P < 0.01) RBC's counts in mice bitten once than those of normal animals or those exposed to twice bites (5.3 and 5.9% increase, respectively). Bedbug biting exerts its effects largely upon the differential WBC's. Mice bitten once or twice showed significantly lower number of neutrophils (1.2% & 12.1% decrease, respectively) than those for normal animals. Mice exposed to twice bites showed significantly (P < 0.01) higher numbers of lymphocyte (18.8%), monocyte (13.6%), eosinophil (200.0%) and basophil (500%) than those of normal mice.

  9. Behavioral changes in female Swiss mice exposed to tannery effluents

    Directory of Open Access Journals (Sweden)

    Sabrina Ferreira de Almeida

    2016-06-01

    Full Text Available Among the anthropic activities generating potentially toxic residues are those involved with bovine hide processing (tannery industries. However, knowledge is scant regarding the damage caused to the health of various organisms by tannery waste and studies are rare, especially in mammalian experimental models. This study therefore aimed to evaluate the physical and behavioral effects of the exposure of female Swiss mice to tannery effluent. To accomplish this, for a period of 15 days the animals were fed tannery effluent diluted with water in the following concentrations: 0% (control group, received only potable water, 5% and 10%. The body mass of the animals was evaluated at the beginning and end of the experiment, as well as the daily consumption of water and food. After 15 days of exposure to the effluent, the animals were submitted to the elevated plus maze (predictive of anxiety and the forced swim test (predictive of depression. The treatments did not affect the animals' body mass, either in eating behavior or in consumption of water. However, it was found that the animals that ingested tannery effluent concentrations of 5% and 10% exhibited an anxiolytic (lower level of anxiety, greater percentage of time in the open arms, longer time and frequency in the diving behavior, less time of lurks and less frequency of freezing and an antidepressant effect (more time in climbing behavior and less time of immobility when compared to the control group. It was concluded that the exposure of female Swiss mice to tannery effluents (5% and 10% diluted with water causes behavioral changes, possibly related to the neurotoxicity of this waste, without causing physical changes in the animals.

  10. Ozone increases airway hyperreactivity and mucus hyperproduction in mice previously exposed to allergen

    DEFF Research Database (Denmark)

    Larsen, Søren T; Matsubara, Shigeki; McConville, Glen

    2010-01-01

    Acute exacerbations of asthma represent a common clinical problem with major economic impact. Air pollutants including ozone have been shown to contribute to asthma exacerbation, but the mechanisms underlying ozone-induced asthma exacerbation are only partially understood. The present study aimed...... exposure to clean air or 100, 250, or 500 ppb ozone. Ozone induced AHR in mice previously exposed to OVA when compared to non-exposed (saline) control mice. After a 10-d exposure to OVA, a single exposure to a low (100 ppb) ozone concentration was sufficient to induce AHR. The AHR response was associated...... with goblet-cell metaplasia. Even the lowest concentration of ozone tested, 100 ppb, which may be exceeded in urban environments and in the workplace, resulted in a significant increase in AHR, most prominent 24 h after exposure in the OVA-exposed mice....

  11. Regional Heterogeneity in Murine Lung Fibroblasts from Normal Mice or Mice Exposed Once to Cigarette Smoke

    Science.gov (United States)

    Preobrazhenska, Olena; Wright, Joanne L.; Churg, Andrew

    2012-01-01

    Chronic obstructive lung disease (COPD) is characterized by matrix deposition in the small airways but matrix loss from the parenchyma, phenomena which must depend on the ability of local fibroblasts to produce matrix after smoke exposure. To investigate this idea, we exposed C57Bl/6 mice once to cigarette smoke or to air (control) and prepared primary cultures of lung fibroblasts by microdissecting large airways (trachea, LAF), medium size airways (major bronchi, MAF) and parenchyma (PF). Control PF showed the lowest rate of wound closure and wound closure was depressed in all lines by a single in vivo smoke exposure. Gene expression of matrix proteins differed considerably among the sites; decorin, which may sequester TGFβ, was markedly higher in PF. PF showed higher intrinsic ratios of pSmad2/Smad2. Smoke caused much greater increases in secreted and matrix deposited collagens 1 and 3 in PF than in LAF or MAF. Expression of Thy-1, a gene that suppresses myofibroblast differentiation, was increased by smoke in PF. We conclude that there is considerable regional heterogeneity in murine lung fibroblasts in terms of matrix production, either basally or after in vivo smoke exposure; that PF have lower ability to repair wounds and higher intrinsic TGFβ signaling; and that a single exposure to smoke produces lasting changes in the pattern of matrix production and wound repair, changes that may be mediated in part by smoke-induced release of TGFβ. However, PF still retain the ability to repair by producing new matrix after a single in vivo smoke exposure. PMID:22761892

  12. Gene expression profile in bone marrow and hematopoietic stem cells in mice exposed to inhaled benzene

    Energy Technology Data Exchange (ETDEWEB)

    Faiola, Brenda; Fuller, Elizabeth S.; Wong, Victoria A.; Recio, Leslie

    2004-05-18

    Acute myeloid leukemia and chronic lymphocytic leukemia are associated with benzene exposure. In mice, benzene induces chromosomal breaks as a primary mode of genotoxicity in the bone marrow (BM). Benzene-induced DNA lesions can lead to changes in hematopoietic stem cells (HSC) that give rise to leukemic clones. To gain insight into the mechanism of benzene-induced leukemia, we investigated the DNA damage repair and response pathways in total bone marrow and bone marrow fractions enriched for HSC from male 129/SvJ mice exposed to benzene by inhalation. Mice exposed to 100 ppm benzene for 6 h per day, 5 days per week for 2 week showed significant hematotoxicity and genotoxicity compared to air-exposed control mice. Benzene exposure did not alter the level of apoptosis in BM or the percentage of HSC in BM. RNA isolated from total BM cells and the enriched HSC fractions from benzene-exposed and air-exposed mice was used for microarray analysis and quantitative real-time RT-PCR. Interestingly, mRNA levels of DNA repair genes representing distinct repair pathways were largely unaffected by benzene exposure, whereas altered mRNA expression of various apoptosis, cell cycle, and growth control genes was observed in samples from benzene-exposed mice. Differences in gene expression profiles were observed between total BM and HSC. Notably, p21 mRNA was highly induced in BM but was not altered in HSC following benzene exposure. The gene expression pattern suggests that HSC isolated immediately following a 2 weeks exposure to 100 ppm benzene were not actively proliferating. Understanding the toxicogenomic profile of the specific target cell population involved in the development of benzene-associated diseases may lead to a better understanding of the mechanism of benzene-induced leukemia and may identify important interindividual and tissue susceptibility factors.

  13. Exacerbation of Soft Tissue Lesions in Lead Exposed Virus Infected Mice

    Institute of Scientific and Technical Information of China (English)

    PRATIBHA GUPTA; M. M. HUSAIN; RAVI SHANKER; R. K. S. DOGRA; P. K. SETH; R. K. MAHESHWARI

    2003-01-01

    Objective To investigate the effect of Lead (Pb) acetate exposure on Semliki forest virus (SFV)pathogenesis in mice. Methods Different doses (62.5, 125, 250 and 500 mg/Kg body weight) of Pb dissolved in normal saline were given to mice by oral intubation in a sub-acute (28 days) and sub-chronic (90 days) regimen followed by SFV infection. Morbidity, mortality, clinical symptoms,mean survival time (MST), changes in body and organ weight, accumulation of lead in soft tissues,virus titre in brain and histopathological alterations were compared between lead exposed and infected groups. Results Early appearance of virus symptoms, increased mortality, decreased MST, enhanced SFV titre and greater tissue damage were observed in lead exposed-SFV-infected mice. Conclusion Pre-exposure to lead increases the susceptibility of mice towards SFV infection. Further studies are suggested in view of the persistence of lead in the environment and the possibility of infection bymicrobial pathogens.

  14. Factors that influence the suppression of pulmonary antibacterial defenses in mice exposed to ozone

    Energy Technology Data Exchange (ETDEWEB)

    Gilmour, M.I.; Park, P.; Doerfler, D.; Selgrade, M.J.K.

    1993-01-01

    Exposure to ozone (O3) has been shown to increase susceptibility of mice to bacterial infection; however, the underlying mechanism has not been well elucidated. The study investigated the effect of O3 exposure on the ability of mice to combat an infectious challenge of Streptococcus zooepidemicus. Following a 3-h exposure to either air, 0.4 ppm O3, or 0.8 ppm O3, 5- and 9-week-old mice received an aerosol infection of bacteria. Intrapulmonary killing of the bacteria was impaired in the O3-exposed mice. The effect was most severe at the higher dose of O3 in the younger mice, and showed good correlation to subsequent mortality assessed over a 20-day period. Alveolar macrophages (AM) from O3-exposed mice had an impaired ability to phagocytose the bacteria. Additionally, prostaglandin E2 (PGE2) levels, which are known to depress AM function, were increased in the bronchoalveolar lavage fluid of the younger mice following exposure to O3, while pretreatment with indomethacin in the drinking water blunted the increased of PGE2 and reduced O3 enhanced mortality from 53 to 33%. The data show that O3 inhalation can reduce the defensive capability of the murine lung and that this is associated with a reduction in AM phagocytosis. (Copyright (c) 1993 Taylor Francis.)

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

    Energy Technology Data Exchange (ETDEWEB)

    Aitken, R.; Wilson, R.A. (Univ. of York, Heslington (England))

    1989-12-01

    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.

  16. Spatial Cognition in Adult and Aged Mice Exposed to High-Fat Diet.

    Science.gov (United States)

    Kesby, James P; Kim, Jane J; Scadeng, Miriam; Woods, Gina; Kado, Deborah M; Olefsky, Jerrold M; Jeste, Dilip V; Achim, Cristian L; Semenova, Svetlana

    2015-01-01

    Aging is associated with a decline in multiple aspects of cognitive function, with spatial cognition being particularly sensitive to age-related decline. Environmental stressors, such as high-fat diet (HFD) exposure, that produce a diabetic phenotype and metabolic dysfunction may indirectly lead to exacerbated brain aging and promote the development of cognitive deficits. The present work investigated whether exposure to HFD exacerbates age-related cognitive deficits in adult versus aged mice. Adult (5 months old) and aged (15 months old) mice were exposed to control diet or HFD for three months prior to, and throughout, behavioral testing. Anxiety-like behavior in the light-dark box test, discrimination learning and memory in the novel object/place recognition tests, and spatial learning and memory in the Barnes maze test were assessed. HFD resulted in significant gains in body weight and fat mass content with adult mice gaining significantly more weight and adipose tissue due to HFD than aged mice. Weight gain was attributed to food calories sourced from fat, but not total calorie intake. HFD increased fasting insulin levels in all mice, but adult mice showed a greater increase relative to aged mice. Behaviorally, HFD increased anxiety-like behavior in adult but not aged mice without significantly affecting spatial cognition. In contrast, aged mice fed either control or HFD diet displayed deficits in novel place discrimination and spatial learning. Our results suggest that adult mice are more susceptible to the physiological and anxiety-like effects of HFD consumption than aged mice, while aged mice displayed deficits in spatial cognition regardless of dietary influence. We conclude that although HFD induces systemic metabolic dysfunction in both adult and aged mice, overall cognitive function was not adversely affected under the current experimental conditions.

  17. Spatial Cognition in Adult and Aged Mice Exposed to High-Fat Diet.

    Directory of Open Access Journals (Sweden)

    James P Kesby

    Full Text Available Aging is associated with a decline in multiple aspects of cognitive function, with spatial cognition being particularly sensitive to age-related decline. Environmental stressors, such as high-fat diet (HFD exposure, that produce a diabetic phenotype and metabolic dysfunction may indirectly lead to exacerbated brain aging and promote the development of cognitive deficits. The present work investigated whether exposure to HFD exacerbates age-related cognitive deficits in adult versus aged mice. Adult (5 months old and aged (15 months old mice were exposed to control diet or HFD for three months prior to, and throughout, behavioral testing. Anxiety-like behavior in the light-dark box test, discrimination learning and memory in the novel object/place recognition tests, and spatial learning and memory in the Barnes maze test were assessed. HFD resulted in significant gains in body weight and fat mass content with adult mice gaining significantly more weight and adipose tissue due to HFD than aged mice. Weight gain was attributed to food calories sourced from fat, but not total calorie intake. HFD increased fasting insulin levels in all mice, but adult mice showed a greater increase relative to aged mice. Behaviorally, HFD increased anxiety-like behavior in adult but not aged mice without significantly affecting spatial cognition. In contrast, aged mice fed either control or HFD diet displayed deficits in novel place discrimination and spatial learning. Our results suggest that adult mice are more susceptible to the physiological and anxiety-like effects of HFD consumption than aged mice, while aged mice displayed deficits in spatial cognition regardless of dietary influence. We conclude that although HFD induces systemic metabolic dysfunction in both adult and aged mice, overall cognitive function was not adversely affected under the current experimental conditions.

  18. Tularemia among free-ranging mice without infection of exposed humans, Switzerland, 2012.

    Science.gov (United States)

    Origgi, Francesco C; König, Barbara; Lindholm, Anna K; Mayor, Désirée; Pilo, Paola

    2015-01-01

    The animals primarily infected by Francisella tularensis are rapidly consumed by scavengers, hindering ecologic investigation of the bacterium. We describe a 2012 natural tularemia epizootic among house mice in Switzerland and the assessment of infection of exposed humans. The humans were not infected, but the epizootic coincided with increased reports of human cases in the area.

  19. Inflammation but no DNA (deoxyribonucleic acid) damage in mice exposed to airborne dust from a biofuel plant

    DEFF Research Database (Denmark)

    Madsen, Anne Mette; Saber, Anne Thoustrup; Nordly, Pernille

    2008-01-01

    . The levels of DNA strand breaks in broncheoalveolar lavage (BAL) cells from the mice exposed to dust did not differ from those in the control samples. Conclusions The results indicate that the instillation of dust from a biofuel plant, at doses corresponding to 2 weeks of exposure to human endotoxins...... not been studied in detail. This study investigated whether exposure to dust from biofuel plants induces DNA (deoxyribonucleic acid) damage and inflammation in exposed mice. Methods DNA damage and inflammation were evaluated in mice exposed through the intratracheal installation of airborne dust collected...... at a biofuel plant at the straw storage hall and in the boiler room. The mice were given either a single dose of dust (18 or 54 mu g) or four doses of 54 mu g on each of four consecutive days. Control mice were exposed to a 0.9% sodium chloride solution. Results In the mice exposed to 4 x 54 mu g of dust...

  20. Potent carcinogenicity of cigarette smoke in mice exposed early in life.

    Science.gov (United States)

    Balansky, Roumen; Ganchev, Gancho; Iltcheva, Marietta; Steele, Vernon E; D'Agostini, Francesco; De Flora, Silvio

    2007-10-01

    In spite of the dominant role of cigarette smoke (CS) in cancer epidemiology, all studies performed during the past 60 years have shown that this complex mixture is either negative or weakly tumorigenic in experimental animals. We implemented studies aimed at evaluating whether exposure of mice early in life may enhance susceptibility to CS carcinogenicity. A total of 98 newborn Swiss albino mice were either untreated (controls) or received a subcutaneous injection of benzo(a)pyrene [B(a)P] (positive control) or were exposed whole-body to mainstream cigarette smoke (MCS) for 120 days, starting within 12 h after birth. Complete necropsy and histopathological analyses were performed at periodical intervals. In contrast with the lack of lung tumors in controls, MCS-exposed mice developed microscopically detectable tumors, starting only 75 days after birth and reaching an overall incidence of 78.3% after 181-230 days. The mean lung tumor multiplicities were 6.1 and 13.6 tumors per mouse in males and females, respectively, showing a significant intergender difference. Most tumors were microadenomas or adenomas, but 18.4% of the mice additionally had malignant lung cancer. MCS also induced bronchial and alveolar epithelial hyperplasia, and blood vessel proliferation. Furthermore, malignant tumors, some of which may have a metastatic origin, were detected in the urinary tract and liver of MCS-exposed mice. A somewhat different spectrum of tumors was observed in B(a)P-treated mice. In conclusion, MCS is a potent and broad spectrum carcinogen in mice when exposure starts early in life, covering stages of life corresponding to neonatal, childhood and adolescence periods in humans. This animal model will be useful to explore the mechanisms involved in CS-induced carcinogenesis and to investigate the protective effects of dietary agents and chemopreventive drugs.

  1. Factors that influence the suppression of pulmonary antibacterial defenses in mice exposed to ozone

    Energy Technology Data Exchange (ETDEWEB)

    Gilmour, M.I.; Park, P.; Doerfler, D.; Selgrade, M.K. (Univ. of North Carolina, Chapel Hill (United States))

    1993-05-01

    Exposure to ozone (O3) has been shown to increase susceptibility of mice to bacterial infection; however, the underlying mechanism has not been well elucidated. This study investigated the effect of O3 exposure on the ability of mice to combat an infectious challenge of Streptococcus zooepidemicus. Following a 3-h exposure to either air, 0.4 ppm O3, or 0.8 ppm O3, 5- and 9-week-old mice received an aerosol infection of bacteria. Intrapulmonary killing of the bacteria was impaired in the O3-exposed mice. The effect was most severe at the higher dose of O3 in the younger mice, and showed good correlation to subsequent mortality assessed over a 20-day period. Alveolar macrophages (AM) from O3-exposed mice had an impaired ability to phagocytose the bacteria. Additionally, prostaglandin E2 (PGE2) levels, which are known to depress AM function, were increased in the bronchoalveolar lavage fluid of the younger mice following exposure to O3, while pretreatment with indomethacin in the drinking water blunted the increased of PGE2 and reduced O3 enhanced mortality from 53 to 33%. The data show that O3 inhalation can reduce the defensive capability of the murine lung and that this is associated with a reduction in AM phagocytosis. The defect is more marked in young mice, suggesting that they may be more susceptible to oxidant exposure. Further studies are required to distinguish between direct toxicity of O3 on the AM and indirect suppression due to modulation of pharmacologic or inflammatory mediators.

  2. TNF-α and temporal changes in sleep architecture in mice exposed to sleep fragmentation.

    Science.gov (United States)

    Kaushal, Navita; Ramesh, Vijay; Gozal, David

    2012-01-01

    TNF-α plays critical roles in host-defense, sleep-wake regulation, and the pathogenesis of various disorders. Increases in the concentration of circulating TNF-α after either sleep deprivation or sleep fragmentation (SF) appear to underlie excessive daytime sleepiness in patients with sleep apnea (OSA). Following baseline recordings, mice were subjected to 15 days of SF (daily for 12 h/day from 07.00 h to 19.00 h), and sleep parameters were recorded on days1, 7 and 15. Sleep architecture and sleep propensity were assessed in both C57BL/6J and in TNF-α double receptor KO mice (TNFR KO). To further confirm the role of TNF-α, we also assessed the effect of treatment with a TNF- α neutralizing antibody in C57BL/6J mice. SF was not associated with major changes in global sleep architecture in C57BL/6J and TNFR KO mice. TNFR KO mice showed higher baseline SWS delta power. Further, following 15 days of SF, mice injected with TNF-α neutralizing antibody and TNFR KO mice showed increased EEG SWS activity. However, SWS latency, indicative of increased propensity to sleep, was only decreased in C57BL/6J, and was unaffected in TNFR KO mice as well as in C57BL/6J mice exposed to SF but treated with TNF-α neutralizing antibody. Taken together, our findings show that the excessive sleepiness incurred by recurrent arousals during sleep may be due to activation of TNF-alpha-dependent inflammatory pathways, despite the presence of preserved sleep duration and global sleep architecture.

  3. TNF-α and temporal changes in sleep architecture in mice exposed to sleep fragmentation.

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    Navita Kaushal

    Full Text Available TNF-α plays critical roles in host-defense, sleep-wake regulation, and the pathogenesis of various disorders. Increases in the concentration of circulating TNF-α after either sleep deprivation or sleep fragmentation (SF appear to underlie excessive daytime sleepiness in patients with sleep apnea (OSA. Following baseline recordings, mice were subjected to 15 days of SF (daily for 12 h/day from 07.00 h to 19.00 h, and sleep parameters were recorded on days1, 7 and 15. Sleep architecture and sleep propensity were assessed in both C57BL/6J and in TNF-α double receptor KO mice (TNFR KO. To further confirm the role of TNF-α, we also assessed the effect of treatment with a TNF- α neutralizing antibody in C57BL/6J mice. SF was not associated with major changes in global sleep architecture in C57BL/6J and TNFR KO mice. TNFR KO mice showed higher baseline SWS delta power. Further, following 15 days of SF, mice injected with TNF-α neutralizing antibody and TNFR KO mice showed increased EEG SWS activity. However, SWS latency, indicative of increased propensity to sleep, was only decreased in C57BL/6J, and was unaffected in TNFR KO mice as well as in C57BL/6J mice exposed to SF but treated with TNF-α neutralizing antibody. Taken together, our findings show that the excessive sleepiness incurred by recurrent arousals during sleep may be due to activation of TNF-alpha-dependent inflammatory pathways, despite the presence of preserved sleep duration and global sleep architecture.

  4. Quercetin prevents progression of disease in elastase/LPS-exposed mice by negatively regulating MMP expression

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    Martinez Fernando J

    2010-09-01

    Full Text Available Abstract Background Chronic obstructive pulmonary disease (COPD is characterized by chronic bronchitis, emphysema and irreversible airflow limitation. These changes are thought to be due to oxidative stress and an imbalance of proteases and antiproteases. Quercetin, a plant flavonoid, is a potent antioxidant and anti-inflammatory agent. We hypothesized that quercetin reduces lung inflammation and improves lung function in elastase/lipopolysaccharide (LPS-exposed mice which show typical features of COPD, including airways inflammation, goblet cell metaplasia, and emphysema. Methods Mice treated with elastase and LPS once a week for 4 weeks were subsequently administered 0.5 mg of quercetin dihydrate or 50% propylene glycol (vehicle by gavage for 10 days. Lungs were examined for elastance, oxidative stress, inflammation, and matrix metalloproteinase (MMP activity. Effects of quercetin on MMP transcription and activity were examined in LPS-exposed murine macrophages. Results Quercetin-treated, elastase/LPS-exposed mice showed improved elastic recoil and decreased alveolar chord length compared to vehicle-treated controls. Quercetin-treated mice showed decreased levels of thiobarbituric acid reactive substances, a measure of lipid peroxidation caused by oxidative stress. Quercetin also reduced lung inflammation, goblet cell metaplasia, and mRNA expression of pro-inflammatory cytokines and muc5AC. Quercetin treatment decreased the expression and activity of MMP9 and MMP12 in vivo and in vitro, while increasing expression of the histone deacetylase Sirt-1 and suppressing MMP promoter H4 acetylation. Finally, co-treatment with the Sirt-1 inhibitor sirtinol blocked the effects of quercetin on the lung phenotype. Conclusions Quercetin prevents progression of emphysema in elastase/LPS-treated mice by reducing oxidative stress, lung inflammation and expression of MMP9 and MMP12.

  5. Mitochondrial dysfunction contributes to alveolar developmental arrest in hyperoxia-exposed mice.

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    Ratner, Veniamin; Starkov, Anatoly; Matsiukevich, Dzmitry; Polin, Richard A; Ten, Vadim S

    2009-05-01

    This study investigated whether mitochondrial dysfunction contributes to alveolar developmental arrest in a mouse model of bronchopulmonary dysplasia (BPD). To induce BPD, 3-day-old mice were exposed to 75% O2. Mice were studied at two time points of hyperoxia (72 h or 2 wk) and after 3 weeks of recovery in room air (RA). A separate cohort of mice was exposed to pyridaben, a complex-I (C-I) inhibitor, for 72 hours or 2 weeks. Alveolarization was quantified by radial alveolar count and mean linear intercept methods. Pulmonary mitochondrial function was defined by respiration rates, ATP-production rate, and C-I activity. At 72 hours, hyperoxic mice demonstrated significant inhibition of C-I activity, reduced respiration and ATP production rates, and significantly decreased radial alveolar count compared with controls. Exposure to pyridaben for 72 hours, as expected, caused significant inhibition of C-I and ADP-phosphorylating respiration. Similar to hyperoxic littermates, these pyridaben-exposed mice exhibited significantly delayed alveolarization compared with controls. At 2 weeks of exposure to hyperoxia or pyridaben, mitochondrial respiration was inhibited and associated with alveolar developmental arrest. However, after 3 weeks of recovery from hyperoxia or 2 weeks after 72 hours of exposure to pyridaben alveolarization significantly improved. In addition, there was marked normalization of C-I and mitochondrial respiration. The degree of hyperoxia-induced pulmonary simplification and recovery strongly (r(2) = 0.76) correlated with C-I activity in lung mitochondria. Thus, the arrest of alveolar development induced by either hyperoxia or direct inhibition of mitochondrial oxidative phosphorylation indicates that bioenergetic failure to maintain normal alveolar development is one of the fundamental mechanisms responsible for BPD.

  6. Effect of adiponectin deficiency on intestinal damage and hematopoietic responses of mice exposed to gamma radiation

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    Ponemone, Venkatesh; Fayad, Raja; Gove, Melissa E.; Pini, Maria [Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612 (United States); Fantuzzi, Giamila, E-mail: giamila@uic.edu [Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612 (United States)

    2010-08-07

    Adiponectin (APN) is an adipose tissue-derived cytokine that regulates insulin sensitivity and inflammation. It is also involved in modulation of cell proliferation by binding to various growth factors. Based on its known effects in modulating cell proliferation and oxidative stress, APN may potentially be involved in regulating tissue damage and repair following irradiation. Adiponectin KO mice and their WT littermates were exposed to a single whole-body dose of 3 or 6 Gy gamma radiation. Radiation-induced alterations were studied in jejunum, blood, bone marrow and thymus at days 1 and 5 post-irradiation and compared with sham-irradiated groups. In WT mice, irradiation did not significantly alter serum APN levels while inducing a significant decrease in serum leptin. Irradiation caused a significant reduction in thymocyte cellularity, with concomitant decrease in CD4{sup +}, CD8{sup +} and CD4{sup +}CD8{sup +} T cell populations, with no significant differences between WT and APN KO mice. Irradiation resulted in a significantly higher increase in the frequency of micronucleated reticulocytes in the blood of APN KO compared with WT mice, whereas frequency of micronucleated normochromatic erythrocytes in the bone marrow at day 5 was significantly higher in WT compared with APN KO mice. Finally, irradiation induced similar alterations in villus height and crypt cell proliferation in the jejunum of WT and APN KO mice. Jejunum explants from sham-irradiated APN KO mice produced higher levels of IL-6 compared with tissue from WT animals, but the difference was no longer apparent following irradiation. Our data indicate that APN deficiency does not play a significant role in modulating radiation-induced gastrointestinal injury in mice, while it may participate in regulation of damage to the hematopoietic system.

  7. Methionine stimulates motor impairment and cerebellar mercury deposition in methylmercury-exposed mice.

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    Zimmermann, Luciana T; dos Santos, Danúbia B; Colle, Dirleise; dos Santos, Alessandra A; Hort, Mariana A; Garcia, Solange C; Bressan, Lucas Paines; Bohrer, Denise; Farina, Marcelo

    2014-01-01

    Methylmercury (MeHg) is a highly toxic environmental contaminant that produces neurological and developmental impairments in animals and humans. Although its neurotoxic properties have been widely reported, the molecular mechanisms by which MeHg enters the cells and exerts toxicity are not yet completely understood. Taking into account that MeHg is found mostly bound to sulfhydryl-containing molecules such as cysteine in the environment and based on the fact that the MeHg-cysteine complex (MeHg-S-Cys) can be transported via the L-type neutral amino acid carrier transport (LAT) system, the potential beneficial effects of L-methionine (L-Met, a well known LAT substrate) against MeHg (administrated as MeHg-S-Cys)-induced neurotoxicity in mice were investigated. Mice were exposed to MeHg (daily subcutaneous injections of MeHg-S-Cys, 10 mg Hg/kg) and/or L-Met (daily intraperitoneal injections, 250 mg/kg) for 10 consecutive days. After treatments, the measured hallmarks of toxicity were mostly based on behavioral parameters related to motor performance, as well as biochemical parameters related to the cerebellar antioxidant glutathione (GSH) system. MeHg significantly decreased motor activity (open-field test) and impaired motor performance (rota-rod task) compared with controls, as well as producing disturbances in the cerebellar antioxidant GSH system. Interestingly, L-Met administration did not protect against MeHg-induced behavioral and cerebellar changes, but rather increased motor impairments in animals exposed to MeHg. In agreement with this observation, cerebellar levels of mercury (Hg) were higher in animals exposed to MeHg plus L-Met compared to those only exposed to MeHg. However, this event was not observed in kidney and liver. These results are the first to demonstrate that L-Met enhances cerebellar deposition of Hg in mice exposed to MeHg and that this higher deposition may be responsible for the greater motor impairment observed in mice simultaneously

  8. Neurobehavioral phenotype of C57BL/6J mice prenatally and neonatally exposed to cigarette smoke.

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    Amos-Kroohs, Robyn M; Williams, Michael T; Braun, Amanda A; Graham, Devon L; Webb, Cynthia L; Birtles, Todd S; Greene, Robert M; Vorhees, Charles V; Pisano, M Michele

    2013-01-01

    Although maternal cigarette smoking during pregnancy is a well-documented risk factor for a variety of adverse pregnancy outcomes, how prenatal cigarette smoke exposure affects postnatal neurobehavioral/cognitive development remains poorly defined. In order to investigate the cause of an altered behavioral phenotype, mice developmentally exposed to a paradigm of 'active' maternal cigarette smoke is needed. Accordingly, cigarette smoke exposed (CSE) and air-exposed C57BL/6J mice were treated for 6h per day in paired inhalation chambers throughout gestation and lactation and were tested for neurobehavioral effects while controlling for litter effects. CSE mice exhibited less than normal anxiety in the elevated zero maze, transient hypoactivity during a 1h locomotor activity test, had longer latencies on the last day of cued Morris water maze testing, impaired hidden platform learning in the Morris water maze during acquisition, reversal, and shift trials, and impaired retention for platform location on probe trials after reversal but not after acquisition or shift. CSE mice also showed a sexually dimorphic response in central zone locomotion to a methamphetamine challenge (males under-responded and females over-responded), and showed reduced anxiety in the light-dark test by spending more time on the light side. No differences on tests of marble burying, acoustic startle response with prepulse inhibition, Cincinnati water maze, matching-to-sample Morris water maze, conditioned fear, forced swim, or MK-801-induced locomotor activation were found. Collectively, the data indicate that developmental cigarette smoke exposure induces subnormal anxiety in a novel environment, impairs spatial learning and reference memory while sparing other behaviors (route-based learning, fear conditioning, and forced swim immobility). The findings add support to mounting evidence that developmental cigarette smoke exposure has long-term adverse effects on brain function. Copyright © 2013

  9. Neuroprotective effects of sildenafil against oxidative stress and memory dysfunction in mice exposed to noise stress.

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    Sikandaner, Hu Erxidan; Park, So Young; Kim, Min Jung; Park, Shi Nae; Yang, Dong Won

    2017-02-15

    Noise exposure has been well characterized as an environmental stressor, and is known to have auditory and non-auditory effects. Phosphodiesterase 5 (PDE5) inhibitors affect memory and hippocampus plasticity through various signaling cascades which are regulated by cGMP. In this study, we investigated the effects of sildenafil on memory deficiency, neuroprotection and oxidative stress in mice caused by chronic noise exposure. Mice were exposed to noise for 4h every day up to 14days at 110dB SPL of noise level. Sildenafil (15mg/kg) was orally administered 30min before noise exposure for 14days. Behavioral assessments were performed using novel object recognition (NOR) test and radial arm maze (RAM) test. Higher levels of memory dysfunction and oxidative stress were observed in noise alone-induced mice compared to control group. Interestingly, sildenafil administration increased memory performance, decreased oxidative stress, and increased neuroprotection in the hippocampus region of noise alone-induced mice likely through affecting memory related pathways such as cGMP/PKG/CREB and p25/CDK5, and induction of free radical scavengers such as SOD1, SOD2, SOD3, Prdx5, and catalase in the brain of stressed mice.

  10. Exacerbation of allergic inflammation in mice exposed to diesel exhaust particles prior to viral infection

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    Chason Kelly D

    2009-08-01

    Full Text Available Abstract Background Viral infections and exposure to oxidant air pollutants are two of the most important inducers of asthma exacerbation. Our previous studies have demonstrated that exposure to diesel exhaust increases the susceptibility to influenza virus infections both in epithelial cells in vitro and in mice in vivo. Therefore, we examined whether in the setting of allergic asthma, exposure to oxidant air pollutants enhances the susceptibility to respiratory virus infections, which in turn leads to increased virus-induced exacerbation of asthma. Ovalbumin-sensitized (OVA male C57BL/6 mice were instilled with diesel exhaust particles (DEP or saline and 24 hours later infected with influenza A/PR/8. Animals were sacrificed 24 hours post-infection and analyzed for markers of lung injury, allergic inflammation, and pro-inflammatory cytokine production. Results Exposure to DEP or infection with influenza alone had no significant effects on markers of injury or allergic inflammation. However, OVA-sensitized mice that were exposed to DEP and subsequently infected with influenza showed increased levels of eosinophils in lung lavage and tissue. In addition Th2-type cytokines, such as IL-4 and IL-13, and markers of eosinophil chemotaxis, such as CCL11 and CCR3, were increased in OVA-sensitized mice exposed to DEP prior to infection with influenza. These mice also showed increased levels of IL-1α, but not IL-10, RANTES, and MCP-1 in lung homogenates. Conclusion These data suggest that in the setting of allergic asthma, exposure to diesel exhaust could enhance virus-induced exacerbation of allergic inflammation.

  11. Cytogenetic damage in adult and newborn mice exposed to Elf magnetic fields

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    Ieradi, L.A. [Istituto per lo Studio degli Ecosistemi, CNR, Rome (Italy); Udroiu, I.; Chiuchiarelli, G.; Migliorini, D.; Cristaldi, M. [Universite La Sapienza, Dipt. di Biologia Animale e dell' Uomo, Rome (Italy); Tanzarella, C. [Roma Univ., Dipt. di Biologia (Italy)

    2006-07-01

    Data obtained in newborn mice show that the chronic exposure during intra-uterine life to a 50 Hz, 650 {mu}T E.L.F. magnetic field induce a genetic damage. Nevertheless, the increase of DNA strand break in brain and in micronuclei frequency in peripheral blood and liver disagree with the data obtained by Abramsson-Zetterberg and Grawe (13) which did not find any genetic alterations in mice exposed to extremely low frequency (E.L.F.) magnetic field. In any case, along with other dissimilarities in the experimental design, the intensity of the field (14 {mu}T) and the time of sampling (35 days) were different. It is important to underline the four-fold increase in C.R.E.S.T.+ micronuclei frequency in circulating erythrocytes in the exposed group in comparison with the control group. Even though this value is quite low, it could indicate that E.L.F. magnetic fields may have different properties to damage the genome integrity. This stresses the need for further investigation on the possible link between electromagnetic fields and aneuploidy in order to elucidate the relationship with carcinogenesis. Preliminary data obtained with sperm abnormality assay show a significant increase of sperm abnormalities in mice exposed to E.L.F. magnetic fields and suggest a possible alteration to the spermatogenic process after exposure. This data agrees with data obtained by Tablado et al. (1998), in mice exposed continually for 35 days to a field of 1 T. Regarding the palatal ridges alterations assay, the results obtained show that the development of the secondary palate is not affected by E.L.F. magnetic field (50 Hz, 0,65 T). Nevertheless further studies at different frequency and intensity should be carried out to detect the possible epigenetic damage induced by E.L.F. exposure (Migliorini, 2005). With regard to the mechanism of action, it is generally believed that the damage induced by the magnetic field is an oxidative damage and that free radicals are involved. Some authors

  12. Environmental enrichment attenuates behavioral abnormalities in valproic acid-exposed autism model mice.

    Science.gov (United States)

    Yamaguchi, Hiroshi; Hara, Yuta; Ago, Yukio; Takano, Erika; Hasebe, Shigeru; Nakazawa, Takanobu; Hashimoto, Hitoshi; Matsuda, Toshio; Takuma, Kazuhiro

    2017-08-30

    We recently demonstrated that prenatal exposure to valproic acid (VPA) at embryonic day 12.5 causes autism spectrum disorder (ASD)-like phenotypes such as hypolocomotion, anxiety-like behavior, social deficits and cognitive impairment in mice and that it decreases dendritic spine density in the hippocampal CA1 region. Previous studies show that some abnormal behaviors are improved by environmental enrichment in ASD rodent models, but it is not known whether environmental enrichment improves cognitive impairment. In the present study, we examined the effects of early environmental enrichment on behavioral abnormalities and neuromorphological changes in prenatal VPA-treated mice. We also examined the role of dendritic spine formation and synaptic protein expression in the hippocampus. Mice were housed for 4 weeks from 4 weeks of age under either a standard or enriched environment. Enriched housing was found to increase hippocampal brain-derived neurotrophic factor mRNA levels in both control and VPA-exposed mice. Furthermore, in VPA-treated mice, the environmental enrichment improved anxiety-like behavior, social deficits and cognitive impairment, but not hypolocomotion. Prenatal VPA treatment caused loss of dendritic spines in the hippocampal CA1 region and decreases in mRNA levels of postsynaptic density protein-95 and SH3 and multiple ankyrin repeat domains 2 in the hippocampus. These hippocampal changes were improved by the enriched housing. These findings suggest that the environmental enrichment improved most ASD-like behaviors including cognitive impairment in the VPA-treated mice by enhancing dendritic spine function. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Reduced inflammatory response in cigarette smoke exposed Mrp1/Mdr1a/1b deficient mice

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    Postma Dirkje S

    2007-07-01

    Full Text Available Abstract Background Tobacco smoke is the principal risk factor for chronic obstructive pulmonary disease (COPD, though the mechanisms of its toxicity are still unclear. The ABC transporters multidrug resistance-associated protein 1 (MRP1 and P-glycoprotein (P-gp/MDR1 extrude a wide variety of toxic substances across cellular membranes and are highly expressed in bronchial epithelium. Their impaired function may contribute to COPD development by diminished detoxification of noxious compounds in cigarette smoke. Methods We examined whether triple knock-out (TKO mice lacking the genes for Mrp1 and Mdr1a/1b are more susceptible to develop COPD features than their wild-type (WT littermates. TKO and WT mice (six per group were exposed to 2 cigarettes twice daily by nose-only exposure or room air for 6 months. Inflammatory infiltrates were analyzed in lung sections, cytokines and chemokines in whole lung homogenates, emphysema by mean linear intercept. Multiple linear regression analysis with an interaction term was used to establish the statistical significances of differences. Results TKO mice had lower levels of interleukin (IL-7, KC (mouse IL-8, IL-12p70, IL-17, TNF-alpha, G-CSF, GM-CSF and MIP-1-alpha than WT mice independent of smoke exposure (P P P Conclusion Mrp1/Mdr1a/1b knock-out mice have a reduced inflammatory response to cigarette smoke. In addition, the expression levels of several cytokines and chemokines were also lower in lungs of Mrp1/Mdr1a/1b knock-out mice independent of smoke exposure. Further studies are required to determine whether dysfunction of MRP1 and/or P-gp contribute to the pathogenesis of COPD.

  14. Small Molecule Metabolite Biomarker Candidates in Urine from Mice Exposed to Formaldehyde

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    Juan Zhang

    2014-09-01

    Full Text Available Formaldehyde (FA is a ubiquitous compound used in a wide variety of industries, and is also a major indoor pollutant emitted from building materials, furniture, etc. Because FA is rapidly metabolized and endogenous to many materials, specific biomarkers for exposure have not been identified. In this study, we identified small metabolite biomarkers in urine that might be related FA exposure. Mice were allowed to inhale FA (0, 4, 8 mg/m3 6 h per day for 7 consecutive days, and urine samples were collected on the 7th day of exposure. Liquid chromatography coupled with time of flight-mass spectrometry and principal component analysis (PCA was applied to determine alterations of endogenous metabolites in urine. Additionally, immune toxicity studies were conducted to ensure that any resultant toxic effects could be attributed to inhalation of FA. The results showed a significant decrease in the relative rates of T lymphocyte production in the spleen and thymus of mice exposed to FA. Additionally, decreased superoxide dismutase activity and increased reactive oxygen species levels were found in the isolated spleen cells of exposed mice. A total of 12 small molecules were found to be altered in the urine, and PCA analysis showed that urine from the control and FA exposed groups could be distinguished from each other based on the altered molecules. Hippuric acid and cinnamoylglycine were identified in urine using exact mass and fragment ions. Our results suggest that the pattern of metabolites found in urine is significantly changed following FA inhalation, and hippuric acid and cinnamoylglycine might represent potential biomarker candidates for FA exposure.

  15. Behavioral differentiation of mice exposed to a water tank social interaction test.

    Science.gov (United States)

    Nejdi, A; Guastavino, J M; Lalonde, R; Desor, D; Krafft, B

    1996-02-01

    Male or female C57BL/6J mice were exposed to a water tank in which food could be obtained only by wading in the water towards a feeder. Behavioral differentiation occurred in that three distinct categories could be distinguished: major carriers (transporting over 80% of the food pellets), sporadic carriers (transporting less than 20% of the food pellets) and non-carriers. In the elevated + -maze, major carriers were more willing to explore open spaces than non-carriers. Sporadic carriers showed some evidence of the same tendency of decreased anxiety, but in a minor way. The willingness of mice to become carriers is associated with their willingness to explore novel areas. This test may be useful for the assessment of anxiolytic compounds in a social situation.

  16. Adult Behavior in Male Mice Exposed to E-Cigarette Nicotine Vapors during Late Prenatal and Early Postnatal Life.

    Directory of Open Access Journals (Sweden)

    Dani Smith

    Full Text Available Timed-pregnant C57BL/6J mice were exposed to 2.4% nicotine in propylene glycol (PG or 0% nicotine /PG once a day from gestational day 15 until delivery. After delivery, offspring and mothers were exposed to E-cigarette vapors for an additional 14 days from postnatal day 2 through 16. Following their last exposure serum cotinine levels were measured in female juvenile mice. Male mice underwent behavioral testing at 14 weeks of age to assess sensorimotor, affective, and cognitive functional domains.Adult male mice exposed to 2.4% nicotine/PG E-cigarette vapors had significantly more head dips in the zero maze test and higher levels of rearing activity in the open field test compared to 0% nicotine/PG exposed mice and untreated controls. In the water maze test after reversal training, the 2.4% nicotine/PG mice spent more than 25% of time in the new location whereas the other groups did not.Adult male mice exhibited increased levels of activity in the zero maze and open field tests when exposed to E-cigarette vapor containing nicotine during late prenatal and early postnatal life. These findings indicate that nicotine exposure from E-cigarettes may cause persistent behavioral changes when exposure occurs during a period of rapid brain growth.

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

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    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.

  18. Streptococcus pneumoniae colonization is required to alter the nasal microbiota in cigarette smoke-exposed mice.

    Science.gov (United States)

    Shen, Pamela; Whelan, Fiona J; Schenck, L Patrick; McGrath, Joshua J C; Vanderstocken, Gilles; Bowdish, Dawn M E; Surette, Michael G; Stämpfli, Martin R

    2017-07-31

    Smokers have nasal microbiota dysbiosis, with an increased frequency of colonizing bacterial pathogens. It is possible that cigarette smoke increases pathogen acquisition by perturbing the microbiota and decreasing colonization resistance. However, it is difficult to disentangle microbiota dysbiosis due to cigarette smoke exposure from microbiota changes caused by increased pathogen acquisition in human smokers. Utilizing an experimental mouse model, we investigated the impact of cigarette smoke on the nasal microbiota in the absence and presence of nasal pneumococcal colonization. We observed that cigarette smoke exposure alone did not alter nasal microbiota composition. Microbiota composition was also unchanged at 12 hours following low dose nasal pneumococcal inoculation, suggesting the ability of the microbiota to resist initial nasal pneumococcal acquisition was not impaired in smoke-exposed mice. However, nasal microbiota dysbiosis occurred as a consequence of established high dose nasal pneumococcal colonization at day 3 in smoke-exposed mice. Similar to clinical reports in human smokers, we observed an enrichment of potentially pathogenic bacterial genera such as Fusobacterium, Gemella, and Neisseria Our findings suggest that cigarette smoke exposure predisposes to pneumococcal colonization independent of changes to the nasal microbiota, and microbiota dysbiosis observed in smokers may occur as a consequence of established pathogen colonization. Copyright © 2017 American Society for Microbiology.

  19. CCR2 knockout exacerbates cerulein-induced chronic pancreatitis with hyperglycemia via decreased GLP-1 receptor expression and insulin secretion.

    Science.gov (United States)

    Nakamura, Yuji; Kanai, Takanori; Saeki, Keita; Takabe, Miho; Irie, Junichiro; Miyoshi, Jun; Mikami, Yohei; Teratani, Toshiaki; Suzuki, Takahiro; Miyata, Naoteru; Hisamatsu, Tadakazu; Nakamoto, Nobuhiro; Yamagishi, Yoshiyuki; Higuchi, Hajime; Ebinuma, Hirotoshi; Hozawa, Shigenari; Saito, Hidetsugu; Itoh, Hiroshi; Hibi, Toshifumi

    2013-04-15

    Glucagon-like peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanism of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b(+)Gr-1(low) macrophages and pancreatic inflammation and significantly upregulated insulin secretion compared with paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b(+)/Gr-1(-) and CD11b(+)/Gr-1(high) cells, but not CD11b(+)/Gr-1(low) cells, in pancreas with severe inflammation and significantly decreased insulin secretion compared with their WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, GLP-1 receptor levels in pancreases of chronic cerulein-administered CCR2-KO mice were significantly lower than in paired WT mice. Nevertheless, a significantly higher hyperglycemia level in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b(+)-cell migration to the pancreas is critically involved in chronic pancreatitis-mediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion.

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

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    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.

  1. Cytokine expression in mice exposed to diesel exhaust particles by inhalation. Role of tumor necrosis factor

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    Loft Steffen

    2006-02-01

    Full Text Available Abstract Background Particulate air pollution has been associated with lung and cardiovascular disease, for which lung inflammation may be a driving mechanism. The pro-inflammatory cytokine, tumor necrosis factor (TNF has been suggested to have a key-role in particle-induced inflammation. We studied the time course of gene expression of inflammatory markers in the lungs of wild type mice and Tnf-/- mice after exposure to diesel exhaust particles (DEPs. Mice were exposed to either a single or multiple doses of DEP by inhalation. We measured the mRNA level of the cytokines Tnf and interleukin-6 (Il-6 and the chemokines, monocyte chemoattractant protein (Mcp-1, macrophage inflammatory protein-2 (Mip-2 and keratinocyte derived chemokine (Kc in the lung tissue at different time points after exposure. Results Tnf mRNA expression levels increased late after DEP-inhalation, whereas the expression levels of Il-6, Mcp-1 and Kc increased early. The expression of Mip-2 was independent of TNF if the dose was above a certain level. The expression levels of the cytokines Kc, Mcp-1 and Il-6, were increased in the absence of TNF. Conclusion Our data demonstrate that Tnf is not important in early DEP induced inflammation and rather exerts negative influence on Mcp-1 and Kc mRNA levels. This suggests that other signalling pathways are important, a candidate being one involving Mcp-1.

  2. Tissue distribution of DNA adducts and their persistence in blood of mice exposed to benzene

    Energy Technology Data Exchange (ETDEWEB)

    Guilan Li; Wang Chunguang; Songnian Yin [Institute of Occupational Medicine Chinese Academy of Preventive Medicine, Beijing (China); Weidong Xin [Medical College of Qingdao, Shandong Province (China)

    1996-12-01

    Chemicals combine with DNA, resulting in DNA damage, which could initiate carcinogenesis. To study whether benzene or benzene metabolites bind to DNA, DNA adducts in various tissues and their persistence in leukocytes were examined using the {sup 32}P-postlabeling assay. LACA mice were dosed in with benzene at 500 mg/kg bw twice daily for 5 days. Two additional spots of DNA adducts are formed in bone marrow cells, liver cells, and peripheral blood compared with control mice. The relative adduct labeling values are 10.39, 11.32, and 13.77 adducts; x 10{sup -8} nucleotides in these tissues, respectively. DNA adducts in blood leukocytes were observed at 1, 4, 7, 14, and 21 days after exposure to benzene, but adduct levels decreased as a function of time. Relative adduct labeling of {open_quotes}adduct B{close_quotes} declined linearly but mildly, while {open_quotes}adduct C{close_quotes} displayed a stepwise decrease. The relative adduct labeling values of both these adducts at day 14 were 50% of those at day 1 after the last treatment. Both adducts were still detectable at day 21 after benzene exposure. These studies demonstrate that benzene could induce DNA adducts; in bone marrow, liver, and white blood cells of mice dosed with benzene and that measurement of adducts in white blood cells may be useful as a biomarker to predict carcinogenic risk of benzene to workers exposed to benzene. 9 refs., 3 figs.

  3. Decreased fertility in mice exposed to environmental air pollution in the city of Sao Paulo.

    Science.gov (United States)

    Mohallem, Soraya Vecci; de Araújo Lobo, Débora Jã; Pesquero, Célia Regina; Assunção, João Vicente; de Andre, Paulo Afonso; Saldiva, Paulo Hilário Nascimento; Dolhnikoff, Marisa

    2005-06-01

    It has largely been shown that air pollution can affect human health. Effects on human fertility have been shown mainly in males by a decrease in semen quality. Few studies have focused on the environmental effects on female fertility. The aim of the present study was to analyze the effects of air pollution in the city of Sao Paulo on mouse female fertility. Four groups of female Balb/c mice were placed in two chambers 10 days (newborn) or 10 weeks (adults) after birth. Mice were maintained in the chambers 24 h a day, 7 days a week, for 4 months. The first chamber received air that had passed through an air filter (clean chamber) and the second received ambient air (polluted chamber). We measured PM10 and NO2 inside both chambers. Mice belonging to the adult groups were bred to male mice after living for 3 months inside the chambers. The newborn groups mated after reaching reproductive age (12 weeks). After 19 days of pregnancy the numbers of live-born pups, reabsorptions, fetal deaths, corpora lutea, and implantation failures were determined. PM10 and NO2 concentrations in the clean chamber were 50% and 77.5% lower than in the polluted chamber, respectively. Differences in fertility parameters between groups were observed only in animals exposed to air pollution at an early age (10 days after birth). We observed a higher number of live-born pups per animal in the clean chamber than per animal from the polluted chamber (median=6.0 and 4.0, respectively; P=0.037). There was a higher incidence of implantation failures in the polluted group than in the clean group (median=3.5 and 2.0, respectively; P=0.048). There were no significant differences in the other reproductive parameters between groups. These results support the concept that female reproductive health represents a target of air pollutants.

  4. Effect of intestinal microflora on the survival time of mice exposed to lethal whole-body. gamma. irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Onoue, M.; Uchida, K.; Yokokura, T.; Takahashi, T.; Mutai, M.

    1981-11-01

    The effect of intestinal microflora on the survival time of mice exposed to 2-kR whole-body ..gamma.. irradiation was studied using germfree, monoassociated, and conventionalized ICR mice. The germfree mice were monoassociated with 1 of 11 bacterial strains, which were isolated from the fresh feces of conventional mice, 2 weeks prior to irradiation. All mice died within 3 weeks after irradiation. Monoassociation with Fusobacterium sp., Streptococcus faecalis, Escherichia coli, or Pseudomonas sp. significantly reduced the mean survival time compared to that of germfree mice. In contrast, monoassociation with Clostridium sp., Bifidobacterium pseudolongum, or Lactobacillus acidophilus significantly prolonged the mean survival time compared to that of germfree mice. This suggests that the latter organisms may perform some activity to protect the mice from radiation injury. In this histopathological autopsy examination, the main lesions were hypocellularity in hematopoietic organs and hemorrhage in various organs. Neither karyorrhexis nor desquamation of intestinal mucosal cells was observed in any mice. From these observations, it is suggested that the death of these mice was related to hematopoietic damage. Bacterial invasion into various organs was observed in conventionalized and Pseudomonas-, E. coli-, or S. faecalis-monoassociated mice but not in Clostridium-, B. pseudolongum-, L. acidophilus-, or Fusobacterium-monoassociated mice.

  5. Statins do not alter the incidence of mesothelioma in asbestos exposed mice or humans.

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    Cleo Robinson

    Full Text Available Mesothelioma is principally caused by asbestos and may be preventable because there is a long latent period between exposure and disease development. The most at-risk are a relatively well-defined population who were exposed as a consequence of their occupations. Although preventative agents investigated so far have not been promising, discovery of such an agent would have a significant benefit world-wide on healthcare costs and personal suffering. Statins are widely used for management of hypercholesterolemia and cardiovascular risk; they can induce apoptosis in mesothelioma cells and epidemiological data has linked their use to a lower incidence of cancer. We hypothesised that statins would inhibit the development of asbestos-induced mesothelioma in mice and humans. An autochthonous murine model of asbestos-induced mesothelioma was used to test this by providing atorvastatin daily in the feed at 100 mg/kg, 200 mg/kg and 400 mg/kg. Continuous administration of atorvastatin did not alter the rate of disease development nor increase the length of time that mice survived. Latency to first symptoms of disease and disease progression were also unaffected. In a parallel study, the relationship between the use of statins and development of mesothelioma was investigated in asbestos-exposed humans. In a cohort of 1,738 asbestos exposed people living or working at a crocidolite mine site in Wittenoom, Western Australia, individuals who reported use of statins did not have a lower incidence of mesothelioma (HR = 1.01; 95% CI = 0.44-2.29, p = 0.99. Some individuals reported use of both statins and non-steroidal anti-inflammatory drugs or COX-2 inhibitors, and these people also did not have an altered risk of mesothelioma development (HR = 1.01; 95% CI = 0.61-1.67, p = 0.97. We conclude that statins do not moderate the rate of development of mesothelioma in either a mouse model or a human cohort exposed to asbestos.

  6. Histological Changes in the Lung and Liver Tissues in Mice Exposed to Pyrethroid Inhalation

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    Nadeem SHEIKH

    2013-12-01

    Full Text Available Cypermethrin, a type II pyrethroid, is one of the most widely used insecticides in Pakistan. It is considered to be a safe pesticide; however, the possible health hazards of this pyrethroid have been ignored. Cypermethrin may become an air pollutant and adversely affect the health of non-target organisms, leading to acute or chronic disorders. The present work aims to investigate the effects of cypermethrin on lung and liver tissues due to inhalation exposure. The study is performed on 16 mature Swiss albino mice, including controls. The animals are divided into 4 groups (4 mice each and exposed to 0.5 % dilution of cypermethrin in an inhalation chamber (40×35×25 cm3 for different time periods, whereas control animals are not exposed to any insecticide. The histopathological changes in lungs and liver tissues reveal that cypermethrin exposure induces time dependent changes in the liver and in the lungs. It damages the normal organization of liver tissues, causing liver injury due to necrosis, significant decrease in number of cells, and widening of sinusoids and fibrosis. Inhalation exposure of cypermethrin results in significant hyperplasia, clumping of cells and necrosis in the lungs. It also induces pulmonary edema, alveolitis, and pulmonary fibrosis by the deposition of collagen. Taking these findings together, it may be concluded that cypermethrin and other pyrethroids cause hazardous effects in non-target organisms through inhalation exposure. Serious efforts and awareness are required to monitor and reduce the insecticide induced health hazards in third world countries.doi:10.14456/WJST.2014.67

  7. Changes in Serum Adiponectin in Mice Chronically Exposed to Inorganic Arsenic in Drinking Water.

    Science.gov (United States)

    Song, Xuanbo; Li, Ying; Liu, Junqiu; Ji, Xiaohong; Zhao, Lijun; Wei, Yudan

    2017-02-11

    Cardiovascular disease and diabetes mellitus are prominent features of glucose and lipid metabolism disorders. Adiponectin is a key adipokine that is largely involved in glucose and lipid metabolism processes. A growing body of evidence suggests that chronic exposure to inorganic arsenic is associated with cardiovascular disease and diabetes mellitus. We hypothesized that arsenic exposure may increase the risk of cardiovascular disease and diabetes mellitus by affecting the level of adiponectin. In this study, we examined serum adiponectin levels, as well as serum levels of metabolic measures (including fasting blood glucose, insulin, total cholesterol, triglyceride, and high-density lipoprotein (HDL)-cholesterol) in C57BL/6 mice exposed to inorganic arsenic in drinking water (5 and 50 ppm NaAsO2) for 18 weeks. Body mass and adiposity were monitored throughout the study. We found no significant changes in serum insulin and glucose levels in mice treated with arsenic for 18 weeks. However, arsenic exposure decreased serum levels of adiponectin, triglyceride, and HDL-cholesterol. Further, an inverse relationship was observed between urinary concentrations of total arsenic and serum levels of adiponectin. This study suggests that arsenic exposure could disturb the metabolism of lipids and increase the risk of cardiovascular disease by reducing the level of adiponectin.

  8. Prophylactic efficacy of Coriandrum sativum (Coriander) on testis of lead-exposed mice.

    Science.gov (United States)

    Sharma, Veena; Kansal, Leena; Sharma, Arti

    2010-09-01

    Lead poisoning is a worldwide health problem, and its treatment is under investigation. The aim of this study was to access the efficacy of Coriandrum sativum (coriander) in reducing lead-induced changes in mice testis. Animal exposed to lead nitrate showed significant decrease in testicular SOD, CAT, GSH, total protein, and tissue lead level. This was accompanied by simultaneous increase in the activities of LPO, AST, ALT, ACP, ALP, and cholesterol level. Serum testosterone level and sperm density were suppressed in lead-treated group compared with the control. These influences of lead were prevented by concurrent daily administration of C. sativum extracts to some extent. Treating albino mice with lead-induced various histological changes in the testis and treatment with coriander led to an improvement in the histological testis picture. The results thus led us to conclude that administration of C. sativum significantly protects against lead-induced oxidative stress. Further work need to be done to isolate and purify the active principle involved in the antioxidant activity of this plant.

  9. Frontal Cortex Transcriptome Analysis of Mice Exposed to Electronic Cigarettes During Early Life Stages

    Directory of Open Access Journals (Sweden)

    Dana E. Lauterstein

    2016-04-01

    Full Text Available Electronic cigarettes (e-cigarettes, battery-powered devices containing nicotine, glycerin, propylene glycol, flavorings, and other substances, are increasing in popularity. They pose a potential threat to the developing brain, as nicotine is a known neurotoxicant. We hypothesized that exposure to e-cigarettes during early life stages induce changes in central nervous system (CNS transcriptome associated with adverse neurobiological outcomes and long-term disease states. To test the hypothesis, pregnant C57BL/6 mice were exposed daily (via whole body inhalation throughout gestation (3 h/day; 5 days/week to aerosols produced from e-cigarettes either with nicotine (13–16 mg/mL or without nicotine; following birth, pups and dams were exposed together to e-cigarette aerosols throughout lactation beginning at postnatal day (PND 4–6 and using the same exposure conditions employed during gestational exposure. Following exposure, frontal cortex recovered from ~one-month-old male and female offspring were excised and analyzed for gene expression by RNA Sequencing (RNA-Seq. Comparisons between the treatment groups revealed that e-cigarette constituents other than nicotine might be partly responsible for the observed biological effects. Transcriptome alterations in both offspring sexes and treatment groups were all significantly associated with downstream adverse neurobiological outcomes. Results from this study demonstrate that e-cigarette exposure during early life alters CNS development potentially leading to chronic neuropathology.

  10. ALTERATIONS IN THE ACETYLCHOLINESTERASE ACTIVITY IN THE BRAIN OF ALBINO MICE EXPOSED TO ACEPHATE

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    M. SIVA PRASAD

    2013-01-01

    Full Text Available Acephate (AP, a widely available organophosphorus (OP insecticide, has low mammalian toxicity and isconsidered non-phytotoxic on many crop plants and therefore it is preferred in agricultural crops. In plants andinsects, AP is metabolized extensively to methamidophos (MP, a more potent OP insecticide. The limitedmammalian metabolism of AP to MP has been studied in laboratory rat models and suggests that initial formationof MP from AP may inhibit further formation. Hence in the present investigation we have studied the effect of anAP in cholinergic mechanisms in the different regions of brain. For the present study the male mice were exposedto 1/10th LD50 of AP via oral gavage (i.e. 40.5mg/kg body weight. Our results indicate a steady decline of AChEactivity in all the regions of the brain of Acephate exposed animals. As expected an increase in ACh activity wasnoticed in all the regions of the AP exposed animals. We suggest that cholinergic system is seriously affected bythe intoxication of Acephate and the effect was more effective in 30 days when compared to 10 days

  11. Frontal Cortex Transcriptome Analysis of Mice Exposed to Electronic Cigarettes During Early Life Stages.

    Science.gov (United States)

    Lauterstein, Dana E; Tijerina, Pamella B; Corbett, Kevin; Akgol Oksuz, Betul; Shen, Steven S; Gordon, Terry; Klein, Catherine B; Zelikoff, Judith T

    2016-04-12

    Electronic cigarettes (e-cigarettes), battery-powered devices containing nicotine, glycerin, propylene glycol, flavorings, and other substances, are increasing in popularity. They pose a potential threat to the developing brain, as nicotine is a known neurotoxicant. We hypothesized that exposure to e-cigarettes during early life stages induce changes in central nervous system (CNS) transcriptome associated with adverse neurobiological outcomes and long-term disease states. To test the hypothesis, pregnant C57BL/6 mice were exposed daily (via whole body inhalation) throughout gestation (3 h/day; 5 days/week) to aerosols produced from e-cigarettes either with nicotine (13-16 mg/mL) or without nicotine; following birth, pups and dams were exposed together to e-cigarette aerosols throughout lactation beginning at postnatal day (PND) 4-6 and using the same exposure conditions employed during gestational exposure. Following exposure, frontal cortex recovered from ~one-month-old male and female offspring were excised and analyzed for gene expression by RNA Sequencing (RNA-Seq). Comparisons between the treatment groups revealed that e-cigarette constituents other than nicotine might be partly responsible for the observed biological effects. Transcriptome alterations in both offspring sexes and treatment groups were all significantly associated with downstream adverse neurobiological outcomes. Results from this study demonstrate that e-cigarette exposure during early life alters CNS development potentially leading to chronic neuropathology.

  12. Erythropoiesis in mice exposed to continuous whole body irradiation of gamma-rays

    Energy Technology Data Exchange (ETDEWEB)

    Joshima, Hisamasa; Fukutsu, Kumiko; Matsushita, Satoru; Kashima, Masatoshi

    1988-09-01

    The erythropoietic effects of continuous ..gamma..-irradiation with a daily regime of 0.029, 0.083 and 0.374 Gy were studied in mice. Irradiation was performed with /sup 137/Cs ..gamma..-rays for 22 hr/day. The length of irradiation time varied from 3 to 112 days. Erythropoiesis was investigated on the basis of clearance of /sup 59/Fe from the circulation and of incorporation of /sup 59/Fe into circulating erythrocytes and erythropoietic tissue. A chemical method for the separation of heme and nonheme iron-containing fractions was employed to examine the uptake of /sup 59/Fe into both the heme and nonheme iron fractions. Daily exposure to 0.029 and 0.083 Gy caused no significant changes in erythropoiesis. Daily exposure to 0.374 Gy caused some significant changes in erythropoiesis. On day 7 of continuous irradiation, the amount of /sup 59/Fe incorporated into erythrocytes decreased, but the values returned to normal on day 14 and 28 of continuous irradiation, indicating recovery within erythropoietic tissues at earlier time. On day 56, depressed incorporation of /sup 59/Fe into erythrocytes with normal rate of disappearance of /sup 59/Fe from the circulation and increased heme level of /sup 59/Fe in the femoral marrow were observed. Results observed on day 56 may suggest the possibility of ineffective erythropoiesis during the continuous irradiation. On day 112, some mice showed almost the same changes in erythropoiesis as those mice exposed to acute X-rays radiation.

  13. Cardiovascular changes in atherosclerotic ApoE-deficient mice exposed to Co60 (γ radiation.

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    Prem Kumarathasan

    Full Text Available BACKGROUND: There is evidence for a role of ionizing radiation in cardiovascular diseases. The goal of this work was to identify changes in oxidative and nitrative stress pathways and the status of the endothelinergic system during progression of atherosclerosis in ApoE-deficient mice after single and repeated exposure to ionizing radiation. METHODS AND RESULTS: B6.129P2-ApoE tmlUnc mice on a low-fat diet were acutely exposed (whole body to Co60 (γ (single dose 0, 0.5, and 2 Gy at a dose rate of 36.32 cGy/min, or repeatedly (cumulative dose 0 and 2 Gy at a dose-rate of 0.1 cGy/min for 5 d/wk, over a period of 4 weeks. Biological endpoints were investigated after 3-6 months of recovery post-radiation. The nitrative stress marker 3-nitrotyrosine and the vasoregulator peptides endothelin-1 and endothelin-3 in plasma were increased (p<0.05 in a dose-dependent manner 3-6 months after acute or chronic exposure to radiation. The oxidative stress marker 8-isoprostane was not affected by radiation, while plasma 8-hydroxydeoxyguanosine and L-3,4-dihydroxyphenylalanine decreased (p<0.05 after treatment. At 2Gy radiation dose, serum cholesterol was increased (p = 0.008 relative to controls. Percent lesion area increased (p = 0.005 with age of animal, but not with radiation treatment. CONCLUSIONS: Our observations are consistent with persistent nitrative stress and activation of the endothelinergic system in ApoE-/- mice after low-level ionizing radiation exposures. These mechanisms are known factors in the progression of atherosclerosis and other cardiovascular diseases.

  14. Role of CD4(+) T cells in the modulation of neurotrophin production in mice exposed to low-level toluene.

    Science.gov (United States)

    Fujimaki, Hidekazu; Win-Shwe, Tin-Tin; Yamamoto, Shoji; Nakajima, Daisuke; Goto, Sumio

    2009-01-01

    To investigate the role of CD4(+) T cells in neurotrophin production following toluene exposure, male C3H mice were exposed to filtered air (control) or 9 ppm of toluene in a nose-only exposure chamber for 30 min on 3 consecutive days followed by weekly sessions for 4 weeks. All the mice were immunized with ovalbumin and some groups of mice were treated with anti-CD4 antibody. BDNF content in BAL fluid and NGF content in plasma were significantly increased in toluene-exposed mice. However, treatment with anti-CD4 mAb completely abrogated these effects. These findings suggest that the CD4(+) T cells may be involved in the toluene-induced modulation of neurotrophin production.

  15. Sex- and Tissue-Specific Methylome Changes in Brains of Mice Perinatally Exposed to Lead

    Science.gov (United States)

    Sánchez-Martín, Francisco Javier; Lindquist, Diana M.; Landero-Figueroa, Julio; Zhang, Xiang; Chen, Jing; Cecil, Kim M.; Medvedovic, Mario; Puga, Alvaro

    2014-01-01

    Changes in DNA methylation and subsequent changes in gene expression regulation are the hallmarks of age- and tissue-dependent epigenetic drift and plasticity resulting from the combinatorial integration of genetic determinants and environmental cues. To determine whether perinatal lead exposure caused persistent DNA methylation changes in target tissues, we exposed mouse dams to 0, 3 or 30 ppm of lead acetate in drinking water for a period extending from 2 months prior to mating, through gestation, until weaning of pups at postnatal day-21, and analyzed whole-genome DNA methylation in brain cortex and hippocampus of 2-month old exposed and unexposed progeny. Lead exposure resulted in hypermethylation of three differentially methylated regions in the hippocampus of females, but not males. These regions mapped to Rn4.5s, Sfi1, and Rn45s loci in mouse chromosomes 2, 11 and 17, respectively. At a conservative fdr<0.001, 1,623 additional CpG sites were differentially methylated in female hippocampus, corresponding to 117 unique genes. Sixty of these genes were tested for mRNA expression and showed a trend towards negative correlation between mRNA expression and methylation in exposed females but not males. No statistically significant methylome changes were detected in male hippocampus or in cortex of either sex. We conclude that exposure to lead during embryonic life, a time when the organism is most sensitive to environmental cues, appears to have a sex- and tissue-specific effect on DNA methylation that may produce pathological or physiological deviations from the epigenetic plasticity operative in unexposed mice. PMID:25530354

  16. Direct assessment of cumulative aryl hydrocarbon receptor agonist activity in sera from experimentally exposed mice and environmentally exposed humans

    DEFF Research Database (Denmark)

    Schlezinger, Jennifer J; Bernard, Pamela L; Haas, Amelia;

    2010-01-01

    readouts to provide a broader context for estimating human risk than that obtained with serum extraction and gas chromatography/mass spectroscopy (GC/MS)-based assays alone. METHODS: AhR agonist activity was quantified in sera from dioxin-treated mice, commercial human sources, and polychlorinated biphenyl...

  17. B cells play key roles in th2-type airway immune responses in mice exposed to natural airborne allergens.

    Science.gov (United States)

    Drake, Li Yin; Iijima, Koji; Hara, Kenichiro; Kobayashi, Takao; Kephart, Gail M; Kita, Hirohito

    2015-01-01

    Humans are frequently exposed to various airborne allergens. In addition to producing antibodies, B cells participate in immune responses via various mechanisms. The roles of B cells in allergic airway inflammation and asthma have been controversial. We examined the functional importance of B cells in a mouse model of asthma, in which mice were exposed repeatedly to common airborne allergens. Naïve wild-type BALB/c mice or B cell-deficient JH-/- mice were exposed intranasally to a cocktail of allergen extracts, including Alternaria, Aspergillus, and house dust mite, every other day for two weeks. Ovalbumin was included in the cocktail to monitor the T cell immune response. Airway inflammation, lung pathology, and airway reactivity were analyzed. The airway exposure of naïve wild type mice to airborne allergens induced robust eosinophilic airway inflammation, increased the levels of Th2 cytokines and chemokines in the lung, and increased the reactivity to inhaled methacholine. These pathological changes and immune responses were attenuated in B cell-deficient JH-/- mice. The allergen-induced expansion of CD4+ T cells was impaired in the lungs and draining lymph nodes of JH-/- mice. Furthermore, lymphocytes from JH-/- mice failed to produce Th2 cytokines in response to ovalbumin re-stimulation in vitro. Our results suggest that B cells are required for the optimal development of Th2-type immune responses and airway inflammation when exposed to common airborne allergens. The therapeutic targeting of B cells may be beneficial to treat asthma in certain patients.

  18. B cells play key roles in th2-type airway immune responses in mice exposed to natural airborne allergens.

    Directory of Open Access Journals (Sweden)

    Li Yin Drake

    Full Text Available Humans are frequently exposed to various airborne allergens. In addition to producing antibodies, B cells participate in immune responses via various mechanisms. The roles of B cells in allergic airway inflammation and asthma have been controversial. We examined the functional importance of B cells in a mouse model of asthma, in which mice were exposed repeatedly to common airborne allergens. Naïve wild-type BALB/c mice or B cell-deficient JH-/- mice were exposed intranasally to a cocktail of allergen extracts, including Alternaria, Aspergillus, and house dust mite, every other day for two weeks. Ovalbumin was included in the cocktail to monitor the T cell immune response. Airway inflammation, lung pathology, and airway reactivity were analyzed. The airway exposure of naïve wild type mice to airborne allergens induced robust eosinophilic airway inflammation, increased the levels of Th2 cytokines and chemokines in the lung, and increased the reactivity to inhaled methacholine. These pathological changes and immune responses were attenuated in B cell-deficient JH-/- mice. The allergen-induced expansion of CD4+ T cells was impaired in the lungs and draining lymph nodes of JH-/- mice. Furthermore, lymphocytes from JH-/- mice failed to produce Th2 cytokines in response to ovalbumin re-stimulation in vitro. Our results suggest that B cells are required for the optimal development of Th2-type immune responses and airway inflammation when exposed to common airborne allergens. The therapeutic targeting of B cells may be beneficial to treat asthma in certain patients.

  19. Response, thermal regulatory threshold and thermal breakdown threshold of restrained RF-exposed mice at 905 MHz

    Energy Technology Data Exchange (ETDEWEB)

    Ebert, S [Swiss Federal Institute of Technology (ETH), Zurich, 8092 Zurich (Switzerland); Eom, S J [Swiss Federal Institute of Technology (ETH), Zurich, 8092 Zurich (Switzerland); Schuderer, J [Foundation for Research on Information Technologies in Society (IT' IS), Zeughausstrasse 43, 8004 Zurich (Switzerland); Apostel, U [Fraunhofer Institute for Toxicology and Experimental Medicine, Nicolai-Fuchs-Strasse 1, 30625 Hannover (Germany); Tillmann, T [Fraunhofer Institute for Toxicology and Experimental Medicine, Nicolai-Fuchs-Strasse 1, 30625 Hannover (Germany); Dasenbrock, C [Fraunhofer Institute for Toxicology and Experimental Medicine, Nicolai-Fuchs-Strasse 1, 30625 Hannover (Germany); Kuster, N [Swiss Federal Institute of Technology (ETH), Zurich, 8092 Zurich (Switzerland)

    2005-11-07

    The objective of this study was the determination of the thermal regulatory and the thermal breakdown thresholds for in-tube restrained B6C3F1 and NMRI mice exposed to radiofrequency electromagnetic fields at 905 MHz. Different levels of the whole-body averaged specific absorption rate (SAR 0, 2, 5, 7.2, 10, 12.6 and 20 W kg{sup -1}) have been applied to the mice inside the 'Ferris Wheel' exposure setup at 22 {+-} 2 {sup 0}C and 30-70% humidity. The thermal responses were assessed by measurement of the rectal temperature prior, during and after the 2 h exposure session. For B6C3F1 mice, the thermal response was examined for three different weight groups (20 g, 24 g, 29 g), both genders and for pregnant mice. Additionally, NMRI mice with a weight of 36 g were investigated for an interstrain comparison. The thermal regulatory threshold of in-tube restrained mice was found at SAR levels between 2 W kg{sup -1} and 5 W kg{sup -1}, whereas the breakdown of regulation was determined at 10.1 {+-} 4.0 W kg{sup -1}(K = 2) for B6C3F1 mice and 7.7 {+-} 1.6 W kg{sup -1}(K = 2) for NMRI mice. Based on a simplified power balance equation, the thresholds show a clear dependence upon the metabolic rate and weight. NMRI mice were more sensitive to thermal stress and respond at lower SAR values with regulation and breakdown. The presented data suggest that the thermal breakdown for in-tube restrained mice, whole-body exposed to radiofrequency fields, may occur at SAR levels of 6 W kg{sup -1}(K = 2) at laboratory conditions.

  20. Dissociation of spontaneous seizures and brainstem seizure thresholds in mice exposed to eight flurothyl-induced generalized seizures.

    Science.gov (United States)

    Kadiyala, Sridhar B; Ferland, Russell J

    2017-03-01

    C57BL/6J mice exposed to eight flurothyl-induced generalized clonic seizures exhibit a change in seizure phenotype following a 28-day incubation period and subsequent flurothyl rechallenge. Mice now develop a complex seizure semiology originating in the forebrain and propagating into the brainstem seizure network (a forebrain→brainstem seizure). In contrast, this phenotype change does not occur in seizure-sensitive DBA/2J mice. The underlying mechanism(s) was the focus of these studies. DBA2/J mice were exposed to eight flurothyl-induced seizures (1/day) followed by 24-hour video-electroencephalographic recordings for 28-days. Forebrain and brainstem seizure thresholds were determined in C57BL/6J and DBA/2J mice following one or eight flurothyl-induced seizures, or after eight flurothyl-induced seizures, a 28-day incubation period, and final flurothyl rechallenge. Similar to C57BL/6J mice, DBA2/J mice expressed spontaneous seizures. However, unlike C57BL/6J mice, DBA2/J mice continued to have spontaneous seizures without remission. Because DBA2/J mice do not express forebrain→brainstem seizures following flurothyl rechallenge after a 28-day incubation period, this indicated that spontaneous seizures were not sufficient for the evolution of forebrain→brainstem seizures. Therefore, we determined whether brainstem seizure thresholds were changing during this repeated-flurothyl model and whether this could account for the expression of forebrain→brainstem seizures. Brainstem seizure thresholds were not different between C57BL/6J and DBA/2J mice on day one or on the last induction seizure trial (day eight). However, brainstem seizure thresholds did differ significantly on flurothyl rechallenge (day 28) with DBA/2J mice showing no lowering of their brainstem seizure thresholds. These results demonstrated that DBA/2J mice exposed to the repeated-flurothyl model develop spontaneous seizures without evidence of seizure remission and provide a new model of

  1. Molecular mechanisms mediating a deficit in recall of fear extinction in adult mice exposed to cocaine in utero.

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    Zeeba D Kabir

    Full Text Available Prenatal cocaine exposure has been shown to alter cognitive processes of exposed individuals, presumed to be a result of long-lasting molecular alterations in the brain. In adult prenatal cocaine exposed (PCOC mice we have identified a deficit in recall of fear extinction, a behavior that is dependent on the medial prefrontal cortex (mPFC and the hippocampus. While we observed no change in the constitutive expression of brain derived neurotrophic factor (BDNF protein and mRNA in the mPFC and hippocampus of adult PCOC mice, we observed blunted BDNF signaling in the mPFC of adult PCOC mice after fear extinction compared to the control animals. Specifically, during the consolidation phase of the extinction memory, we observed a decrease in BDNF protein and it's phospho-TrkB receptor expression. Interestingly, at this same time point there was a significant increase in total Bdnf mRNA levels in the mPFC of PCOC mice as compared with controls. In the Bdnf gene, we identified decreased constitutive binding of the transcription factors, MeCP2 and P-CREB at the promoters of Bdnf exons I and IV in the mPFC of PCOC mice, that unlike control mice remained unchanged when measured during the behavior. Finally, bilateral infusion of recombinant BDNF protein into the infralimbic subdivision of the mPFC during the consolidation phase of the extinction memory rescued the behavioral deficit in PCOC mice. In conclusion, these findings extend our knowledge of the neurobiologic impact of prenatal cocaine exposure on the mPFC of mice, which may lead to improved clinical recognition and treatment of exposed individuals.

  2. Serological responses and biomarker evaluation in mice and pigs exposed to tsetse fly bites.

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    Guy Caljon

    2014-05-01

    Full Text Available BACKGROUND: Tsetse flies are obligate blood-feeding insects that transmit African trypanosomes responsible for human sleeping sickness and nagana in livestock. The tsetse salivary proteome contains a highly immunogenic family of the endonuclease-like Tsal proteins. In this study, a recombinant version of Tsal1 (rTsal1 was evaluated in an indirect ELISA to quantify the contact with total Glossina morsitans morsitans saliva, and thus the tsetse fly bite exposure. METHODOLOGY/PRINCIPAL FINDINGS: Mice and pigs were experimentally exposed to different G. m. morsitans exposure regimens, followed by a long-term follow-up of the specific antibody responses against total tsetse fly saliva and rTsal1. In mice, a single tsetse fly bite was sufficient to induce detectable IgG antibody responses with an estimated half-life of 36-40 days. Specific antibody responses could be detected for more than a year after initial exposure, and a single bite was sufficient to boost anti-saliva immunity. Also, plasmas collected from tsetse-exposed pigs displayed increased anti-rTsal1 and anti-saliva IgG levels that correlated with the exposure intensity. A strong correlation between the detection of anti-rTsal1 and anti-saliva responses was recorded. The ELISA test performance and intra-laboratory repeatability was adequate in the two tested animal models. Cross-reactivity of the mouse IgGs induced by exposure to different Glossina species (G. m. morsitans, G. pallidipes, G. palpalis gambiensis and G. fuscipes and other hematophagous insects (Stomoxys calcitrans and Tabanus yao was evaluated. CONCLUSION: This study illustrates the potential use of rTsal1 from G. m. morsitans as a sensitive biomarker of exposure to a broad range of Glossina species. We propose that the detection of anti-rTsal1 IgGs could be a promising serological indicator of tsetse fly presence that will be a valuable tool to monitor the impact of tsetse control efforts on the African continent.

  3. Sub-chronically exposing mice to a polycyclic aromatic hydrocarbon increases lipid accumulation in their livers.

    Science.gov (United States)

    Jin, Yuanxiang; Miao, Wenyu; Lin, Xiaojian; Wu, Tao; Shen, Hangjie; Chen, Shan; Li, Yanhong; Pan, Qiaoqiao; Fu, Zhengwei

    2014-09-01

    The potential for exposing humans and wildlife to environmental polycyclic aromatic hydrocarbons (PAHs) has increased. Risk assessments describing how PAHs disturb lipid metabolism and induce hepatotoxicity have only received limited attention. In the present study, seven-week-old male ICR mice received intraperitoneal injections of 0, 0.01, 0.1 or 1mg/kg body weight 3-methylcholanthrene (3MC) per week for 10 weeks. A high-fat diet was provided during the exposure. Histopathological lipid accumulation and lipid metabolism-related genes were measured. We observed that sub-chronic 3MC exposure significantly increased lipid droplet and triacylglycerol (TG) levels in the livers. A low dose of 3MC activated the aryl hydrocarbon receptor, which negatively regulated lipid synthesis in the livers. The primary genes including acetyl-CoA carboxylase (Acc), fatty acid synthase (Fas) and stearoyl-CoA desaturase 1 (Scd1) decreased significantly when compared with those in the control group, indicating that de novo fatty acid synthesis in the hepatocytes was significantly inhibited by the sub-chronic 3MC exposure. However, the free fatty acid (FFA) synthesis in the adipose tissue was greatly enhanced by up-regulating the expression of peroxisome proliferator-activated receptor γ (PPARγ) and sterol regulatory element binding protein-1c (SREBP1C) and target genes including Acc, Fas and Scd1. The synthesized FFA was released into the blood and then transported into the liver by the up-regulation of Fat and Fatp2, which resulted in the gradual accumulation of lipids in the liver. In conclusion, histological examinations and molecular level analyses highlighted the development of lipid accumulation and confirmed that 3MC significantly impaired lipid metabolism in mice. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Menthol attenuates respiratory irritation and elevates blood cotinine in cigarette smoke exposed mice.

    Science.gov (United States)

    Ha, Michael A; Smith, Gregory J; Cichocki, Joseph A; Fan, Lu; Liu, Yi-Shiuan; Caceres, Ana I; Jordt, Sven Eric; Morris, John B

    2015-01-01

    Addition of menthol to cigarettes may be associated with increased initiation of smoking. The potential mechanisms underlying this association are not known. Menthol, likely due to its effects on cold-sensing peripheral sensory neurons, is known to inhibit the sensation of irritation elicited by respiratory irritants. However, it remains unclear whether menthol modulates cigarette smoke irritancy and nicotine absorption during initial exposures to cigarettes, thereby facilitating smoking initiation. Using plethysmography in a C57Bl/6J mouse model, we examined the effects of L-menthol, the menthol isomer added to cigarettes, on the respiratory sensory irritation response to primary smoke irritants (acrolein and cyclohexanone) and smoke of Kentucky reference 2R4 cigarettes. We also studied L-menthol's effect on blood levels of the nicotine metabolite, cotinine, immediately after exposure to cigarette smoke. L-menthol suppressed the irritation response to acrolein with an apparent IC₅₀ of 4 ppm. Suppression was observed even at acrolein levels well above those necessary to produce a maximal response. Cigarette smoke, at exposure levels of 10 mg/m³ or higher, caused an immediate and marked sensory irritation response in mice. This response was significantly suppressed by L-menthol even at smoke concentrations as high as 300 mg/m³. Counterirritation by L-menthol was abolished by treatment with a selective inhibitor of Transient Receptor Potential Melastatin 8 (TRPM8), the neuronal cold/menthol receptor. Inclusion of menthol in the cigarette smoke resulted in roughly a 1.5-fold increase in plasma cotinine levels over those observed in mice exposed to smoke without added menthol. These findings document that, L-menthol, through TRPM8, is a strong suppressor of respiratory irritation responses, even during highly noxious exposures to cigarette smoke or smoke irritants, and increases blood cotinine. Therefore, L-menthol, as a cigarette additive, may promote smoking

  5. Brain deposition and neurotoxicity of manganese in adult mice exposed via the drinking water.

    Science.gov (United States)

    Krishna, Saritha; Dodd, Celia A; Hekmatyar, Shahryar K; Filipov, Nikolay M

    2014-01-01

    Natural leaching processes and/or anthropogenic contamination can result in ground water concentrations of the essential metal manganese (Mn) that far exceed the current regulatory standards. Neurological consequences of Mn drinking water (DW) overexposure to experimental animals, i.e., mice, including its brain deposition/distribution and behavioral effects are understudied. Adult male C57BL/6 mice were exposed to Mn via the DW for 8 weeks. After 5 weeks of Mn exposure, magnetic resonance imaging revealed significant Mn deposition in all examined brain regions; the degree of Mn deposition did not increase further a week later. Behaviorally, early hyperactivity and more time spent in the center of the arenas in an open field test, decreased forelimb grip strength and less time swimming in a forced swim test were observed after 6 weeks of Mn DW exposure. Eight-week Mn DW exposure did not alter striatal dopamine, its metabolites, or the expression of key dopamine homeostatic proteins, but it significantly increased striatal 5-hydroxyindoleacetic acid (a serotonin metabolite) levels, without affecting the levels of serotonin itself. Increased expression (mRNA) of glial fibrillary acidic protein (GFAP, an astrocyte activation marker), heme oxygenase-1 and inducible nitric oxide synthase (oxidative and nitrosative stress markers, respectively) were observed 8 weeks post-Mn DW exposure in the substantia nigra. Besides mRNA increases, GFAP protein expression was increased in the substantia nigra pars reticulata. In summary, the neurobehavioral deficits, characterized by locomotor and emotional perturbations, and nigral glial activation associated with significant brain Mn deposition are among the early signs of Mn neurotoxicity caused by DW overexposure.

  6. Menthol attenuates respiratory irritation and elevates blood cotinine in cigarette smoke exposed mice.

    Directory of Open Access Journals (Sweden)

    Michael A Ha

    Full Text Available Addition of menthol to cigarettes may be associated with increased initiation of smoking. The potential mechanisms underlying this association are not known. Menthol, likely due to its effects on cold-sensing peripheral sensory neurons, is known to inhibit the sensation of irritation elicited by respiratory irritants. However, it remains unclear whether menthol modulates cigarette smoke irritancy and nicotine absorption during initial exposures to cigarettes, thereby facilitating smoking initiation. Using plethysmography in a C57Bl/6J mouse model, we examined the effects of L-menthol, the menthol isomer added to cigarettes, on the respiratory sensory irritation response to primary smoke irritants (acrolein and cyclohexanone and smoke of Kentucky reference 2R4 cigarettes. We also studied L-menthol's effect on blood levels of the nicotine metabolite, cotinine, immediately after exposure to cigarette smoke. L-menthol suppressed the irritation response to acrolein with an apparent IC₅₀ of 4 ppm. Suppression was observed even at acrolein levels well above those necessary to produce a maximal response. Cigarette smoke, at exposure levels of 10 mg/m³ or higher, caused an immediate and marked sensory irritation response in mice. This response was significantly suppressed by L-menthol even at smoke concentrations as high as 300 mg/m³. Counterirritation by L-menthol was abolished by treatment with a selective inhibitor of Transient Receptor Potential Melastatin 8 (TRPM8, the neuronal cold/menthol receptor. Inclusion of menthol in the cigarette smoke resulted in roughly a 1.5-fold increase in plasma cotinine levels over those observed in mice exposed to smoke without added menthol. These findings document that, L-menthol, through TRPM8, is a strong suppressor of respiratory irritation responses, even during highly noxious exposures to cigarette smoke or smoke irritants, and increases blood cotinine. Therefore, L-menthol, as a cigarette additive, may

  7. Reciprocal Translocation in Somatic and Germ Cells of Mice Chronically Exposed by Inhalation to Ethylene Oxide: Implication for Risk Assessment

    Science.gov (United States)

    Groups of male B6C3F1 mice were exposed by inhalation to 0, 25, 50, 100 or 200 ppm EO for up to 48 weeks (6 hours/day, 5 days/week). Animals were sacrificed at 6, 12, 24, and 48 weeks after the startt of the exposure for analyses of reciprocal translocations in peripheral blood ...

  8. DEVELOPMENTAL TOXICITY OF METHANOL: PATHOGENESIS IN CD-1 AND C57BL/6J MICE EXPOSED IN WHOLE EMBRYO CULTURE

    Science.gov (United States)

    BACKGROUND: Methanol causes axial skeleton and craniofacial defects in both CD-1 and C57BL/6J mice during gastrulation, but C57BL/6J embryos are more severely affected. We evaluated methanol-induced pathogenesis in CD-1 and C57BL/6J embryos exposed during gastrulation in whole em...

  9. Micronuclei in peripheral blood and bone marrow cells of mice exposed to 42 GHz electromagnetic millimeter waves.

    Science.gov (United States)

    Vijayalaxmi; Logani, Mahendra K; Bhanushali, Ashok; Ziskin, Marvin C; Prihoda, Thomas J

    2004-03-01

    The genotoxic potential of 42.2 +/- 0.2 GHz electromagnetic millimeter-wave radiation was investigated in adult male BALB/c mice. The radiation was applied to the nasal region of the mice for 30 min/day for 3 consecutive days. The incident power density used was 31.5 +/- 5.0 mW/cm2. The peak specific absorption rate was calculated as 622 +/- 100 W/kg. Groups of mice that were injected with cyclophosphamide (15 mg/kg body weight), a drug used in the treatment of human malignancies, were also included to determine if millimeter-wave radiation exposure had any influence on drug-induced genotoxicity. Concurrent sham-exposed and untreated mice were used as controls. The extent of genotoxicity was assessed from the incidence of micronuclei in polychromatic erythrocytes of peripheral blood and bone marrow cells collected 24 h after treatment. The results indicated that the incidence of micronuclei in 2000 polychromatic erythrocytes was not significantly different among untreated, millimeter wave-exposed, and sham-exposed mice. The group mean incidences were 6.0 +/- 1.6, 5.1 +/- 1.5 and 5.1 +/- 1.3 in peripheral blood and 9.1 +/- 1.1, 9.3 +/- 1.6 and 9.1 +/- 1.6 in bone marrow cells, respectively. Mice that were injected with cyclophosphamide exhibited significantly increased numbers of micronuclei, 14.6 +/- 2.7 in peripheral blood and 21.3 +/- 3.9 in bone marrow cells (Pwave-exposed and sham-exposed mice; the mean incidences were 14.3 +/- 2.8 and 15.4 +/- 3.0 in peripheral blood and 23.5 +/- 2.3 and 22.1 +/- 2.5 in bone marrow cells, respectively. Thus there was no evidence for the induction of genotoxicity in the peripheral blood and bone marrow cells of mice exposed to electromagnetic millimeter-wave radiation. Also, millimeter-wave radiation exposure did not influence cyclophosphamide-induced micronuclei in either type of cells.

  10. Protective Effect of Porcine Cerebral Hydrolysate Peptides on Learning and Memory Deficits and Oxidative Stress in Lead-Exposed Mice.

    Science.gov (United States)

    Zou, Ye; Feng, Weiwei; Wang, Wei; Chen, Yao; Zhou, Zhaoxiang; Li, Qian; Zhao, Ting; Mao, Guanghua; Wu, Xiangyang; Yang, Liuqing

    2015-12-01

    In this study, lead acetate solution and porcine cerebral hydrolysate peptides (PCHPs) were administered to developing mice. Porcine cerebral protein pretreated by ultrasound was hydrolyzed with alcalase, and 11 peptide fragments were obtained by Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis of PCHPs. Our data showed that PCHPs significantly decreased Pb2+-induced spontaneous locomotor activity, latencies to reach the platform, and the time in target quadrant. It also decreased the accumulation of lead in the blood and brain of Pb2+-exposed developing mice. Co-administration of PCHPs and dimercaptosuccinic acid (DMSA) did not only reduce the accumulation of lead in blood but also increased the absorption of zinc and iron in Pb2+-exposed mice. Administration of PCHPs individually significantly enhanced hematopoietic parameters compared with the Pb2+-exposed group. PCHPs significantly reduced the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) but increased glutathione (GSH) content and anti-oxidant enzymes and nitric oxide synthase (NOS) activities in Pb2+-exposed brain. Our findings suggest that PCHPs have the ability to protect against Pb2+-exposed learning and memory deficits and oxidative damage.

  11. NanoTIO2 (UV-Titan does not induce ESTR mutations in the germline of prenatally exposed female mice

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    Boisen Anne Mette

    2012-06-01

    Full Text Available Abstract Background Particulate air pollution has been linked to an increased risk of cardiovascular disease and cancer. Animal studies have shown that inhalation of air particulates induces mutations in the male germline. Expanded simple tandem repeat (ESTR loci in mice are sensitive markers of mutagenic effects on male germ cells resulting from environmental exposures; however, female germ cells have received little attention. Oocytes may be vulnerable during stages of active cell division (e.g., during fetal development. Accordingly, an increase in germline ESTR mutations in female mice prenatally exposed to radiation has previously been reported. Here we investigate the effects of nanoparticles on the female germline. Since pulmonary exposure to nanosized titanium dioxide (nanoTiO2 produces a long-lasting inflammatory response in mice, it was chosen for the present study. Findings Pregnant C57BL/6 mice were exposed by whole-body inhalation to the nanoTiO2 UV-Titan L181 (~42.4 mg UV-Titan/m3 or filtered clean air on gestation days (GD 8–18. Female C57BL/6 F1 offspring were raised to maturity and mated with unexposed CBA males. The F2 descendents were collected and ESTR germline mutation rates in this generation were estimated from full pedigrees (mother, father, offspring of F1 female mice (192 UV-Titan-exposed F2 offspring and 164 F2 controls. ESTR mutation rates of 0.029 (maternal allele and 0.047 (paternal allele in UV-Titan-exposed F2 offspring were not statistically different from those of F2 controls: 0.037 (maternal allele and 0.061 (paternal allele. Conclusions We found no evidence for increased ESTR mutation rates in F1 females exposed in utero to UV-Titan nanoparticles from GD8-18 relative to control females.

  12. Cardiovascular protection by ezetimibe and influence on oxidative stress in mice exposed to intermittent hypoxia.

    Science.gov (United States)

    Kato, Ryuji; Nishioka, Satoshi; Nomura, Atsuo; Ijiri, Yoshio; Miyamura, Masatoshi; Ukimura, Akira; Okada, Yoshikatsu; Kitaura, Yasushi; Hayashi, Tetsuya

    2015-10-15

    Ezetimibe is as an inhibitor of NPC1L1 protein, which has a key role in cholesterol absorption. The aim of this study was to evaluate the influence of ezetimibe on the plasma lipid profile, atherosclerotic lesions, and cardiomyocyte ultrastructure in an animal model of atherosclerosis with intermittent hypoxia. Apolipoprotein E-knockout mice received a high-fat diet for 30 days. Then animals were exposed to intermittent hypoxia for 10 days or were maintained under normoxic conditions. In the ezetimibe group, ezetimibe (5 mg/kg/day) was added to the diet. Under normoxic conditions, the total cholesterol level was significantly lower in the ezetimibe group (63.6±6.6 mg/dl) than in the control group (116.3±16.9 mg/dl, PIntermittent hypoxia accelerated atherosclerosis associated with increased superoxide production, which also caused degeneration of cardiomyocytes, mitochondrial abnormalities, and interstitial fibrosis. Compared with the control group, the ezetimibe group showed significantly less advanced atherosclerotic lesions and lower superoxide production in the thoracic aorta, as well as reduced oxidative stress, preservation of cardiomyocyte ultrastructure, and reduced interstitial fibrosis in the left ventricular myocardium. In conclusion, ezetimibe not only reduces total cholesterol, but also prevents the development of atherosclerosis and cardiovascular events due to intermittent hypoxia at least partly through suppression of oxidative stress.

  13. Expression profiling reveals novel hypoxic biomarkers in peripheral blood of adult mice exposed to chronic hypoxia.

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    Matias Mosqueira

    Full Text Available Hypoxia induces a myriad of changes including an increase in hematocrit due to erythropoietin (EPO mediated erythropoiesis. While hypoxia is of importance physiologically and clinically, lacunae exist in our knowledge of the systemic and temporal changes in gene expression occurring in blood during the exposure and recovery from hypoxia. To identify these changes expression profiling was conducted on blood obtained from cohorts of C57Bl-10 wild type mice that were maintained at normoxia (NX, exposed for two weeks to normobaric chronic hypoxia (CH or two weeks of CH followed by two weeks of normoxic recovery (REC. Using stringent bioinformatic cut-offs (0% FDR, 2 fold change cut-off, 230 genes were identified and separated into four distinct temporal categories. Class I contained 1 transcript up-regulated in both CH and REC; Class II contained 202 transcripts up-regulated in CH but down-regulated after REC; Class III contained 9 transcripts down-regulated both in CH and REC; Class IV contained 18 transcripts down-regulated after CH exposure but up-regulated after REC. Profiling was independently validated and extended by analyzing expression levels of selected genes as novel biomarkers from our profile (e.g. spectrin alpha-1, ubiquitin domain family-1 and pyrroline-5-carboxylate reductase-1 by performing qPCR at 7 different time points during CH and REC. Our identification and characterization of these genes define transcriptome level changes occurring during chronic hypoxia and normoxic recovery as well as novel blood biomarkers that may be useful in monitoring a variety of physiological and pathological conditions associated with hypoxia.

  14. Effects of pentoxifylline on Wnt/β-catenin signaling in mice chronically exposed to cigarette smoke

    Institute of Scientific and Technical Information of China (English)

    WANG Zheng; ZHANG Jin-nong; HU Xiao-fei; CHEN Xue-lin; WANG Xiao-rong; ZHAO Ting-ting; PENG Mei-jun; ZOU Ping

    2010-01-01

    Background Previous discovery that long-term administration of pentoxifylline (PTX) to mice chronically exposed to smoke led to the development of pulmonary fibrosis rather than emphysema initiated our curiosity on whether the Wnt/β-catenin pathway, a set of signaling proteins essential to organ development and lung morphogenesis in particular were activated in the pathogenesis of pulmonary fibrosis.Methods Male BALB/c mice were randomized into four study groups: Group Sm, smoke exposure and taken regular forage; Group PTX, no smoke but taken PTX-rich forage; Group Sm+PTX, smoke exposure and taken PTX-rich forage;Group control: shamed smoke exposure and taken regular forage. Animals were sacrificed at day 120. Morphometry of the lung sections and the expressions of TGF-β, hydroxyproline, β-catenin, cyclin D1, T cell factor 1 (Tcf-1) and lymphoid enhancer factor 1 (Lef-1) mRNA, etc, in the lung homogenate or in situ were qualitatively or quantitatively analyzed.Results As expected, smoke exposure along with PTX administration for 120 days, lungs of the mice progressed to be a fibrosis-like phenotype, with elevated fibrosis score (3.9±1.1 vs. 1.7±-0.6 in Group Sm, P <0.05). TGF-β (pg/g)(1452.4±465.7 vs. 818.9±202.8 in Group Sm, P <0.05) and hydroxyproline (mg/g) (5.6±0.6, vs. 2.4±0.1 in Group Sm, P<0.05) were also consistently increased. The upregulation of β-catenin measured either by counting the cell with positive staining in microscopic field (17.4±7.9 vs. 9.9±2.9 in Group Sm, P <0.05) or by estimation of the proportion of blue-stained area by Masson's trichrome (11.8±5.6 vs. 4.7±2.4 in Group Sm) in Group SM+PTX was much more noticeable as than those in Group Sm. The expression of β-catenin measured by positive cell counts was correlated to TGF-β1 concentration in lung tissue (r=0.758, P <0.001). PTX per se caused neither fibrosis nor emphysema though expression of β-catenin and downstream gene cyclin D1 may also be altered by this

  15. NanoTIO2 (UV-Titan) does not induce ESTR mutations in the germline of prenatally exposed female mice

    DEFF Research Database (Denmark)

    Boisen, Anne Mette Zenner; Shipley, Thomas; Hougaard, Karin Sørig

    2012-01-01

    Particulate air pollution has been linked to an increased risk of cardiovascular disease and cancer. Animal studies have shown that inhalation of air particulates induces mutations in the male germline. Expanded simple tandem repeat (ESTR) loci in mice are sensitive markers of mutagenic effects...... on male germ cells resulting from environmental exposures; however, female germ cells have received little attention. Oocytes may be vulnerable during stages of active cell division (e.g., during fetal development). Accordingly, an increase in germline ESTR mutations in female mice prenatally exposed...... exposed by whole-body inhalation to the nanoTiO2 UV-Titan L181 (~42.4 mg UV-Titan/m3) or filtered clean air on gestation days (GD) 8–18. Female C57BL/6 F1 offspring were raised to maturity and mated with unexposed CBA males. The F2 descendents were collected and ESTR germline mutation rates...

  16. Ethylene oxide in blood of ethylene-exposed B6C3F1 mice, Fischer 344 rats, and humans.

    Science.gov (United States)

    Filser, Johannes Georg; Kessler, Winfried; Artati, Anna; Erbach, Eva; Faller, Thomas; Kreuzer, Paul Erich; Li, Qiang; Lichtmannegger, Josef; Numtip, Wanwiwa; Klein, Dominik; Pütz, Christian; Semder, Brigitte; Csanády, György András

    2013-12-01

    The gaseous olefin ethylene (ET) is metabolized in mammals to the carcinogenic epoxide ethylene oxide (EO). Although ET is the largest volume organic chemical worldwide, the EO burden in ET-exposed humans is still uncertain, and only limited data are available on the EO burden in ET-exposed rodents. Therefore, EO was quantified in blood of mice, rats, or 4 volunteers that were exposed once to constant atmospheric ET concentrations of between 1 and 10 000 ppm (rodents) or 5 and 50 ppm (humans). Both the compounds were determined by gas chromatography. At ET concentrations of between 1 and 10 000 ppm, areas under the concentration-time curves of EO in blood (µmol × h/l) ranged from 0.039 to 3.62 in mice and from 0.086 to 11.6 in rats. At ET concentrations ≤ 30 ppm, EO concentrations in blood were 8.7-fold higher in rats and 3.9-fold higher in mice than that in the volunteer with the highest EO burdens. Based on measured EO concentrations, levels of EO adducts to hemoglobin and lymphocyte DNA were calculated for diverse ET concentrations and compared with published adduct levels. For given ET exposure concentrations, there were good agreements between calculated and measured levels of adducts to hemoglobin in rats and humans and to DNA in rats and mice. Reported hemoglobin adduct levels in mice were higher than calculated ones. Furthermore, information is given on species-specific background adduct levels. In summary, the study provides most relevant data for an improved assessment of the human health risk from exposure to ET.

  17. Modest effect on plaque progression and vasodilatory function in atherosclerosis-prone mice exposed to nanosized TiO2

    Directory of Open Access Journals (Sweden)

    Mikkelsen Lone

    2011-11-01

    Full Text Available Abstract Background There is growing evidence that exposure to small size particulate matter increases the risk of developing cardiovascular disease. Methods We investigated plaque progression and vasodilatory function in apolipoprotein E knockout (ApoE-/- mice exposed to TiO2. ApoE-/- mice were intratracheally instilled (0.5 mg/kg bodyweight with rutile fine TiO2 (fTiO2, 288 nm, photocatalytic 92/8 anatase/rutile TiO2 (pTiO2, 12 nm, or rutile nano TiO2 (nTiO2, 21.6 nm at 26 and 2 hours before measurement of vasodilatory function in aorta segments mounted in myographs. The progression of atherosclerotic plaques in aorta was assessed in mice exposed to nanosized TiO2 (0.5 mg/kg bodyweight once a week for 4 weeks. We measured mRNA levels of Mcp-1, Mip-2, Vcam-1, Icam-1 and Vegf in lung tissue to assess pulmonary inflammation and vascular function. TiO2-induced alterations in nitric oxide (NO production were assessed in human umbilical vein endothelial cells (HUVECs. Results The exposure to nTiO2 was associated with a modest increase in plaque progression in aorta, whereas there were unaltered vasodilatory function and expression levels of Mcp-1, Mip-2, Vcam-1, Icam-1 and Vegf in lung tissue. The ApoE-/- mice exposed to fine and photocatalytic TiO2 had unaltered vasodilatory function and lung tissue inflammatory gene expression. The unaltered NO-dependent vasodilatory function was supported by observations in HUVECs where the NO production was only increased by exposure to nTiO2. Conclusion Repeated exposure to nanosized TiO2 particles was associated with modest plaque progression in ApoE-/- mice. There were no associations between the pulmonary TiO2 exposure and inflammation or vasodilatory dysfunction.

  18. Short-term social memory deficits in adult female mice exposed to tannery effluent and possible mechanism of action.

    Science.gov (United States)

    Estrela, Fernanda Neves; Rabelo, Letícia Martins; Vaz, Boniek Gontijo; de Oliveira Costa, Denys Ribeiro; Pereira, Igor; de Lima Rodrigues, Aline Sueli; Malafaia, Guilherme

    2017-10-01

    The accumulated organic residues in tannery-plant courtyards are an eating attraction to small rodents; however, the contact of these animals with these residues may change their social behavior. Thus, the aim of the present study is to investigate whether the exposure to tannery effluent (TE) can damage the social recognition memory of female Swiss mice, as well as to assess whether vitamin C supplementation could provide information about how TE constituents can damage these animals' memory. We have observed that resident females exposed to TE (without vitamin supplementation) did not explore the anogenital region, their body or chased intruding females for shorter time or with lower frequency during the retest session of the social recognition test, fact that indicates social recognition memory deficit in these animals. Such finding is reinforced by the confirmation that there was no change in the animals' olfactory function during the buried food test, or locomotor changes in females exposed to the pollutant. Since no behavioral change was observed in the females exposed to TE and treated with vitamin C (before or after the exposure), it is possible saying that these social cognitive impairments seem to be directly related to the imbalance between the cellular production of reactive oxygen species and the counteracting antioxidant mechanisms (oxidative stress) in female mice exposed to the pollutant (without vitamin supplementation). Therefore, the present study evidences that the direct contact with tannery effluent, even for a short period-of-time, may cause short-term social memory deficits in adult female Swiss mice. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Antidepressant Effects of Aripiprazole Augmentation for Cilostazol-Treated Mice Exposed to Chronic Mild Stress after Ischemic Stroke

    Science.gov (United States)

    Kim, Yu Ri; Kim, Ha Neui; Hong, Ki Whan; Shin, Hwa Kyoung; Choi, Byung Tae

    2017-01-01

    The aim of this study was to determine the effects and underlying mechanism of aripiprazole (APZ) augmentation for cilostazol (CLS)-treated post-ischemic stroke mice that were exposed to chronic mild stress (CMS). Compared to treatment with either APZ or CLS alone, the combined treatment resulted in a greater reduction in depressive behaviors, including anhedonia, despair-like behaviors, and memory impairments. This treatment also significantly reduced atrophic changes in the striatum, cortex, and midbrain of CMS-treated ischemic mice, and inhibited neuronal cell apoptosis, particularly in the striatum and the dentate gyrus of the hippocampus. Greater proliferation of neuronal progenitor cells was also observed in the ipsilateral striatum of the mice receiving combined treatment compared to mice receiving either drug alone. Phosphorylation of the cyclic adenosine monophosphate response element binding protein (CREB) was increased in the striatum, hippocampus, and midbrain of mice receiving combined treatment compared to treatment with either drug alone, particularly in the neurons of the striatum and hippocampus, and dopaminergic neurons of the midbrain. Our results suggest that APZ may augment the antidepressant effects of CLS via co-regulation of the CREB signaling pathway, resulting in the synergistic enhancement of their neuroprotective effects. PMID:28208711

  20. Association of EGF Receptor and NLRs signaling with Cardiac Inflammation and Fibrosis in Mice Exposed to Fine Particulate Matter.

    Science.gov (United States)

    Jin, Yuefei; Wu, Zhaoke; Wang, Na; Duan, Shuyin; Wu, Yongjun; Wang, Jing; Wu, Weidong; Feng, Feifei

    2016-09-01

    ЄAmbient fine particulate matter (PM2.5 ) could induce cardiovascular diseases (CVD), but the mechanism remains unknown. To investigate the roles of epidermal growth factor receptor (EGFR) and NOD-like receptors (NLRs) in PM2.5 -induced cardiac injury, we set up a BALB/c mice model of PM2.5 -induced cardiac inflammation and fibrosis with intratracheal instillation of PM2.5 suspension (4.0 mg/kg b.w.) for 5 consecutive days (once per day). After exposure, we found that mRNA levels of CXCL1, interleukin (IL)-6, and IL-18 were elevated, but interestingly, mRNA level of NLRP12 was significant decreased in heart tissue from PM2.5 -induced mice compared with those of saline-treated mice using real-time PCR. Protein levels of phospho-EGFR (Tyr1068), phospho-Akt (Thr308), NLRP3, NF-κB-p52/p100, and NF-κB-p65 in heart tissue of PM2.5 -exposed mice were all significantly increased using immunohistochemistry or Western blotting. Therefore, PM2.5 exposure could induce cardiac inflammatory injury in mice, which may be involved with EGFR/Akt signaling, NLRP3, and NLRP12.

  1. Expression of c-fos and c-jun protooncogenes in the uteri of immature mice neonatally exposed to diethylstilbestrol.

    Science.gov (United States)

    Yamashita, S; Takayanagi, A; Shimizu, N

    2003-01-01

    We studied the cell-type-specific and temporal expression of c-fos and c-jun protooncogenes after 17beta-estradiol (E2) stimulation in the uteri of immature 3-week-old mice neonatally exposed to diethylstilbestrol (DES), DES-mice, and the ontogenic expression of these genes in the uteri of DES-mice using immunohistochemistry and in situ hybridization. A single E2 injection induced the transient and rapid expression of c-fos mRNA and c-Fos protein in the endometrial epithelium and endothelial cells of the blood vessels in both 3-week-old vehicle-treated controls and DES-mice; a peak of mRNA expression was 2 hours after E2 injection and that of protein expression was 2 to 3 hours after the injection. The expression of c-fos mRNA and protein after E2 stimulation was lower in the DES-mice than in the control animals. There were no significant differences in the c-jun expression patterns in both experimental groups before and after the E2 injection. The E2 injection transiently down-regulated the c-jun expression in the epithelium and up-regulated it in the stroma and myometrium. The uterine epithelium of DES-mice showed much stronger c-Jun immunostaining on days 4 and 10, compared with those of controls. Neonatal DES treatment reduced c-Jun immunoreactivity in the uterine epithelium on days 4 and 10, and increased the reaction in the stroma on day 4. These results suggested that the neonatal DES treatment induces permanent changes in the c-fos expression pattern independent of the postpuberal secretion of ovarian steroids. The changes in the expression of c-fos and c-jun protooncogenes, particularly during postnatal development, are likely to play important roles in the production of uterine abnormalities in the DES-mice.

  2. Vascular hyperpermeability in response to inflammatory mustard oil is mediated by Rho kinase in mice systemically exposed to arsenic.

    Science.gov (United States)

    Chen, Shih-Chieh; Liu, Chun-Chih; Huang, Shin-Yin; Chiou, Shean-Jaw

    2011-09-01

    The mechanisms underlying vascular dysfunction and cardiovascular disease induced by chronic arsenic exposure are not completely understood. We have previously shown that mice chronically fed sodium arsenite are hypersensitive to the permeability-increasing effects of inflammatory mustard oil. The aim of this study was to investigate whether RhoA/Rho kinase (ROCK)-mediated vascular leakage (hyperpermeability) is induced by mustard oil in mice systemically exposed to arsenic. Animals were orally fed water (control group) or sodium arsenite for 8weeks. We compared the blood pressure and microvessel density of the ears between these two groups. Both control and arsenic groups exhibited a similar mean arterial pressure and microvessel density. Microvessel permeability changes that occurred following mustard oil treatment in the presence of Y-27632, a ROCK inhibitor, were quantified using the Evans blue (EB) technique and vascular labeling with carbon particles. Both the excessive leakiness of EB and the high density of carbon-labeled microvessels upon stimulation with mustard oil in the arsenic-fed mice were reduced by Y-27632 treatment. However, RhoA and ROCK2 expression levels were similar between control and arsenic-fed mice. We further investigated ROCK2 levels and ROCK activity in the ears following mustard oil challenge. ROCK2 levels in mouse ears treated with mustard oil were higher in the arsenic group as compared with the control group. Following mustard oil application, ROCK activity was significantly higher in the arsenic-fed mice compared with the control mice. These findings indicate that increased ROCK2 levels and enhanced ROCK activity are responsible for mustard oil-induced vascular hyperpermeability in arsenic-fed mice. Copyright © 2011 Elsevier Inc. All rights reserved.

  3. Protective effect of taurine on the decreased biogenic amine neurotransmitter levels in the brain of mice exposed to arsenic.

    Science.gov (United States)

    Liu, Xiaohui; Piao, Fengyuan; Li, Yachen

    2013-01-01

    Arsenic (As) exposure has a toxic effect on the central nervous system, especially on learning and memory. Norepinephrine (NE), dopamine (DA), and serotonin (5-HT) play an important role in learning and memory function of the brain. In the present study, the protective effect of taurine on the disturbed biogenic amine neurotransmitter levels in the mouse brain induced by arsenic was examined. Sixty SPF mice were divided into three groups. The As exposure group was administered with 4 ppm As(2)O(3) through drinking water for 60 days. The protective group was treated with both 4 ppm As(2)O(3) and 150 mg/kg taurine. The control group was given drinking water alone. The levels of NE, DA, and 5-HT were determined by HPLC in the cerebrum and cerebellum of mice. Ultrastructure of synapses in brain tissue of mice was observed in these groups by transmission electron microscopy. The mRNA expressions of dopamine beta hydroxylase (DBH), tyrosine hydroxylase (TH), and tryptophan hydroxylase (TPH) as NE, DA, and 5-HT synzymes were also analyzed by real-time RT-PCR. The results showed that the concentrations of NE, DA, and 5-HT; the number of synaptic vesicles; and the expressions of TH, TPH, and DBH genes in the brains of mice exposed to As alone were significantly decreased. However, administration of taurine significantly alleviated the toxic effect on biochemicals detected in the experiment, compared with that in the brain of mice exposed to As alone. These results indicated that taurine was effective in counteracting the decreased biogenic amine neurotransmitter level and the mRNA expressions of their synzymes induced by arsenic.

  4. Acute Toxicity of Amorphous Silica Nanoparticles in Intravenously Exposed ICR Mice

    OpenAIRE

    Yang Yu; Yang Li; Wen Wang; Minghua Jin; Zhongjun Du; Yanbo Li; Junchao Duan; Yongbo Yu; Zhiwei Sun

    2013-01-01

    This study aimed to evaluate the acute toxicity of intravenously administrated amorphous silica nanoparticles (SNPs) in mice. The lethal dose, 50 (LD50), of intravenously administrated SNPs was calculated in mice using Dixon's up-and-down method (262.45±33.78 mg/kg). The acute toxicity was evaluated at 14 d after intravenous injection of SNPs at 29.5, 103.5 and 177.5 mg/kg in mice. A silicon content analysis using ICP-OES found that SNPs mainly distributed in the resident macrophages of the l...

  5. Tolerance, sensitization and dependence to diazepam in Balb/c mice exposed to a novel open space anxiety test.

    Science.gov (United States)

    Ennaceur, A; Michalikova, S; van Rensburg, R; Chazot, P L

    2010-05-01

    Balb/c mice were exposed to an elevated platform that is extended on two opposite sides with lowered steep slopes. They were tested for 12min per session in 6 successive days. They received i.p. administration of either saline or one dose of diazepam (DZP 0.5, 1, 3mg/kg) in sessions 1-3, and saline in sessions 4 and 5. All groups of mice received a single dose of DZP (1mg/kg) in session 6. DZP produced inverted U-shaped dose-responses on the number of entries into different areas of the apparatus, with a peak in mean response at 1mg/kg whereas its effect on the duration of entries was mostly comparable between the 3 doses. It increased the number of crossings on the surface of the platform and facilitated entries onto the slopes. DZP-treated mice crossed frequently onto and spent longer time on the slopes in sessions 1-3 whereas saline-treated mice remained on the platform in sessions 1-6. Withdrawal of DZP in sessions 4-5 increased the latency of first entry and decreased the number and duration of entries onto the slopes which was reversed with the administration of 1mg/kg of DZP in the next session. This ON-OFF the drug may be due to the half-life of DZP which is very short in mice and rats ( approximately 0.88h). It also indicates that DZP-treated mice did not benefit from previous experience of entries onto the slopes which suggests a possible "state-dependent" effect. Administration of DZP after repeated exposures to the test did not facilitate entries onto the slopes but instead increased significantly the number of crossings on the surface of the platform; this increase was much higher than that observed in mice initially treated with DZP and exposed to the test. There is no evidence of habituation in saline-treated mice: the number of crossings on the platform was comparable between the first 5 sessions of the test. These results demonstrate that repeated exposures to the same anxiogenic environment resulted in avoidance responses developing tolerance and

  6. Modest effect on plaque progression and vasodilatory function in atherosclerosis-prone mice exposed to nanosized TiO2

    DEFF Research Database (Denmark)

    Mikkelsen, Lone; Sheykhzade, Majid; Jensen, Keld A

    2011-01-01

    ABSTRACT: BACKGROUND: There is growing evidence that exposure to small size particulate matter increases the risk of developing cardiovascular disease. METHODS: We investigated plaque progression and vasodilatory function in apolipoprotein E knockout (ApoE-/-) mice exposed to TiO2. ApoE-/- mice...... were intratracheally instilled (0.5 mg/kg bodyweight) with rutile fine TiO2 (fTiO2, 288 nm), photocatalytic 92/8 anatase/rutile TiO2 (pTiO2, 12 nm), or rutile nano TiO2 (nTiO2, 21.6 nm) at 26 and 2 hours before measurement of vasodilatory function in aorta segments mounted in myographs. The progression...... of atherosclerotic plaques in aorta was assessed in mice exposed to nanosized TiO2 (0.5 mg/kg bodyweight) once a week for 4 weeks. We measured mRNA levels of Mcp-1, Mip-2, Vcam-1, Icam-1 and Vegf in lung tissue to assess pulmonary inflammation and vascular function. TiO2-induced alterations in nitric oxide (NO...

  7. Lack of acute phase response in the livers of mice exposed to diesel exhaust particles or carbon black by inhalation

    Directory of Open Access Journals (Sweden)

    Williams Andrew

    2009-04-01

    Full Text Available Abstract Background Epidemiologic and animal studies have shown that particulate air pollution is associated with increased risk of lung and cardiovascular diseases. Although the exact mechanisms by which particles induce cardiovascular diseases are not known, studies suggest involvement of systemic acute phase responses, including C-reactive protein (CRP and serum amyloid A (SAA in humans. In this study we test the hypothesis that diesel exhaust particles (DEP – or carbon black (CB-induced lung inflammation initiates an acute phase response in the liver. Results Mice were exposed to filtered air, 20 mg/m3 DEP or CB by inhalation for 90 minutes/day for four consecutive days; we have previously shown that these mice exhibit pulmonary inflammation (Saber AT, Bornholdt J, Dybdahl M, Sharma AK, Loft S, Vogel U, Wallin H. Tumor necrosis factor is not required for particle-induced genotoxicity and pulmonary inflammation., Arch. Toxicol. 79 (2005 177–182. As a positive control for the induction of an acute phase response, mice were exposed to 12.5 mg/kg of lipopolysaccharide (LPS intraperitoneally. Quantitative real time RT-PCR was used to examine the hepatic mRNA expression of acute phase proteins, serum amyloid P (Sap (the murine homologue of Crp and Saa1 and Saa3. While significant increases in the hepatic expression of Sap, Saa1 and Saa3 were observed in response to LPS, their levels did not change in response to DEP or CB. In a comprehensive search for markers of an acute phase response, we analyzed liver tissue from these mice using high density DNA microarrays. Globally, 28 genes were found to be significantly differentially expressed in response to DEP or CB. The mRNA expression of three of the genes (serine (or cysteine proteinase inhibitor, clade A, member 3C, apolipoprotein E and transmembrane emp24 domain containing 3 responded to both exposures. However, these changes were very subtle and were not confirmed by real time RT

  8. Tissue distribution of DNA adducts and their persistence in blood of mice exposed to benzene.

    OpenAIRE

    Li, G.; Wang, C.; Xin, W. (Weidong); Yin, S

    1996-01-01

    Chemicals combine with DNA, resulting in DNA damage, which could initiate carcinogenesis. To study whether benzene or benzene metabolites bind to DNA, DNA adducts in various tissues and their persistence in leukocytes were examined using the 32P-postlabeling assay. LACA mice were dosed ip with benzene at 500 mg/kg bw twice for 5 days. Two additional spots of DNA adducts are formed in bone marrow cells, liver cells, and peripheral blood compared with control mice. The relative adduct labeling ...

  9. Abnormal Behaviors and Microstructural Changes in White Matter of Juvenile Mice Repeatedly Exposed to Amphetamine

    Directory of Open Access Journals (Sweden)

    Hong-Ju Yang

    2011-01-01

    Full Text Available Amphetamine (AMP is an addictive CNS stimulant and has been commonly abused by adolescents and young adults, during which period brain white matter is still developing. This study was to examine the effect of a nonneurotoxic AMP on the white matter of juvenile mice. d-AMP (1.0 mg/kg was given to young male C57BL/6 mice once a day for 21 days. The spatial working memory and locomotion of mice were measured at the end. Then, mice were sacrificed and their brains were processed for morphological analyses to examine the white matter structure and for Western blot analysis to measure three main proteins expressed in mature oligodendrocytes. AMP-treated mice displayed higher locomotion and spatial working memory impairment and showed lower levels of Nogo-A and GST-pi proteins in frontal cortex and lower MBP protein in the frontal cortex and hippocampus. They also had fewer mature oligodendrocytes and weak MBP immunofluorescent staining in the same two brain regions. But the striatum was spared. These results suggest that the late-developing white matter is vulnerable to AMP treatment which is able to increase striatal and cortical dopamine. Both the compromised white matter and increased dopamine may contribute to the observed behavioral changes in AMP-treated mice.

  10. Histological Changes of the Ovary in Pregnant Mice Vaginally Exposed to Toxoplasma gondii.

    Science.gov (United States)

    Eslamirad, Zahra; Bayat, Parvin-Dokht; Babaei, Saeid

    2015-01-01

    Congenital toxoplasmosis is one cause of abortion. Infection can disrupt ovarian cycles and because toxoplasmosis is an infectious disease may have a similar effect on the ovaries. The purpose of this study was to investigate the pathological changes in the ovaries due to toxoplasmosis. Tachyzoites of Toxoplasma gondii were harvested from peritoneal fluid of mice, experimentally infected. Two females and one male mouse were housed per cage for mating in the overnight. The pregnant mice were divided into experimental and control groups. Experimental group were infected by parasite but the control group received the normal saline. The experimental and control mice were euthanized. Ovaries and uterine horns of animals were removed and prepared for light microscopy. Ovaries of infected pregnant mice presented gross morphological differences compared to the control groups. In ovaries of experimental groups, changes of corpus luteum were observed. The comparison of experimental and control groups revealed that the number of primary follicles, secondary follicle, atretic primary follicles and atretic secondary follicles had significant differences (P≤0.001). Toxoplasma gondii alters ovarian follicular growth and development in mice. In addition, it alters number of different phases of follicles and corpus luteum in ovaries of mice.

  11. Attentional processing in C57BL/6J mice exposed to developmental vitamin D deficiency.

    Directory of Open Access Journals (Sweden)

    Lauren R Harms

    Full Text Available Epidemiological evidence suggests that Developmental Vitamin D (DVD deficiency is associated with an increased risk of schizophrenia. DVD deficiency in mice is associated with altered behaviour, however there has been no detailed investigation of cognitive behaviours in DVD-deficient mice. The aim of this study was to determine the effect of DVD deficiency on a range of cognitive tasks assessing attentional processing in C57BL/6J mice. DVD deficiency was established by feeding female C57BL/6J mice a vitamin D-deficient diet from four weeks of age. After six weeks on the diet, vitamin D-deficient and control females were mated with vitamin D-normal males and upon birth of the pups, all dams were returned to a diet containing vitamin D. The adult offspring were tested on a range of cognitive behavioural tests, including the five-choice serial reaction task (5C-SRT and five-choice continuous performance test (5C-CPT, as well as latent inhibition using a fear conditioning paradigm. DVD deficiency was not associated with altered attentional performance on the 5C-SRT. In the 5C-CPT DVD-deficient male mice exhibited an impairment in inhibiting repetitive responses by making more perseverative responses, with no changes in premature or false alarm responding. DVD deficiency did not affect the acquisition or retention of cued fear conditioning, nor did it affect the expression of latent inhibition using a fear conditioning paradigm. DVD-deficient mice exhibited no major impairments in any of the cognitive domains tested. However, impairments in perseverative responding in DVD-deficient mice may indicate that these animals have specific alterations in systems governing compulsive or reward-seeking behaviour.

  12. Nitric Oxide Synthase Enzymes in the Airways of Mice Exposed to Ovalbumin: NOS2 Expression Is NOS3 Dependent

    Directory of Open Access Journals (Sweden)

    Jennifer M. Bratt

    2010-01-01

    Full Text Available Objectives and Design. The function of the airway nitric oxide synthase (NOS isoforms and the lung cell types responsible for its production are not fully understood. We hypothesized that NO homeostasis in the airway is important to control inflammation, which requires upregulation, of NOS2 protein expression by an NOS3-dependent mechanism. Materials or Subjects. Mice from a C57BL/6 wild-type, NOS1−/−, NOS2−/−, and NOS3−/− genotypes were used. All mice strains were systemically sensitized and exposed to filtered air or ovalbumin (OVA aerosol for two weeks to create a subchronic model of allergen-induced airway inflammation. Methods. We measured lung function, lung lavage inflammatory and airway epithelial goblet cell count, exhaled NO, nitrate and nitrite concentration, and airway NOS1, NOS2, and NOS3 protein content. Results. Deletion of NOS1 or NOS3 increases NOS2 protein present in the airway epithelium and smooth muscle of air-exposed animals. Exposure to allergen significantly reduced the expression of NOS2 protein in the airway epithelium and smooth muscle of the NOS3−/− strain only. This reduction in NOS2 expression was not due to the replacement of epithelial cells with goblet cells as remaining epithelial cells did not express NOS2. NOS1−/− animals had significantly reduced goblet cell metaplasia compared to C57Bl/6 wt, NOS2−/−, and NOS3−/− allergen-exposed mice. Conclusion. The airway epithelial and smooth muscle cells maintain a stable airway NO concentration under noninflammatory conditions. This “homeostatic” mechanism is unable to distinguish between NOS derived from the different constitutive NOS isoforms. NOS3 is essential for the expression of NOS2 under inflammatory conditions, while NOS1 expression contributes to allergen-induced goblet cell metaplasia.

  13. Nitric oxide synthase enzymes in the airways of mice exposed to ovalbumin: NOS2 expression is NOS3 dependent.

    Science.gov (United States)

    Bratt, Jennifer M; Williams, Keisha; Rabowsky, Michelle F; Last, Michael S; Franzi, Lisa M; Last, Jerold A; Kenyon, Nicholas J

    2010-01-01

    The function of the airway nitric oxide synthase (NOS) isoforms and the lung cell types responsible for its production are not fully understood. We hypothesized that NO homeostasis in the airway is important to control inflammation, which requires upregulation, of NOS2 protein expression by an NOS3-dependent mechanism. Mice from a C57BL/6 wild-type, NOS1(-/-), NOS2(-/-), and NOS3(-/-) genotypes were used. All mice strains were systemically sensitized and exposed to filtered air or ovalbumin (OVA) aerosol for two weeks to create a subchronic model of allergen-induced airway inflammation. We measured lung function, lung lavage inflammatory and airway epithelial goblet cell count, exhaled NO, nitrate and nitrite concentration, and airway NOS1, NOS2, and NOS3 protein content. Deletion of NOS1 or NOS3 increases NOS2 protein present in the airway epithelium and smooth muscle of air-exposed animals. Exposure to allergen significantly reduced the expression of NOS2 protein in the airway epithelium and smooth muscle of the NOS3(-/-) strain only. This reduction in NOS2 expression was not due to the replacement of epithelial cells with goblet cells as remaining epithelial cells did not express NOS2. NOS1(-/-) animals had significantly reduced goblet cell metaplasia compared to C57Bl/6 wt, NOS2(-/-), and NOS3(-/-) allergen-exposed mice. The airway epithelial and smooth muscle cells maintain a stable airway NO concentration under noninflammatory conditions. This "homeostatic" mechanism is unable to distinguish between NOS derived from the different constitutive NOS isoforms. NOS3 is essential for the expression of NOS2 under inflammatory conditions, while NOS1 expression contributes to allergen-induced goblet cell metaplasia.

  14. Induction of the Adaptive Response in Mice Exposed to He-Ne Laser and X-Ray Radiation.

    Science.gov (United States)

    Zaichkina, S I; Dyukina, A R; Rozanova, O M; Simonova, N B; Romanchenko, S P; Sorokina, S S; Zakrzhevskaya, D T; Yusupov, V I; Bagratashvili, V N

    2016-05-01

    We studied the dose-dependent induction of in vivo adaptive response in the bone marrow and blood of mice exposed to low-intensity radiation of He-Ne laser (633 nm) and X-ray radiation by the severity of cytogenetic injury and intensity of ROS production, respectively. Induction of the adaptive response in mice preexposed to He-Ne laser and X-ray radiation depended on the adaptive dose and the interval between the adaptive and main doses and correlated with changes in ROS generation. The adaptive response after exposure to low-intensity ionizing and non-ionizing radiation was observed in the same dose range, which attests to similar mechanisms of its induction.

  15. Noninvasive assessment of cutaneous alterations in mice exposed to whole body gamma irradiation using optical imaging techniques.

    Science.gov (United States)

    Sharma, P; Sahu, K; Kushwaha, P K; Kumar, S; Swami, M K; Kumawat, J; Patel, H S; Kher, S; Sahani, P K; Haridas, G; Gupta, P K

    2017-07-11

    We report the results of a study carried out to investigate the potential of optical techniques such as optical coherence tomography, Mueller matrix spectroscopy, and cross-polarization imaging for noninvasive monitoring of the ionizing radiation exposure-induced alterations in cutaneous tissue of mice. Radiation dose-dependent changes were observed in tissue microvasculature and tissue optical parameters like retardance and depolarization as early as 1 h post radiation exposure. Results suggest that these optical techniques may allow early detection of radiation dose-dependent alterations which could help in screening of population exposed to radiation.

  16. Sclerostin antibody inhibits skeletal deterioration in mice exposed to partial weight-bearing

    Science.gov (United States)

    Spatz, J. M.; Ellman, R.; Cloutier, A. M.; Louis, L.; van Vliet, M.; Dwyer, D.; Stolina, M.; Ke, H. Z.; Bouxsein, M. L.

    2017-02-01

    Whereas much is known regarding the musculoskeletal responses to full unloading, little is known about the physiological effects and response to pharmacological agents in partial unloading (e.g. Moon and Mars) environments. To address this, we used a previously developed ground-based model of partial weight-bearing (PWB) that allows chronic exposure to reduced weight-bearing in mice to determine the effects of murine sclerostin antibody (SclAbII) on bone microstructure and strength across different levels of mechanical unloading. We hypothesize that treatment with SclAbII would improve bone mass, microarchitecture and strength in all loading conditions, but that there would be a greater skeletal response in the normally loaded mice than in partially unloaded mice suggesting the importance of combined countermeasures for exploration-class long duration spaceflight missions. Eleven-week-old female mice were assigned to one of four loading groups: normal weight-bearing controls (CON) or weight-bearing at 20% (PWB20), 40% (PWB40) or 70% (PWB70) of normal. Mice in each group received either SclAbII (25 mg/kg) or vehicle (VEH) via twice weekly subcutaneous injection for 3 weeks. In partially-unloaded VEH-treated groups, leg BMD decreased -5 to -10% in a load-dependent manner. SclAbII treatment completely inhibited bone deterioration due to PWB, with bone properties in SclAbII-treated groups being equal to or greater than those of CON, VEH-treated mice. SclAbII treatment increased leg BMD from +14 to +18% in the PWB groups and 30 ± 3% in CON (p antibody therapy in preventing astronaut bone loss during terrestrial solar system exploration.

  17. Artificial daylight photodynamic therapy with "non-inflammatory" doses of hexyl aminolevulinate only marginally delays SCC development in UV-exposed hairless mice

    DEFF Research Database (Denmark)

    Togsverd-Bo, Katrine; Lerche, Catharina M; Philipsen, Peter A;

    2013-01-01

    -concentration PDT combined with artificial daylight on SCC development. Mice (n = 265) were exposed to simulated solar UV-irradiation (UVR) 3 times weekly mimicking "summer-dose"-exposure (3 SED). Selected groups of mice received a "winter-dose"-exposure (0.6 SED) for the first 90 days. PDT was delivered with 0...

  18. Inflammation and emphysema in cigarette smoke-exposed mice when instilled with poly (I:C) or infected with influenza A or respiratory syncytial viruses

    Science.gov (United States)

    Background: The length of time for cigarette smoke (CS) exposure to cause emphysema in mice is drastically reduced when CS exposure is combined with viral infection. However, the extent of inflammatory responses and lung pathologies of mice exposed to CS and infected with influenza A virus (IAV), re...

  19. Modulatory Influence of Segmented Filamentous Bacteria on Transcriptomic Response of Gnotobiotic Mice Exposed to TCDD

    Directory of Open Access Journals (Sweden)

    Robert D. Stedtfeld

    2017-09-01

    Full Text Available Environmental toxicants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, an aryl hydrocarbon receptor (AhR, are known to induce host toxicity and structural shifts in the gut microbiota. Key bacterial populations with similar or opposing functional responses to AhR ligand exposure may potentially help regulate expression of genes associated with immune dysfunction. To examine this question and the mechanisms for AhR ligand-induced bacterial shifts, C57BL/6 gnotobiotic mice were colonized with and without segmented filamentous bacteria (SFB – an immune activator. Mice were also colonized with polysaccharide A producing Bacteroides fragilis – an immune suppressor to serve as a commensal background. Following colonization, mice were administered TCDD (30 μg/kg every 4 days for 28 days by oral gavage. Quantified with the nCounter® mouse immunology panel, opposing responses in ileal gene expression (e.g., genes associated with T-cell differentiation via the class II major histocompatibility complex as a result of TCDD dosing and SFB colonization were observed. Genes that responded to TCDD in the presence of SFB did not show a significant response in the absence of SFB, and vice versa. Regulatory T-cells examined in the mesenteric lymph-nodes, spleen, and blood were also less impacted by TCDD in mice colonized with SFB. TCDD-induced shifts in abundance of SFB and B. fragilis compared with previous studies in mice with a traditional gut microbiome. With regard to the mouse model colonized with individual populations, results indicate that TCDD-induced host response was significantly modulated by the presence of SFB in the gut microbiome, providing insight into therapeutic potential between AhR ligands and key commensals.

  20. L-Arginine improves multiple physiological parameters in mice exposed to diet-induced metabolic disturbances

    DEFF Research Database (Denmark)

    Clemmensen, Christoffer; Madsen, Andreas Nygaard; Smajilovic, Sanela

    2012-01-01

    : -Arg supplementation to male C57BL/6 mice on an array of physiological parameters. L: -Arg supplemented mice were maintained on a low-protein diet and body composition, appetite regulation, glucose tolerance, insulin sensitivity and energy expenditure were evaluated. A significant reduction......L: -Arginine (L: -Arg) is a conditionally essential amino acid and a natural constituent of dietary proteins. Studies in obese rats and type 2 diabetic humans have indicated that dietary supplementation with L: -Arg can diminish gain in white adipose tissue (WAT) and improve insulin sensitivity....... However, the effects of L: -Arg on glucose homeostasis, body composition and energy metabolism remain unclear. In addition, no studies have, to our knowledge, examined whether L: -Arg has beneficial effects as a dietary supplement in the mouse model. In the present study, we investigated the effects of L...

  1. Exaggerated phosphorylation of brain tau protein in CRH KO mice exposed to repeated immobilization stress.

    Science.gov (United States)

    Kvetnansky, Richard; Novak, Petr; Vargovic, Peter; Lejavova, Katarina; Horvathova, Lubica; Ondicova, Katarina; Manz, George; Filipcik, Peter; Novak, Michal; Mravec, Boris

    2016-07-01

    Neuroendocrine and behavioral stress responses are orchestrated by corticotropin-releasing hormone (CRH) and norepinephrine (NE) synthesizing neurons. Recent findings indicate that stress may promote development of neurofibrillary pathology in Alzheimer's disease. Therefore, we investigated relationships among stress, tau protein phosphorylation, and brain NE using wild-type (WT) and CRH-knockout (CRH KO) mice. We assessed expression of phosphorylated tau (p-tau) at the PHF-1 epitope and NE concentrations in the locus coeruleus (LC), A1/C1 and A2/C2 catecholaminergic cell groups, hippocampus, amygdala, nucleus basalis magnocellularis, and frontal cortex of unstressed, singly stressed or repeatedly stressed mice. Moreover, gene expression and protein levels of tyrosine hydroxylase (TH) and CRH receptor mRNA were determined in the LC. Plasma corticosterone levels were also measured. Exposure to a single stress increases tau phosphorylation throughout the brain in WT mice when compared to singly stressed CRH KO animals. In contrast, repeatedly stressed CRH KO mice showed exaggerated tau phosphorylation relative to WT controls. We also observed differences in extent of tau phosphorylation between investigated structures, e.g. the LC and hippocampus. Moreover, CRH deficiency leads to different responses to stress in gene expression of TH, NE concentrations, CRH receptor mRNA, and plasma corticosterone levels. Our data indicate that CRH effects on tau phosphorylation are dependent on whether stress is single or repeated, and differs between brain regions. Our findings indicate that CRH attenuates mechanisms responsible for development of stress-induced tau neuropathology, particularly in conditions of chronic stress. However, the involvement of central catecholaminergic neurons in these mechanisms remains unclear and is in need of further investigation.

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

    Science.gov (United States)

    2011-03-01

    about 1% a day. Diazepam is only used in cases of extreme nerve agent exposure to prevent brain injury caused by convulsions and seizures (USAMRID...These mice were evaluated at week nine and then micro -osmotic pumps (model 1007D from Alzet®) were implanted to administer doses of saline (20mg...using Schwartz micro -serrefine clips. The first lead was placed below the neck line in the dorsal thoracic region near the front right leg; the second

  3. Histopathological and Ultrastructural Studies of Liver Tissue from TCDD-Exposed Beach Mice (Peromyscus polionotus).

    Science.gov (United States)

    1980-03-01

    gross developmental .7so-i defects such as cleft palate , cleft lip and polydactyly. Body and organ weights were recorded, internal organs were examined...according to the study, sex and treatment , placed in glass jars, frozed and subnitted for TCDD analysis. Hepatic Ultrastructural Study After the liver was...weights per se was not attempted since the ages of the beach mice were not known and the animals could only be classified by sex and treatment . The

  4. Acute Toxicity of Amorphous Silica Nanoparticles in Intravenously Exposed ICR Mice

    Science.gov (United States)

    Wang, Wen; Jin, Minghua; Du, Zhongjun; Li, Yanbo; Duan, Junchao; Yu, Yongbo; Sun, Zhiwei

    2013-01-01

    This study aimed to evaluate the acute toxicity of intravenously administrated amorphous silica nanoparticles (SNPs) in mice. The lethal dose, 50 (LD50), of intravenously administrated SNPs was calculated in mice using Dixon's up-and-down method (262.45±33.78 mg/kg). The acute toxicity was evaluated at 14 d after intravenous injection of SNPs at 29.5, 103.5 and 177.5 mg/kg in mice. A silicon content analysis using ICP-OES found that SNPs mainly distributed in the resident macrophages of the liver (10.24%ID/g), spleen (34.78%ID/g) and lung (1.96%ID/g). TEM imaging showed only a small amount in the hepatocytes of the liver and in the capillary endothelial cells of the lung and kidney. The levels of serum LDH, AST and ALT were all elevated in the SNP treated groups. A histological examination showed lymphocytic infiltration, granuloma formation, and hydropic degeneration in liver hepatocytes; megakaryocyte hyperplasia in the spleen; and pneumonemia and pulmonary interstitial thickening in the lung of the SNP treated groups. A CD68 immunohistochemistry stain indicated SNPs induced macrophage proliferation in the liver and spleen. The results suggest injuries induced by the SNPs in the liver, spleen and lungs. Mononuclear phagocytic cells played an important role in the injury process. PMID:23593469

  5. Acute toxicity of amorphous silica nanoparticles in intravenously exposed ICR mice.

    Directory of Open Access Journals (Sweden)

    Yang Yu

    Full Text Available This study aimed to evaluate the acute toxicity of intravenously administrated amorphous silica nanoparticles (SNPs in mice. The lethal dose, 50 (LD50, of intravenously administrated SNPs was calculated in mice using Dixon's up-and-down method (262.45±33.78 mg/kg. The acute toxicity was evaluated at 14 d after intravenous injection of SNPs at 29.5, 103.5 and 177.5 mg/kg in mice. A silicon content analysis using ICP-OES found that SNPs mainly distributed in the resident macrophages of the liver (10.24%ID/g, spleen (34.78%ID/g and lung (1.96%ID/g. TEM imaging showed only a small amount in the hepatocytes of the liver and in the capillary endothelial cells of the lung and kidney. The levels of serum LDH, AST and ALT were all elevated in the SNP treated groups. A histological examination showed lymphocytic infiltration, granuloma formation, and hydropic degeneration in liver hepatocytes; megakaryocyte hyperplasia in the spleen; and pneumonemia and pulmonary interstitial thickening in the lung of the SNP treated groups. A CD68 immunohistochemistry stain indicated SNPs induced macrophage proliferation in the liver and spleen. The results suggest injuries induced by the SNPs in the liver, spleen and lungs. Mononuclear phagocytic cells played an important role in the injury process.

  6. Hypothalamic transcriptomic alterations in male and female California mice (Peromyscus californicus) developmentally exposed to bisphenol A or ethinyl estradiol.

    Science.gov (United States)

    Johnson, Sarah A; Spollen, William G; Manshack, Lindsey K; Bivens, Nathan J; Givan, Scott A; Rosenfeld, Cheryl S

    2017-02-01

    Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) prevalent in many household items. Rodent models and human epidemiological studies have linked this chemical to neurobehavior impairments. In California mice, developmental exposure to BPA results in sociosexual disorders at adulthood, including communication and biparental care deficits, behaviors that are primarily regulated by the hypothalamus. Thus, we sought to examine the transcriptomic profile in this brain region of juvenile male and female California mice offspring exposed from periconception through lactation to BPA or ethinyl estradiol (EE, estrogen present in birth control pills and considered a positive estrogen control for BPA studies). Two weeks prior to breeding, P0 females were fed a control diet, or this diet supplemented with 50 mg BPA/kg feed weight or 0.1 ppb EE, and continued on the diets through lactation. At weaning, brains from male and female offspring were collected, hypothalamic RNA isolated, and RNA-seq analysis performed. Results indicate that BPA and EE groups clustered separately from controls with BPA and EE exposure leading to unique set of signature gene profiles. Kcnd3 was downregulated in the hypothalamus of BPA- and EE-exposed females, whereas Tbl2, Topors, Kif3a, and Phactr2 were upregulated in these groups. Comparison of transcripts differentially expressed in BPA and EE groups revealed significant enrichment of gene ontology terms associated with microtubule-based processes. Current results show that perinatal exposure to BPA or EE can result in several transcriptomic alterations, including those associated with microtubule functions, in the hypothalamus of California mice. It remains to be determined whether these genes mediate BPA-induced behavioral disruptions. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  7. 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).

  8. Histopathology related to cadmium and lead bioaccumulation in chronically exposed wood mice, Apodemus sylvaticus, around a former smelter.

    Science.gov (United States)

    Tête, Nicolas; Durfort, Mercè; Rieffel, Dominique; Scheifler, Renaud; Sánchez-Chardi, Alejandro

    2014-05-15

    The ceasing of industrial activities often reduces the emission of pollutants but also often leaves disturbed areas without remediation and with persistent pollutants that can still be transferred along the food chain. This study examines the potential relationships between non-essential trace metals and histopathology in target tissues of wood mice (Apodemus sylvaticus) collected along a gradient of contamination around the former smelter, Metaleurop Nord (northern France). Cadmium and lead concentrations were measured, and histological alterations attributable to chronic trace metal exposure were assessed in the liver and the kidneys of 78 individuals. Metal concentrations quantified in the present study were among the highest observed for this species. Some histological alterations significantly increased with Cd or Pb concentrations in the soil and in the organs. Sixteen mice from polluted sites were considered at risk for metal-induced stress because their Cd and/or Pb tissue concentrations exceeded the LOAELs for single exposure to these elements. These mice also exhibited a higher severity of histological alterations in their organs than individuals with lower metal burdens. These results indicate that the Metaleurop smelter, despite its closure in 2003, still represents a threat to the local ecosystem because of the high levels and high bioavailability of Cd and Pb in the soil. However, among the mice not considered at risk for metal-induced stress based on the metal levels in their tissues, a large percentage of individuals still exhibited histological alterations. Thus, the present study suggests that the evaluation of toxic effects based only on the LOAELs for single metal exposure may result in the underestimation of the real risks when specimens are exposed to multiple stressors.

  9. Gender dependent evaluation of autism like behavior in mice exposed to prenatal zinc deficiency

    Directory of Open Access Journals (Sweden)

    Stefanie eGrabrucker

    2016-03-01

    Full Text Available Zinc deficiency has recently been linked to the etiology of autism spectrum disorders (ASD as environmental risk factor. With an estimated 17% of the world population being at risk of zinc deficiency, especially zinc deficiency during pregnancy might be a common occurrence, also in industrialized nations. On molecular level, zinc deficiency has been shown to affect a signaling pathway at glutamatergic synapses that has previously been identified through genetic mutations in ASD patients, the Neurexin-Neuroligin-Shank pathway, via altering zinc binding Shank family members. In particular, prenatal zinc deficient but not acute zinc deficient animals have been reported to display autism like behavior in some behavioral tests. However, a full behavioral analysis of a possible autism like behavior has been lacking so far. Here, we performed an extensive behavioral phenotyping of mice born from mothers with mild zinc deficiency during all trimesters of pregnancy. Prenatal zinc deficient animals were investigated as adults and gender differences were assessed. Our results show that prenatal zinc deficient mice display increased anxiety, deficits in nest building and various social interaction paradigm, as well as mild alterations in ultrasonic vocalizations. A gender specific analysis revealed only few sex specific differences. Taken together, given that similar behavioral abnormalities as reported here are frequently observed in ASD mouse models, we conclude that prenatal zinc deficient animals even without specific genetic susceptibility for ASD, already show some features of ASD like behavior.

  10. Increased hippocampal Disrupted-In-Schizophrenia 1 expression in mice exposed prenatally to lead

    Institute of Scientific and Technical Information of China (English)

    Yuanyuan You; Liguang Sun; Bo Peng; Yan Li; Songbin Ben; Shuang Gao

    2012-01-01

    Disrupted-In-Schizophrenia 1 is a susceptibility gene for schizophrenia and other psychiatric disorders.Developmental lead exposure can cause neurological disorders similar to hyperactivity disorder,dyslexia and schizophrenia. In the present study, we examined the impact of developmental lead exposure, administered in vitro and in vivo, on hippocampal Disrupted-In- Schizophrenia 1 expression. Our results show that in cultured hippocampal neurons, in vitro exposure to 0.1-10 μM lead, inhibited neurite growth and increased Disrupted-In-Schizophrenia 1 mRNA and protein expression dose-dependently. In addition, blood lead levels in mice were increased with increasing mouse maternal lead (0.01-1 mM) exposure. Hippocampal neurons from these mice showed a concomitant increase in Disrupted-In-Schizophrenia 1 mRNA and protein expression. Overall our findings suggest that in vivo and in vitro lead exposure increases Disrupted-In-Schizophrenia 1 expression in hippocampal neurons dose-dependently, and consequently may influence synapse formation in newborn neurons.

  11. [Cytogenetic investigations of bone marrow cells from mice exposed onboard biosatellite "Bion-M1"].

    Science.gov (United States)

    Dorozhkina, O V; Ivanov, A A

    2015-01-01

    The results of studying the mitotic activities and chromosomal aberrations in bone marrow cells from C57/BL6N mice with the help of the anaphase technique in 12 hours after completion of the 30-day "Bion-M1" mission and ground-based experiment using flight equipment are presented. A statistically reliable decline of the mitotic activity (0.74%) was found in cells taken from the space flown animals. In the ground-based experiment, a statistically reliable downward trend in proliferative activity (1.37%) was revealed after the comparison with groups of vivarium control (1.46-1.53%). In both experiments mice increased the number of initial mitotic phases (prophase + metaphase) relative to the sum of anaphases and telophases. The number of aberrant mitoses grew reliably in the group of flight animals by 29.7%, whereas in the ground-based experiment an upward trend was insignificant as their number increased up to 2.3% only. In the vivarium controls aberrant mitoses constituted 1.75-1.8%. An increase in chromosomal aberrations was largely due to such abnormalities as fragments. These findings seem to have been a result of summation of the effects of radiation and other stressful factors in space flight.

  12. Gender Dependent Evaluation of Autism like Behavior in Mice Exposed to Prenatal Zinc Deficiency.

    Science.gov (United States)

    Grabrucker, Stefanie; Boeckers, Tobias M; Grabrucker, Andreas M

    2016-01-01

    Zinc deficiency has recently been linked to the etiology of autism spectrum disorders (ASD) as environmental risk factor. With an estimated 17% of the world population being at risk of zinc deficiency, especially zinc deficiency during pregnancy might be a common occurrence, also in industrialized nations. On molecular level, zinc deficiency has been shown to affect a signaling pathway at glutamatergic synapses that has previously been identified through genetic mutations in ASD patients, the Neurexin-Neuroligin-Shank pathway, via altering zinc binding Shank family members. In particular, prenatal zinc deficient but not acute zinc deficient animals have been reported to display autism like behavior in some behavioral tests. However, a full behavioral analysis of a possible autism like behavior has been lacking so far. Here, we performed an extensive behavioral phenotyping of mice born from mothers with mild zinc deficiency during all trimesters of pregnancy. Prenatal zinc deficient animals were investigated as adults and gender differences were assessed. Our results show that prenatal zinc deficient mice display increased anxiety, deficits in nest building and various social interaction paradigm, as well as mild alterations in ultrasonic vocalizations. A gender specific analysis revealed only few sex specific differences. Taken together, given that similar behavioral abnormalities as reported here are frequently observed in ASD mouse models, we conclude that prenatal zinc deficient animals even without specific genetic susceptibility for ASD, already show some features of ASD like behavior.

  13. Investigation of possible teratogenic effects in the offspring of mice exposed to methylphenidate during pregnancy.

    Science.gov (United States)

    Costa, Gabriel de Araújo; Galvão, Talita Cristina; Bacchi, André Demambre; Moreira, Estefânia Gastaldello; Salles, Maria José Sparça

    2016-02-01

    Methylphenidate (MPH) is a central nervous system stimulant drug that increases concentration and energy level. The safety of MPH use during pregnancy is not well established. Considering the high rate of unplanned pregnancy among young women, potential for accidental exposure to MPH in early pregnancy is high. This study aimed to investigate if MPH administered during pregnancy would induce maternotoxicity, teratogenicity in mice, or both. Pregnant Swiss mice were treated with MPH (5 mg/kg, subcutaneously) or 0.9% saline (control group) from the 5th to the 17th day of pregnancy. In the MPH-treated group, a significant increase in the total number of resorptions with a consequent increase in post-implantation loss and a decrease in fetal viability were detected (all P < 0.05). A total of 91.43% of resorptions were classified as early resorptions. The group treated with MPH presented significant external (polydactyly P < 0.01), skeletal (incomplete ossification of the skull P < 0.01) and visceral (dilated ventricles P < 0.05) malformations. Behavioural effects (motor activity, memory of habituation and anxiety) were not observed in both male and female offspring evaluated at postnatal days 22, 35 and 75. The results suggest that MPH is an embryotoxic and teratogenic drug.

  14. Western diet enhances hepatic inflammation in mice exposed to cecal ligation and puncture

    Directory of Open Access Journals (Sweden)

    Houghton Jeff

    2010-10-01

    Full Text Available Abstract Background Obese patients display an exaggerated morbidity during sepsis. Since consumption of a western-style diet (WD is a major factor for obesity in the United States, the purpose of the present study was to examine the influence of chronic WD consumption on hepatic inflammation in mice made septic via cecal ligation and puncture (CLP. Feeding mice diets high in fat has been shown to enhance evidence of TLR signaling and this pathway also mediates the hepatic response to invading bacteria. Therefore, we hypothesized that the combined effects of sepsis and feeding WD on TRL-4 signaling would exacerbate hepatic inflammation. Male C57BL/6 mice were fed purified control diet (CD or WD that was enriched in butter fat (34.4% of calories for 3 weeks prior to CLP. Intravital microscopy was used to evaluate leukocyte adhesion in the hepatic microcirculation. To demonstrate the direct effect of saturated fatty acid on hepatocytes, C3A human hepatocytes were cultured in medium containing 100 μM palmitic acid (PA. Quantitative real-time PCR was used to assess mRNA expression of tumor necrosis factor-alpha (TNF-α, monocyte chemotactic protein-1 (MCP-1, intercellular adhesion molecule-1 (ICAM-1, toll-like receptor-4 (TLR-4 and interleukin-8 (IL-8. Results Feeding WD increased firm adhesion of leukocytes in the sinusoids and terminal hepatic venules by 8-fold six hours after CLP; the increase in platelet adhesion was similar to the response observed with leukocytes. Adhesion was accompanied by enhanced expression of TNF-α, MCP-1 and ICAM-1. Messenger RNA expression of TLR-4 was also exacerbated in the WD+CLP group. Exposure of C3A cells to PA up-regulated IL-8 and TLR-4 expression. In addition, PA stimulated the static adhesion of U937 monocytes to C3A cells, a phenomenon blocked by inclusion of an anti-TLR-4/MD2 antibody in the culture medium. Conclusions These findings indicate a link between obesity-enhanced susceptibility to sepsis and

  15. Studies on antioxidant enzymes in mice exposed to pulsed electromagnetic fields.

    Science.gov (United States)

    Eraslan, Gokhan; Bilgili, Ali; Akdogan, Mehmet; Yarsan, Ender; Essiz, Dinc; Altintas, Levent

    2007-02-01

    In this study, 56 female albino mice weighing 30-35 g were used. The animals were divided into a control and an experimental group. The animals in the experimental group were subjected to a pulsed electromagnetic field (PEMF) with a field magnitude of 50 Hz and 2 mT for 8h each day between 0900 and 1700 for 90 days. In both control and experimental groups, blood was sampled at 45, 60, and 90 days in heparinized tubes and erythrocyte malondialdehyde levels, and superoxide dismutase, glutathione peroxidase, catalase, and glucose-6-phosphate dehydrogenase activities were determined. The results revealed that the PEMF applied chronically within the given period and field magnitude does not cause oxidative damage.

  16. Differential proteome and gene expression for testis of mice exposed to carbon ion radiation

    Science.gov (United States)

    Zhang, Hong; Li, Hongyan

    Objective To investigate the effect and mechanism of high linear energy transfer (LET) carbon ion irradiation (CIR) on reproduction in the testis of male Swiss Webster mice, and assess the risk associated with space environment. Methods Male mice underwent whole-body irradiation with CIR (0.5, 1 and 4Gy), and matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF) analysis was used to determine the alteration in protein expression in 2-DE (two-dimensional gel electrophoresis) gels of testes caused by irradiation after 7, 14 days. Results 15 differentially expressed proteins, such as glucose-regulated protein(GRP78), aconitate hydratase-mitochondrial precursor (ACO), pyruvate kinase isozymes M1/M2 (PKM1/M2), glutathione-S-transferaseA3 (GSTA3), glutathione S-transferase Pi 1 (GSTP1), Cu/Zn super-oxide dismutase (SOD1), Peptidyl-prolyl cis-trans isomerase (Pin1) and Heat shock 70 kDa protein 4L (HSPa4L), were identified and these proteins were mainly involved in energy supply, the endoplasmic reticulum, cell proliferation, cell cycle, antioxidant capacity and mitochondrial respiration, which play important roles in the inhibition of testicular function in response to CIR. Furthermore, we confirmed the relationship between transcription of mRNA and the abundance of proteins. Conclusion The findings of the present study demonstrated that these proteins may lead to new insights into the molecular mechanism of CIR toxicity, and suggested that the gene expression response to CIR involves diverse regulatory mechanisms from transcription of mRNA to the formation of functional proteins. These data also may provide a scientific basis for protecting astronauts and space traveler’s health and safety.

  17. Suppression of NMDA receptor function in mice prenatally exposed to valproic acid improves social deficits and repetitive behaviors

    Directory of Open Access Journals (Sweden)

    Jaeseung eKang

    2015-05-01

    Full Text Available Animals prenatally exposed to valproic acid (VPA, an antiepileptic agent, have been used as a model for autism spectrum disorders (ASDs. Previous studies have identified enhanced NMDA receptor (NMDAR function in the brain of VPA rats, and demonstrated that pharmacological suppression of NMDAR function normalizes social deficits in these animals. However, whether repetitive behavior, another key feature of ASDs, can be rescued by NMDAR inhibition remains unknown. We report here that memantine, an NMDAR antagonist, administered to VPA mice rescues both social deficits and repetitive behaviors such as self-grooming and jumping. These results suggest that suppression of elevated NMDAR function in VPA animals normalizes repetitive behaviors in addition to social deficits.

  18. The humoral immune response of mice exposed to simulated road paving-like asphalt fumes.

    Science.gov (United States)

    Anderson, Stacey E; Munson, Albert E; Tomblyn, Seth; Meade, B Jean; Diotte, Nicole M

    2008-07-01

    Asphalt is a complex mixture of organic molecules, including polycyclic aromatic hydrocarbons (PAH), which have been reported to cause serious adverse health effects in humans. Workers in manufacturing and construction trades exposed to asphalt are potentially at risk for being exposed to asphalt fumes and PAHs. Epidemiological investigations have collected mounting evidence that chemicals found in asphalt fumes present carcinogenic and possibly immunotoxic hazards. Studies evaluating the immunotoxic effects of asphalt fume are limited due to the large number of variables associated with asphalt fume exposures. This work investigates the immuno-toxic effects of road paving-like asphalt fume by analyzing the in vivo IgM response to a T-dependent antigen after exposure to whole, vapor, and particulate phase road paving-like asphalt fumes and asphalt fume condensate. Systemic exposures via intraperitoneal injection of asphalt fume condensate (at 0.625 mg/kg) and the particulate phase (at 5 mg/kg) resulted in significant reductions in the specific spleen IgM response to SRBC. Pharyngeal aspiration of the asphalt fume condensate (at 5 mg/kg) also resulted in significant suppression of the IgM response to SRBC. A significant reduction in the specific spleen IgM activity was observed after inhalation exposure to whole asphalt fumes (35 mg/m(3)) and the vapor components (11 mg/m(3)). Dermal exposures to the asphalt fume condensate resulted in significant reductions in the total (at 50 mg/kg) and specific (at 250 mg/kg) spleen IgM response to SRBC. These results demonstrate that exposure to road paving-like asphalt fumes is immunosuppressive through systemic, respiratory, and dermal routes of exposure in a murine model and raise concerns regarding the potential for adverse immunological effects.

  19. Generation and characterization of RAG2 knockout pigs as animal model for severe combined immunodeficiency.

    Science.gov (United States)

    Suzuki, Shunichi; Iwamoto, Masaki; Hashimoto, Michiko; Suzuki, Misae; Nakai, Michiko; Fuchimoto, Daiichiro; Sembon, Shoichiro; Eguchi-Ogawa, Tomoko; Uenishi, Hirohide; Onishi, Akira

    2016-10-01

    Pigs with severe combined immunodeficiency (SCID) are versatile animal models for human medical research because of their biological similarities to humans, suitable body size, and longevity for practical research. SCID pigs with defined mutation(s) can be an invaluable tool for research on porcine immunity. In this study, we produced RAG2-knockout pigs via somatic cell nuclear transfer and analyzed their phenotype. The V(D)J recombination processes were confirmed as being inactivated. They consistently lacked mature T and B cells but had substantial numbers of cells considered to be T- or B-cell progenitors as well as NK cells. They also lacked thymic medulla and lymphoid aggregations in the spleen, mesenteric lymph nodes, and ileal Peyer's patches. We showed more severe immunological defects in the RAG2 and IL2RG double-knockout pig through this study. Thus, SCID pigs could be promising animal models not only for translational medical research but also for immunological studies of pigs themselves.

  20. Deficient Cholesterol Esterification in Plasma of apoc2 Knockout Zebrafish and Familial Chylomicronemia Patients

    Science.gov (United States)

    Liu, Chao; Gaudet, Daniel; Miller, Yury I.

    2017-01-01

    Hypertriglyceridemia is an independent risk factor for cardiovascular disease. Apolipoprotein C-II (APOC2) is an obligatory cofactor for lipoprotein lipase (LPL), the major enzyme catalyzing plasma triglyceride hydrolysis. We have created an apoc2 knockout zebrafish model, which mimics the familial chylomicronemia syndrome (FCS) in human patients with a defect in the APOC2 or LPL gene. In this study, we measured plasma levels of free cholesterol (FC) and cholesterol esters (CE) and found that apoc2 mutant zebrafish have a significantly higher FC to CE ratio (FC/CE), when compared to the wild type. Feeding apoc2 mutant zebrafish a low-fat diet reduced triglyceride levels but not the FC/CE ratio. In situ hybridization and qPCR results demonstrated that the hepatic expression of lecithin-cholesterol acyltransferase (lcat), the enzyme responsible for esterifying plasma FC to CE, and of apolipoprotein A-I, a major protein component of HDL, were dramatically decreased in apoc2 mutants. Furthermore, the FC/CE ratio was significantly increased in the whole plasma and in a chylomicron-depleted fraction of human FCS patients. The FCS plasma LCAT activity was significantly lower than that of healthy controls. In summary, this study, using a zebrafish model and human patient samples, reports for the first time the defect in plasma cholesterol esterification associated with LPL deficiency. PMID:28107429

  1. iRhom2 deficiency relieves TNF-α associated hepatic dyslipidemia in long-term PM2.5-exposed mice.

    Science.gov (United States)

    Ge, Chen-Xu; Qin, Yu-Ting; Lou, De-Shuai; Li, Qiang; Li, Yuan-Yuan; Wang, Zhong-Ming; Yang, Wei-Wei; Wang, Ming; Liu, Nan; Wang, Zhen; Zhang, Peng-Xing; Tu, Yan-Yang; Tan, Jun; Xu, Min-Xuan

    2017-09-28

    Accumulating researches reported that particulate matter (PM2.5) is a risk factor for developing various diseases, including metabolic syndrome. Recently, inactive rhomboid protein 2 (iRhom2) was considered as a necessary modulator for shedding of tumor necrosis factor-α (TNF-α) in immune cells. TNF-α, a major pro-inflammatory cytokine, was linked to various pathogenesis of diseases, including dyslipidemia. Here, wild type (WT) and iRhom2-knockout (iRhom2(-/-)) mice were used to investigate the effects of iRhom2 on PM2.5-induced hepatic dyslipidemia. The hepatic histology, inflammatory response, glucose tolerance, serum parameters and gene expressions were analyzed. We found that long-term inhalation of PM2.5 resulted in hepatic steatosis. And a significant up-regulation of iRhom2 in liver tissues was observed, accompanied with elevated TNF-α, TNF-α converting enzyme (TACE), TNFα receptor (TNFR)2 and various inflammatory cytokines expressions. Additionally, PM2.5 treatment caused TG and TC accumulation in serum and liver, probably attributed to changes of genes modulating lipid metabolism. Intriguingly, hepatic injury and dyslipidemia were attenuated by iRhom2(-/-) in mice with PM2.5 challenge. In vitro, iRhom2-knockdwon reduced TNF-α expressions and its associated inflammatory cytokines in Kupffer cells, implying that liver-resident macrophages played an important role in regulating hepatic inflammation and lipid metabolism in cells treated with PM2.5. The findings indicated that long-term PM2.5 exposure caused hepatic steatosis and dyslipidemia through triggering inflammation, which was, at least partly, dependent on iRhom2/TNF-α pathway in liver-resident macrophages. Copyright © 2017. Published by Elsevier Inc.

  2. Sulforaphane Prevents Testicular Damage in Kunming Mice Exposed to Cadmium via Activation of Nrf2/ARE Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Shu-Hua Yang

    2016-10-01

    Full Text Available Sulforaphane (SFN is a natural and highly effective antioxidant. Studies suggest that SFN protects cells and tissues against cadmium (Cd toxicity. This study investigated the protective effect of SFN against oxidative damage in the testes of Kunming mice exposed to cadmium, and explored the possible molecular mechanisms involved. Cadmium greatly reduced the serum testosterone levels in mice, reduced sperm motility, total sperm count, and increased the sperm deformity rate. Cadmium also reduces superoxide dismutase (T-SOD and glutathione (GSH levels and increases malondialdehyde (MDA concentrations. SFN intervention improved sperm quality, serum testosterone, and antioxidant levels. Both mRNA and protein expression of mouse testicular nuclear factor-erythroid 2-related factor 2 (Nrf2 was reduced in cadmium-treated group. Furthermore, the downstream genes of Nrf2, glutathione peroxidase (GSH-Px, γ-glutamyl cysteine synthetase (γ-GCS, heme oxygenase-1 (HO-1, and NAD(PH:quinone oxidoreductase-1 (NQO1 were also decreased in cadmium-treated group. SFN intervention increases the expression of these genes. Sulforaphane prevents cadmium-induced testicular damage, probably via activation of Nrf2/ARE signaling.

  3. Sulforaphane Prevents Testicular Damage in Kunming Mice Exposed to Cadmium via Activation of Nrf2/ARE Signaling Pathways.

    Science.gov (United States)

    Yang, Shu-Hua; Long, Miao; Yu, Li-Hui; Li, Lin; Li, Peng; Zhang, Yi; Guo, Yang; Gao, Feng; Liu, Ming-Da; He, Jian-Bin

    2016-10-11

    Sulforaphane (SFN) is a natural and highly effective antioxidant. Studies suggest that SFN protects cells and tissues against cadmium (Cd) toxicity. This study investigated the protective effect of SFN against oxidative damage in the testes of Kunming mice exposed to cadmium, and explored the possible molecular mechanisms involved. Cadmium greatly reduced the serum testosterone levels in mice, reduced sperm motility, total sperm count, and increased the sperm deformity rate. Cadmium also reduces superoxide dismutase (T-SOD) and glutathione (GSH) levels and increases malondialdehyde (MDA) concentrations. SFN intervention improved sperm quality, serum testosterone, and antioxidant levels. Both mRNA and protein expression of mouse testicular nuclear factor-erythroid 2-related factor 2 (Nrf2) was reduced in cadmium-treated group. Furthermore, the downstream genes of Nrf2, glutathione peroxidase (GSH-Px), γ-glutamyl cysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), and NAD(P)H:quinone oxidoreductase-1 (NQO1) were also decreased in cadmium-treated group. SFN intervention increases the expression of these genes. Sulforaphane prevents cadmium-induced testicular damage, probably via activation of Nrf2/ARE signaling.

  4. Diverse ability of maternal immune stimulation to reduce birth defects in mice exposed to teratogens: a review.

    Science.gov (United States)

    Hrubec, T C; Prater, M R; Mallela, M K; Gogal, R M; Guo, T L; Holladay, S D

    2012-06-01

    Stimulating the maternal immune system before or during pregnancy can dramatically improve morphologic outcome in mice that have been exposed to teratogens. For example, maternal immune stimulation in mice reduced craniofacial and palate defects, heart defects, digit and limb defects, tail malformations and neural tube defects caused by diverse teratogens that included chemical agents, hyperthermia, X-rays and diabetes mellitus. Several different procedures of immune stimulation were effective and included footpad injection with Freund's Complete Adjuvant, intraperitoneal (IP) injection with inert particles or attenuated Bacillus Calmette-Guerin, intrauterine injection with allogenic or xenogenic lymphocytes, or intravascular, intrauterine or IP injection with immunomodulatory cytokines. Limited information is available regarding mechanisms by which such immune stimulation reduces fetal dysmorphogenesis; however, cytokines of maternal origin have been suggested as effector molecules that act on the placenta or fetus to improve development. These collective data raise novel questions about the possibility of unrecognized maternal immune system regulatory activity in normal fetal development. This manuscript reviews the literature showing maternal immune protection against morphologic birth defects. Potential operating mechanisms are discussed, and the possibility is considered that a suppressed maternal immune system may negatively impact fetal development.

  5. Commentary to Krishna et al. (2014): brain deposition and neurotoxicity of manganese in adult mice exposed via the drinking water.

    Science.gov (United States)

    Kumasaka, Mayuko Y; Yajima, Ichiro; Ohgami, Nobutaka; Naito, Hisao; Omata, Yasuhiro; Kato, Masashi

    2014-05-01

    Krishna et al. (Arch Toxicol 88(1):47-64, 2014) recently published the results of a study in which adult C57BL/6 mice were subchronically exposed to 400,000 μg/L manganese (Mn) using manganese chloride via drinking water for 8 weeks and examined the neurotoxic effects. After 5 weeks of Mn exposure, significant deposition of Mn in all of the brain regions examined by magnetic resonance imaging was detected. After 6 weeks of Mn exposure, neurobehavioral deficits in an open field test, a grip strength test, and a forced swim test were observed. Eight weeks of Mn exposure increased striatal 5-hydroxyindoleacetic acid (a serotonin metabolite) levels, but did not alter the levels of striatal dopamine, its metabolites and serotonin. Krishna et al. also reported significant increases in mRNA levels of GFAP (an astrocyte activation marker), HO-1 (an oxidative stress marker) and NOS2 (a nitrosative stress marker), and in protein expression level of GFAP in the substantia nigra pars reticulata after 8 weeks of Mn exposure. These results suggest that 400,000 μg/L Mn exposure via drinking water in mice induces neurobehavioral deficits, serotonergic imbalance, and glial activation accompanied by an increase in brain Mn deposition. The report by Krishna et al. is interesting because the studies on the neurobehavioral effect of Mn exposure by drinking water in mice are very limited. However, Mn concentrations previously reported in well drinking water (Agusa et al. in Vietnam Environ Pollut 139(1):95-106, 2006; Buschmann et al. in Environ Int 34(6):756-764, 2008; Hafeman et al. in Environ Health Perspect 115(7):1107-1112, 2007; Wasserman et al. in Bangladesh Environ Health Perspect 114(1):124-129, 2006) were lower than 400,000 μg/L.

  6. Cell cycle arrest and gene expression profiling of testis in mice exposed to fluoride.

    Science.gov (United States)

    Su, Kai; Sun, Zilong; Niu, Ruiyan; Lei, Ying; Cheng, Jing; Wang, Jundong

    2017-05-01

    Exposure to fluoride results in low reproductive capacity; however, the mechanism underlying the impact of fluoride on male productive system still remains obscure. To assess the potential toxicity in testis of mice administrated with fluoride, global genome microarray and real-time PCR were performed to detect and identify the altered transcriptions. The results revealed that 763 differentially expressed genes were identified, including 330 up-regulated and 433 down-regulated genes, which were involved in spermatogenesis, apoptosis, DNA damage, DNA replication, and cell differentiation. Twelve differential expressed genes were selected to confirm the microarray results using real-time PCR, and the result kept the same tendency with that of microarray. Furthermore, compared with the control group, more apoptotic spermatogenic cells were observed in the fluoride group, and the spermatogonium were markedly increased in S phase and decreased in G2/M phase by fluoride. Our findings suggested global genome microarray provides an insight into the reproductive toxicity induced by fluoride, and several important biological clues for further investigations. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1558-1565, 2017. © 2016 Wiley Periodicals, Inc.

  7. Toxicogenomic analysis of placenta samples from mice exposed to different doses of BPA

    Directory of Open Access Journals (Sweden)

    Sabrina Tait

    2015-06-01

    Full Text Available Bisphenol A (BPA, a widespread Endocrine Disrupter mainly used in food contact plastics, may induce adverse effects especially on susceptible lifestages, first of all pregnancy. The present study considered placental development as a potential target of BPA and investigated potential differences in the modes of action of two doses of BPA by a toxicogenomic approach. Pregnant CD-1 mice were administered with vehicle, 0.5 (BPA05 or 50 mg/kg (BPA50 body weight (bw/die of BPA, from gestational day (GD 1 to GD11. At GD12 dams were sacrificed and transcriptomic analysis was performed on placenta samples. Histological, histomorphometrical and immunohistochemical analyses were also performed to phenotypically anchor transcriptional changes associated with BPA exposure. The interpretation and description of the overall data are included in a manuscript under revision [1]. Here we describe the experimental design and the analysis performed on the gene expression data which are publicly available through the Gene Expression Omnibus (GEO database with accession number GSE63852.

  8. Gallic acid regulates skin photoaging in UVB-exposed fibroblast and hairless mice.

    Science.gov (United States)

    Hwang, Eunson; Park, Sang-Yong; Lee, Hyun Ji; Lee, Tae Youp; Sun, Zheng-Wang; Yi, Tae Hoo

    2014-12-01

    Ultraviolet (UV) radiation is the primary factor in skin photoaging, which is characterized by wrinkle formation, dryness, and thickening. The mechanisms underlying skin photoaging are closely associated with degradation of collagen via upregulation of matrix metalloproteinase (MMP) activity, which is induced by reactive oxygen species (ROS) production. Gallic acid (GA), a phenolic compound, possesses a variety of biological activities including antioxidant and antiinflammatory activities. We investigated the protective effects of GA against photoaging caused by UVB irradiation using normal human dermal fibroblasts (NHDFs) in vitro and hairless mice in vivo. The production levels of ROS, interlukin-6, and MMP-1 were significantly suppressed, and type I procollagen expression was stimulated in UVB-irradiated and GA-treated NHDFs. GA treatment inhibited the activity of transcription factor activation protein 1. The effects of GA following topical application and dietary administration were examined by measuring wrinkle formation, histological modification, protein expression, and physiological changes such as stratum corneum hydration, transepidermal water loss, and erythema index. We found that GA decreased dryness, skin thickness, and wrinkle formation via negative modulation of MMP-1 secretion and positive regulation of elastin, type I procollagen, and transforming growth factor-β1. Our data indicate that GA is a potential candidate for the prevention of UVB-induced premature skin aging.

  9. Post-weaning diet determines metabolic risk in mice exposed to overnutrition in early life.

    Science.gov (United States)

    King, Vicky; Norman, Jane E; Seckl, Jonathan R; Drake, Amanda J

    2014-08-01

    Maternal overnutrition during pregnancy is associated with an increased risk of obesity and cardiometabolic disease in the offspring; a phenomenon attributed to 'developmental programming'. The post-weaning development of obesity may associate with exacerbation of the programmed metabolic phenotype. In mice, we have previously shown that exposure to maternal overnutrition causes increased weight gain in offspring before weaning, but exerts no persistent effects on weight or glucose tolerance in adulthood. In order to determine whether post-weaning exposure to a cafeteria diet might lead to an exacerbation of programmed effects, offspring born and raised by mothers on control (CON) or cafeteria (DIO) diets were transferred onto either CON or DIO diets at weaning. Post-weaning DIO caused the development of obesity, with hyperglycaemia and hyperinsulinaemia in males; and obesity with hyperinsulinaemia in females and with increased cholesterol levels in both sexes. Exposure to maternal overnutrition during pregnancy and lactation caused only subtle additional effects on offspring phenotype. These results suggest that post-weaning exposure to a high-fat high-sugar diet has a more profound effect on offspring weight gain and glucose tolerance than exposure to maternal overnutrition. These data emphasise the importance of optimising early life nutrition in offspring of both obese and lean mothers.

  10. The effect of oxidative stress in myocardial cell injury in mice exposed to chronic intermittent hypoxia

    Institute of Scientific and Technical Information of China (English)

    LIU Jian-nan; ZHANG Jie-xin; LIU gan; QIU Yan; YANG Di; YIN Guo-yong; ZHANG Xi-long

    2010-01-01

    Background Obstructive sleep apnea syndrome (OSAS) is an important risk factor for cardiovascular diseases. Chronic intermittent hypoxia (CIH) is considered to be one of the most important causes of cardiovascular diseases in OSA patients. This repeated hypoxia and reoxygenation cycle is similar to hypoxia-reperfusion injury, which initiates oxidative stress. In this study, we observed cardiocytes injury induced by CIH and the effect of N-acetylcysteine (NAC). Methods Thirty ICR mice were randomly assigned to 3 groups: control, CIH and NAC (CIH+NAC) groups. Malondialdehyde (MDA) and superoxide dismutase (SOD) of cardiocyte homogenates were measured. Serum lipids were measured by an instrument method. Serum cardiac troponin I (cTnl) was detected by enzyme-linked immunosorbent assays (ELISA). Myocardium pathological sections were observed.Results (1) The SOD activity and MDA concentration of cardiocyte homogenates in the CIH group were significantly higher than in other groups (P <0.005). The MDA concentration of the NAC group was lower than that of the control group (P <0.01). (2) The serum cTnl concentration of the CIH and NAC groups was significantly higher than that of the control group (P<0.01). (3) Serum triglyceride levels in the NAC group were lower than in the other groups (P<0.01), while there were no significant differences in low density lipoprotein and high density lipoprotein among the three groups. (4) The degeneration of myocardium, transverse striation blurred, and fabric effusion were observed in tissue sections in the CIH and NAC groups. However, normal tissue was found in the control group.Conclusion The oxidative stress induced by CIH can injure cardiocytes and the injury effect can be partially inhibited by NAC.

  11. Metabolomic and lipidomic analysis of serum from mice exposed to an internal emitter, cesium-137, using a shotgun LC-MS(E) approach.

    Science.gov (United States)

    Goudarzi, Maryam; Weber, Waylon M; Mak, Tytus D; Chung, Juijung; Doyle-Eisele, Melanie; Melo, Dunstana R; Brenner, David J; Guilmette, Raymond A; Fornace, Albert J

    2015-01-02

    In this study ultra performance liquid chromatography (UPLC) coupled to time-of-flight mass spectrometry in the MS(E) mode was used for rapid and comprehensive analysis of metabolites in the serum of mice exposed to internal exposure by Cesium-137 ((137)Cs). The effects of exposure to (137)Cs were studied at several time points after injection of (137)CsCl in mice. Over 1800 spectral features were detected in the serum of mice in positive and negative electrospray ionization modes combined. Detailed statistical analysis revealed that several metabolites associated with amino acid metabolism, fatty acid metabolism, and the TCA cycle were significantly perturbed in the serum of (137)Cs-exposed mice compared with that of control mice. While metabolites associated with the TCA cycle and glycolysis increased in their serum abundances, fatty acids such as linoleic acid and palmitic acid were detected at lower levels in serum after (137)Cs exposure. Furthermore, phosphatidylcholines (PCs) were among the most perturbed ions in the serum of (137)Cs-exposed mice. This is the first study on the effects of exposure by an internal emitter in serum using a UPLC-MS(E) approach. The results have put forth a panel of metabolites, which may serve as potential serum markers to (137)Cs exposure.

  12. Differential effect of dehydroepiandrosterone and its steroid precursor pregnenolone against the behavioural deficits in CO-exposed mice.

    Science.gov (United States)

    Maurice, T; Phan, V; Sandillon, F; Urani, A

    2000-02-25

    The neuroactive steroids pregnenolone (3beta-hydroxy-5-pregnen-20-one) and dehydroepiandrosterone (DHEA, 3alpha-hydroxy-5-androstene-17-one) are negative allosteric modulators of the GABA(A) receptors and positive modulators of acetylcholine, NMDA and sigma(1) receptors. Pregnenolone was recently shown to potentiate the neuronal damage induced by excessive glutamate in cell culture models, whereas dehydroepiandrosterone was reported to present some neuroprotective activity. The in vivo relevance of these effects was investigated in mice submitted to an hypoxic insult, the repeated exposure to carbon monoxide (CO) gas, a model that leads to neurodegeneration in the CA(1) hippocampal area and learning deficits. Recording spontaneous alternation behaviour in the Y-maze assessed short-term memory and long-term memory was examined using a passive avoidance task. After exposure to CO, mice showed a progressive deterioration of their learning ability, reaching significance after 3 days and being maximal after 7 days. Pregnenolone administered before CO significantly facilitated the hypoxia-related deficits, which could be measured 1 day after CO and appeared maximal after 3 days. Dizocilpine blocked the deficits in vehicle- and pregnenolone-treated CO-exposed animals, showing that pregnenolone selectively facilitated the NMDA receptor-dependent excitotoxicity. Dehydroepiandrosterone blocked the appearance of the CO-induced deficits, even after 7 days. Interestingly, the sigma(1) receptor antagonist N, N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine (NE-100) failed to affect the dehydroepiandrosterone-induced protection, showing the lack of involvement of sigma(1) receptors. Cresyl violet-stained sections of the mouse hippocampal formation showed that the neurodegeneration observed in the CA(1) area after exposure to CO was augmented by pregnenolone and blocked by dehydroepiandrosterone. These results show that pregnenolone and dehydroepiandrosterone, although

  13. Augmented atherogenesis in ApoE-null mice co-exposed to polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin.

    Science.gov (United States)

    Shan, Qiuli; Wang, Jing; Huang, Fengchen; Lv, Xiaowen; Ma, Min; Du, Yuguo

    2014-04-15

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) are persistent organic pollutants found as complex mixtures in the environment throughout the world. Therefore, humans are ubiquitously and simultaneously exposed to TCDD and PCBs. TCDD and PCBs alone have been linked to atherosclerosis. However, the effects of interactions or synergism between TCDD and PCBs on atherogenesis are unknown. We investigated the possible enhanced atherogenesis by co-exposure to TCDD and PCBs and the potential mechanism(s) involved in this enhancement. Male ApoE(-/-) mice were exposed to TCDD (15 μg/kg) and Aroclor1254 (55 mg/kg, a representative mixture of PCBs) alone or in combination by intraperitoneal injection four times over six weeks of duration. Our results showed that mice exposed to TCDD alone, but not Aroclor1254 alone, developed atherosclerotic lesions. Moreover, we found that atherosclerotic disease was exacerbated to the greatest extent in mice co-exposed to TCDD and Aroclor1254. The enhanced lesions correlated with several pro-atherogenic changes, including a marked increase in the accumulation of the platelet-derived chemokine PF4, and the expression of the proinflammatory cytokine MCP-1 and the critical immunity gene-RIG-I. Our data demonstrated that co-exposure to TCDD and Aroclor1254 markedly enhanced atherogenesis in ApoE(-/-) mice. Significantly, our observations suggest that combined exposure to TCDD and PCBs may be a greater cardiovascular health risk than previously anticipated from individual studies.

  14. Suppression of antigen-specific antibody responses in mice exposed to perfluorooctanoic acid: Role of PPARalpha and T- and B-cell targeting

    Science.gov (United States)

    T-cell-dependent antibody responses (TDAR) are suppressed in female C57BL/6N mice exposed to ≥3.75 mg/kg of perfluorooctanoic acid (PFOA) for 15 days. To determine if suppression of humoral immunity by PFOA is peroxisome proliferator activated receptor alpha (PPARa)-dependent and...

  15. Metabolomic profiling of urine samples from mice exposed to protons reveals radiation quality and dose specific differences.

    Science.gov (United States)

    Laiakis, Evagelia C; Trani, Daniela; Moon, Bo-Hyun; Strawn, Steven J; Fornace, Albert J

    2015-04-01

    As space travel is expanding to include private tourism and travel beyond low-Earth orbit, so is the risk of exposure to space radiation. Galactic cosmic rays and solar particle events have the potential to expose space travelers to significant doses of radiation that can lead to increased cancer risk and other adverse health consequences. Metabolomics has the potential to assess an individual's risk by exploring the metabolic perturbations in a biofluid or tissue. In this study, C57BL/6 mice were exposed to 0.5 and 2 Gy of 1 GeV/nucleon of protons and the levels of metabolites were evaluated in urine at 4 h after radiation exposure through liquid chromatography coupled to time-of-flight mass spectrometry. Significant differences were identified in metabolites that map to the tricarboxylic acid (TCA) cycle and fatty acid metabolism, suggesting that energy metabolism is severely impacted after exposure to protons. Additionally, various pathways of amino acid metabolism (tryptophan, tyrosine, arginine and proline and phenylalanine) were affected with potential implications for DNA damage repair and cognitive impairment. Finally, presence of products of purine and pyrimidine metabolism points to direct DNA damage or increased apoptosis. Comparison of these metabolomic data to previously published data from our laboratory with gamma radiation strongly suggests a more pronounced effect on metabolism with protons. This is the first metabolomics study with space radiation in an easily accessible biofluid such as urine that further investigates and exemplifies the biological differences at early time points after exposure to different radiation qualities.

  16. Loss of Metabotropic Glutamate Receptor 5 Function on Peripheral Benzodiazepine Receptor in Mice Prenatally Exposed to LPS.

    Directory of Open Access Journals (Sweden)

    Dany Arsenault

    Full Text Available Parental microglial induced neuroinflammation, triggered by bacterial- or viral infections, can induce neuropsychiatric disorders like schizophrenia and autism to offspring in animal models. Recent investigations suggest that microglia, the resident immune cells of the brain, provides a link between neurotransmission, immune cell activation, brain inflammation and neuronal dysfunction seen with the offspring. Relatively little is known about how reduction of brain inflammation and restoration of glial function are associated with diminution of brain degeneration and behavioral deficits in offspring. Increased mGluR5 expression and the long-lasting excitotoxic effects of the neurotoxin during brain development are associated with the glial dysfunctions. We investigated the relationship of mGluR5 and PBR and how they regulate glial function and inflammatory processes in mice prenatally exposed to LPS (120μg/kg, between gestational days 15 and 17, an inflammatory model of a psychiatric disorder. Using PET imaging, we showed that pharmacological activation of mGluR5 during 5 weeks reduced expression of classic inflammation marker PBR in many brain areas and that this molecular association was not present in LPS-exposed offspring. The post-mortem analysis revealed that the down regulation of PBR was mediated through activation of mGluR5 in astrocytes. In addition, we demonstrated that this interaction is defective in a mouse model of the psychiatric deficit offering a novel insight of mGluR5 involvement to brain related disorders and PBR related imaging studies. In conclusion, mGluR5 driven glutamatergic activity regulates astrocytic functions associated with PBR (cholesterol transport, neurosteroidogenesis, glial phenotype during maturation and could be associated with neuropsychiatric disorders in offspring.

  17. DNA damage and apoptosis of endometrial cells cause loss of the early embryo in mice exposed to carbon disulfide

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Bingzhen [Department of Epidemiology and Health Statistics, School of Public Health, Shandong University, Jinan (China); Shen, Chunzi [Centers for Disease Control and Prevention, Zibo (China); Yang, Liu; Li, Chunhui; Yi, Anji [Department of Epidemiology and Health Statistics, School of Public Health, Shandong University, Jinan (China); Wang, Zhiping, E-mail: zhipingw@sdu.edu.cn [Department of Epidemiology and Health Statistics, School of Public Health, Shandong University, Jinan (China)

    2013-12-01

    Carbon disulfide (CS{sub 2}) may lead to spontaneous abortion and very early pregnancy loss in women exposed in the workplace, but the mechanism remains unclear. We designed an animal model in which gestating Kunming strain mice were exposed to CS{sub 2} via i.p. on gestational day 4 (GD4). We found that the number of implanted blastocysts on GD8 was significantly reduced by each dose of 0.1 LD{sub 50} (157.85 mg/kg), 0.2 LD{sub 50} (315.7 mg/kg) and 0.4 LD{sub 50} (631.4 mg/kg). In addition, both the level of DNA damage and apoptosis rates of endometrial cells on GD4.5 were increased, showed definite dose–response relationships, and inversely related to the number of implanted blastocysts. The expressions of mRNA and protein for the Bax and caspase-3 genes in the uterine tissues on GD4.5 were up-regulated, while the expressions of mRNA and protein for the Bcl-2 gene were dose-dependently down-regulated. Our results indicated that DNA damage and apoptosis of endometrial cells were important reasons for the loss of implanted blastocysts induced by CS{sub 2}. - Highlights: • We built an animal model of CS2 exposure during blastocyst implantation. • Endometrial cells were used in the comet assay to detect DNA damage. • CS2 exposure caused DNA damage and endometrial cell apoptosis. • DNA damage and endometrial cell apoptosis were responsible for embryo loss.

  18. Protein damage from electrophiles and oxidants in lungs of mice chronically exposed to the tumor promoter butylated hydroxytoluene.

    Science.gov (United States)

    Shearn, Colin T; Fritz, Kristofer S; Thompson, John A

    2011-07-15

    The food additive butylated hydroxytoluene (BHT) promotes tumorigenesis in mouse lung. Chronic BHT exposure is accompanied by pulmonary inflammation and several studies indicate that elevated levels of reactive oxygen species (ROS) are involved in its promoting activity. The link between BHT and elevated ROS involves formation of quinone methide (QM) metabolites; these electrophiles form adducts with a variety of lung proteins including several enzymes that protect cells from oxidative stress. Studies in vitro demonstrated that QM alkylation of cytoprotective enzymes is accompanied by inactivation, so an objective of the present investigation was to determine if inactivation also occurs in vivo. Two groups of mice were exposed to BHT by intraperitoneal injection, one for 10 days and the other for 24 days, and proteins from lung cytosols were examined for damage. Analysis by Western blotting demonstrated that BHT treatment caused substantial increases in protein carbonylation, nitration and adduction by 4-hydroxynonenal, confirming the occurrence of sustained oxidative and nitrosative stress over the treatment period required for tumor promotion. Effects of BHT on the activities and/or levels of a representative group of antioxidant/protective enzymes in mouse lung also were assessed; NAD(P)H:quinone reductase and glutathione reductase were unaffected, however carbonyl reductase activity decreased 50-60%. Superoxide dismutase and glutathione peroxidase activities increased 2- and 1.5-fold, respectively, and glutamate-cysteine ligase catalytic subunit expression increased 32-39% relative to untreated mice. Glutathione S-transferase (GST) activity decreased 50-60% but concentrations of the predominant isoforms, GSTM1 and P1, were not affected. GSTP1 was substantially more susceptible than M1 to adduction and inhibition by treatment with BHT-QM in vitro, suggesting that lower GST activity in mice after BHT treatment is due to adduction of the P1 isoform. The results of

  19. Radio-protective effect of vitamin E on spermatogenesis in mice exposed to γ-irradiation: a flow cytometric study

    Institute of Scientific and Technical Information of China (English)

    C.Songthaveesin; J.Saikhun; Y.Kitiyanant; K.Pavasuthipaisit

    2004-01-01

    Aim: To investigate the effect of vitamin E on the radioprotection of spermatogenesis and chromatin condensation of spermatozoa during passage through the epididymis in mice exposed to irradiation. Methods: Adult outbred male ICR mice were orally administered natural vitamin E (VE,D-a-tocopheryl acetate) at 400 IU/kg for 7 days before exposure to 1 Gy of y-irradiation. The animals were sacrificed at day 1,7,14,21, 28, 35 and 70 post-irradiation (IR) and the percentage of testicular germ cells and epididymal sperm chromatin condensation was analyzed using flow cytometry. Results: Serum D-a-tocopheryl acetate levels were 47.4±3.2μg/dL in the treatedgroup, yet it could not be detected in the control group. The testicular weight of irradiated mice pretreated with VE+IR was significantly (P<0.05) higher than that of those without VE treatment (IR) at day 14 and 21 post-irradiation. The percentage of primary spermatocytes (4C) in the VE+IR group was comparable to the controls but significantly (P<0.05) higher than those in the IR group from day 7 to 35 post-irradiation. The percentage of round spermatids (1C) in the VE+IR group was also significantly (P<0.05) higher than those in the IR group at day 28 postirradiation. The primary spermatocytes:spermatogonia ratio in the IR group was significantly (P<0.05) declined at day 7 to 35 post-irradiation when compared to the VE+IR and control groups. The round spermatid:spermatogonia ratio in the VE+IR group was significantly (P<0.05) higher than that of the IR group at day 14 and 28 post-irradiation.The chromatin condensation of epididymal spermatozoa measured by propidium iodide uptake was not affected by 1 Gy of γ-irradiation. Conclusion: The administration of VE prior to irradiation protects spermatogenic cells fromradiation. (Asian J Androl 2004 Dec; 6: 331-336)

  20. Epigenomic profiling in visceral white adipose tissue of offspring of mice exposed to late gestational sleep fragmentation.

    Science.gov (United States)

    Cortese, R; Khalyfa, A; Bao, R; Andrade, J; Gozal, D

    2015-07-01

    Sleep fragmentation during late gestation (LG-SF) is one of the major perturbations associated with sleep apnea and other sleep disorders during pregnancy. We have previously shown that LG-SF induces metabolic dysfunction in offspring mice during adulthood. To investigate the effects of late LG-SF on metabolic homeostasis in offspring and to determine the effects of LG-SF on the epigenome of visceral white adipose tissue (VWAT) in the offspring. Time-pregnant mice were exposed to LG-SF or sleep control during LG (LG-SC) conditions during the last 6 days of gestation. At 24 weeks of age, lipid profiles and metabolic parameters were assessed in the offspring. We performed large-scale DNA methylation analyses using methylated DNA immunoprecipitation (MeDIP) coupled with microarrays (MeDIP-chip) in VWAT of 24-week-old LG-SF and LG-SC offspring (n=8 mice per group). Univariate multiple-testing adjusted statistical analyses were applied to identify differentially methylated regions (DMRs) between the groups. DMRs were mapped to their corresponding genes, and tested for potential overlaps with biological pathways and gene networks. We detected significant increases in body weight (31.7 vs 28.8 g; P=0.001), visceral (642.1 vs 497.0 mg; P=0.002) and subcutaneous (293.1 vs 250.1 mg; P=0.001) fat mass, plasma cholesterol (110.6 vs 87.6 mg dl(-1); P=0.001), triglycerides (87.3 vs 84.1 mg dl(-1); P=0.003) and homeostatic model assessment-insulin resistance values (8.1 vs 6.1; P=0.007) in the LG-SF group. MeDIP analyses revealed that 2148 DMRs (LG-SF vs LG-SC; P<0.0001, model-based analysis of tilling-arrays algorithm). A large proportion of the DMR-associated genes have reported functions that are altered in obesity and metabolic syndrome, such as Cartpt, Akt2, Apoe, Insr1 and so on. Overrepresented pathways and gene networks were related to metabolic regulation and inflammatory response. Our findings show a major role for epigenomic regulation of pathways

  1. Augmented atherogenesis in ApoE-null mice co-exposed to polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin

    Energy Technology Data Exchange (ETDEWEB)

    Shan, Qiuli [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085 (China); Wang, Jing, E-mail: avaecn@gmail.com [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085 (China); Huang, Fengchen [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085 (China); Lv, Xiaowen [Feed Safety Reference Laboratory of Ministry of Agriculture, Feed Research Institute, Chinese Academy of Agricultural Sciences, Zhongguancun South Street 12, Beijing 100081 (China); Ma, Min [Laboratory of Biotechnology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085 (China); Du, Yuguo [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085 (China)

    2014-04-15

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) are persistent organic pollutants found as complex mixtures in the environment throughout the world. Therefore, humans are ubiquitously and simultaneously exposed to TCDD and PCBs. TCDD and PCBs alone have been linked to atherosclerosis. However, the effects of interactions or synergism between TCDD and PCBs on atherogenesis are unknown. We investigated the possible enhanced atherogenesis by co-exposure to TCDD and PCBs and the potential mechanism(s) involved in this enhancement. Male ApoE{sup −/−} mice were exposed to TCDD (15 μg/kg) and Aroclor1254 (55 mg/kg, a representative mixture of PCBs) alone or in combination by intraperitoneal injection four times over six weeks of duration. Our results showed that mice exposed to TCDD alone, but not Aroclor1254 alone, developed atherosclerotic lesions. Moreover, we found that atherosclerotic disease was exacerbated to the greatest extent in mice co-exposed to TCDD and Aroclor1254. The enhanced lesions correlated with several pro-atherogenic changes, including a marked increase in the accumulation of the platelet-derived chemokine PF4, and the expression of the proinflammatory cytokine MCP-1 and the critical immunity gene-RIG-I. Our data demonstrated that co-exposure to TCDD and Aroclor1254 markedly enhanced atherogenesis in ApoE{sup −/−} mice. Significantly, our observations suggest that combined exposure to TCDD and PCBs may be a greater cardiovascular health risk than previously anticipated from individual studies. - Highlights: • Augmented atherogenesis was found in ApoE{sup −/−} mice co-exposed to Aroclor1254 and TCDD. • Enhanced expression of PF4, MCP-1 and RIG-I correlated with augmented lesions. • POPs combination may be a greater cardiovascular health risk than individual POPs.

  2. Spatial learning and memory deficits in young adult mice exposed to a brief intense noise at postnatal age

    Institute of Scientific and Technical Information of China (English)

    Shan Tao; Lijie Liu; Lijuan Shi; Xiaowei Li; Pei Shen; Qingying Xun; Xiaojing Guo; Zhiping Yu; Jian Wang

    2015-01-01

    Noise pollution is a major hazardous factor to human health and is likely harmful for vulnerable groups such as pre-term infants under life-support system in an intensive care unit. Previous studies have suggested that noise exposure impairs children's learning ability and cognitive performance and cognitive functions in animal models in which the effect is mainly attributed to the oxidant stress of noise on the cognitive brain. The potential role of noise induced hearing loss (NIHL), rather than the oxidant stress, has also been indicated by a depression of neurogenesis in the hippocampus long after a brief noise exposure, which produces only a tentative oxidant stress. It is not clear if noise exposure and NIHL during early development exerts a long term impact on cognitive function and neurogenesis towards adulthood. In the present study, a brief noise exposure at high sound level was performed in neonatal C57BL/6J mice (15 days after birth) to produce a significant amount of permanent hearing loss as proved 2 months after the noise. At this age, the noise-exposed animals showed deteriorated spatial learning and memory abilities and a reduction of hippocampal neurogenesis as compared with the control. The averaged hearing threshold was found to be strongly correlated with the scores for spatial learning and memory. We consider the effects observed are largely due to the loss of hearing sensitivity, rather than the oxidant stress, due to the long interval between noise exposure and the observations.

  3. Genomics-based screening of differentially expressed genes in the brains of mice exposed to silver nanoparticles via inhalation

    Science.gov (United States)

    Lee, Hye-Young; Choi, You-Jin; Jung, Eun-Jung; Yin, Hu-Quan; Kwon, Jung-Taek; Kim, Ji-Eun; Im, Hwang-Tae; Cho, Myung-Haing; Kim, Ju-Han; Kim, Hyun-Young; Lee, Byung-Hoon

    2010-06-01

    Silver nanoparticles (AgNP) are among the fastest growing product categories in the nanotechnology industry. Despite the importance of AgNP in consumer products and clinical applications, relatively little is known regarding AgNP toxicity and its associated risks. We investigated the effects of AgNP on gene expression in the mouse brain using Affymetrix Mouse Genome Arrays. C57BL/6 mice were exposed to AgNP (geometric mean diameter, 22.18 ± 1.72 nm; 1.91 × 107 particles/cm3) for 6 h/day, 5 days/week using the nose-only exposure system for 2 weeks. Total RNA isolated from the cerebrum and cerebellum was subjected to hybridization. From over 39,000 probe sets, 468 genes in the cerebrum and 952 genes in the cerebellum were identified as AgNP-responsive (one-way analysis of variance; p cerebrum and 144 genes in the cerebellum. AgNP exposure modulated the expression of several genes associated with motor neuron disorders, neurodegenerative disease, and immune cell function, indicating potential neurotoxicity and immunotoxicity associated with AgNP exposure. Real-time PCR data for five genes analyzed from whole blood showed good correlation with the observed changes in the brain. Following rigorous validation and substantiation, these genes may assist in the development of surrogate markers for AgNP exposure and/or toxicity.

  4. Hepatic and Nephric NRF2 Pathway Up-Regulation, an Early Antioxidant Response, in Acute Arsenic-Exposed Mice

    Directory of Open Access Journals (Sweden)

    Jinlong Li

    2015-10-01

    Full Text Available Inorganic arsenic (iAs, a proven human carcinogen, damages biological systems through multiple mechanisms, one of them being reactive oxygen species (ROS production. NRF2 is a redox-sensitive transcription factor that positively regulates the genes of encoding antioxidant and detoxification enzymes to neutralize ROS. Although NRF2 pathway activation by iAs has been reported in various cell types, however, the experimental data in vivo are very limited and not fully elucidated in humans. The present investigation aimed to explore the hepatic and nephric NRF2 pathway upregulation in acute arsenic-exposed mice in vivo. Our results showed 10 mg/kg NaAsO2 elevated the NRF2 protein and increased the transcription of Nrf2 mRNA, as well as up-regulated NRF2 downstream targets HO-1, GST and GCLC time- and dose-dependently both in the liver and kidney. Acute NaAsO2 exposure also resulted in obvious imbalance of oxidative redox status represented by the increase of GSH and MDA, and the decrease of T-AOC. The present investigation reveals that hepatic and nephric NRF2 pathway expression is an early antioxidant defensive response upon iAs exposure. A better knowledge about the NRF2 pathway involvment in the cellular response against arsenic could help improve the strategies for reducing the cellular toxicity related to this metalloid.

  5. 39. Ultrastructural Changes of Neurons Located at Anterior Horn of Lumbar Spinal cord in Ethylene Oxide Exposed Mice

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Mice inhaled ethylene oxide at concentration of 360 mg/m3 for two hours a day, six days a week for 14 weeks. At the end of second and third month, the neurons located at anterior horn of lumbar spinal cord were observed under transmission electron microscope and scanning electron microscope with freeze etching. The results showed that the morphological changes in neuron cells became more obvious as the inhalation period prolonged. Following changes were observed : The distribution of integrating proteins in neuron membrane changed from normal stochastic into clustered one, the endoplasmic reticulum reduced in number and appeared as small vesicles, the ribosomes attached to the surface of rough endoplasmic reticulum were also decreased in number, arranged irregularly, disintegrated or even degranulated. The numher of mitochondria was also decreased. Observed aiso were the swelling of the axons of myelinated nerve fibers and loss of stratification of their myelin sheaths. The above results indicated that the ethylene oxide can induce structural changes in neuron cells, and this inevitably may cause functional abnormality of nervous system and manifestation of neurotoxic symptoms in ethylene oxide exposed individuals.

  6. Effect of Ocimum sanctum, ascorbic acid, and verapamil on macrophage function and oxidative stress in mice exposed to cocaine

    Directory of Open Access Journals (Sweden)

    Bhattacharya S

    2009-01-01

    Full Text Available Objective: To investigate the effect of Ocimum sanctum, ascorbic acid, and verapamil on macrophage function and oxidative stress in experimental animals exposed to cocaine. Materials and Methods: Mice were used in this study and were divided randomly into different groups of six animals each. They were either treated with intraperitoneal injection of saline or cocaine hydrochloride or an oral feeding of oil of Ocimum sanctum, ascorbic acid or verapamil, or both (ascorbic acid and verapamil, and were evaluated for a respiratory burst of macrophages, superoxide and nitric oxide (NO production, estimation of TNF-a in the serum and supernatant of cultured macrophages, estimation of lipid peroxidation (malondialdehyde- MDA in the serum, and superoxide dismutase activity in the erythrocytes. Results: Unstimulated respiratory burst as well as superoxide production was enhanced on treatment with cocaine and all the three drugs were found to attenuate this enhancement. The bactericidal capacity of macrophages decreased significantly on chronic cocaine exposure, as it was associated with decreased respiratory burst and superoxide production. There was a significant decrease in NO production by macrophages on chronic cocaine exposure and all the test drugs were found to restore nitrite formation to a normal level. There was an increase in the malonylodialdehyde (MDA level and decrease in the superoxide dismutase level on chronic cocaine exposure, and all the three drugs effectively decreased the MDA level and increased superoxide dismutase level. There was an increase in serum TNF-α on chronic cocaine exposure, which was decreased significantly by ascorbic acid and verapamil. Conclusion: O. sanctum, ascorbic acid, and verapamil were equally effective in improving the macrophage function and reducing oxidative stress. These findings suggested that O. sanctum, ascorbic acid, and verapamil attenuated acute and chronic cocaine-mediated effects.

  7. Genomics-based screening of differentially expressed genes in the brains of mice exposed to silver nanoparticles via inhalation

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Hye-Young; Choi, You-Jin; Jung, Eun-Jung; Yin, Hu-Quan [Seoul National University, College of Pharmacy and Research Institute of Pharmaceutical Sciences (Korea, Republic of); Kwon, Jung-Taek; Kim, Ji-Eun; Im, Hwang-Tae; Cho, Myung-Haing [Seoul National University, College of Veterinary Medicine (Korea, Republic of); Kim, Ju-Han [Seoul National University, College of Medicine (Korea, Republic of); Kim, Hyun-Young [Occupational Safety and Health Research Institute, Chemical Safety and Health Research Center (Korea, Republic of); Lee, Byung-Hoon, E-mail: lee@snu.ac.k [Seoul National University, College of Pharmacy and Research Institute of Pharmaceutical Sciences (Korea, Republic of)

    2010-06-15

    Silver nanoparticles (AgNP) are among the fastest growing product categories in the nanotechnology industry. Despite the importance of AgNP in consumer products and clinical applications, relatively little is known regarding AgNP toxicity and its associated risks. We investigated the effects of AgNP on gene expression in the mouse brain using Affymetrix Mouse Genome Arrays. C57BL/6 mice were exposed to AgNP (geometric mean diameter, 22.18 {+-} 1.72 nm; 1.91 x 10{sup 7} particles/cm{sup 3}) for 6 h/day, 5 days/week using the nose-only exposure system for 2 weeks. Total RNA isolated from the cerebrum and cerebellum was subjected to hybridization. From over 39,000 probe sets, 468 genes in the cerebrum and 952 genes in the cerebellum were identified as AgNP-responsive (one-way analysis of variance; p < 0.05). The largest groups of gene products affected by AgNP exposure included 73 genes in the cerebrum and 144 genes in the cerebellum. AgNP exposure modulated the expression of several genes associated with motor neuron disorders, neurodegenerative disease, and immune cell function, indicating potential neurotoxicity and immunotoxicity associated with AgNP exposure. Real-time PCR data for five genes analyzed from whole blood showed good correlation with the observed changes in the brain. Following rigorous validation and substantiation, these genes may assist in the development of surrogate markers for AgNP exposure and/or toxicity.

  8. Neuroprotective peptide ADNF-9 in fetal brain of C57BL/6 mice exposed prenatally to alcohol

    Directory of Open Access Journals (Sweden)

    Karty Jonathan A

    2011-10-01

    Full Text Available Abstract Background A derived peptide from activity-dependent neurotrophic factor (ADNF-9 has been shown to be neuroprotective in the fetal alcohol exposure model. We investigated the neuroprotective effects of ADNF-9 against alcohol-induced apoptosis using TUNEL staining. We further characterize in this study the proteomic architecture underlying the role of ADNF-9 against ethanol teratogenesis during early fetal brain development using liquid chromatography in conjunction with tandem mass spectrometry (LC-MS/MS. Methods Pregnant C57BL/6 mice were exposed from embryonic days 7-13 (E7-E13 to a 25% ethanol-derived calorie [25% EDC, Alcohol (ALC] diet, a 25% EDC diet simultaneously administered i.p. ADNF-9 (ALC/ADNF-9, or a pair-fed (PF liquid diet. At E13, fetal brains were collected from 5 dams from each group, weighed, and frozen for LC-MS/MS procedure. Other fetal brains were fixed for TUNEL staining. Results Administration of ADNF-9 prevented alcohol-induced reduction in fetal brain weight and alcohol-induced increases in cell death. Moreover, individual fetal brains were analyzed by LC-MS/MS. Statistical differences in the amounts of proteins between the ALC and ALC/ADNF-9 groups resulted in a distinct data-clustering. Significant upregulation of several important proteins involved in brain development were found in the ALC/ADNF-9 group as compared to the ALC group. Conclusion These findings provide information on potential mechanisms underlying the neuroprotective effects of ADNF-9 in the fetal alcohol exposure model.

  9. Mice repeatedly exposed to Group-A β-Haemolytic Streptococcus show perseverative behaviors, impaired sensorimotor gating, and immune activation in rostral diencephalon

    OpenAIRE

    Simone Macrì; Chiara Ceci; Martina Proietti Onori; Roberto William Invernizzi; Erika Bartolini; Luisa Altabella; Rossella Canese; Monica Imperi; Graziella Orefici; Roberta Creti; Immaculada Margarit; Roberta Magliozzi; Giovanni Laviola

    2015-01-01

    Repeated exposure to Group-A β-Haemolytic Streptococcus (GAS) may constitute a vulnerability factor in the onset and course of pediatric motor disturbances. GAS infections/colonization can stimulate the production of antibodies, which may cross the blood brain barrier, target selected brain areas (e.g. basal ganglia), and exacerbate motor alterations. Here, we exposed developing SJL male mice to four injections with a GAS homogenate and evaluated the following domains: motor coordination; gen...

  10. Executive function deficits and social-behavioral abnormality in mice exposed to a low dose of dioxin in utero and via lactation.

    Directory of Open Access Journals (Sweden)

    Toshihiro Endo

    Full Text Available An increasing prevalence of mental health problems has been partly ascribed to abnormal brain development that is induced upon exposure to environmental chemicals. However, it has been extremely difficult to detect and assess such causality particularly at low exposure levels. To address this question, we here investigated higher brain function in mice exposed to dioxin in utero and via lactation by using our recently developed automated behavioral flexibility test and immunohistochemistry of neuronal activation markers Arc, at the 14 brain areas. Pregnant C57BL/6 mice were given orally a low dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD at a dose of either 0, 0.6 or 3.0 µg/kg on gestation day 12.5. When the pups reached adulthood, they were group-housed in IntelliCage to assess their behavior. As a result, the offspring born to dams exposed to 0.6 µg TCDD/kg were shown to have behavioral inflexibility, compulsive repetitive behavior, and dramatically lowered competitive dominance. In these mice, immunohistochemistry of Arc exhibited the signs of hypoactivation of the medial prefrontal cortex (mPFC and hyperactivation of the amygdala. Intriguingly, mice exposed to 3.0 µg/kg were hardly affected in both the behavioral and neuronal activation indices, indicating that the robust, non-monotonic dose-response relationship. In conclusion, this study showed for the first time that perinatal exposure to a low dose of TCDD in mice develops executive function deficits and social behavioral abnormality accompanied with the signs of imbalanced mPFC-amygdala activation.

  11. Rsk2 Knockout Affects Emotional Behavior in the IntelliCage.

    Science.gov (United States)

    Fischer, Matthias; Cabello, Victoria; Popp, Sandy; Krackow, Sven; Hommers, Leif; Deckert, Jürgen; Lesch, Klaus-Peter; Schmitt-Böhrer, Angelika G

    2017-07-01

    Ribosomal s6 kinase 2 is a growth factor activated serine/threonine kinase and member of the ERK signaling pathway. Mutations in the Rsk2 gene cause Coffin-Lowry syndrome, a rare syndromic form of intellectual disability. The Rsk2 KO mouse model was shown to have learning and memory defects. We focused on the investigation of the emotional behavioral phenotype of Rsk2 KO mice mainly in the IntelliCage. They exhibited an anti-depressive, sucrose reward seeking phenotype and showed reduced anxiety. Spontaneous activity was increased in some conventional tests. However, KO mice did not show defects in place learning, working memory and motor impulsivity. In addition, we found changes of the monoaminergic system in HPLC and qRT-PCR experiments. Taken together, RSK2 not only plays a role in cognitive processes but also in emotional and reward-related behaviors.

  12. Effects of Methimepip and JNJ-5207852 in Wistar rats exposed to an open-field with and without object and in Balb/c mice exposed to an open-space spatial maze

    Directory of Open Access Journals (Sweden)

    Abdel eEnnaceur

    2012-07-01

    Full Text Available The role of the histamine H3 receptor in anxiety is controversial, due to limitations in drug selectivity and limited validity of behavioral tests in previous studies. When exposed to an empty open field, Wistar rats spent more time in the outer area and made very low number of brief crossings in the central area. However, when an object occupied the central area, rats crossed frequently into and spent a long time in the central area. Administration of a range of different doses of methimepip (H3 receptor agonist reduced the entries into the central area with a novel object, indicating enhanced avoidance response. When balb/c mice were exposed to an open space 3D maze, neither methimepip nor JNJ-5207852 (H3 receptor antagonist/inverse agonist induced entry into the arms of the apparatus, indicative of lack of anxiolytic effects.

  13. Organ specific mapping of in vivo redox state in control and cigarette smoke-exposed mice using EPR/NMR co-imaging

    Science.gov (United States)

    Caia, George L.; Efimova, Olga V.; Velayutham, Murugesan; El-Mahdy, Mohamed A.; Abdelghany, Tamer M.; Kesselring, Eric; Petryakov, Sergey; Sun, Ziqi; Samouilov, Alexandre; Zweier, Jay L.

    2012-03-01

    In vivo mapping of alterations in redox status is important for understanding organ specific pathology and disease. While electron paramagnetic resonance imaging (EPRI) enables spatial mapping of free radicals, it does not provide anatomic visualization of the body. Proton MRI is well suited to provide anatomical visualization. We applied EPR/NMR co-imaging instrumentation to map and monitor the redox state of living mice under normal or oxidative stress conditions induced by secondhand cigarette smoke (SHS) exposure. A hybrid co-imaging instrument, EPRI (1.2 GHz)/proton MRI (16.18 MHz), suitable for whole-body co-imaging of mice was utilized with common magnet and gradients along with dual EPR/NMR resonators that enable co-imaging without sample movement. The metabolism of the nitroxide probe, 3-carbamoyl-proxyl (3-CP), was used to map the redox state of control and SHS-exposed mice. Co-imaging allowed precise 3D mapping of radical distribution and reduction in major organs such as the heart, lungs, liver, bladder and kidneys. Reductive metabolism was markedly decreased in SHS-exposed mice and EPR/NMR co-imaging allowed quantitative assessment of this throughout the body. Thus, in vivo EPR/NMR co-imaging enables in vivo organ specific mapping of free radical metabolism and redox stress and the alterations that occur in the pathogenesis of disease.

  14. The Lack of Cytotoxic Effect and Radioadaptive Response in Splenocytes of Mice Exposed to Low Level Internal β-Particle Irradiation through Tritiated Drinking Water in Vivo

    Directory of Open Access Journals (Sweden)

    Matthew Flegal

    2013-12-01

    Full Text Available Health effects of tritium, a β-emitter and a by-product of the nuclear industry, is a subject of significant controversy. This mouse in vivo study was undertaken to monitor biological effects of low level tritium exposure. Mice were exposed to tritiated drinking water (HTO at 10 KBq/L, 1 MBq/L and 20 MBq/L concentrations for one month. The treatment did not result in a significant increase of apoptosis in splenocytes. To examine if this low level tritium exposure alters radiosensitivity, the extracted splenocytes were challenged in vitro with 2 Gy γ-radiation, and apoptotic responses at 1 and 24 h were measured. No alterations in the radiosensitivity were detected in cells from mice exposed to tritium compared to sham-treated mice. In contrast, low dose γ-irradiation at 20 or 100 mGy, resulted in a significant increase in resistance to apoptotic cell death after 2 Gy irradiation; an indication of the radioadaptive response. Overall, our data suggest that low concentrations of tritium given to mice as HTO in drinking water do not exert cytotoxic effect in splenocytes, nor do they change cellular sensitivity to additional high dose γ-radiation. The latter may be considered as the lack of a radioadaptive response, typically observed after low dose γ-irradiation.

  15. Presence of subclinical infection in gene-targeted human prion protein transgenic mice exposed to atypical bovine spongiform encephalopathy.

    Science.gov (United States)

    Wilson, Rona; Dobie, Karen; Hunter, Nora; Casalone, Cristina; Baron, Thierry; Barron, Rona M

    2013-12-01

    The transmission of bovine spongiform encephalopathy (BSE) to humans, leading to variant Creutzfeldt-Jakob disease has demonstrated that cattle transmissible spongiform encephalopathies (TSEs) can pose a risk to human health. Until recently, TSE disease in cattle was thought to be caused by a single agent strain, BSE, also known as classical BSE, or BSE-C. However, due to the initiation of a large-scale surveillance programme throughout Europe, two atypical BSE strains, bovine amyloidotic spongiform encephalopathy (BASE, also named BSE-L) and BSE-H have since been discovered. To model the risk to human health, we previously inoculated these two forms of atypical BSE (BASE and BSE-H) into gene-targeted transgenic (Tg) mice expressing the human prion protein (PrP) (HuTg) but were unable to detect any signs of TSE pathology in these mice. However, despite the absence of TSE pathology, upon subpassage of some BASE-challenged HuTg mice, a TSE was observed in recipient gene-targeted bovine PrP Tg (Bov6) mice but not in HuTg mice. Disease transmission from apparently healthy individuals indicates the presence of subclinical BASE infection in mice expressing human PrP that cannot be identified by current diagnostic methods. However, due to the lack of transmission to HuTg mice on subpassage, the efficiency of mouse-to-mouse transmission of BASE appears to be low when mice express human rather than bovine PrP.

  16. DNA adducts, mutant frequencies, and mutation spectra in various organs of λlacZ mice exposed to ethylating agents

    NARCIS (Netherlands)

    Mientjes, E.J.; Luiten-Schuite, A.; Wolf, E. van der; Borsboom, Y.; Bergmans, A.; Berends, F.; Lohman, P.H.M.; Baan, R.A.; Delft, J.H.M. van

    1998-01-01

    To investigate tissue-specific relations between DNA adducts and mutagenesis in vivo, λlacZ transgenic mice were treated i.p. with N-ethyl-N-nitrosourea (ENU), diethylnitrosamine (DEN), and ethyl methanesulphonate (EMS). In liver, bone marrow, and brain DNA from mice sacrificed at several time point

  17. Tpl2 knockout keratinocytes have increased biomarkers for invasion and metastasis

    Science.gov (United States)

    DeCicco-Skinner, Kathleen L.; Jung, Sarah A.

    2013-01-01

    Skin cancer is the most common form of cancer in the USA, with an estimated two million cases diagnosed annually. Tumor progression locus 2 (Tpl2), also known as MAP3K8, is a serine/threonine protein kinase in the mitogen-activated protein kinase signal transduction cascade. Tpl2 was identified by our laboratory as having a tumor suppressor function in skin carcinogenesis, with the absence of this gene contributing to heightened inflammation and increased skin carcinogenesis. In this study, we used gene expression profiling to compare expression levels between Tpl2 +/+ and Tpl2 − /− keratinocytes. We identified over 2000 genes as being differentially expressed between genotypes. Functional annotation analysis identified cancer, cell growth/proliferation, cell death, cell development, cell movement and cell signaling as the top biological processes to be differentially regulated between genotypes. Further microarray analysis identified several candidate genes, including Mmp1b, Mmp2, Mmp9 and Mmp13, involved in migration and invasion to be upregulated in Tpl2 − /− keratinocytes. Moreover, Tpl2 −/− keratinocytes had a significant downregulation in the matrix metalloproteinase (MMP) inhibitor Timp3. Real-time PCR validated the upregulation of the MMPs in Tpl2 −/− keratinocytes and zymography confirmed that MMP2 and MMP9 activity was higher in conditioned media from Tpl2 −/− keratinocytes. Immunohistochemistry confirmed higher MMP9 staining in 12-O-tetradecanoylphorbol-13-acetate-treated skin from Tpl2 −/− mice and grafted tumors formed from v-rasHa retrovirus-infected Tpl2 −/− keratinocytes. Additionally, Tpl2 −/− keratinocytes had significantly higher invasion, malignant conversion rates and increased endothelial cell tube formation when compared with Tpl2 +/+ keratinocytes. In summary, our studies reveal that keratinocytes from Tpl2 −/− mice demonstrate a higher potential to be invasive and metastatic. PMID:24067898

  18. Mice Exposed to Chronic Intermittent Hypoxia Simulate Clinical Features of Deficiency of both Qi and Yin Syndrome in Traditional Chinese Medicine.

    Science.gov (United States)

    Chai, Chengzhi; Kou, Junping; Zhu, Danni; Yan, Yongqing; Yu, Boyang

    2011-01-01

    Deficiency of both Qi and Yin Syndrome (DQYS) is one of the common syndromes in traditional Chinese medicine (TCM), mainly characterized by tiredness, emaciation, anorexia, fidget, palpitation and rapid pulse, and so forth. Currently, there is no available animal model which can reflect the clinical features of this syndrome. In the present paper, we observed the time-course changes of whole behavior, body weight, food intake, locomotive activity and electrocardiogram in mice exposed to chronic intermittent hypoxia for 6 weeks, and measured bleeding time at last according to the clinical features of DQYS and one key pathological factor. The results showed that the mice exposed to intermittent hypoxia for certain time presented lackluster hair, dull looking hair, resistance, attacking, body weight loss, food intake decline, locomotive activity decrease, heart rate quickening and T wave elevating, which were similar to the major clinical features of DQYS. Meanwhile, bleeding time shortening was also found, which was consistent with the clinical fact that DQYS often accompanied with blood stasis. The possible explanation was also outlined according to the available literature. Such findings suggested chronic intermittent hypoxia could induce similar symptoms and signs in mice accorded with the clinical features of DQYS, which provided a suitable animal model for evaluation of drugs for the treatment of this syndrome and further exploration of pathological process or correlation of the syndrome and related diseases.

  19. Mice Exposed to Chronic Intermittent Hypoxia Simulate Clinical Features of Deficiency of both Qi and Yin Syndrome in Traditional Chinese Medicine

    Directory of Open Access Journals (Sweden)

    Chengzhi Chai

    2011-01-01

    Full Text Available Deficiency of both Qi and Yin Syndrome (DQYS is one of the common syndromes in traditional Chinese medicine (TCM, mainly characterized by tiredness, emaciation, anorexia, fidget, palpitation and rapid pulse, and so forth. Currently, there is no available animal model which can reflect the clinical features of this syndrome. In the present paper, we observed the time-course changes of whole behavior, body weight, food intake, locomotive activity and electrocardiogram in mice exposed to chronic intermittent hypoxia for 6 weeks, and measured bleeding time at last according to the clinical features of DQYS and one key pathological factor. The results showed that the mice exposed to intermittent hypoxia for certain time presented lackluster hair, dull looking hair, resistance, attacking, body weight loss, food intake decline, locomotive activity decrease, heart rate quickening and T wave elevating, which were similar to the major clinical features of DQYS. Meanwhile, bleeding time shortening was also found, which was consistent with the clinical fact that DQYS often accompanied with blood stasis. The possible explanation was also outlined according to the available literature. Such findings suggested chronic intermittent hypoxia could induce similar symptoms and signs in mice accorded with the clinical features of DQYS, which provided a suitable animal model for evaluation of drugs for the treatment of this syndrome and further exploration of pathological process or correlation of the syndrome and related diseases.

  20. [Effects of blockage of hypothalamic-pituitary-adrenal cortex axis by metyrapone and Jiawei Xiaoyao Pills on immune system in mice exposed to chronic emotional stress].

    Science.gov (United States)

    Zhang, Yun; Wu, Zhen-Yu; Xiao, Jian; Geng, Xiao-Feng; Guo, Yan-Xia; Li, Shi-Jie

    2006-07-01

    To explore the effects of Jiawei Xiaoyao Pills (JWXYP) on immune system of mice exposed to chronic emotional stress, and to compare its effects with blockage of hypothalamic-pituitary-adrenal cortex axis (HPAA) by metyrapone. Eighty male mice were randomly divided into eight groups: normal saline-treated group, normal saline-treated stress group, JWXYP-treated group, JWXYP-treated stress group, metyrapone-treated group, metyrapone-treated stress group, metyrapone and JWXYP-treated group and metyrapone and JWXYP-treated stress group. A box of electrical shock was used to induce chronic emotional stress in mice. The metyrapone was applied to blocking the HPAA. The JWXYP, a classical formula of traditional Chinese medicine, which can alleviate the damages caused by chronic emotional stress, was also used to compare its effects with that of metyrapone. The body weight, thymus index, rate of apoptosis in thymus, serum concentration of glucocorticoid, activity of natural killer cells, lymphocyte transmission rate of mice were all measured and examined after interventions. The pathological changes of thymus tissue were observed. The thymus index, activity of natural killer cells and lymphocyte transmission rate were lower while the rate of apoptosis in thymus as well as the severity degree of pathological damages in thymus tissue were increased in the different drug-treated stress groups as compared with those in the corresponding drug-treated groups without stress. The activity of natural killer cells and the lymphocyte transmission rate induced by lipopolysaccharide were increased while the serum concentration of glucocorticoid and the severity degree of pathological damages in thymus tissue were decreased in both the metyrapone-treated stress group and JWXYP-treated stress group as compared with those in the normal saline-treated stress group. The combined intervention of metyrapone and JWXYP did not show better effects on immune system in mice exposed to chronic

  1. Modulation by aspirin and naproxen of nucleotide alterations and tumors in the lung of mice exposed to environmental cigarette smoke since birth.

    Science.gov (United States)

    La Maestra, Sebastiano; D'Agostini, Francesco; Izzotti, Alberto; Micale, Rosanna T; Mastracci, Luca; Camoirano, Anna; Balansky, Roumen; Trosko, James E; Steele, Vernon E; De Flora, Silvio

    2015-12-01

    Chemoprevention provides an important strategy for cancer control in passive smokers. Due to the crucial role played by smoke-related chronic inflammation in lung carcinogenesis, of special interest are extensively used pharmacological agents, such as nonsteroidal anti-inflammatory drugs (NSAIDs). We evaluated the ability of aspirin and naproxen, inhibitors of both cyclooxygenase-1 and cyclooxygenase -2, to modulate environmental cigarette smoke (ECS)-induced lung carcinogenesis in A/J mice of both genders. Based on a subchronic toxicity study in 180 postweaning mice, we used 1600 mg/kg diet aspirin and 320 mg/kg diet naproxen. In the tumor chemoprevention study, using 320 mice, exposure to ECS started soon after birth and administration of NSAIDs started after weaning. At 10 weeks of life, the NSAIDs did not affect the presence of occult blood in feces. As assessed in a subset of 40 mice, bulky DNA adducts and 8-hydroxy-2'-deoxyguanosine levels were considerably increased in ECS-exposed mice and, irrespective of gender, both NSAIDs remarkably inhibited these nucleotide alterations. After exposure for 4 months followed by 5 months in filtered air, ECS induced a significant increase in the yield of surface lung tumors, the 43.7% of which were adenomas and the 56.3% were adenocarcinomas. Oct-4 (octamer-binding transcription factor 4), a marker of cell stemness, was detected in some adenocarcinoma cells. The NAIDs attenuated the yield of lung tumors, but prevention of ECS-induced lung adenomas was statistically significant only in female mice treated with aspirin, which supports a role for estrogens in ECS-related lung carcinogenesis and highlights the antiestrogenic properties of NSAIDs.

  2. Biomedical Analyses of Mice Body Hair Exposed to Long-term Space Flight as a Compliment of Human Research

    Science.gov (United States)

    Mukai, Chiaki

    Introduction: To understand the effect of space environment characterized by microgravity and radiation on protein and mineral metabolisms is important for developing the countermeasures to the adverse effects happening on the astronauts who stay long-term in space. Thus JAXA has started a human research to study the effects of long-term exposure in space flight on gene expression and mineral metabolism by analyzing astronaut's hair grown in space since December 2009 (Experiment nicknamed "HAIR"). Ten human subjects who are the crew of the International Space Station (ISS) will be expected to complete this experiment. Thanks to the tissue sharing program of space-flown mice which is presented and organized by AGI(Italian Space Agency), we can also have an opportunity to analyze rodents samples which will greatly compliment human hair experiment by enable us to conduct more detailed analysis with the expansion of skin analysis which is not include in human experiment. The purpose of this flown-mice experiment is to study the effects of long-term exposure to space environment such as microgravity and space radiation on mineral and protein metabolism, the biological responses to the stress levels, and the initial process of skin carcinogenesis by analyzing hair shaft, its root cells, and skin. Approach and Method In this experiment, we analyzed hair shaft, hair root and skin. Hair samples with skin were taken from 3-month space-flown mice and ground-control mice in the AGI's tissue sharing program in 2009. The sample numbers of space-flown mice and control-mice were three and six, respectively. And they were at the Mice Drawer System (MDS) in ISS and in the laboratory of Geneva University. For the hair shaft, the mineral balance is investi-gated by energy dispersive X-ray spectroscopy (SEM-EDX). For hair root, the extracted RNA undergoes DNA microarray analysis, and will be further examined particular interests of gene-expression by real time Reverse Transcription

  3. Altered gene expression and spine density in nucleus accumbens of adolescent and adult male mice exposed to emotional and physical stress.

    Science.gov (United States)

    Warren, Brandon L; Sial, Omar K; Alcantara, Lyonna F; Greenwood, Maria A; Brewer, Jacob S; Rozofsky, John P; Parise, Eric M; Bolaños-Guzmán, Carlos A

    2014-01-01

    Stressful early life experiences are implicated in lifelong health. However, little is known about the consequences of emotional stress (ES) or physical stress (PS) on neurobiology. Therefore, the following set of experiments was designed to assess changes in transcription and translation of key proteins within the nucleus accumbens (NAc). Male adolescent (postnatal day 35) or adult (8-week-old) mice were exposed to ES or PS using a witness social defeat paradigm. Then, 24 h after the last stress session, we measured levels of specific mRNAs and proteins within the NAc. Spine density was also assessed in separate groups of mice. Exposure to ES or PS disrupted extracellular signal-related kinase 2 (ERK2), reduced transcription of ΔFosB and had no effect on cAMP response element-binding protein (CREB) mRNA. Western blots revealed that exposure to ES or PS decreased ERK2 phosphorylation in adolescents, whereas the same stress regimen increased ERK2 phosphorylation in adults. Exposure to ES or PS had no effect on ΔFosB or CREB phosphorylation. ES and PS increased spine density in the NAc of adolescent exposed mice, but only exposure to PS increased spine density in adults. Together, these findings demonstrate that exposure to ES or PS is a potent stressor in adolescent and adult mice and can disturb the integrity of the NAc by altering transcription and translation of important signaling molecules in an age-dependent manner. Furthermore, exposure to ES and PS induces substantial synaptic plasticity of the NAc.

  4. Evidence for humoral immunodepression in NO/sub 2/-exposed mice: influence of food restriction and stress

    Energy Technology Data Exchange (ETDEWEB)

    Azoulay-Dupuis, E.; Bouley, G.; Moreau, J.; Muffat-Joly, M.; Pocidalo, J.J.

    1987-04-01

    The effects of food restriction or 20 ppm NO/sub 2/ exposure on humoral immunity were investigated in normal and adrenalectomized C/sub 57/B1/6 mice. The thymic and splenic weights of sham-operated mice were similarly diminished after 4 days of NO/sub 2/ exposure or 4 days of food depletion. The responses of corresponding adrenalectomized mice were less depressed. Undernutrition induced lymphoid organ involution and corticosteroids were partly involved. Plaque-forming cells (PFC) per spleen and per 10/sup 6/ cells were markedly depressed after 4 days of NO/sub 2/ exposure, but less so after food deprivation. The same significant suppression of PFC was observed in adrenalectomized groups. Depression of humoral immunity was independent of stress-induced endogenous steroids. Moreover, NO/sub 2/ had a specific effect on humoral immunodepression, food restriction being an associated factor.

  5. Quantification of DNA adducts formed in liver, lungs, and isolated lung cells of rats and mice exposed to (14)C-styrene by nose-only inhalation.

    Science.gov (United States)

    Boogaard, P J; de Kloe, K P; Wong, B A; Sumner, S C; Watson, W P; van Sittert, N J

    2000-10-01

    Bronchiolo-alveolar tumors were observed in mice exposed chronically to 160 ppm styrene, whereas no tumors were seen in rats up to concentrations of 1000 ppm. Clara cells, which are predominant in the bronchiolo-alveolar region in mouse lungs but less numerous in rat and human lung, contain various cytochrome P450s, which may oxidize styrene to the rodent carcinogen styrene-7,8-oxide (SO) and other reactive metabolites. Reactive metabolites may form specific DNA adducts and induce the tumors observed in mice. To determine DNA adducts in specific tissues and cell types, rats and mice were exposed to 160 ppm [ring-U-(14)C]styrene by nose-only inhalation for 6 h in a recirculating exposure system. Liver and lungs were isolated 0 and 42 h after exposure. Fractions enriched in Type II cells and Clara cells were isolated from rat and mouse lung, respectively. DNA adduct profiles differed quantitatively and qualitatively in liver, total lung, and enriched lung cell fractions. At 0 and 42 h after exposure, the two isomeric N:7-guanine adducts of SO (measured together, HPEG) were present in liver at 3.0 +/- 0.2 and 1.9 +/- 0.3 (rat) and 1.2 +/- 0.2 and 3.2 +/- 0.5 (mouse) per 10(8) bases. Several other, unidentified adducts were present at two to three times higher concentrations in mouse, but not in rat liver. In both rat and mouse lung, HPEG was the major adduct at approximately 1 per 10(8) bases at 0 h, and these levels halved at 42 h. In both rat Type II and non-Type II cells, HPEG was the major adduct and was about three times higher in Type II cells than in total lung. For mice, DNA adduct levels in Clara cells and non-Clara cells were similar to total lung. The hepatic covalent binding index (CBI) at 0 and 42 h was 0.19 +/- 0.06 and 0.14 +/- 0.03 (rat) and 0. 25 +/- 0.11 and 0.44 +/- 0.23 (mouse), respectively. The pulmonary CBIs, based on tissues combined for 0 and 42 h, were 0.17 +/- 0.04 (rat) and 0.24 +/- 0.04 (mouse). Compared with CBIs for other genotoxicants

  6. The administration of a high refined carbohydrate diet promoted an increase in pulmonary inflammation and oxidative stress in mice exposed to cigarette smoke

    Directory of Open Access Journals (Sweden)

    Pena KB

    2016-12-01

    Full Text Available Karina Braga Pena,1 Camila de Oliveira Ramos,1 Nícia Pedreira Soares,1 Pamela Félix da Silva,1 Ana Carla Balthar Bandeira,2 Guilherme de Paula Costa,3 Sílvia Dantas Cangussú,1 André Talvani,3 Frank Silva Bezerra1 1Laboratory of Experimental Pathophysiology (LAFEx, 2Laboratory of Metabolic Biochemistry (LBM, 3Laboratory of Immunobiology of Inflammation (LABIIN, Department of Biological Sciences (DECBI, Center of Research in Biological Sciences (NUPEB, Federal University of Ouro Preto (UFOP, Ouro Preto, MG, Brazil Abstract: This study aimed to evaluate the effects of a high refined carbohydrate diet and pulmonary inflammatory response in C57BL/6 mice exposed to cigarette smoke (CS. Twenty-four male mice were divided into four groups: control group (CG, which received a standard diet; cigarette smoke group (CSG, which was exposed to CS; a high refined carbohydrate diet group (RG, which received a high refined carbohydrate diet; and a high refined carbohydrates diet and cigarette smoke group (RCSG, which received a high refined carbohydrate diet and was exposed to CS. The animals were monitored for food intake and body weight gain for 12 weeks. After this period, the CSG and RCSG were exposed to CS for five consecutive days. At the end of the experimental protocol, all animals were euthanized for subsequent analyses. There was an increase of inflammatory cells in the bronchoalveolar lavage fluid (BALF of CSG compared to CG and RCSG compared to CG, CSG, and RG. In addition, in the BALF, there was an increase of tumor necrosis factor alpha in RCSG compared to CG, CSG, and RG; interferon gamma increase in RCSG compared to the CSG; and increase in interleukin-10 in RCSG compared to CG and RG. Lipid peroxidation increased in RCSG compared to CG, CSG, and RG. Furthermore, the oxidation of proteins increased in CSG compared to CG. The analysis of oxidative stress showed an increase in superoxide dismutase in RCSG compared to CG, CSG, and RG and an

  7. The Effect of Dehydroepiandrosterone (DHEA) on Survival of Mice Inoculated wtih West Nile Virus and Exposed to Cold Stress,

    Science.gov (United States)

    1991-09-01

    such as Coxackie virus B4 Herpes Simplex Type 2 or Encephalitis viruses (Loria et al. 1988, Ben-Nathan et al. 1991). It was suggested that DHEA may...Johnson T., Lavender J. F., Multin E. and Rasmussen A. F. (1963). The influence of avoidance - learning stress on resistance to Coxackie B virus in mice

  8. Thyroid hormones and fear learning but not anxiety are affected in adult apoE transgenic mice exposed postnatally to decabromodiphenyl ether (BDE-209).

    Science.gov (United States)

    Reverte, Ingrid; Pujol, Andreu; Domingo, José L; Colomina, Maria Teresa

    2014-06-22

    Polybrominated diphenyl ethers (PBDEs) are a family of industrial chemicals used as flame retardants. The fully brominated deca-BDE (BDE-209) is the most used and its potential risk for humans is controversial. The ability of PBDEs to target nervous and endocrine systems suggests multiple enduring effects after perinatal exposure. Cognitive and motor behavior alterations have been reported after developmental exposure to PBDEs, including BDE-209, whereas very little work has been carried out on anxiety and emotional learning. We have previously reported long-term effects of postnatal BDE-209 exposure on spatial memory dependent upon apolipoprotein E (apoE) polymorphism and age. ApoE is involved in lipid transport and its different polymorphisms (ε2, ε3, ε4) confer different vulnerabilities to neurodegeneration, cognitive impairment and anxiety. In the present study we assessed the long term effects of early exposure to BDE-209 on anxiety, fear learning and thyroid hormone levels in mice carrying different apoE polymorphisms (ε2, ε3, ε4). BDE-209 (0, 10 and 30 mg/kg) was orally administered on postnatal day 10 (PND 10). At 4 and 12 months of age mice were tested in an open field (OF) and an elevated zero maze (EZM). Fear conditioning and thyroid hormone levels were evaluated in mice at 5-6 months of age. Postnatal exposure to BDE-209 impaired cued fear learning in apoE2 and apoE3 mice. Levels of thyroid hormones were increased in apoE3 female mice exposed to BDE-209. Our findings indicate long lasting effects of BDE-209 on emotional learning and thyroid hormone levels after a single postnatal exposure. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Protective role of diet supplements Spirulina and Tamarind fruit pulp on kidney in sodium fluoride exposed Swiss albino mice: Histological and biochemical indices.

    Science.gov (United States)

    Yadav, N; Sharma, Shweta; Sharma, K p; Pandey, A; Pareek, P; Sharma, Subhasini

    2016-01-01

    Fluoride toxicity through potable water, particularly ground water, is not uncommon in countries such as India, China, Iran, Iraq, Turkey, parts of Africa and Afghanistan. Kidney being the main organ involved in fluoride removal, it accumulates considerable amount of fluoride. Here, we report toxic effects of oral exposure of Swiss albino mice to fluoride (sub-acute: 190 mg/kg body wt. for 7 days; and sub-chronic: 94 mg/kg body wt. for 90 days) and recovery of sub-chronic fluoride exposed mice after 90 days of sodium fluoride (NaF) withdrawal. The role of diet supplements (Spirulina and tamarind fruit pulp @ 230 mg/kg body wt. independently as well as in combination) in amelioration of fluoride toxicity has also been screened. Compared with controls, feed intake decreased from 3-43%, body wt. 4-18%, and kidney wt. 5-12% in treated mice (except diet supplement groups of sub-chronic exposure) while their water intake increased from 4-43%. Histopathological changes in the cortical region of kidney in fluoride treated mice were as follows: dilation of bowman's capsule and thickening of its parietal and visceral layer; alterations in glomeruli size and their sclerotization; increase in bowman's space; proliferation of mesangial cells; reduction in podocyte counts; and dilation of proximal and distal tubules. Fluoride exposure altered tissue biochemistry (protein, acid phosphatase and alkaline phosphatase content) and increased urea (23-58%) and creatinine content (14-127%) in the serum. Sub-acute exposure was found more toxic. The diet modulation not only reduced fluoride toxicity but also led to better recovery of treated mice after withdrawal, especially in combination.

  10. Allogeneic compact bone-derived mesenchymal stem cell transplantation increases survival of mice exposed to lethal total body irradiation: a potential immunological mechanism

    Institute of Scientific and Technical Information of China (English)

    Qiao Shukai; Ren Hanyun; Shi Yongjin; Liu Wei

    2014-01-01

    Background Radiation-induced injury after accidental or therapeutic total body exposure to ionizing radiation has serious pathophysiological consequences,and currently no effective therapy exists.This study was designed to investigate whether transplantation of allogeneic murine compact bone derived-mesenchymal stem cells (CB-MSCs) could improve the survival of mice exposed to lethal dosage total body irradiation (TBI),and to explore the potential immunoprotective role of MSCs.Methods BALB/c mice were treated with 8 Gy TBI,and then some were administered CB-MSCs isolated from C57BL/6 mice.Survival rates and body weight were analyzed for 14 days post-irradiation.At three days post-irradiation,we evaluated IFN-Y and IL-4 concentrations; CD4+CD25+Foxp3+ regulatory T cell (Treg) percentage; CXCR3,CCR5,and CCR7 expressions on CD3+T cells; and splenocyte T-bet and GATA-3 mRNA levels.CB-MSC effects on bone marrow hemopoiesis were assessed via colony-forming unit granulocyte/macrophage (CFU-GM) assay.Results After lethal TBI,compared to non-transplanted mice,CB-MSC-transplanted mice exhibited significantly increased survival,body weight,and CFU-GM counts of bone marrow cells (P<0.05),as well as higher Treg percentages,reduced IFN-Y,CXCR3 and CCR5 down-regulation,and CCR7 up-regulation.CB-MSC transplantation suppressed Th1 immunity.Irradiated splenocytes directly suppressed CFU-GM formation from bone marrow cells,and CB-MSC co-culture reversed this inhibition.Conclusion Allogeneic CB-MSC transplantation attenuated radiation-induced hematopoietic toxicity,and provided immunoprotection by alleviating lymphocyte-mediated CFU-GM inhibition,expanding Tregs,regulating T cell chemokine receptor expressions,and skewing the Th1/Th2 balance toward anti-inflammatory Th2 polarization.

  11. Long-term preservation of cone photoreceptors and visual acuity in rd10 mutant mice exposed to continuous environmental enrichment.

    Science.gov (United States)

    Barone, Ilaria; Novelli, Elena; Strettoi, Enrica

    2014-01-01

    In human patients and animal models of retinitis pigmentosa (RP), a gradual loss of rod photoreceptors and decline in scotopic vision are the primary manifestations of the disease. Secondary death of cones and gradual, regressive remodeling of the inner retina follow and progress at different speeds according to the underlying genetic defect. In any case, the final outcome is near-blindness without a conclusive cure yet. We recently reported that environmental enrichment (EE), an experimental manipulation based on exposure to enhanced motor, sensory, and social stimulation, when started at birth, exerts clear beneficial effects on a mouse model of RP, by slowing vision loss. The purpose of this study was to investigate in the same mouse the long-term effects of chronic exposure to an EE and assess the outcome of this manipulation on cone survival, inner retinal preservation, and visual behavior. Two groups of rd10 mutant mice were maintained in an EE or standard (ST) laboratory conditions up to 1 year of age. Then, retinal preservation was assessed with immunocytochemistry, confocal microscopy examination, cone counts, and electron microscopy of the photoreceptor layer, while visual acuity was tested behaviorally with a Prusky water maze. rd10 mice are a model of autosomal recessive RP with a typical rod-cone, center to the periphery pattern of photoreceptor degeneration. They carry a mutation of the rod-specific phosphodiesterase gene and undergo rod death that peaks at around P24, while cone electroretinogram (ERG) is extinct by P60. We previously showed that early exposure to an EE efficiently delays photoreceptor degeneration in these mutants, extending the time window of cone viability and cone-mediated vision well beyond the phase of maximum rod death. Here we find that a maintained EE can delay the degeneration of cones even in the long term. Confocal and electron microscopy examination of the retinas of the rd10 EE and ST mice at 1 year of age showed major

  12. Ciguatoxin reduces regenerative capacity of axotomized peripheral neurons and delays functional recovery in pre-exposed mice after peripheral nerve injury

    Science.gov (United States)

    Au, Ngan Pan Bennett; Kumar, Gajendra; Asthana, Pallavi; Tin, Chung; Mak, Yim Ling; Chan, Leo Lai; Lam, Paul Kwan Sing; Ma, Chi Him Eddie

    2016-01-01

    Ciguatera fish poisoning (CFP) results from consumption of tropical reef fish containing ciguatoxins (CTXs). Pacific (P)-CTX-1 is among the most potent known CTXs and the predominant source of CFP in the endemic region responsible for the majority of neurological symptoms in patients. Chronic and persistent neurological symptoms occur in some CFP patients, which often result in incomplete functional recovery for years. However, the direct effects of exposure to CTXs remain largely unknown. In present study, we exposed mice to CTX purified from ciguatera fish sourced from the Pacific region. P-CTX-1 was detected in peripheral nerves within hours and persisted for two months after exposure. P-CTX-1 inhibited axonal regrowth from axotomized peripheral neurons in culture. P-CTX-1 exposure reduced motor function in mice within the first two weeks of exposure before returning to baseline levels. These pre-exposed animals exhibited delayed sensory and motor functional recovery, and irreversible motor deficits after peripheral nerve injury in which formation of functional synapses was impaired. These findings are consistent with reduced muscle function, as assessed by electromyography recordings. Our study provides strong evidence that the persistence of P-CTX-1 in peripheral nerves reduces the intrinsic growth capacity of peripheral neurons, resulting in delayed functional recovery after injury. PMID:27229176

  13. Ciguatoxin reduces regenerative capacity of axotomized peripheral neurons and delays functional recovery in pre-exposed mice after peripheral nerve injury.

    Science.gov (United States)

    Au, Ngan Pan Bennett; Kumar, Gajendra; Asthana, Pallavi; Tin, Chung; Mak, Yim Ling; Chan, Leo Lai; Lam, Paul Kwan Sing; Ma, Chi Him Eddie

    2016-05-27

    Ciguatera fish poisoning (CFP) results from consumption of tropical reef fish containing ciguatoxins (CTXs). Pacific (P)-CTX-1 is among the most potent known CTXs and the predominant source of CFP in the endemic region responsible for the majority of neurological symptoms in patients. Chronic and persistent neurological symptoms occur in some CFP patients, which often result in incomplete functional recovery for years. However, the direct effects of exposure to CTXs remain largely unknown. In present study, we exposed mice to CTX purified from ciguatera fish sourced from the Pacific region. P-CTX-1 was detected in peripheral nerves within hours and persisted for two months after exposure. P-CTX-1 inhibited axonal regrowth from axotomized peripheral neurons in culture. P-CTX-1 exposure reduced motor function in mice within the first two weeks of exposure before returning to baseline levels. These pre-exposed animals exhibited delayed sensory and motor functional recovery, and irreversible motor deficits after peripheral nerve injury in which formation of functional synapses was impaired. These findings are consistent with reduced muscle function, as assessed by electromyography recordings. Our study provides strong evidence that the persistence of P-CTX-1 in peripheral nerves reduces the intrinsic growth capacity of peripheral neurons, resulting in delayed functional recovery after injury.

  14. Environmental enrichment increases doublecortin-associated new neurons and decreases neuronal death without modifying anxiety-like behavior in mice chronically exposed to toluene.

    Science.gov (United States)

    Paez-Martinez, Nayeli; Flores-Serrano, Zoraida; Ortiz-Lopez, Leonardo; Ramirez-Rodriguez, Gerardo

    2013-11-01

    Toluene misuse is a health problem worldwide with broad effects at the level of the central nervous system; however, therapeutic alternatives for inhalant abusers are limited. Chronic use of volatile substances is associated with different neurological and cognitive alterations, being anxiety a psychiatric condition with high prevalence. At cellular level toluene reduces neurogenesis and induces neuronal death. On the other hand, environmental enrichment has demonstrated to produce positive effects at behavioral and neuronal levels. Thus, the aim of the present work was to model alterations occasioned after repeated exposure to toluene (anxiety, reduction in neurogenesis - measured as doublecortin-labeled cells - and neuronal death). Subsequently, the influence of environmental enrichment on these effects was evaluated. Adolescent mice were exposed to toluene vapors from 1 to 4 weeks. Effects on anxiety were evaluated with the burying behavior test, whereas neurogenesis and hippocampal cell death were analyzed with immunohistochemistry, using anti-doublecortin or anti-active-Caspase-3 antibodies, respectively. Results showed that chronic toluene exposure increased anxiety in the burying behavior test; additionally, toluene decreased neurogenesis and enhanced neuronal death. Environmental enrichment (EE) enhanced the anxiety like response in air-exposed mice but did not modify the toluene anxiety response. Additionally, EE enhanced neurogenesis in toluene-pretreated animals at the same level to that found in animals unexposed to toluene and decreased neuronal death. Overall, the present study showed that environmental enrichment positively impacts some effects produced by repeated exposure to toluene.

  15. Mice repeatedly exposed to Group-A β-Haemolytic Streptococcus show perseverative behaviors, impaired sensorimotor gating, and immune activation in rostral diencephalon.

    Science.gov (United States)

    Macrì, Simone; Ceci, Chiara; Onori, Martina Proietti; Invernizzi, Roberto William; Bartolini, Erika; Altabella, Luisa; Canese, Rossella; Imperi, Monica; Orefici, Graziella; Creti, Roberta; Margarit, Immaculada; Magliozzi, Roberta; Laviola, Giovanni

    2015-08-25

    Repeated exposure to Group-A β-Haemolytic Streptococcus (GAS) may constitute a vulnerability factor in the onset and course of pediatric motor disturbances. GAS infections/colonization can stimulate the production of antibodies, which may cross the blood brain barrier, target selected brain areas (e.g. basal ganglia), and exacerbate motor alterations. Here, we exposed developing SJL male mice to four injections with a GAS homogenate and evaluated the following domains: motor coordination; general locomotion; repetitive behaviors; perseverative responses; and sensorimotor gating (pre-pulse inhibition, PPI). To demonstrate that behavioral changes were associated with immune-mediated brain alterations, we analyzed, in selected brain areas, the presence of infiltrates and microglial activation (immunohistochemistry), monoamines (HPLC), and brain metabolites (in vivo Magnetic Resonance Spectroscopy). GAS-exposed mice showed increased repetitive and perseverative behaviors, impaired PPI, and reduced concentrations of serotonin in prefrontal cortex, a brain area linked to the behavioral domains investigated, wherein they also showed remarkable elevations in lactate. Active inflammatory processes were substantiated by the observation of infiltrates and microglial activation in the white matter of the anterior diencephalon. These data support the hypothesis that repeated GAS exposure may elicit inflammatory responses in brain areas involved in motor control and perseverative behavior, and result in phenotypic abnormalities.

  16. Strain Specific Induction of Pyometra and Differences in Immune Responsiveness in Mice Exposed to 17α-Ethinyl Estradiol or the Endocrine Disrupting Chemical Bisphenol A

    Science.gov (United States)

    Kendziorski, Jessica A.; Kendig, Eric L.; Gear, Robin L.; Belcher, Scott M.

    2012-01-01

    Pyometra is an inflammatory disease of the uterus that can be caused by chronic exposure to estrogens. It is unknown whether weakly estrogenic endocrine disruptors can cause pyometra. We investigated whether dietary exposures to the estrogenic endocrine disruptor bisphenol A (BPA) induced pyometra. Pyometra did not occur in CD1 mice exposed to different dietary doses of BPA ranging from 4.1 to >4000 µg/kg/day or 17α-ethinyl estradiol (EE; 1.2 to >150 µg/kg/day). In the C57BL/6 strain, pyometra occurred in the 15 µg/kg/day EE and 33 µg/kg/day BPA treatment groups. At the effective concentration of BPA, histological analysis revealed pathological alterations of uterine morphology associated with a >5.3-fold increase in macrophage numbers in non-pyometra uteri of C57BL/6 mice exposed to BPA. These results suggest that BPA enhances immune responsiveness of the uterus and that heightened responsiveness in C57BL/6 females is related to increased susceptibility to pyometra. PMID:22429997

  17. Topical AC-11 abates actinic keratoses and early squamous cell cancers in hairless mice exposed to Ultraviolet A (UVA) radiation.

    Science.gov (United States)

    Mentor, Julian M; Etemadi, Amir; Patta, Abrienne M; Scheinfeld, Noah

    2015-04-16

    AC-11 is an aqueous extract of the botanical, Uncaria tomentosa, which has a variety of effects that enhance DNA repair and down regulate inflammation. AC-11 is essentially free of oxindole alkaloids (AC-11 at 0.5%, 1.5%, and 3.0% in a non-irritating, dye-free, perfume-free, and fragrance-free vanishing cream vehicle. Ten mice used vehicle only and 10 were untreated. Each concentration of AC-11 and was applied daily to the backs of the mice prior to exposure to a 1,600-watt solar simulator used in this work (Solar Light Co. Philadelphia, PA) emitting (mainly Ultraviolet A (UVA) and B (UVB) radiation) duration of the experimental period with UVB wavelengths was filtered out with a 1.0 cm Schott WG 345 filter. AC-11 with a peak absorption at 200nm does act as a sun block. We tested for and focused on clinical appearance of mice and histological appearance of tumors in mice rather than metrics of radiation generated inflammation. Tumor progression scores were assigned as follows: 4+ = extensive tumor development; 3+ = early malignancies (raised palpable plaques)(early squamous cell cancers) 2+ = firm scaling, palpable keratosis (actinic keratoses); 1+ = light scaling with erythema. Following a total cumulative dose of 738 J/cm2, 85.7% all of the irradiated control animals, which did not receive AC-11 had precancerous actinic keratosis (AK)-type lesions (2+) (64.3% versus 42.9%) or early squamous cell carcinoma (SCC) (3+) (21.4% vs. 4.8%), in comparison with 47.7 % of AC-11-treated animals. There were no significant differences between the AC-11 groups. Three months after cessation of exposure to UVA radiation, the lesions in all but three of the 14 animals which were treated with AC-11 that were still evaluable irradiated with UVA radiation progressed to papillomas and frank squamous cell carcinomas (+4 responses). AC-11 retarded, but did not stop, carcinogenesis progression. It is possible that if AC-11 was continuously applied tumors would not have in mice treated

  18. Des-Aspartate-Angiotensin I Attenuates Mortality of Mice Exposed to Gamma Radiation via a Novel Mechanism of Action.

    Directory of Open Access Journals (Sweden)

    Hong Wang

    Full Text Available ACE inhibitors and ARBs (angiotensin receptor blockers have been shown to attenuate radiation injuries in animal models of lethal gamma irradiation. These two classes of drug act by curtailing the actions of angiotensin II-linked inflammatory pathways that are up-regulated during gamma radiation in organ systems such as the brain, lung, kidney, and bone marrow. ACE inhibitors inhibit ACE and attenuate the formation of angiotensin II from angiotensin I; ARBs block the angiotensin AT1 receptor and attenuate the actions of angiotensin II that are elicited through the receptor. DAA-I (des-aspartate-angiotensin I, an orally active angiotensin peptide, also attenuates the deleterious actions of angiotensin II. It acts as an agonist on the angiotensin AT1 receptor and elicits responses that oppose those of angiotensn II. Thus, DAA-I was investigated for its anticipated radioprotection in gamma irradiated mice. DAA-I administered orally at 800 nmole/kg/day for 30 days post exposure (6.4 Gy attenuated the death of mice during the 30-day period. The attenuation was blocked by losartan (50 nmole/kg/day, i.p. that was administered sequential to DAA-I administration. This shows that the radioprotection was mediated via the angiotensin AT1 receptor. Furthermore, the radioprotection correlated to an increase in circulating PGE2 of surviving animals, and this suggests that PGE2 is involved in the radioprotection in DAA-I-treated mice. At the hematopoietic level, DAA-I significantly improved two syndromes of myelosuppression (leucopenia and lymphocytopenia, and mice pre-treated with DAA-I prior to gamma irradiation showed significant improvement in the four myelodysplastic syndromes that were investigated, namely leucopenia, lymphocytopenia, monocytopenia and thrombocytopenia. Based on the known ability of PGE2 to attenuate the loss of functional hematopoietic stem and progenitor cells in radiation injury, we hypothesize that PGE2 mediated the action of DAA

  19. Effect of Dietary Treatment with n-Propyl Gallate or Vitamin E on the Survival of Mice Exposed to Phosgene

    Science.gov (United States)

    2001-01-01

    a gallate acid ester compound used infood preservation—and vitamin E. Five groups of male mice were studied: group 1, control-fed with Purina...perchloric acid -2 mM EDTA to precipitate proteins, homogenized for 30 s using a polytron tissue tearator (PT 10-3S Kinematic, Brinkman Ins. Westbury, NY...cal systems. «-Propyl gallate, a synthetic polyhydric phenol, is a member of the gallic acid ester family. Propyl gallates are good scavengers of

  20. Pharmacological reduction of adult hippocampal neurogenesis modifies functional brain circuits in mice exposed to a cocaine conditioned place preference paradigm.

    Science.gov (United States)

    Castilla-Ortega, Estela; Blanco, Eduardo; Serrano, Antonia; Ladrón de Guevara-Miranda, David; Pedraz, María; Estivill-Torrús, Guillermo; Pavón, Francisco Javier; Rodríguez de Fonseca, Fernando; Santín, Luis J

    2016-05-01

    We investigated the role of adult hippocampal neurogenesis in cocaine-induced conditioned place preference (CPP) behaviour and the functional brain circuitry involved. Adult hippocampal neurogenesis was pharmacologically reduced with temozolomide (TMZ), and mice were tested for cocaine-induced CPP to study c-Fos expression in the hippocampus and in extrahippocampal addiction-related areas. Correlational and multivariate analysis revealed that, under normal conditions, the hippocampus showed widespread functional connectivity with other brain areas and strongly contributed to the functional brain module associated with CPP expression. However, the neurogenesis-reduced mice showed normal CPP acquisition but engaged an alternate brain circuit where the functional connectivity of the dentate gyrus was notably reduced and other areas (the medial prefrontal cortex, accumbens and paraventricular hypothalamic nucleus) were recruited instead of the hippocampus. A second experiment unveiled that mice acquiring the cocaine-induced CPP under neurogenesis-reduced conditions were delayed in extinguishing their drug-seeking behaviour. But if the inhibited neurons were generated after CPP acquisition, extinction was not affected but an enhanced long-term CPP retention was found, suggesting that some roles of the adult-born neurons may differ depending on whether they are generated before or after drug-contextual associations are established. Importantly, cocaine-induced reinstatement of CPP behaviour was increased in the TMZ mice, regardless of the time of neurogenesis inhibition. The results show that adult hippocampal neurogenesis sculpts the addiction-related functional brain circuits, and reduction of the adult-born hippocampal neurons increases cocaine seeking in the CPP model.

  1. Exacerbation of N-nitrosodiethylamine Induced Hepatotoxicity and DNA Damage in Mice Exposed to Chronic Unpredictable Stress

    Directory of Open Access Journals (Sweden)

    Nayeem Bilal

    2017-06-01

    Full Text Available Psychological stress contributes to increased susceptibility to a number of diseases including cancer. The present study was designed to assess the effect of chronic unpredictable stress on N-nitrosodiethylamine induced liver toxicity in terms of in vivo antioxidant status and DNA damage in Swiss albino mice. The animals used in this study were randomized into different groups based on the treatment with N-nitrosodiethylamine or chronic unpredictable stress alone and post-stress administration of N-nitrosodiethylamine. The mice were sacrificed after 12 weeks of treatment, and the status of major enzymatic and non-enzymatic antioxidants, liver function markers, lipid peroxidation and the extent of DNA damage were determined in circulation and liver tissues of all the groups. The N-nitrosodiethylamine treated group showed significantly compromised levels of the antioxidant enzymes, lipid peroxidation, and the liver function markers with enhanced DNA damage as compared to chronic unpredictable stress or control groups. A similar but less typical pattern observed in the chronic unpredictable stress treated mice. All the measured biochemical parameters were significantly altered in the group treated with the combination of chronic unpredictable stress and N-nitrosodiethylamine when compared to controls, or chronic unpredictable stress alone and/or N-nitrosodiethylamine alone treated groups. Thus, exposure to continuous, unpredictable stress conditions even in general life may significantly enhance the hepatotoxic potential of N-nitrosodiethylamine through an increase in the oxidative stress and DNA damage.

  2. Role of Spirulina in mitigating hemato-toxicity in Swiss albino mice exposed to aluminum and aluminum fluoride.

    Science.gov (United States)

    Sharma, Shweta; Sharma, K P; Sharma, Subhasini

    2016-12-01

    Aluminum is ingested through foods, water, air, and even drugs. Its intake is potentiated further through foods and tea prepared in aluminum utensils and Al salt added in the drinking water for removal of suspended impurities and also fluoride in the affected areas. The ameliorating role of a blue green alga Spirulina is well documented to various pollutants in the animal models. We, therefore, examined its protective role (230 mg/kg body weight) on the hematology of male Swiss albino mice treated with aluminum (sub-acute = 78.4 mg/kg body weight for 7 days, sub-chronic = 7.8 mg/kg body weight for 90 days) and aluminum fluoride (sub-acute = 103 mg/kg body weight, sub-chronic = 21 mg/kg body weight), along with their recovery after 90 days of sub-chronic exposure. This study revealed significant reduction in the values of RBC (5-18 %), Hb (15-17 %), PCV (8-14 %), and platelets (26-36 %), and increase in WBC (54-124 %) in the treated mice, particularly after sub-acute exposure. Aluminum fluoride was comparatively more toxic than aluminum. Further, Spirulina supplement not only alleviated toxicity of test chemicals in Swiss albino mice but also led to their better recovery after withdrawal.

  3. Exacerbation of N-nitrosodiethylamine Induced Hepatotoxicity and DNA Damage in Mice Exposed to Chronic Unpredictable Stress.

    Science.gov (United States)

    Bilal, Nayeem; Suhail, Nida; Hasan, Shirin; Ashraf, Ghulam M; Fatima, Sabiha; Khan, Husain Y; Alharbi, Mariam S; Alexiou, Athanasios; Banu, Naheed

    2017-01-01

    Psychological stress contributes to increased susceptibility to a number of diseases including cancer. The present study was designed to assess the effect of chronic unpredictable stress on N-nitrosodiethylamine induced liver toxicity in terms of in vivo antioxidant status and DNA damage in Swiss albino mice. The animals used in this study were randomized into different groups based on the treatment with N-nitrosodiethylamine or chronic unpredictable stress alone and post-stress administration of N-nitrosodiethylamine. The mice were sacrificed after 12 weeks of treatment, and the status of major enzymatic and non-enzymatic antioxidants, liver function markers, lipid peroxidation and the extent of DNA damage were determined in circulation and liver tissues of all the groups. The N-nitrosodiethylamine treated group showed significantly compromised levels of the antioxidant enzymes, lipid peroxidation, and the liver function markers with enhanced DNA damage as compared to chronic unpredictable stress or control groups. A similar but less typical pattern observed in the chronic unpredictable stress treated mice. All the measured biochemical parameters were significantly altered in the group treated with the combination of chronic unpredictable stress and N-nitrosodiethylamine when compared to controls, or chronic unpredictable stress alone and/or N-nitrosodiethylamine alone treated groups. Thus, exposure to continuous, unpredictable stress conditions even in general life may significantly enhance the hepatotoxic potential of N-nitrosodiethylamine through an increase in the oxidative stress and DNA damage.

  4. Neurotoxic, inflammatory, and mucosecretory responses in the nasal airways of mice repeatedly exposed to the macrocyclic trichothecene mycotoxin roridin A: dose-response and persistence of injury.

    Science.gov (United States)

    Corps, Kara N; Islam, Zahidul; Pestka, James J; Harkema, Jack R

    2010-04-01

    Macrocyclic trichothecene mycotoxins encountered in water-damaged buildings have been suggested to contribute to illnesses of the upper respiratory tract. Here, the authors characterized the adverse effects of repeated exposures to roridin A (RA), a representative macrocyclic trichothecene, on the nasal airways of mice and assessed the persistence of these effects. Young, adult, female C57BL/6 mice were exposed to single daily, intranasal, instillations of RA (0.4, 2, 10, or 50 microg/kg body weight [bw]) in saline (50 microl) or saline alone (controls) over 3 weeks or 250 microg/kg RA over 2 weeks. Histopathologic, immunohistochemical, and morphometric analyses of nasal airways conducted 24 hr after the last instillation revealed that the lowest-effect level was 10 microg/kg bw. RA exposure induced a dose-dependent, neutrophilic rhinitis with mucus hypersecretion, atrophy and exfoliation of nasal transitional and respiratory epithelium, olfactory epithelial atrophy and loss of olfactory sensory neurons (OSNs). In a second study, the persistence of lesions in mice instilled with 250 microg/kg bw RA was assessed. Nasal inflammation and excess luminal mucus were resolved after 3 weeks, but OSN loss was still evident in olfactory epithelium (OE). These results suggest that nasal inflammation, mucus hypersecretion, and olfactory neurotoxicity could be important adverse health effects associated with short-term, repeated, airborne exposures to macrocyclic trichothecenes.

  5. In vivo evaluation of the potential neurotoxicity of aerosols released from mechanical stress of nano-TiO2 additived paints in mice chronically exposed by inhalation

    Science.gov (United States)

    Manixay, S.; Delaby, S.; Gaie-Levrel, F.; Wiart, M.; Motzkus, C.; Bencsik, A.

    2017-06-01

    Engineered Nanomaterials (ENM) provide technical and specific benefits due to their physical-chemical properties at the nanometer scale. For instance, many ENM are used to improve products in the building industry. Nanoscaled titanium dioxide (TiO2) is one of the most used ENM in this industry. Incorporated in different matrix, cement, glass, paints… TiO2 nanoparticles (NPs) provide the final product with anti-UV, air purification and self-cleaning properties, thanks to their photocatalytic activity. However, ageing processes of such products, as photocatalytic paints, during a mechanical stress have been shown to release TiO2 NPs from this matrix associated with sanding dust. Thus, workers who sand painted walls could be exposed to TiO2 NPs through inhalation. As inhalation may lead to a translocation of particulate matter to the brain via olfactory or trigeminal nerves, there is an urgent need for evaluating a potential neurotoxicity. In order to provide new knowledge on this topic, we developed a dedicated experimental set-up using a rodent model exposed via inhalation. The aerosol released from a mechanical stress of photocatalytic paints containing TiO2 NPs was characterized and coupled to an exposition chamber containing group of mice free to move and chronically exposed (2 hours per day for 5 days a week during 8 weeks).

  6. Defensive effect of lansoprazole in dementia of AD type in mice exposed to streptozotocin and cholesterol enriched diet.

    Directory of Open Access Journals (Sweden)

    Rupinder K Sodhi

    Full Text Available The present study investigates the potential of lansoprazole (a proton pump inhibitor and agonist of liver x receptors in experimental dementia of AD type. Streptozotocin [STZ, 3 mg/kg, injected intracerebroventricular (i.c.v, and high fat diet (HFD, administered for 90 days] were used to induce dementia in separate groups of Swiss mice. Morris water maze (MWM test was performed to assess learning and memory of the animals. A battery of biochemical and histopathological studies were also performed. Extent of oxidative stress was measured by estimating the levels of brain reduced glutathione (GSH and thiobarbituric acid reactive species (TBARS. Brain acetylcholinestrase (AChE activity and serum cholesterol levels were also estimated. The brain level of myeloperoxidase (MPO was measured as a marker of inflammation. STZ and HFD produced a marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ/HFD treated mice exhibited a marked accentuation of AChE activity, TBARS and MPO levels along with a fall in GSH levels. Further, the stained micrographs of STZ/HFD treated mice indicated pathological changes, severe neutrophilic infiltration and amyloid deposition. Lansoprazole treatment significantly attenuated STZ and HFD -induced memory deficits, biochemical and histopathological alterations. It also prevented HFD-induced rise in the cholesterol level. Therefore, the findings demonstrate potential of lansoprazole in memory dysfunctions which may probably be attributed to its anti-cholinesterase, anti-oxidative and anti-inflammatory effects. Moreover, both cholesterol-dependent as well as cholesterol-independent effects of lansoprazole appear to play a role. In addition study indicates the role of liver x receptors in dementia.

  7. The immunogenicity of tetravalent dengue DNA vaccine in mice pre-exposed to Japanese encephalitis or Dengue virus antigens.

    Science.gov (United States)

    Prompetchara, Eakachai; Ketloy, Chutitorn; Keelapang, Poonsook; Sittisombut, Nopporn; Ruxrungtham, Kiat

    2015-09-01

    Asian countries are an endemic area for both dengue (DENV) and Japanese encephalitis viruses (JEV). While JEV vaccines have been used extensively in this region, DENV vaccines remains under development. Whether preexisting naturally acquired or vaccination-induced immunity against JEV may affect the immune response to dengue vaccine candidate is unclear. In this study we used mice previously immunized with JEV vaccines to evaluate the impact on dengue-specific neutralizing antibody responses to a tetravalent dengue DNA vaccine candidate (TDNA). A tetravalent cocktail of plasmids encoding pre-membrane and envelope proteins from each dengue serotype was administered into mice which had been previously primed with inactivated or live-attenuated JEV vaccines, or dengue serotype2 virus (DENV-2). Neutralizing antibody response was measured employing a plaque reduction neutralization test at two weeks after the priming and at four weeks after the second dose of the dengue tetravalent plasmids. Inactivated or live-attenuated JEV vaccines, or DENV-2 induced low levels of neutralizing antibodies against the homologous viruses (JE and dengue virus, respectively). DENV-2 injection induced also low levels of cross-reactive antibodies against DENV-1, -3 and -4. JEV vaccines have no effect on the dengue-specific neutralizing antibody responses to the subsequent TDNA immunization. Pre-exposure to DENV-2 infection increased DENV-2 specific response neutralizing antibody to two doses of TDNA plasmids by six folds, but did not affect antibody response to other serotypes. Priming with JEV vaccines did not impact on dengue virus-specific neutralizing antibody response to a dengue TDNA vaccine candidate in mice.

  8. Lack of acute phase response in the livers of mice exposed to diesel exhaust particles or carbon black by inhalation

    DEFF Research Database (Denmark)

    Saber, Anne T; Halappanavar, Sabina; Folkmann, Janne K

    2009-01-01

    BACKGROUND: Epidemiologic and animal studies have shown that particulate air pollution is associated with increased risk of lung and cardiovascular diseases. Although the exact mechanisms by which particles induce cardiovascular diseases are not known, studies suggest involvement of systemic acute...... analyzed liver tissue from these mice using high density DNA microarrays. Globally, 28 genes were found to be significantly differentially expressed in response to DEP or CB. The mRNA expression of three of the genes (serine (or cysteine) proteinase inhibitor, clade A, member 3C, apolipoprotein E...

  9. Protective effect of Melissa officinalis aqueous extract against Mn-induced oxidative stress in chronically exposed mice.

    Science.gov (United States)

    Martins, Eduarda N; Pessano, Naira T C; Leal, Luiza; Roos, Daniel H; Folmer, Vanderlei; Puntel, Gustavo O; Rocha, João Batista Teixeira; Aschner, Michael; Ávila, Daiana Silva; Puntel, Robson Luiz

    2012-01-04

    Manganese (Mn) is an essential element for biological systems; however occupational exposure to high levels of this metal may lead to neurodegenerative disorders, resembling Parkinson's disease (PD). While its mechanisms of neurotoxicity have yet to be fully understood, oxidative stress plays a critical role. Thus, the main goal of this study was to investigate the efficacy of aqueous extract of Melissa officinalis in attenuating Mn-induced brain oxidative stress in mice. Sixteen male mice were randomly divided into two groups and treated for 3 months: the first group consumed tap water (control group) and the second group was treated with Mn (50 mg/kg/day for habituation during the first 15 days followed by 100 mg/kg/day for additional 75 days) in the drinking water. After 3 months both groups were sub divided (n=4 per group) and treated for additional 3 months with Mn and/or M. officinalis in the drinking water. The first group (control) was treated with water and served as control; the second group (M. officinalis) was treated with M. officinalis (100 mg/kg/day); the third group was treated with Mn (100 mg/kg/day); the fourth group (Mn+M. officinalis) was treated with both Mn and M. officinalis (100 mg/kg/day each). Mn-treated mice showed a significant increase in thiobarbituric acid reactive species (TBARS) levels (a marker of oxidative stress) in both the hippocampus and striatum. These changes were accompanied by a decrease in total thiol content in the hippocampus and a significant increase in antioxidant enzyme activity (superoxide dismutase and catalase) in the hippocampus, striatum, cortex and cerebellum. Co-treatment with M. officinalis aqueous extract in Mn-treated mice significantly inhibited the antioxidant enzyme activities and attenuated the oxidative damage (TBARS and decreased total thiol levels). These results establish that M. officinalis aqueous extract possesses potent antioxidative properties, validating its efficacy in attenuating Mn

  10. Late-occurring chromosome aberrations and global DNA methylation in hematopoietic stem/progenitor cells of CBA/CaJ mice exposed to silicon ({sup 28}Si) ions

    Energy Technology Data Exchange (ETDEWEB)

    Rithidech, Kanokporn Noy, E-mail: kanokporn.rithidech@stonybrookmedicine.edu [Pathology Department, Stony Brook University, Stony Brook, NY 11794-8691 (United States); Honikel, Louise M. [Pathology Department, Stony Brook University, Stony Brook, NY 11794-8691 (United States); Reungpathanaphong, Paiboon [Pathology Department, Stony Brook University, Stony Brook, NY 11794-8691 (United States); Department of Applied Radiation and Isotopes, Faculty of Sciences, Kasetsart University, Chatuchuck, Bangkok 10900 (Thailand); Tungjai, Montree [Pathology Department, Stony Brook University, Stony Brook, NY 11794-8691 (United States); Department of Radiologic Technology, Faculty of Associated Medical Sciences, Center of Excellence for Molecular Imaging, Chiang Mai University, Chiang Mai 50200 (Thailand); Jangiam, Witawat [Pathology Department, Stony Brook University, Stony Brook, NY 11794-8691 (United States); Department of Chemical Engineering, Faculty of Engineering, Burapha University, Chonburi 20131 (Thailand); Whorton, Elbert B. [StatCom, PO Box 3041, Galveston, TX 77551 (United States)

    2015-11-15

    Highlights: • Late-occurring chromosome aberrations were found in HSPCs of exposed CBA/CaJ mice. • A dose-dependent reduction in the level of global 5hmC was detected in HSPCs. • There is a link between reduced global 5hmC levels and genomic instability in vivo. • The level of global 5hmC is a better marker of radiation exposure than that of 5mC. - Abstract: Although myeloid leukemia (ML) is one of the major health concerns from exposure to space radiation, the risk prediction for developing ML is unsatisfactory. To increase the reliability of predicting ML risk, a much improved understanding of space radiation-induced changes in the target cells, i.e. hematopoietic stem/progenitor cells (HSPCs), is important. We focused on the in vivo induction of late-occurring damage in HSPCs of mice exposed to {sup 28}Si ions since such damage is associated with radiation-induced genomic instability (a key event of carcinogenesis). We gave adult male CBA/CaJ mice, known to be sensitive to radiation-induced ML, a whole-body exposure (2 fractionated exposures, 15 days apart, that totaled each selected dose, delivered at the dose-rate of 1 cGy/min) to various doses of 300 MeV/n {sup 28}Si ions, i.e. 0 (sham controls), 0.1, 0.25, or 0.5 Gy. At 6 months post-irradiation, we collected bone marrow cells from each mouse (five mice per treatment-group) for obtaining the myeloid-lineage of HSPC-derived clones for analyses. We measured the frequencies of late-occurring chromosome aberrations (CAs), using the genome-wide multicolor fluorescence in situ hybridization method. The measurement of CAs was coupled with the characterization of the global DNA methylation patterns, i.e. 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). A dose-dependent increase in the frequencies of CAs was detected (Analysis of Variance or ANOVA, p < 0.01), indicating the induction of genomic instability after exposure of mice to 300 MeV/n {sup 28}Si ions. Slight increases in the levels of 5m

  11. CDRI-08 Attenuates REST/NRSF-Mediated Expression of NMDAR1 Gene in PBDE-209-Exposed Mice Brain.

    Science.gov (United States)

    Verma, Priya; Gupta, Rajaneesh K; Gandhi, Behrose S; Singh, Poonam

    2015-01-01

    CDRI-08 is a standardized bacoside enriched ethanolic extract of Bacopa monnieri, a nootropic plant. We reported that CDRI-08 attenuated oxidative stress and memory impairment in mice, induced by a flame retardant, PBDE-209. In order to explore the mechanism, present study was designed to examine the role of CDRI-08 on the expression of NMDAR1 (NR1) and the binding of REST/NRSF to NR1 promoter against postnatal exposure of PBDE-209. Male mice pups were orally supplemented with CDRI-08 at the doses of 40, 80, or 120 mg/kg along with PBDE-209 (20 mg/kg) during PND 3-10 and frontal cortex and hippocampus were collected at PND 11 and 60 to study the expression and regulation of NR1 by RT-PCR and electrophoretic mobility shift assay, respectively. The findings showed upregulated expression of NR1 and decreased binding of REST/NRSF to NR1 promoter after postnatal exposure of PBDE-209. Interestingly, supplementation with CDRI-08 significantly restored the expression of NR1 and binding of REST/NRSF to NR1 promoter near to the control value at the dose of 120 mg/kg. In conclusion, the results suggest that CDRI-08 possibly acts on glutamatergic system through expression and regulation of NR1 and may restore memory, impaired by PBDE-209 as reported in our previous study.

  12. CDRI-08 Attenuates REST/NRSF-Mediated Expression of NMDAR1 Gene in PBDE-209-Exposed Mice Brain

    Directory of Open Access Journals (Sweden)

    Priya Verma

    2015-01-01

    Full Text Available CDRI-08 is a standardized bacoside enriched ethanolic extract of Bacopa monnieri, a nootropic plant. We reported that CDRI-08 attenuated oxidative stress and memory impairment in mice, induced by a flame retardant, PBDE-209. In order to explore the mechanism, present study was designed to examine the role of CDRI-08 on the expression of NMDAR1 (NR1 and the binding of REST/NRSF to NR1 promoter against postnatal exposure of PBDE-209. Male mice pups were orally supplemented with CDRI-08 at the doses of 40, 80, or 120 mg/kg along with PBDE-209 (20 mg/kg during PND 3–10 and frontal cortex and hippocampus were collected at PND 11 and 60 to study the expression and regulation of NR1 by RT-PCR and electrophoretic mobility shift assay, respectively. The findings showed upregulated expression of NR1 and decreased binding of REST/NRSF to NR1 promoter after postnatal exposure of PBDE-209. Interestingly, supplementation with CDRI-08 significantly restored the expression of NR1 and binding of REST/NRSF to NR1 promoter near to the control value at the dose of 120 mg/kg. In conclusion, the results suggest that CDRI-08 possibly acts on glutamatergic system through expression and regulation of NR1 and may restore memory, impaired by PBDE-209 as reported in our previous study.

  13. Absolute quantification of superoxide dismutase in cytosol and mitochondria of mice hepatic cells exposed to mercury by a novel metallomic approach

    Energy Technology Data Exchange (ETDEWEB)

    García-Sevillano, M.A.; García-Barrera, T. [Department of Chemistry and Materials Science, Faculty of Experimental Sciences, University of Huelva, Campus de El Carmen, Huelva 21007 (Spain); Research Center on Health and Environment (CYSMA), University of Huelva (Spain); International Campus of Excellence on Agrofood (ceiA3), University of Huelva (Spain); Navarro, F. [International Campus of Excellence on Agrofood (ceiA3), University of Huelva (Spain); Department of Environmental Biology and Public Health, Cell Biology, Faculty of Experimental Sciences, University of Huelva, Campus El Carmen, Huelva 21007 (Spain); Gómez-Ariza, J.L., E-mail: ariza@uhu.es [Department of Chemistry and Materials Science, Faculty of Experimental Sciences, University of Huelva, Campus de El Carmen, Huelva 21007 (Spain); Research Center on Health and Environment (CYSMA), University of Huelva (Spain); International Campus of Excellence on Agrofood (ceiA3), University of Huelva (Spain)

    2014-09-09

    Highlights: • Identification and quantification of Cu,Zn-superoxide dismutase in mice hepatic cells. • IDA-ICP-MSis applied to obtain a high degree of accuracy, precision and sensibility. • This methodology reduces the time of analysis and avoids clean-up procedures. • The application of this method to Hg-exposed mice reveals perturbations in Cu,Zn-SOD. - Abstract: In the last years, the development of new methods for analyzing accurate and precise individual metalloproteins is of increasing importance, since numerous metalloproteins are excellent biomarkers of oxidative stress and diseases. In that way, methods based on the use of post column isotopic dilution analysis (IDA) or enriched protein standards are required to obtain a sufficient degree of accuracy, precision and high limits of detection. This paper reports the identification and absolute quantification of Cu,Zn-superoxide dismutase (Cu,Zn-SOD) in cytosol and mitochondria from mice hepatic cells using a innovative column switching analytical approach. The method consisted of orthogonal chromatographic systems coupled to inductively coupling plasma-mass spectrometry equipped with a octopole reaction systems (ICP-ORS-MS) and UV detectors: size exclusion fractionation (SEC) of the cytosolic and mitochondrial extracts followed by online anion exchange chromatographic (AEC) separation of Cu/Zn containing species. After purification, Cu,Zn-SOD was identified after tryptic digestion by molecular mass spectrometry (MS). The MS/MS spectrum of a doubly charged peptide was used to obtain the sequence of the protein using the MASCOT searching engine. This optimized methodology reduces the time of analysis and avoids the use of sample preconcentration and clean-up procedures, such as cut-off centrifuged filters, solid phase extraction (SPE), precipitation procedures, off-line fractions insolates, etc. In this sense, the method is robust, reliable and fast with typical chromatographic run time less than 20 min

  14. Evaluation of biochemical, hematological and oxidative parameters in mice exposed to the herbicide glyphosate-Roundup®

    Science.gov (United States)

    Jasper, Raquel; Locatelli, Gabriel Olivo; Pilati, Celso

    2012-01-01

    We evaluated the toxicity of hepatic, hematological, and oxidative effects of glyphosate-Roundup® on male and female albino Swiss mice. The animals were treated orally with either 50 or 500 mg/kg body weight of the herbicide, on a daily basis for a period of 15 days. Distilled water was used as control treatment. Samples of blood and hepatic tissue were collected at the end of the treatment. Hepatotoxicity was monitored by quantitative analysis of the serum enzymes ALT, AST, and γ-GT and renal toxicity by urea and creatinine. We also investigated liver tissues histopathologically. Alterations of hematological parameters were monitored by RBC, WBC, hemoglobin, hematocrit, MCV, MCH, and MCHC. TBARS (thiobarbituric acid reactive substances) and NPSH (non-protein thiols) were analyzed in the liver to assess oxidative damage. Significant increases in the levels of hepatic enzymes (ALT, AST, and γ-GT) were observed for both herbicide treatments, but no considerable differences were found by histological analysis. The hematological parameters showed significant alterations (500 mg/kg body weight) with reductions of RBC, hematocrit, and hemoglobin, together with a significant increase of MCV, in both sexes of mice. In males, there was an important increase in lipid peroxidation at both dosage levels, together with an NPSH decrease in the hepatic tissue, whereas in females significant changes in these parameters were observed only at the higher dose rate. The results of this study indicate that glyphosate-Roundup® can promote hematological and hepatic alterations, even at subacute exposure, which could be related to the induction of reactive oxygen species. PMID:23554553

  15. Evaluation of biochemical, hematological and oxidative parameters in mice exposed to the herbicide glyphosate-Roundup(®).

    Science.gov (United States)

    Jasper, Raquel; Locatelli, Gabriel Olivo; Pilati, Celso; Locatelli, Claudriana

    2012-09-01

    We evaluated the toxicity of hepatic, hematological, and oxidative effects of glyphosate-Roundup(®) on male and female albino Swiss mice. The animals were treated orally with either 50 or 500 mg/kg body weight of the herbicide, on a daily basis for a period of 15 days. Distilled water was used as control treatment. Samples of blood and hepatic tissue were collected at the end of the treatment. Hepatotoxicity was monitored by quantitative analysis of the serum enzymes ALT, AST, and γ-GT and renal toxicity by urea and creatinine. We also investigated liver tissues histopathologically. Alterations of hematological parameters were monitored by RBC, WBC, hemoglobin, hematocrit, MCV, MCH, and MCHC. TBARS (thiobarbituric acid reactive substances) and NPSH (non-protein thiols) were analyzed in the liver to assess oxidative damage. Significant increases in the levels of hepatic enzymes (ALT, AST, and γ-GT) were observed for both herbicide treatments, but no considerable differences were found by histological analysis. The hematological parameters showed significant alterations (500 mg/kg body weight) with reductions of RBC, hematocrit, and hemoglobin, together with a significant increase of MCV, in both sexes of mice. In males, there was an important increase in lipid peroxidation at both dosage levels, together with an NPSH decrease in the hepatic tissue, whereas in females significant changes in these parameters were observed only at the higher dose rate. The results of this study indicate that glyphosate-Roundup(®) can promote hematological and hepatic alterations, even at subacute exposure, which could be related to the induction of reactive oxygen species.

  16. Influence of the leaf extract of mentha arvensis linn. (Mint) on the survival of mice exposed to different doses of gamma radiation

    Energy Technology Data Exchange (ETDEWEB)

    Jagetia, G.C.; Baliga, M.S. [Kasturba Medical Coll., Manipal (India). Dept. of Radiobiology

    2002-02-01

    Background: The aim of the present study was to evaluate the radioprotective effect of Mentha arvensis (mint) on the survival of mice exposed to various doses of whole-body gamma radiation. Material and Methods: The radioprotective effect of various doses (0, 2.5, 5, 10, 20, 40 and 80 mg/kg body weight) of chloroform extract of mint (Mentha arvensis Linn.) was studied in mice exposed to 10 Gy gamma radiation. Results: The 10 mg/kg of mint extract was found to afford best protection as evidenced by the highest number of survivors in this group at 30 days post-irradiation, and further experiments were carried out using this dose of mint extract. The mice treated with 10 mg/kg body weight mint extract or oil were exposed to 6, 7, 8, 9 and 10 Gy of gamma radiation and observed for the induction of radiation-sickness and mortality up to 30 days post-irradiation. The mint extract pretreatment was found to reduce the severity of symptoms of radiation sickness and mortality at all exposure doses and a significant increase in the animal survival was observed when compared with the oil + irradiation group. All of the animals that were treated with 10 mg/kg mint extract and then exposed to 7 Gy irradiation were protected against the radiation-induced mortality when compared with the concurrent oil + irradiation group, in which 20% animals died by 30 days post-irradiation. The mint extract treatment protected the mice against the gastrointestinal death as well as bone marrow deaths. The DRF was found to be 1.2. The drug was non-toxic up to a dose of 1 000 mg/kg body weight, the highest drug dose that could be tested for acute toxicity. Conclusion: From our study it is clear that mint extract provides protection against the radiation-induced sickness and mortality and the optimum protective dose of 10 mg/kg is safe from the point of drug-induced toxicity. (orig.) [German] Hintergrund: Ziel der vorliegenden Studie war es, den radioprotektiven Effekt von Mentha arvensis (Minze

  17. Assessment of the reproductive toxicity of inhalation exposure to ethyl tertiary butyl ether in male mice with normal, low active and inactive ALDH2.

    Science.gov (United States)

    Weng, Zuquan; Ohtani, Katsumi; Suda, Megumi; Yanagiba, Yukie; Kawamoto, Toshihiro; Nakajima, Tamie; Wang, Rui-Sheng

    2014-04-01

    No data are available regarding aldehyde dehydrogenase 2 (ALDH2) polymorphisms related to the reproductive toxicity possibly caused by ethyl tertiary butyl ether (ETBE). In this study, two inhalation experiments were performed in Aldh2 knockout (KO), heterogeneous (HT) and wild type (WT) C57BL/6 male mice exposed to ETBE, and the data about general toxicity, testicular histopathology, sperm head numbers, sperm motility and sperm DNA damage were collected. The results showed that the 13-week exposure to 0, 500, 1,750 and 5,000 ppm ETBE significantly decreased sperm motility and increased levels of sperm DNA strand breaks and 8-hydroxy-deoxyguanosine in both WT and KO mice, the effects were found in 1,750 and 5,000 ppm groups of WT mice, and all of the three exposed groups of KO mice compared to the corresponding control; furthermore, ETBE also caused decrease in the relative weights of testes and epididymides, the slight atrophy of seminiferous tubules of testis and reduction in sperm numbers of KO mice exposed to ≥500 ppm. In the experiment of exposure to lower concentrations of ETBE (0, 50, 200 and 500 ppm) for 9 weeks, the remarkable effects of ETBE on sperm head numbers, sperm motility and sperm DNA damage were further observed in KO and HT mice exposed to 200 ppm ETBE, but not in WT mice. Our findings suggested that only exposure to high concentrations of ETBE might result in reproductive toxicity in mice with normal active ALDH2, while low active and inactive ALDH2 enzyme significantly enhanced the ETBE-induced reproductive toxicity in mice, even exposed to low concentrations of ETBE, mainly due to the accumulation of acetaldehyde as a primary metabolite of ETBE.

  18. Sex differences in the rapid and the sustained antidepressant-like effects of ketamine in stress-naïve and "depressed" mice exposed to chronic mild stress.

    Science.gov (United States)

    Franceschelli, A; Sens, J; Herchick, S; Thelen, C; Pitychoutis, P M

    2015-04-02

    During the past decade, one of the most striking discoveries in the treatment of major depression was the clinical finding that a single infusion of a sub-anesthetic dose of the N-methyl-d-aspartate receptor antagonist ketamine produces a rapid (i.e. within a few hours) and long-lasting (i.e. up to two weeks) antidepressant effect in both treatment-resistant depressed patients and in animal models of depression. Notably, converging clinical and preclinical evidence support that responsiveness to antidepressant drugs is sex-differentiated. Strikingly, research regarding the antidepressant-like effects of ketamine has focused almost exclusively on the male sex. Herein we report that female C57BL/6J stress-naïve mice are more sensitive to the rapid and the sustained antidepressant-like effects of ketamine in the forced swim test (FST). In particular, female mice responded to lower doses of ketamine (i.e. 3mg/kg at 30 min and 5mg/kg at 24h post-injection), doses that were not effective in their male counterparts. Moreover, tissue levels of the excitatory amino acids glutamate and aspartate, as well as serotonergic activity, were affected in a sex-dependent manner in the prefrontal cortex and the hippocampus, at the same time-points. Most importantly, a single injection of ketamine (10mg/kg) induced sex-dependent behavioral effects in mice subjected to the chronic mild stress (CMS) model of depression. Intriguingly, female mice were more reactive to the earlier effects of ketamine, as assessed in the open field and the FST (at 30 min and 24h post-treatment, respectively) but the antidepressant potential of the drug proved to be longer lasting in males, as assessed in the splash test and the FST (days 5 and 7 post-treatment, respectively). Taken together, present data revealed that ketamine treatment induces sex-dependent rapid and sustained neurochemical and behavioral antidepressant-like effects in stress-naïve and CMS-exposed C57BL/6J mice.

  19. Genetic alterations in K-ras and p53 cancer genes in lung neoplasms from B6C3F1 mice exposed to cumene.

    Science.gov (United States)

    Hong, Hue-Hua L; Ton, Thai-Vu T; Kim, Yongbaek; Wakamatsu, Nobuko; Clayton, Natasha P; Chan, Po-Chuen; Sills, Robert C; Lahousse, Stephanie A

    2008-07-01

    The incidences of alveolar/bronchiolar adenomas and carcinomas in cumene-treated B6C3F1 mice were significantly greater than those of the control animals. We evaluated these lung neoplasms for point mutations in the K-ras and p53 genes that are often mutated in humans. K-ras and p53 mutations were detected by cycle sequencing of PCR-amplified DNA isolated from paraffin-embedded neoplasms. K-ras mutations were detected in 87% of cumene-induced lung neoplasms, and the predominant mutations were exon 1 codon 12 G to T transversions and exon 2 codon 61 A to G transitions. P53 protein expression was detected by immunohistochemistry in 56% of cumene-induced neoplasms, and mutations were detected in 52% of neoplasms. The predominant mutations were exon 5, codon 155 G to A transitions, and codon 133 C to T transitions. No p53 mutations and one of seven (14%) K-ras mutations were detected in spontaneous neoplasms. Cumene-induced lung carcinomas showed loss of heterozygosity (LOH) on chromosome 4 near the p16 gene (13%) and on chromosome 6 near the K-ras gene (12%). No LOH was observed in spontaneous carcinomas or normal lung tissues examined. The pattern of mutations identified in the lung tumors suggests that DNA damage and genomic instability may be contributing factors to the mutation profile and development of lung cancer in mice exposed to cumene.

  20. Induction of apoptosis in placentas of pregnant mice exposed to lipopolysaccharides: possible involvement of Fas/Fas ligand system.

    Science.gov (United States)

    Ejima, K; Koji, T; Tsuruta, D; Nanri, H; Kashimura, M; Ikeda, M

    2000-01-01

    To explore the pathogenesis in placental dysfunction and abruptio placentae, we analyzed the occurrence of placental cell apoptosis and the role of Fas and Fas ligand (L) in that process in an inflammatory placental dysfunction model of pregnant mice, using lipopolysaccharides (LPS). In the present study, Day 13 pregnant mice were injected i.p. with LPS (50 microg/kg) or saline as a control, and the placentas were isolated at various time points after the injection. Analysis of the isolated DNA in agarose-gel electrophoresis revealed a typical ladder pattern of bands consisting of 180-200 base pairs (bp), which is regarded as a hallmark of apoptosis. The intensity of the bands increased time-dependently, reaching a maximum level at 12 h after LPS injection. In accord with the biochemical data, histochemical analysis using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) revealed that nuclei positive for double-stranded DNA breaks were found in decidua, diploid trophoblasts in the basal zone, and spongiotrophoblasts. The number of positive nuclei was maximized at 12 h after LPS injection. As a next step, we investigated the possible involvement of Fas and Fas L in the induction of apoptosis of the placental cells after LPS injection. Western blot analysis indicated that LPS increased the expression of Fas and Fas L in the placenta by about 4-fold at 12 h and 18 h, respectively, after injection. The cells expressing Fas and Fas L were identified, using immunohistochemistry and nonradioactive in situ hybridization, as decidua, diploid trophoblasts in the basal zone, and spongiotrophoblasts. Furthermore, when the expression of 4-hydroxy-2-nonenal (HNE)-modified proteins was assessed to evaluate the relation of oxidative stress elicited by LPS to the induction of apoptosis, once again decidua, diploid trophoblasts in the basal zone, and spongiotrophoblasts were positive. Therefore, the placental dysfunction by LPS may be brought about

  1. Induction of micronuclei and sister chromatid exchange in bone-marrow cells and abnormalities in sperm of Algerian mice (Mus spretus) exposed to cadmium, lead and zinc.

    Science.gov (United States)

    Tapisso, Joaquim Torres; Marques, Carla Cristina; Mathias, Maria da Luz; Ramalhinho, Maria da Graça

    2009-08-01

    As a consequence of human activities, large amounts of cadmium, lead and zinc are released in the environment, often simultaneously. The aim of this study was to investigate under experimental conditions the DNA damage induced in Algerian mice (Mus spretus) exposed to cadmium (Cd), lead (Pb) and zinc (Zn) separately, or in selected combinations. Three cytogenetic end points were considered: the frequencies of micronucleated cells (MN) and sister chromatid exchange (SCE) in the bone marrow and the frequency of sperm abnormalities. Mice were treated by intraperitoneal (i.p.) injections with 5 or 10 doses of aqueous solutions of cadmium acetate, lead acetate and zinc acetate in concentrations corresponding to 1/10 of the LD50, respectively, 21.5, 0.46 and 1.5 mg/kg bw. The control groups were injected in the same way with distilled water. With only one exception (Cd + Zn group treated with 5 doses), the results show a significant increase of MN in all groups for both treatments (5 and 10 doses). Similarly, the results concerning the SCE revealed a statistically significant increase in all treated animals, with the exception of the Zn group treated with 5 doses. The number of sperm abnormalities was significantly higher in animals treated with 5 doses, except in the group Pb + Zn. In animals treated with 10 doses the number of sperm abnormalities was always statistically higher compared with controls. This study indicates that cadmium, lead and zinc can induce MN, SCEs and sperm abnormalities in Algerian mice and that the clastogenic potential is dependent on the time of exposure and the interaction between the three elements, confirming the environmental damage that may result from the simultaneous action of several metals. Most relevant is the toxic potential for Zn, related with the dose, which may compromise its protective effect against other metal contaminations, such as cadmium.

  2. Early skin shrinkage, late skin contraction and leg contracture of mice exposed to two equal fractions of neutron

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    Uehara, Satoru; Masuda, Kouji [Kyushu Univ., Fukuoka (Japan). Faculty of Medicine; Miyoshi, Makoto; Andou, Kouichi; Koike, Sachiko

    1996-03-01

    We evaluated the effects of fractioned intervals on normal tissue recovery from radiation injury after neutron exposure. Doses ranging from 9 to 25 Gy of 30 MeV deuteron-beryllium neutrons (0.7 Gy/min.) were imposed on the hind legs of C3H/He female mice in single or in two equally divided doses at various intervals ranging from 6 hours to 14 days. The effective doses 50% for early skin shrinkage measured at around 40 to 50 days, late skin contraction and leg contracture at 250 days after irradiation were evaluated. With recovery ratios, (D2-D1)/D1, the patterns obtained were similar to those observed in the isoeffect curves. However, with one or two day intervals, they remarkably decreased to less than 10% irrespective of the response evaluated especially in late skin contraction. This might indicate the induction of hypersensitivity and/or very little recovery at these intervals. Therefore, fractioned intervals of more than five days and around one and/or two days seem less beneficial from the view point of normal tissue recovery. (author).

  3. Lead induces similar gene expression changes in brains of gestationally exposed adult mice and in neurons differentiated from mouse embryonic stem cells.

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    Francisco Javier Sánchez-Martín

    Full Text Available Exposure to environmental toxicants during embryonic life causes changes in the expression of developmental genes that may last for a lifetime and adversely affect the exposed individual. Developmental exposure to lead (Pb, an ubiquitous environmental contaminant, causes deficits in cognitive functions and IQ, behavioral effects, and attention deficit hyperactivity disorder (ADHD. Long-term effects observed after early life exposure to Pb include reduction of gray matter, alteration of myelin structure, and increment of criminal behavior in adults. Despite growing research interest, the molecular mechanisms responsible for the effects of lead in the central nervous system are still largely unknown. To study the molecular changes due to Pb exposure during neurodevelopment, we exposed mice to Pb in utero and examined the expression of neural markers, neurotrophins, transcription factors and glutamate-related genes in hippocampus, cortex, and thalamus at postnatal day 60. We found that hippocampus was the area where gene expression changes due to Pb exposure were more pronounced. To recapitulate gestational Pb exposure in vitro, we differentiated mouse embryonic stem cells (ESC into neurons and treated ESC-derived neurons with Pb for the length of the differentiation process. These neurons expressed the characteristic neuronal markers Tubb3, Syp, Gap43, Hud, Ngn1, Vglut1 (a marker of glutamatergic neurons, and all the glutamate receptor subunits, but not the glial marker Gafp. Importantly, several of the changes observed in Pb-exposed mouse brains in vivo were also observed in Pb-treated ESC-derived neurons, including those affecting expression of Ngn1, Bdnf exon IV, Grin1, Grin2D, Grik5, Gria4, and Grm6. We conclude that our ESC-derived model of toxicant exposure during neural differentiation promises to be a useful model to analyze mechanisms of neurotoxicity induced by Pb and other environmental agents.

  4. CXCL12 expression in hematopoietic tissues of mice exposed to sublethal dose of ionizing radiation in the presence od iNOS inhibitor

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    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

  5. ESR evidence for in vivo formation of free radicals in tissue of mice exposed to single-walled carbon nanotubes.

    Science.gov (United States)

    Shvedova, A A; Kisin, E R; Murray, A R; Mouithys-Mickalad, A; Stadler, K; Mason, R P; Kadiiska, M

    2014-08-01

    Nanomaterials are being utilized in an increasing variety of manufactured goods. Because of their unique physicochemical, electrical, mechanical, and thermal properties, single-walled carbon nanotubes (SWCNTs) have found numerous applications in the electronics, aerospace, chemical, polymer, and pharmaceutical industries. Previously, we have reported that pharyngeal exposure of C57BL/6 mice to SWCNTs caused dose-dependent formation of granulomatous bronchial interstitial pneumonia, fibrosis, oxidative stress, acute inflammatory/cytokine responses, and a decrease in pulmonary function. In the current study, we used electron spin resonance (ESR) to directly assess whether exposure to respirable SWCNTs caused formation of free radicals in the lungs and in two distant organs, the heart and liver. Here we report that exposure to partially purified SWCNTs (HiPco technique, Carbon Nanotechnologies, Inc., Houston, TX, USA) resulted in the augmentation of oxidative stress as evidenced by ESR detection of α-(4-pyridyl-1-oxide)-N-tert-butylnitrone spin-trapped carbon-centered lipid-derived radicals recorded shortly after the treatment. This was accompanied by a significant depletion of antioxidants and elevated biomarkers of inflammation presented by recruitment of inflammatory cells and an increase in proinflammatory cytokines in the lungs, as well as development of multifocal granulomatous pneumonia, interstitial fibrosis, and suppressed pulmonary function. Moreover, pulmonary exposure to SWCNTs also caused the formation of carbon-centered lipid-derived radicals in the heart and liver at later time points (day 7 postexposure). Additionally, SWCNTs induced a significant accumulation of oxidatively modified proteins, increase in lipid peroxidation products, depletion of antioxidants, and inflammatory response in both the heart and the liver. Furthermore, the iron chelator deferoxamine noticeably reduced lung inflammation and oxidative stress, indicating an important role for

  6. Activation of 5-HT(2C) receptors in the dorsal periaqueductal gray increases antinociception in mice exposed to the elevated plus-maze.

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    Baptista, Daniela; Nunes-de-Souza, Ricardo Luiz; Canto-de-Souza, Azair

    2012-11-01

    Several findings have pointed to the role of the dorsal periaqueductal gray (dPAG) serotonin 5-HT(1A) and 5-HT(2A-C) receptor subtypes in the modulation of defensive behavior in animals exposed to the elevated plus-maze (EPM). Besides displaying anxiety-like behavior, rodents also exhibit antinociception in the EPM. This study investigated the effects of intra-dPAG injections of 5-HT(1A) and 5-HT(2B/2C) receptor ligands on EPM-induced antinociception in mice. Male Swiss mice received 0.1 μl intra-dPAG injections of vehicle, 5.6 and 10 nmol of 8-OHDPAT, a 5-HT(1A) receptor agonist (Experiment 1), or 0.01, 0.03 and 0.1 nmol of mCPP, a 5-HT(2B/2C) receptor agonist (Experiment 2). Five minutes later, each mouse received an intraperitoneal injection of 0.6% acetic acid (0.1 ml/10 g body weight; nociceptive stimulus) and was individually confined in the open (OA) or enclosed (EA) arms of the EPM for 5 min, during which the number of abdominal writhes induced by the acetic acid was recorded. While intra-dPAG injection of 8-OHDPAT did not change open-arm antinociception (OAA), mCPP (0.01 nmol) enhanced it. Combined injections of ketanserin (10 nmol/0.1 μl), a 5-HT(2A/2C) receptor antagonist, and 0.01 nmol of mCPP (Experiment 3), selectively and completely blocked the OAA enhancement induced by mCPP. Although intra-dPAG injection of mCPP (0.01 nmol) also produced antinociception in EA-confined mice (Experiment 2), this effect was not confirmed in Experiment 3. Moreover, no other compound changed the nociceptive response in EA-confined animals. These results suggest that the 5-HT(2C) receptors located within the PAG play a role in this type of environmentally induced pain inhibition in mice.

  7. Oxidative stress, inflammation, and DNA damage in multiple organs of mice acutely exposed to amorphous silica nanoparticles

    Directory of Open Access Journals (Sweden)

    Nemmar A

    2016-03-01

    Full Text Available Abderrahim Nemmar,1 Priya Yuvaraju,1 Sumaya Beegam,1 Javed Yasin,2 Elsadig E Kazzam,2 Badreldin H Ali3 1Department of Physiology, 2Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE; 3Department of Pharmacology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Al-Khoudh, Sultanate of Oman Abstract: The use of amorphous silica (SiO2 in biopharmaceutical and industrial fields can lead to human exposure by injection, skin penetration, ingestion, or inhalation. However, the in vivo acute toxicity of amorphous SiO2 nanoparticles (SiNPs on multiple organs and the mechanisms underlying these effects are not well understood. Presently, we investigated the acute (24 hours effects of intraperitoneally administered 50 nm SiNPs (0.25 mg/kg on systemic toxicity, oxidative stress, inflammation, and DNA damage in the lung, heart, liver, kidney, and brain of mice. Lipid peroxidation was significantly increased by SiNPs in the lung, liver, kidney, and brain, but was not changed in the heart. Similarly, superoxide dismutase and catalase activities were significantly affected by SiNPs in all organs studied. While the concentration of tumor necrosis factor α was insignificantly increased in the liver and brain, its increase was statistically significant in the lung, heart, and kidney. SiNPs induced a significant elevation in pulmonary and renal interleukin 6 and interleukin-1 beta in the lung, liver, and brain. Moreover, SiNPs caused a significant increase in DNA damage, assessed by comet assay, in all the organs studied. SiNPs caused leukocytosis and increased the plasma activities of lactate dehydrogenase, creatine kinase, alanine aminotranferase, and aspartate aminotransferase. These results indicate that acute systemic exposure to SiNPs causes oxidative stress, inflammation, and DNA damage in several major organs, and highlight the need for thorough evaluation

  8. Claudin-2 knockout by TALEN-mediated gene targeting in MDCK cells: claudin-2 independently determines the leaky property of tight junctions in MDCK cells.

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    Shinsaku Tokuda

    Full Text Available Tight junctions (TJs regulate the movements of substances through the paracellular pathway, and claudins are major determinants of TJ permeability. Claudin-2 forms high conductive cation pores in TJs. The suppression of claudin-2 expression by RNA interference in Madin-Darby canine kidney (MDCK II cells (a low-resistance strain of MDCK cells was shown to induce a three-fold increase in transepithelial electrical resistance (TER, which, however, was still lower than in high-resistance strains of MDCK cells. Because RNA interference-mediated knockdown is not complete and only reduces gene function, we considered the possibility that the remaining claudin-2 expression in the knockdown study caused the lower TER in claudin-2 knockdown cells. Therefore, we investigated the effects of claudin-2 knockout in MDCK II cells by establishing claudin-2 knockout clones using transcription activator-like effector nucleases (TALENs, a recently developed genome editing method for gene knockout. Surprisingly, claudin-2 knockout increased TER by more than 50-fold in MDCK II cells, and TER values in these cells (3000-4000 Ω·cm2 were comparable to those in the high-resistance strains of MDCK cells. Claudin-2 re-expression restored the TER of claudin-2 knockout cells dependent upon claudin-2 protein levels. In addition, we investigated the localization of claudin-1, -2, -3, -4, and -7 at TJs between control MDCK cells and their respective knockout cells using their TALENs. Claudin-2 and -7 were less efficiently localized at TJs between control and their knockout cells. Our results indicate that claudin-2 independently determines the 'leaky' property of TJs in MDCK II cells and suggest the importance of knockout analysis in cultured cells.

  9. Urine arsenic methylated metabolism in mice exposed to acute arsenic%急性砷暴露小鼠尿砷甲基化代谢的研究

    Institute of Scientific and Technical Information of China (English)

    董丹丹; 王欣; 赵朔; 段晓旭; 李炜; 李冰

    2013-01-01

    Objective To investigate the level of urine arsenic excretion and methylated metabolism pattern in mice exposed to acute arsenic. Methods Healthy female Kunming mice were exposed to sodium arsenite ( NaAsO2) by intragastric infusion at doses of 2.5 mg/kg, 5.0 mg/kg, 10.0 mg/kg and 20.0 mg/kg, the exposure time for each group were 12 hours, 24 hours, 48 hours and 72 hours. The mice were placed in metabolic cages and urine samples of 24 - hour group were collected (urine samples of 12 hours were collect from 12 - hour group) before the end of exposure day. The level of inorganic arsenic (iAs) , monomethy-lated arsenic [ MMA) and dimethylated arsenic ( DMA) in urine were determined by cold trap hydride generation atomic absorption spectrophotometer respectively, the level of T-As, iAs% , MMA% , DMA% , primary methylation index (PMI) and secondary methylation index ( SMI) were calculated. Results Urine T - As level, iAs% and MMA in the mice exposed to acute arsenic increased significantly with the increase of arsenic concentration, but DMA% and SMI decreased with stable PMI. With the increase of time after exposure, urine T - As level, iAs% and MMA% gradually decreased, while DMA% , PMI and SMI increased significantly. The most urine arsenic were excreted within 24 hours, and its percentage content and methylation index were at same level, the level of urine arsenic excretion was very low in 48 - hour and 72 hour groups and their percentage content and methylation index were at same level. Conclusion Urine arsenic excretion in mice exposed to acute arsenic has obvious dose deffect relation and time - effect relation; High concentration of arsenic exposure may effectively inhibit methylated metabolism , and urine arsenic content within 24 hours could be used as an indicator to determine the arsenic burden of an acute arsenic poisoned body.%目的 探讨急性砷暴露小鼠尿砷排泄及其甲基化代谢模式.方法 健康雌性昆明种小鼠一次性灌

  10. Relationships between pulmonary micro-RNA and proteome profiles, systemic cytogenetic damage and lung tumors in cigarette smoke-exposed mice treated with chemopreventive agents.

    Science.gov (United States)

    Izzotti, Alberto; Balansky, Roumen; D'Agostini, Francesco; Longobardi, Mariagrazia; Cartiglia, Cristina; La Maestra, Sebastiano; Micale, Rosanna T; Camoirano, Anna; Ganchev, Gancho; Iltcheva, Marietta; Steele, Vernon E; De Flora, Silvio

    2013-10-01

    Assessing the correlation between molecular endpoints and cancer induction or prevention aims at validating the use of intermediate biomarkers. We previously developed murine models that are suitable to detect both the carcinogenicity of mainstream cigarette smoke (MCS) and the induction of molecular alterations. In this study, we used 931 Swiss mice in two parallel experiments and in a preliminary toxicity study. The chemopreventive agents included vorinostat, myo-inositol, bexarotene, pioglitazone and a combination of bexarotene and pioglitazone. Pulmonary micro-RNAs and proteins were evaluated by microarray analyses at 10 weeks of age in male and female mice, either unexposed or exposed to MCS since birth, and either untreated or receiving each one of the five chemopreventive regimens with the diet after weaning. At 4 months of age, the frequency of micronucleated normochromatic erythrocytes was evaluated. At 7 months, the lungs were subjected to standard histopathological analysis. The results showed that exposure to MCS significantly downregulated the expression of 79 of 694 lung micro-RNAs (11.4%) and upregulated 66 of 1164 proteins (5.7%). Administration of chemopreventive agents modulated the baseline micro-RNA and proteome profiles and reversed several MCS-induced alterations, with some intergender differences. The stronger protective effects were produced by the combination of bexarotene and pioglitazone, which also inhibited the MCS-induced clastogenic damage and the yield of malignant tumors. Pioglitazone alone increased the yield of lung adenomas. Thus, micro-RNAs, proteins, cytogenetic damage and lung tumors were closely related. The molecular biomarkers contributed to evaluate both protective and adverse effects of chemopreventive agents and highlighted the mechanisms involved.

  11. Methylation changes in muscle and liver tissues of male and female mice exposed to acute and chronic low-dose X-ray-irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Kovalchuk, Olga; Burke, Paula; Besplug, Jill; Slovack, Mark; Filkowski, Jody; Pogribny, Igor

    2004-04-14

    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{sup INKa} and DNA repair gene O{sup 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{sup INKa} promoter methylation upon LDR exposure. In male liver tissue, p16{sup INKa} promoter methylation was more pronounced than in female tissue. In contrast, no significant radiation-induced changes in p16{sup 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{sup 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.

  12. Chlorophyllin in the intra-uterine development of mice exposed or not to cyclophosphamide - doi: 10.4025/actascihealthsci.v35i2.12470

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    Vessia Silva Leite

    2013-06-01

    Full Text Available Chlorophyllin, a sodium-copper salt synthesized from chlorophyll, has already proved to have anticlastogenic, antimutagenic and anticarcinogenic activity, however few are the studies in the teratogenicity area. The present study evaluated the effects of chlorophyllin in intra-uterine development of mice exposed or not to cyclophosphamide. Pregnant females were divided into 8 groups of 15 animals each, G01 - PBS (0.1 mL 10.0-1 g orally; G02 – cyclophosphamide (20.0 mg kg-1 i.p.; G03, G04 and G05 - chlorophyllin at concentrations of (5.0, 10.0 and 15.0 mg kg-1 orally; G06, G07 and G08 (5.0, 10.0 and 15.0 mg kg-1 orally, of chlorophyllin, respectively, and (20.0 mg kg-1 i.p. of cyclophosphamide. In the 18th day the females were submitted to laparotomy and females and fetuses analyzed. The results showed that the chlorophyllin was not effective in protecting the reproductive parameters as well as teratogenicity. Finally, it was observed that the presence of chlorophyllin increased the frequency of some malformations when combined with cyclophosphamide. However, it was not teratogenic and not embryo lethal in this experimental design.

  13. A role of phosphatidylserine externalization in clearance of erythrocytes exposed to stress but not in eliminating aging populations of erythrocyte in mice.

    Science.gov (United States)

    Khandelwal, Sanjay; Saxena, Rajiv K

    2008-08-01

    Age dependent changes in phosphatidylserine (PS) externalization were studied in mouse erythrocytes of different age groups (range 1-55 days) by using a newly developed double in vivo biotinylation (DIB) technique. Around 3-4% of the erythrocytes freshly released in the circulation were PS(+) but this proportion fell rapidly to 1% or less and did not increase at later time points. Blocking erythrocyte clearance from the circulation by in vivo depletion of macrophages (by treatment with clodronate loaded liposomes) for up to 7 days did not result in accumulation of PS(+) erythrocytes in the circulation indicating that the low percentage of PS(+) cells within old erythrocytes (age >40 days) was not related to the clearance of PS(+) erythrocytes by macrophages. In vitro treatment with stress inducing agents like deoxyglucose or Ca(++)/calcium ionophore resulted in a marked induction of PS externalization in mouse erythrocytes and this effect was most prominent in the youngest erythrocyte population (age erythrocytes after intravenous infusion into recipient mice indicated that the young erythrocytes were cleared at fastest rate from the circulation as compared to erythrocytes of older age groups. Within young erythrocytes exposed to stress, PS(+) erythrocytes were preferentially cleared. Taken together our results suggest that PS externalization is unlikely to have a role in the removal of old erythrocytes from blood circulation but may have a role in the clearance of stressed and damaged young erythrocytes in blood circulation.

  14. Rapid, sequential activation of mitogen-activated protein kinases and transcription factors precedes proinflammatory cytokine mRNA expression in spleens of mice exposed to the trichothecene vomitoxin.

    Science.gov (United States)

    Zhou, Hui-Ren; Islam, Zahidul; Pestka, James J

    2003-03-01

    , splenic TNF-alpha, IL-1beta, and IL-6 mRNA were found to peak at 3 h and were still significantly elevated at 6 h but not at 9 h. Taken together, VT first activated MAPKs in vivo and either concurrently (AP-1, C/EBP) or subsequently (AP-1, CREB, NF-kappaB) modulated binding activities of transcription factors specific for potential regulatory motifs in cytokine promoters. The timing of these events was highly consistent with the kinetics of proinflammatory gene expression in the spleens of mice exposed to VT. This study provides a novel model for studying the interrelationship of MAPK phosphorylation, transcription factor activation, and cytokine gene expression in an intact animal exposed to a toxic compound.

  15. Effects of acamprosate on attentional set-shifting and cellular function in the prefrontal cortex of chronic alcohol-exposed mice

    Science.gov (United States)

    Hu, Wei

    Background: The medial prefrontal cortex (mPFC) inhibits impulsive and compulsive behaviors that characterize drug abuse and dependence. Acamprosate is the leading medication approved for the maintenance of abstinence, shown to reduce craving and relapse in animal models and human alcoholics. Whether acamprosate can modulate executive functions that are impaired by chronic ethanol exposure is unknown. Here we explored the effects of acamprosate on an attentional set-shifting task, and tested whether these behavioral effects are correlated with modulation of glutamatergic synaptic transmission and intrinsic excitability of mPFC neurons. Methods: We induced alcohol dependence in mice via chronic intermittent ethanol (CIE) exposure in vapor chambers and measured changes in alcohol consumption in a limited access 2-bottle choice paradigm. Impairments of executive function were assessed in an attentional set-shifting task. Acamprosate was applied subchronically for 2 days during withdrawal before the final behavioral test. Alcohol-induced changes in cellular function of layer 5/6 pyramidal neurons, and the potential modulation of these changes by acamprosate, were measured using patch clamp recordings in brain slices. Results: Chronic ethanol exposure impaired cognitive flexibility in the attentional set-shifting task. Acamprosate improved overall performance and reduced perseveration. Recordings of mPFC neurons showed that chronic ethanol exposure increased use-dependent presynaptic transmitter release and enhanced postsynaptic N-methyl-D-aspartate receptor (NMDAR) function. Moreover, CIE-treatment lowered input resistance, and decreased the threshold and the afterhyperpolarization (AHP) of action potentials, suggesting chronic ethanol exposure also impacted membrane excitability of mPFC neurons. However, acamprosate treatment did not reverse these ethanol-induced changes cellular function. Conclusion: Acamprosate improved attentional control of ethanol exposed animals

  16. Effect of Brazilian Propolis on Exacerbation of Respiratory Syncytial Virus Infection in Mice Exposed to Tetrabromobisphenol A, a Brominated Flame Retardant

    Science.gov (United States)

    Takeshita, Tomomi; Toyama, Satomi; Hayashi, Yuya; Honda, Shiori; Sakamoto, Shuichi; Matsuoka, Sayuri; Hidaka, Muneaki; Tsutsumi, Shigetoshi; Yasukawa, Ken; Park, Yong Kun

    2013-01-01

    Tetrabromobisphenol A (TBBPA), a brominated flame retardant, has been found to exacerbate pneumonia in respiratory syncytial virus- (RSV-) infected mice. We examined the effect of Brazilian propolis (AF-08) on the exacerbation of RSV infection by TBBPA exposure in mice. Mice were fed a powdered diet mixed with 1% TBBPA alone, 0.02% AF-08 alone, or 1% TBBPA and 0.02% AF-08 for four weeks and then intranasally infected with RSV. TBBPA exposure increased the pulmonary virus titer and level of IFN-γ, a representative marker of pneumonia due to RSV infection, in the lungs of infected mice without toxicity. AF-08 was significantly effective in reducing the virus titers and IFN-γ level increased by TBBPA exposure. Also, AF-08 significantly reduced proinflammatory cytokine (TNF-α and IL-6) levels in the lungs of RSV-infected mice with TBBPA exposure, but Th2 cytokine (IL-4 and IL-10) levels were not evidently increased. Neither TBBPA exposure nor AF-08 treatment affected the anti-RSV antibody production in RSV-infected mice. In flow cytometry analysis, AF-08 seemed to be effective in reducing the ratio of pulmonary CD8a+ cells in RSV-infected mice with TBBPA exposure. TBBPA and AF-08 did not exhibit anti-RSV activity in vitro. Thus, AF-08 probably ameliorated pneumonia exacerbated by TBBPA exposure in RSV-infected mice by limiting excess cellular immune responses. PMID:24250719

  17. Forebrain GABAergic interneuron connectivity and BDNF signaling deficits in Engrailed-2 knockout (En2-/-) mice, a mouse model for autism spectrum disorder

    OpenAIRE

    Zunino, Giulia

    2015-01-01

    Autism spectrum disorders (ASD) comprise a genetically heterogeneous group of neurodevelopmental disabilities characterized by repetitive behaviors as well as deficits in communication and social/emotional interactions and behaviors. Defects in GABA transmission have been hypothesized to underlie the symptoms of ASD (Ben-Ari, Khalilov, Kahle, & Cherubini, 2012). Engrailed-2 (En2) is a homeodomain transcription factor involved in regionalization and patterning of the midbrain and hindbrain reg...

  18. New Hippocampal Neurons Are Not Obligatory for Memory Formation; Cyclin D2 Knockout Mice with No Adult Brain Neurogenesis Show Learning

    Science.gov (United States)

    Jaholkowski, Piotr; Kiryk, Anna; Jedynak, Paulina; Abdallah, Nada M. Ben; Knapska, Ewelina; Kowalczyk, Anna; Piechal, Agnieszka; Blecharz-Klin, Kamilla; Figiel, Izabela; Lioudyno, Victoria; Widy-Tyszkiewicz, Ewa; Wilczynski, Grzegorz M.; Lipp, Hans-Peter; Kaczmarek, Leszek; Filipkowski, Robert K.

    2009-01-01

    The role of adult brain neurogenesis (generating new neurons) in learning and memory appears to be quite firmly established in spite of some criticism and lack of understanding of what the new neurons serve the brain for. Also, the few experiments showing that blocking adult neurogenesis causes learning deficits used irradiation and various drugs…

  19. Curcumin-induced heme oxygenase-1 expression prevents H2O2-induced cell death in wild type and heme oxygenase-2 knockout adipose-derived mesenchymal stem cells.

    Science.gov (United States)

    Cremers, Niels A J; Lundvig, Ditte M S; van Dalen, Stephanie C M; Schelbergen, Rik F; van Lent, Peter L E M; Szarek, Walter A; Regan, Raymond F; Carels, Carine E; Wagener, Frank A D T G

    2014-10-08

    Mesenchymal stem cell (MSC) administration is a promising adjuvant therapy to treat tissue injury. However, MSC survival after administration is often hampered by oxidative stress at the site of injury. Heme oxygenase (HO) generates the cytoprotective effector molecules biliverdin/bilirubin, carbon monoxide (CO) and iron/ferritin by breaking down heme. Since HO-activity mediates anti-apoptotic, anti-inflammatory, and anti-oxidative effects, we hypothesized that modulation of the HO-system affects MSC survival. Adipose-derived MSCs (ASCs) from wild type (WT) and HO-2 knockout (KO) mice were isolated and characterized with respect to ASC marker expression. In order to analyze potential modulatory effects of the HO-system on ASC survival, WT and HO-2 KO ASCs were pre-treated with HO-activity modulators, or downstream effector molecules biliverdin, bilirubin, and CO before co-exposure of ASCs to a toxic dose of H2O2. Surprisingly, sensitivity to H2O2-mediated cell death was similar in WT and HO-2 KO ASCs. However, pre-induction of HO-1 expression using curcumin increased ASC survival after H2O2 exposure in both WT and HO-2 KO ASCs. Simultaneous inhibition of HO-activity resulted in loss of curcumin-mediated protection. Co-treatment with glutathione precursor N-Acetylcysteine promoted ASC survival. However, co-incubation with HO-effector molecules bilirubin and biliverdin did not rescue from H2O2-mediated cell death, whereas co-exposure to CO-releasing molecules-2 (CORM-2) significantly increased cell survival, independently from HO-2 expression. Summarizing, our results show that curcumin protects via an HO-1 dependent mechanism against H2O2-mediated apoptosis, and likely through the generation of CO. HO-1 pre-induction or administration of CORMs may thus form an attractive strategy to improve MSC therapy.

  20. Curcumin-Induced Heme Oxygenase-1 Expression Prevents H2O2-Induced Cell Death in Wild Type and Heme Oxygenase-2 Knockout Adipose-Derived Mesenchymal Stem Cells

    Directory of Open Access Journals (Sweden)

    Niels A. J. Cremers

    2014-10-01

    Full Text Available Mesenchymal stem cell (MSC administration is a promising adjuvant therapy to treat tissue injury. However, MSC survival after administration is often hampered by oxidative stress at the site of injury. Heme oxygenase (HO generates the cytoprotective effector molecules biliverdin/bilirubin, carbon monoxide (CO and iron/ferritin by breaking down heme. Since HO-activity mediates anti-apoptotic, anti-inflammatory, and anti-oxidative effects, we hypothesized that modulation of the HO-system affects MSC survival. Adipose-derived MSCs (ASCs from wild type (WT and HO-2 knockout (KO mice were isolated and characterized with respect to ASC marker expression. In order to analyze potential modulatory effects of the HO-system on ASC survival, WT and HO-2 KO ASCs were pre-treated with HO-activity modulators, or downstream effector molecules biliverdin, bilirubin, and CO before co-exposure of ASCs to a toxic dose of H2O2. Surprisingly, sensitivity to H2O2-mediated cell death was similar in WT and HO-2 KO ASCs. However, pre-induction of HO-1 expression using curcumin increased ASC survival after H2O2 exposure in both WT and HO-2 KO ASCs. Simultaneous inhibition of HO-activity resulted in loss of curcumin-mediated protection. Co-treatment with glutathione precursor N-Acetylcysteine promoted ASC survival. However, co-incubation with HO-effector molecules bilirubin and biliverdin did not rescue from H2O2-mediated cell death, whereas co-exposure to CO-releasing molecules-2 (CORM-2 significantly increased cell survival, independently from HO-2 expression. Summarizing, our results show that curcumin protects via an HO-1 dependent mechanism against H2O2-mediated apoptosis, and likely through the generation of CO. HO-1 pre-induction or administration of CORMs may thus form an attractive strategy to improve MSC therapy.

  1. SOCS2 deletion protects against hepatic steatosis but worsens insulin resistance in high-fat-diet-fed mice

    DEFF Research Database (Denmark)

    Zadjali, Fahad; Santana-Farre, Ruyman; Vesterlund, Mattias

    2012-01-01

    in the development of diet-induced hepatic steatosis and insulin resistance. SOCS2-knockout (SOCS2(-/-)) mice and wild-type littermates were fed for 4 mo with control or high-fat diet, followed by assessment of insulin sensitivity, hepatic lipid content, and expression of inflammatory cytokines. SOCS2(-/-) mice...

  2. Antibiotic radioprotection of mice exposed to supralethal whole-body irradiation independent of antibacterial activity. [Gamma radiation, streptomycin, kanamycin, neomycin, gentamycin

    Energy Technology Data Exchange (ETDEWEB)

    Mastromarino, A.; Wilson, R.

    1976-11-01

    Oral administration of streptomycin, kanamycin, neomycin, or gentamicin to specific pathogen-free C57 x Af mice in their drinking water (4 mg/ml) for 2 weeks before supralethal whole-body irradiation very significantly prolonged their mean survival times (8.2 to 8.9 days vs 6.9 for controls) to values which exceed those reported for germ-free mice (7.3 days). The total fecal concentrations of aerobes and anaerobes were reduced by kanamycin, neomycin, and gentamicin. Streptomycin reduced the anaerobes significantly, but not the aerobes. Unlike germ-free mice, these antibiotic-treated mice did excrete free bile acids, products of bacterial action. Oral antibiotic treatment was ineffective in altering the transit time of the intestinal mucosal cells. Previously reported studies had indicated a correlation between decreased transit time and increased survival after irradiation. No significant correlation between mean survival time after irradiation and mucosal transit time was observed. The data demonstrate that certain antibiotics alter the character of the intestinal bacterial flora and increase protection against supralethal doses of whole-body irradiation. It is concluded that the mechanisms of radioresistance in antibiotic-treated mice and germ-free mice are different and that in both groups radioresistance is the result of more than elimination of postirradiation infection.

  3. Enhancement of behavioral sensitization, anxiety-like behavior, and hippocampal and frontal cortical CREB levels following cocaine abstinence in mice exposed to cocaine during adolescence.

    Directory of Open Access Journals (Sweden)

    Maria Cristina Valzachi

    Full Text Available Adolescence has been linked to greater risk-taking and novelty-seeking behavior and a higher prevalence of drug abuse and risk of relapse. Decreases in cyclic adenosine monophosphate response element binding protein (CREB and phosphorylated CREB (pCREB have been reported after repeated cocaine administration in animal models. We compared the behavioral effects of cocaine and abstinence in adolescent and adult mice and investigated possible age-related differences in CREB and pCREB levels. Adolescent and adult male Swiss mice received one daily injection of saline or cocaine (10 mg/kg, i.p. for 8 days. On day 9, the mice received a saline injection to evaluate possible environmental conditioning. After 9 days of withdrawal, the mice were tested in the elevated plus maze to evaluate anxiety-like behavior. Twelve days after the last saline/cocaine injection, the mice received a challenge injection of either cocaine or saline, and locomotor activity was assessed. One hour after the last injection, the brains were extracted, and CREB and pCREB levels were evaluated using Western blot in the prefrontal cortex (PFC and hippocampus. The cocaine-pretreated mice during adolescence exhibited a greater magnitude of the expression of behavioral sensitization and greater cocaine withdrawal-induced anxiety-like behavior compared with the control group. Significant increases in CREB levels in the PFC and hippocampus and pCREB in the hippocampus were observed in cocaine-abstinent animals compared with the animals treated with cocaine in adulthood. Interestingly, significant negative correlations were observed between cocaine sensitization and CREB levels in both regions. These results suggest that the behavioral and neurochemical consequences of psychoactive substances in a still-developing nervous system can be more severe than in an already mature nervous system.

  4. In vivo modulation of epidermal growth factor receptor phosphorylation in mice expressing different gangliosides.

    Science.gov (United States)

    Daniotti, Jose L; Crespo, Pilar M; Yamashita, Tadashi

    2006-12-01

    We studied in this work the in vivo phosphorylation of the epidermal growth factor receptor (EGFr) in skin from knockout mice lacking different ganglioside glycosyltransferases. Results show an enhancement of EGFr phosphorylation, after EGF stimulation, in skin from Sial-T2 knockout and Sial-T2/GalNAc-T double knockout mice as compared with wild-type and Sial-T1 knockout mice. Qualitative analysis of ganglioside composition in mice skin suggest that the increase of EGFr phosphorylation observed in skin from Sial-T2 knockout and Sial-T2/GalNAc-T double knockout mice in response to EGF might not be primary attributed to the expression of GD3 or a-series gangliosides in mice skin. These studies provide, for the first time, an approach for studying the molecular mechanisms involved in the in vivo regulation of EGFr function by gangliosides.

  5. Sm29, but not Sm22.6 retains its ability to induce a protective immune response in mice previously exposed to a Schistosoma mansoni infection.

    Directory of Open Access Journals (Sweden)

    Clarice Carvalho Alves

    2015-02-01

    Full Text Available BACKGROUND: A vaccine against schistosomiasis would have a great impact in disease elimination. Sm29 and Sm22.6 are two parasite tegument proteins which represent promising antigens to compose a vaccine. These antigens have been associated with resistance to infection and reinfection in individuals living in endemic area for the disease and induced partial protection when evaluated in immunization trials using naïve mice. METHODOLOGY/PRINCIPALS FINDINGS: In this study we evaluated rSm29 and rSm22.6 ability to induce protection in Balb/c mice that had been previously infected with S. mansoni and further treated with Praziquantel. Our results demonstrate that three doses of the vaccine containing rSm29 were necessary to elicit significant protection (26%-48%. Immunization of mice with rSm29 induced a significant production of IL-2, IFN-γ, IL-17, IL-4; significant production of specific antibodies; increased percentage of CD4+ central memory cells in comparison with infected and treated saline group and increased percentage of CD4+ effector memory cells in comparison with naïve Balb/c mice immunized with rSm29. On the other hand, although immunization with Sm22.6 induced a robust immune response, it failed to induce protection. CONCLUSION/SIGNIFICANCE: Our results demonstrate that rSm29 retains its ability to induce protection in previously infected animals, reinforcing its potential as a vaccine candidate.

  6. Kualitas Spermatozoa Mencit yang Terpapar Radiasi Sinar-X Secara Berulang (SPERMATOZOA QUALITY OF MICE EXPOSED TO X-RAYS RADIATION IN REPEATED

    Directory of Open Access Journals (Sweden)

    Ni Wayan Sudatri

    2015-05-01

    Full Text Available In radiology, X-ray has been used to diagnose disease and therapy. However, behind the technologybenefits provided by the radiation, the negative effects are often debated. The purpose of this study was toinvestigate the effects of repeated radiation on sperm quality mice (Mus musculus L. Thirty- two adultmale mice aged three months were divided into groups P1 (1x 200 rad, P2 (2x200 rad, P3 (3x200 rad andcontrol irradiated with x-rays according to the experimental design . Spermatozoa quality parametersobserved were : number of spermatozoa, motility, viability and morphology of spermatozoa. The results ofthe Post Hoc LSD tests for significant differences (P>0.05 between the control and treatment showed thatthe X-ray radiation exposure to 1x200 rad, 2x200 rad, and 3x200 rad decreases the motility, viability,normal morphology and number spermatozoa produced compared with controls. This is caused by exposureto X-ray radiation causes the formation of free radicals in the body that damage sperm cells mice. Exposureto X-ray radiation repeatedly lowered the quality of spermatozoa of mice.

  7. Attenuation of γ-aminobutyric acid (GABA) transaminase activity contributes to GABA increase in the cerebral cortex of mice exposed to β-cypermethrin.

    Science.gov (United States)

    Han, Y; Cao, D; Li, X; Zhang, R; Yu, F; Ren, Y; An, L

    2014-03-01

    The current study investigated the γ-aminobutyric acid (GABA) levels and GABA metabolic enzymes (GABA transaminase (GABA(T)) and glutamate decarboxylase (GAD)) activities at 2 and 4 h after treatment, using a high-performance liquid chromatography with ultraviolet detectors and colorimetric assay, in the cerebral cortex of mice treated with 20, 40 or 80 mg/kg β-cypermethrin by a single oral gavage, with corn oil as vehicle control. In addition, GABA protein (4 h after treatment), GABA(T) protein (2 h after treatment) and GABA receptors messenger RNA (mRNA) expression were detected by immunohistochemistry, Western blot and real-time quantitative reverse transcriptase polymerase chain reaction, respectively. β-Cypermethrin (80 mg/kg) significantly increased GABA levels in the cerebral cortex of mice, at both 2 and 4 h after treatment, compared with the control. Also, GABA immunohistochemistry results suggested that the number of positive granules was increased in the cerebral cortex of mice 4 h after exposure to 80 mg/kg β-cypermethrin when compared with the control. Furthermore, the results also showed that GABA(T) activity detected was significantly decreased in the cerebral cortex of mice 2 h after β-cypermethrin administration (40 or 80 mg/kg). No significant changes were found in GAD activity, or the expression of GABA(T) protein and GABAB receptors mRNA, in the cerebral cortex of mice, except that 80 mg/kg β-cypermethrin caused a significant decrease, compared with the vehicle control, in GABAA receptors mRNA expression 4 h after administration. These results suggested that attenuated GABA(T) activity induced by β-cypermethrin contributed to increased GABA levels in the mouse brain. The downregulated GABAA receptors mRNA expression is most likely a downstream event.

  8. Effects of Duloxetine Treatment on Cognitive Flexibility and BDNF Expression in the mPFC of Adult Male Mice Exposed to Social Stress during Adolescence

    Science.gov (United States)

    Xu, Hang; Zhang, Yu; Zhang, Fan; Yuan, San-na; Shao, Feng; Wang, Weiwen

    2016-01-01

    Early stress is a significant risk factor for the onset of mood disorders such as depression during adulthood. Impairments in cognitive flexibility mediated by prefrontal cortex (PFC) dysfunction are increasingly recognized as important etiological and pathological factors in the development of depression. Our previous study demonstrated that social defeat stress during early adolescence produced delayed deficits in cognitive flexibility in adult mice. The potential molecular mechanisms underlying these long-term consequences remain unclear. One candidate molecule is brain-derived neurotrophic factor (BDNF), which plays a vital role in neural development and synaptic plasticity. In this study, we initially examined the effects of adolescent social stress on cognitive flexibility and PFC BDNF expression within a week after the last stress exposure and 6 weeks later during adulthood. Adolescent (PND 28) male mice were subjected to stress or control manipulation for 10 days. The attentional set-shifting task (AST) was used to assess cognitive flexibility. Levels of BDNF mRNA and protein in the PFC were examined after behavioral testing. The results demonstrated that previously stressed mice exhibited delayed extra-dimensional set-shifting deficits in AST when tested as adults but not when tested as adolescents. Consistent with the cognitive alterations, adolescent stress induced dynamic alterations in BDNF expression in the medial PFC (mPFC), with a transient increase observed shortly after the stress, followed by a decrease 6 weeks later during adulthood. Next, we further determined the effects of chronic treatment with the antidepressant duloxetine during early adulthood on cognitive and molecular alterations induced by adolescent stress. Compared with the controls, duloxetine treatment reversed the cognitive deficits and increased the BDNF protein expression in the mPFC during adulthood in previously stressed mice. These findings demonstrated that BDNF expression

  9. Gene Expression Profiling in Wild-Type and PPAR-Null Mice Exposed to Perfluorooctane Sulfonate Reveals PPAR-Independent Effects

    Directory of Open Access Journals (Sweden)

    Mitchell B. Rosen

    2010-01-01

    Full Text Available Perfluorooctane sulfonate (PFOS is a perfluoroalkyl acid (PFAA and a persistent environmental contaminant found in the tissues of humans and wildlife. Although blood levels of PFOS have begun to decline, health concerns remain because of the long half-life of PFOS in humans. Like other PFAAs, such as, perfluorooctanoic acid (PFOA, PFOS is an activator of peroxisome proliferator-activated receptor-alpha (PPAR and exhibits hepatocarcinogenic potential in rodents. PFOS is also a developmental toxicant in rodents where, unlike PFOA, its mode of action is independent of PPAR. Wild-type (WT and PPAR-null (Null mice were dosed with 0, 3, or 10 mg/kg/day PFOS for 7 days. Animals were euthanized, livers weighed, and liver samples collected for histology and preparation of total RNA. Gene profiling was conducted using Affymetrix 430_2 microarrays. In WT mice, PFOS induced changes that were characteristic of PPAR transactivation including regulation of genes associated with lipid metabolism, peroxisome biogenesis, proteasome activation, and inflammation. PPAR-independent changes were indicated in both WT and Null mice by altered expression of genes related to lipid metabolism, inflammation, and xenobiotic metabolism. Such results are similar to studies done with PFOA and are consistent with modest activation of the constitutive androstane receptor (CAR, and possibly PPAR and/or PPAR/. Unique treatment-related effects were also found in Null mice including altered expression of genes associated with ribosome biogenesis, oxidative phosphorylation, and cholesterol biosynthesis. Of interest was up-regulation of Cyp7a1, a gene which is under the control of various transcription regulators. Hence, in addition to its ability to modestly activate PPAR, PFOS induces a variety of PPAR-independent effects as well.

  10. Investigation of the neuroprotective action of saffron (Crocus sativus L.) in aluminum-exposed adult mice through behavioral and neurobiochemical assessment.

    Science.gov (United States)

    Linardaki, Zacharoula I; Orkoula, Malvina G; Kokkosis, Alexandros G; Lamari, Fotini N; Margarity, Marigoula

    2013-02-01

    In the present study, the possible reversal effects of saffron against established aluminum (Al)-toxicity in adult mice, were investigated. Control, Al-treated (50 mg AlCl(3)/kg/day diluted in the drinking water for 5 weeks) and Al+saffron (Al-treatment as previously plus 60 mg saffron extract/kg/day intraperitoneally for the last 6 days), groups of male Balb-c mice were used. We assessed learning/memory, the activity of acetylcholinesterase [AChE, salt-(SS)/detergent-soluble(DS) isoforms], butyrylcholinesterase (BuChE, SS/DS isoforms), monoamine oxidase (MAO-A, MAO-B), the levels of lipid peroxidation (MDA) and reduced glutathione (GSH), in whole brain and cerebellum. Brain Al was determined by atomic absorption spectrometry, while, for the first time, crocetin, the main active metabolite of saffron, was determined in brain after intraperitoneal saffron administration by HPLC. Al intake caused memory impairment, significant decrease of AChE and BuChE activity, activation of brain MAO isoforms but inhibition of cerebellar MAO-B, significant elevation of brain MDA and significant reduction of GSH content. Although saffron extract co-administration had no effect on cognitive performance of mice, it reversed significantly the Al-induced changes in MAO activity and the levels of MDA and GSH. AChE activity was further significantly decreased in cerebral tissues of Al+saffron group. The biochemical changes support the neuroprotective potential of saffron under toxicity.

  11. Exposing diversity

    DEFF Research Database (Denmark)

    Nørtoft, Kamilla; Nordentoft, Helle Merete

    . A prominent research theme in health care studies is, therefore, to explicate the gap between theory and practice. The question this paper addresses is how a learning environment can be designed to bridge this theory-practice gap, expose the differences in situated interactions and qualify health...... in the homes of older people and in pedagogical institutions targeting older people. In the paper we look at the potentials and challenges in working with ethnographic video narratives as a pedagogical tool. Our findings indicate that the use of video narratives has the potential to expose the diversity...

  12. Metal components analysis of metallothionein-III in the brain sections of metallothionein-I and metallothionein-II null mice exposed to mercury vapor with HPLC/ICP-MS

    Energy Technology Data Exchange (ETDEWEB)

    Kameo, Satomi; Nakai, Kunihiko; Kurokawa, Naoyuki; Satoh, Hiroshi [Tohoku University, Graduate School of Medicine, Aoba-ku, Sendai (Japan); Kanehisa, Tomokazu; Naganuma, Akira [Tohoku University, Graduate School of Pharmaceutical Sciences, Sendai (Japan)

    2005-04-01

    Mercury vapor is effectively absorbed via inhalation and easily passes through the blood-brain barrier; therefore, mercury poisoning with primarily central nervous system symptoms occurs. Metallothionein (MT) is a cysteine-rich metal-binding protein and plays a protective role in heavy-metal poisoning and it is associated with the metabolism of trace elements. Two MT isoforms, MT-I and MT-II, are expressed coordinately in all mammalian tissues, whereas MT-III is a brain-specific member of the MT family. MT-III binds zinc and copper physiologically and is seemed to have important neurophysiological and neuromodulatory functions. The MT functions and metal components of MTs in the brain after mercury vapor exposure are of much interest; however, until now they have not been fully examined. In this study, the influences of the lack of MT-I and MT-II on mercury accumulation in the brain and the changes of zinc and copper concentrations and metal components of MTs were examined after mercury vapor exposure by using MT-I, II null mice and 129/Sv (wild-type) mice as experimental animals. MT-I, II null mice and wild-type mice were exposed to mercury vapor or an air stream for 2 h and were killed 24 h later. The brain was dissected into the cerebral cortex, the cerebellum, and the hippocampus. The concentrations of mercury in each brain section were determined by cold vapor atomic absorption spectrometry. The concentrations of mercury, copper, and zinc in each brain section were determined by inductively coupled plasma mass spectrometry (ICP-MS). The mercury accumulated in brains after mercury vapor exposure for MT-I, II null mice and wild-type mice. The mercury levels of MT-I, II null mice in each brain section were significantly higher than those of wild-type mice after mercury vapor exposure. A significant change of zinc concentrations with the following mercury vapor exposure for MT-I, II null mice was observed only in the cerebellum analyzed by two-way analysis of

  13. Exposing diversity

    DEFF Research Database (Denmark)

    Nørtoft, Kamilla; Nordentoft, Helle Merete

    in the homes of older people and in pedagogical institutions targeting older people. In the paper we look at the potentials and challenges in working with ethnographic video narratives as a pedagogical tool. Our findings indicate that the use of video narratives has the potential to expose the diversity...

  14. Serotonin and corticosterone rhythms in mice exposed to cigarette smoke and in patients with COPD: implication for COPD-associated neuropathogenesis.

    Directory of Open Access Journals (Sweden)

    Isaac K Sundar

    Full Text Available The circadian timing system controls daily rhythms of physiology and behavior, and disruption of clock function can trigger stressful life events. Daily exposure to cigarette smoke (CS can lead to alteration in diverse biological and physiological processes. Smoking is associated with mood disorders, including depression and anxiety. Patients with chronic obstructive pulmonary disease (COPD have abnormal circadian rhythms, reflected by daily changes in respiratory symptoms and lung function. Corticosterone (CORT is an adrenal steroid that plays a considerable role in stress and anti-inflammatory responses. Serotonin (5-hydroxytryptamine; 5HT is a neurohormone, which plays a role in sleep/wake regulation and affective disorders. Secretion of stress hormones (CORT and 5HT is under the control of the circadian clock in the suprachiasmatic nucleus. Since smoking is a contributing factor in the development of COPD, we hypothesize that CS can affect circadian rhythms of CORT and 5HT secretion leading to sleep and mood disorders in smokers and patients with COPD. We measured the daily rhythms of plasma CORT and 5HT in mice following acute (3 d, sub-chronic (10 d or chronic (6 mo CS exposure and in plasma from non-smokers, smokers and patients with COPD. Acute and chronic CS exposure affected both the timing (peak phase and amplitude of the daily rhythm of plasma CORT and 5HT in mice. Acute CS appeared to have subtle time-dependent effects on CORT levels but more pronounced effects on 5HT. As compared with CORT, plasma 5HT was slightly elevated in smokers but was reduced in patients with COPD. Thus, the effects of CS on plasma 5HT were consistent between mice and patients with COPD. Together, these data reveal a significant impact of CS exposure on rhythms of stress hormone secretion and subsequent detrimental effects on cognitive function, depression-like behavior, mood/anxiety and sleep quality in smokers and patients with COPD.

  15. Recovery of behavioral changes and compromised white matter in C57BL/6 mice exposed to cuprizone: Effects of antipsychotic drugs

    Directory of Open Access Journals (Sweden)

    Haiyun eXu

    2011-07-01

    Full Text Available Recent animal and human studies have suggested that the cuprizone (CPZ, a copper chelator-feeding C57BL/6 mouse may be used as an animal model of schizophrenia. The goals of this study were to see the recovery processes of CPZ-induced behavioral changes and damaged white matter and to examine possible effects of antipsychotic drugs on the recovery processes. Mice were fed a CPZ-containing diet for five weeks then returned to normal food for three weeks, during which period mice were treated with different antipsychotic drugs. Various behaviors were measured at the end of CPZ-feeding phase as well as on the 14th and 21st days after CPZ-withdrawal. The damage to and recovery status of white matter in the brains of mice were examined. Dietary CPZ resulted in white matter damage and behavioral abnormalities in the elevated plus-maze, social interaction and Y-maze test. Elevated plus-maze performance recovered to normal range within two weeks after CPZ withdrawal. But, alterations in social interaction showed no recovery. Antipsychotics did not alter animals’ behavior in either of these tests during the recovery period. Altered performance in the Y-maze showed some recovery in the vehicle group; atypical antipsychotics, but not haloperidol, significantly promoted this recovery process. The recovery of damaged white matter was incomplete during the recovery period. None of the drugs significantly promoted the recovery of damaged white matter. These results suggest that CPZ-induced white matter damage and social interaction deficit may be resistant to the antipsychotic treatment employed in this study. They are in good accordance with the clinical observations that positive symptoms in schizophrenic patients respond well to antipsychotic drugs while social dysfunction is usually intractable.

  16. Increased accumulation of neutrophils and decreased fibrosis in the lung of NADPH oxidase-deficient C57BL/6 mice exposed to carbon nanotubes.

    Science.gov (United States)

    Shvedova, A A; Kisin, E R; Murray, A R; Kommineni, C; Castranova, V; Fadeel, B; Kagan, V E

    2008-09-01

    Single-walled carbon nanotubes (SWCNT) have been introduced into a large number of new technologies and consumer products. The combination of their exceptional features with very broad applications raised concerns regarding their potential health effects. The prime target for SWCNT toxicity is believed to be the lung where exposure may occur through inhalation, particularly in occupational settings. Our previous work has demonstrated that SWCNT cause robust inflammatory responses in rodents with very early termination of the acute phase and rapid onset of chronic fibrosis. Timely elimination of polymorphonuclear neutrophils (PMNs) through apoptosis and their subsequent clearance by macrophages is a necessary stage in the resolution of pulmonary inflammation whereby NADPH oxidase contributes to control of apoptotic cell death and clearance of PMNs. Thus, we hypothesized that NADPH oxidase may be an important regulator of the transition from the acute inflammation to the chronic fibrotic stage in response to SWCNT. To experimentally address the hypothesis, we employed NADPH oxidase-deficient mice which lack the gp91(phox) subunit of the enzymatic complex. We found that NADPH oxidase null mice responded to SWCNT exposure with a marked accumulation of PMNs and elevated levels of apoptotic cells in the lungs, production of pro-inflammatory cytokines, decreased production of the anti-inflammatory and pro-fibrotic cytokine, TGF-beta, and significantly lower levels of collagen deposition, as compared to C57BL/6 control mice. These results demonstrate a role for NADPH oxidase-derived reactive oxygen species in determining course of pulmonary response to SWCNT.

  17. Experimental study of gene expression in lung and bronchus of radon-exposed mice%氡染毒小鼠肺及支气管组织的基因表达

    Institute of Scientific and Technical Information of China (English)

    郭志英; 田梅; 刘建香; 阮健磊; 朴春南; 苏旭

    2008-01-01

    目的 构建氡染毒小鼠肺及支气管组织差异表达基因的cDNA文库,并对其进行初步鉴定和同源性分析.方法 采用SR-NIM02型氡室对小鼠进行吸入染毒后,常规饲养3个月,分别提取和纯化染毒组(30工作水平月,WLM)与对照组(0.02 WLM)小鼠的肺及支气管组织的总RNA,采用Super SMART技术和抑制性差减杂交技术(SSH),构建氡染毒后肺及支气管组织的正、反向差减杂交的cDNA文库;常规连接pGEM-T-easy载体,转化DH5α感受态细胞,巢式PCR鉴定;对阳性克隆测序,并与GeneBank数据库进行BLAST同源性比对,进行初步功能分类.结果 共获得克隆460个,其中含有插入片段的克隆146个,经BLAST同源性比对后有48个正向差减cDNA片段与61个反向差减cDNA片段与GeneBank中的序列有不同程度的同源性.结论 成功构建了氡染毒小鼠肺支气管差异表达cDNA文库,染毒后小鼠肺及支气管组织中某些基因会发生差异表达,其中部分基因可能参与细胞凋亡和周期调控、机体免疫调节及细胞间信号传导等过程.%Objective To construct and identify differentially expressed cDNA library in lung and bronchus of mice exposed to radon.Methods 2 week old,weishing(18-22)g,male BALB/c mice were placed in a SR-NIM02 radon chamber.One group of mice was exposed to radon,which was equivalent to the accumulative dose of 30 WLM.The control group was about 0.02 WLM.To construct a subtracted cDNA library enriched with differentially expressed genes,the Super SMART technique and the suppression subtractive hybridization(SSH)were performed.The obtained forward and revere cDNA fragments were directly inserted into pGEM-T-easy vector and transformed into E.coli DH5a.The inserts in plasmid were amplified by nested polymerasc chain reaction(PCR).and some of which were sequenced.In the end these sequences were BLASTed with GeneBank.Results 146 of 460 clones obtained randomly were positive clones contained(1000-1500)bp

  18. Genetic Alterations in K-ras and p53 Cancer Genes in Lung Neoplasms From B6C3F1 Mice Exposed to Cumene

    OpenAIRE

    Hong, Hue-Hua L.; Ton, Thai-Vu T.; Kim, Yongbaek; Wakamatsu, Nobuko; Clayton, Natasha P.; Chan, Po-Chuen; Sills, Robert C.; Lahousse, Stephanie A.

    2008-01-01

    The incidences of alveolar/bronchiolar adenomas and carcinomas in cumene-treated B6C3F1 mice were significantly greater than those of the controls. We evaluated these lung neoplasms for point mutations in the K-ras and p53 genes that are often mutated in humans. K-ras and p53 mutations were detected by cycle sequencing of PCR-amplified DNA isolated from paraffin-embedded neoplasms. K-ras mutations were detected in 87 % cumene-induced lung neoplasms, and the predominant mutations were exon 1 c...

  19. Palmoplantar keratoderma in Slurp2-deficient mice

    Science.gov (United States)

    Allan, Christopher M.; Procaccia, Shiri; Tran, Deanna; Tu, Yiping; Barnes, Richard H.; Larsson, Mikael; Allan, Bernard B.; Young, Lorraine C.; Hong, Cynthia; Tontonoz, Peter; Fong, Loren G.; Young, Stephen G.; Beigneux, Anne P.

    2015-01-01

    SLURP1, a member of the Ly6 protein family, is secreted by suprabasal keratinocytes. Mutations in SLURP1 cause a palmoplantar keratoderma (PPK) known as mal de Meleda. Another secreted Ly6 protein, SLURP2, is encoded by a gene located ~20 kb downstream from SLURP1. SLURP2 is produced by suprabasal keratinocytes. To investigate the importance of SLURP2, we first examined Slurp2 knockout mice in which exon 2–3 sequences had been replaced with lacZ and neo cassettes. Slurp2−/− mice exhibited hyperkeratosis on the volar surface of the paws (i.e., PPK), increased keratinocyte proliferation, and an accumulation of lipid droplets in the stratum corneum. They also exhibited reduced body weight and hind limb clasping. These phenotypes are very similar to those of Slurp1−/− mice. To solidify a link between Slurp2 deficiency and PPK and to be confident that the disease phenotypes in Slurp2−/− mice were not secondary to the effects of the lacZ and neo cassettes on Slurp1 expression, we created a new line of Slurp2 knockout mice (Slurp2X−/−) in which Slurp2 was inactivated with a simple nonsense mutation. Slurp2X−/− mice exhibited the same disease phenotypes. Thus, Slurp2 deficiency and Slurp1 deficiencies cause the same disease phenotypes. PMID:26967477

  20. Micro-computed tomography assisted distal femur metaphyseal blunt punch compression for determining trabecular bone strength in mice.

    Science.gov (United States)

    Sankar, Uma; Pritchard, Zachary J; Voor, Michael J

    2016-05-03

    Shorter generation time and the power of genetic manipulation make mice an ideal model system to study bone biology as well as bone diseases. However their small size presents a challenge to perform strength measurements, particularly of the weight-bearing cancellous bone in the murine long bones. We recently developed an improved method to measure the axial compressive strength of the cancellous bone in the distal femur metaphysis in mice. Transverse micro-computed tomography image slices that are 7µm thick were used to locate the position where the epiphysis-metaphysis transition occurs. This enabled the removal of the distal femur epiphysis at the exact transition point exposing the full extent of metaphyseal trabecular bone, allowing more accurate and consistent measurement of its strength. When applied to a murine model system consisting of five month old male wild-type (WT) and Ca(2+)/calmodulin dependent protein kinase kinase 2 (CaMKK2) knockout (KO) Camkk2(-/-) mice that possess recorded differences in trabecular bone volume, data collected using this method showed good correlation between bone volume fraction and strength of trabecular bone. In combination with micro-computed tomography and histology, this method will provide a comprehensive and consistent assessment of the microarchitecture and tissue strength of the cancellous bone in murine mouse models.

  1. Investigation into Variation of Endogenous Metabolites in Bone Marrow Cells and Plasma in C3H/He Mice Exposed to Benzene

    Directory of Open Access Journals (Sweden)

    Rongli Sun

    2014-03-01

    Full Text Available Benzene is identified as a carcinogen. Continued exposure of benzene may eventually lead to damage to the bone marrow, accompanied by pancytopenia, aplastic anemia or leukemia. This paper explores the variations of endogenous metabolites to provide possible clues for the molecular mechanism of benzene-induced hematotoxicity. Liquid chromatography coupled with time of flight-mass spectrometry (LC-TOF-MS and principal component analysis (PCA was applied to investigate the variation of endogenous metabolites in bone marrow cells and plasma of male C3H/He mice. The mice were injected subcutaneously with benzene (0, 300, 600 mg/day once daily for seven days. The body weights, relative organ weights, blood parameters and bone marrow smears were also analyzed. The results indicated that benzene caused disturbances in the metabolism of oxidation of fatty acids and essential amino acids (lysine, phenylalanine and tyrosine in bone marrow cells. Moreover, fatty acid oxidation was also disturbed in plasma and thus might be a common disturbed metabolic pathway induced by benzene in multiple organs. This study aims to investigate the underlying molecular mechanisms involved in benzene hematotoxicity, especially in bone marrow cells.

  2. Different behavioral effect dose–response profiles in mice exposed to two-carbon chlorinated hydrocarbons: Influence of structural and physical properties

    Energy Technology Data Exchange (ETDEWEB)

    Umezu, Toyoshi, E-mail: umechan2@nies.go.jp; Shibata, Yasuyuki, E-mail: yshibata@nies.go.jp

    2014-09-01

    The present study aimed to clarify whether dose–response profiles of acute behavioral effects of 1,2-dichloroethane (DCE), 1,1,1-trichloroethane (TCE), trichloroethylene (TRIC), and tetrachloroethylene (PERC) differ. A test battery involving 6 behavioral endpoints was applied to evaluate the effects of DCE, TCE, TRIC, and PERC in male ICR strain mice under the same experimental conditions. The behavioral effect dose–response profiles of these compounds differed. Regression analysis was used to evaluate the relationship between the dose–response profiles and structural and physical properties of the compounds. Dose–response profile differences correlated significantly with differences in specific structural and physical properties. These results suggest that differences in specific structural and physical properties of DCE, TCE, TRIC, and PERC are responsible for differences in behavioral effects that lead to a variety of dose–response profiles. - Highlights: • We examine effects of 4 chlorinated hydrocarbons on 6 behavioral endpoints in mice. • The behavioral effect dose–response profiles for the 4 compounds are different. • We utilize regression analysis to clarify probable causes of the different profiles. • The compound's physicochemical properties probably produce the different profiles.

  3. A Specific Mixture of Fructo-Oligosaccharides and Bifidobacterium breve M-16V Facilitates Partial Non-Responsiveness to Whey Protein in Mice Orally Exposed to β-Lactoglobulin-Derived Peptides

    Science.gov (United States)

    Kostadinova, Atanaska I.; Meulenbroek, Laura A. P. M.; van Esch, Betty C. A. M.; Hofman, Gerard A.; Garssen, Johan; Willemsen, Linette E. M.; Knippels, Léon M. J.

    2017-01-01

    Oral tolerance is a promising approach for allergy prevention in early life, but it strongly depends on allergen exposure and proper immune environment. Small tolerance-inducing peptides and dietary immunomodulatory components may comprise an attractive method for allergy prevention in at-risk infants. This study aimed to investigate whether early oral exposure to β-lactoglobulin-derived peptides (BLG-peptides) and a specific synbiotic mixture of short- and long- chain fructo-oligosaccharides (scFOS/lcFOS, FF) and Bifidobacterium breve (Bb) M-16V (FF/Bb) can prevent cow’s milk allergy (CMA). Three-week-old female C3H/HeOuJ mice were orally exposed to phosphate buffered saline (PBS), whey protein, or a mixture of four synthetic BLG-peptides combined with a FF/Bb-enriched diet prior to intragastric sensitization with whey protein and cholera toxin. To assess the acute allergic skin response and clinical signs of allergy, mice were challenged intradermally with whole whey protein. Serum immunoglobulins were analyzed after a whey protein oral challenge. Cytokine production by allergen-reactivated splenocytes was measured and changes in T cells subsets in the spleen, mesenteric lymph nodes, and intestinal lamina propria were investigated. Pre-exposing mice to a low dosage of BLG-peptides and a FF/Bb-enriched diet prior to whey protein sensitization resulted in a significant reduction of the acute allergic skin response to whey compared to PBS-pretreated mice fed a control diet. Serum immunoglobulins were not affected, but anaphylactic symptom scores remained low and splenocytes were non-responsive in whey-induced cytokine production. In addition, preservation of the Th1/Th2 balance in the small intestine lamina propria was a hallmark of the mechanism underlying the protective effect of the BLG-peptides–FF/Bb intervention. Prior exposure to BLG-peptides and a FF/Bb-enriched diet is a promising approach for protecting the intestinal Th1/Th2 balance and reducing the

  4. Remarkable induction of UV-signature mutations at the 3'-cytosine of dipyrimidine sites except at 5'-TCG-3' in the UVB-exposed skin epidermis of xeroderma pigmentosum variant model mice.

    Science.gov (United States)

    Ikehata, Hironobu; Chang, Yumin; Yokoi, Masayuki; Yamamoto, Masayuki; Hanaoka, Fumio

    2014-10-01

    The human POLH gene is responsible for the variant form of xeroderma pigmentosum (XP-V), a genetic disease highly susceptible to cancer on sun-exposed skin areas, and encodes DNA polymerase η (polη), which is specialized for translesion DNA synthesis (TLS) of UV-induced DNA photolesions. We constructed polη-deficient mice transgenic with lacZ mutational reporter genes to study the effect of Polh null mutation (Polh(-/-)) on mutagenesis in the skin after UVB irradiation. UVB induced lacZ mutations with remarkably higher frequency in the Polh(-/-) epidermis and dermis than in the wild-type (Polh(+/+)) and heterozygote. DNA sequences of a hundred lacZ mutants isolated from the epidermis of four UVB-exposed Polh(-/-) mice were determined and compared with mutant sequences from irradiated Polh(+)(/)(+) mice. The spectra of the mutations in the two genotypes were both highly UV-specific and dominated by C→T transitions at dipyrimidines, namely UV-signature mutations. However, sequence preferences of the occurrence of UV-signature mutations were quite different between the two genotypes: the mutations occurred at a higher frequency preferentially at the 5'-TCG-3' sequence context than at the other dipyrimidine contexts in the Polh(+/+) epidermis, whereas the mutations were induced remarkably and exclusively at the 3'-cytosine of almost all dipyrimidine contexts with no preference for 5'-TCG-3' in the Polh(-/-) epidermis. In addition, in Polh(-/-) mice, a small but remarkable fraction of G→T transversions was also observed exclusively at the 3'-cytosine of dipyrimidine sites, strongly suggesting that these transversions resulted not from oxidative damage but from UV photolesions. These results would reflect the characteristics of the error-prone TLS functioning in the bypass of UV photolesions in the absence of polη, which would be mediated by mechanisms based on the two-step model of TLS. On the other hand, the deamination model would explain well the mutation

  5. L-histidine provokes a state-dependent memory retrieval deficit in mice re-exposed to the elevated plus-maze

    Directory of Open Access Journals (Sweden)

    K.R. Serafim

    2010-01-01

    Full Text Available The effects of L-histidine (LH on anxiety and memory retrieval were investigated in adult male Swiss Albino mice (weight 30-35 g using the elevated plus-maze. The test was performed on two consecutive days: trial 1 (T1 and trial 2 (T2. In T1, mice received an intraperitoneal injection of saline (SAL or LH before the test and were then injected again and retested 24 h later. LH had no effect on anxiety at the dose of 200 mg/kg since there was no difference between the SAL-SAL and LH-LH groups at T1 regarding open-arm entries (OAE and open-arm time (OAT (mean ± SEM; OAE: 4.0 ± 0.71, 4.80 ± 1.05; OAT: 40.55 ± 9.90, 51.55 ± 12.10, respectively; P > 0.05, Kruskal-Wallis test, or at the dose of 500 mg/kg (OAE: 5.27 ± 0.73, 4.87 ± 0.66; OAT: 63.93 ± 11.72, 63.58 ± 10.22; P > 0.05, Fisher LSD test. At T2, LH-LH animals did not reduce open-arm activity (OAE and OAT at the dose of 200 mg/kg (T1: 4.87 ± 0.66, T2: 5.47 ± 1.05; T1: 63.58 ± 10.22; T2: 49.01 ± 8.43 for OAE and OAT, respectively; P > 0.05, Wilcoxon test or at the dose of 500 mg/kg (T1: 4.80 ± 1.60, T2: 4.70 ± 1.04; T1: 51.55 ± 12.10, T2: 43.88 ± 10.64 for OAE and OAT, respectively; P > 0.05, Fisher LSD test, showing an inability to evoke memory 24 h later. These data suggest that LH does not act on anxiety but does induce a state-dependent memory retrieval deficit in mice.

  6. L-histidine provokes a state-dependent memory retrieval deficit in mice re-exposed to the elevated plus-maze.

    Science.gov (United States)

    Serafim, K R; Kishi, M; Canto-de-Souza, A; Mattioli, R

    2010-01-01

    The effects of L-histidine (LH) on anxiety and memory retrieval were investigated in adult male Swiss Albino mice (weight 30-35 g) using the elevated plus-maze. The test was performed on two consecutive days: trial 1 (T1) and trial 2 (T2). In T1, mice received an intraperitoneal injection of saline (SAL) or LH before the test and were then injected again and retested 24 h later. LH had no effect on anxiety at the dose of 200 mg/kg since there was no difference between the SAL-SAL and LH-LH groups at T1 regarding open-arm entries (OAE) and open-arm time (OAT) (mean +/- SEM; OAE: 4.0 +/- 0.71, 4.80 +/- 1.05; OAT: 40.55 +/- 9.90, 51.55 +/- 12.10, respectively; P > 0.05, Kruskal-Wallis test), or at the dose of 500 mg/kg (OAE: 5.27 +/- 0.73, 4.87 +/- 0.66; OAT: 63.93 +/- 11.72, 63.58 +/- 10.22; P > 0.05, Fisher LSD test). At T2, LH-LH animals did not reduce open-arm activity (OAE and OAT) at the dose of 200 mg/kg (T1: 4.87 +/- 0.66, T2: 5.47 +/- 1.05; T1: 63.58 +/- 10.22; T2: 49.01 +/- 8.43 for OAE and OAT, respectively; P > 0.05, Wilcoxon test) or at the dose of 500 mg/kg (T1: 4.80 +/- 1.60, T2: 4.70 +/- 1.04; T1: 51.55 +/- 12.10, T2: 43.88 +/- 10.64 for OAE and OAT, respectively; P > 0.05, Fisher LSD test), showing an inability to evoke memory 24 h later. These data suggest that LH does not act on anxiety but does induce a state-dependent memory retrieval deficit in mice.

  7. Acute Hematological Effects in Mice Exposed to the Expected Doses, Dose-rates, and Energies of Solar Particle Event-like Proton Radiation

    Science.gov (United States)

    Sanzari, Jenine K.; Cengel, Keith A.; Wan, X. Steven; Rusek, Adam; Kennedy, Ann R.

    2014-01-01

    NASA has funded several projects that have provided evidence for the radiation risk in space. One radiation concern arises from solar particle event (SPE) radiation, which is composed of energetic electrons, protons, alpha particles and heavier particles. SPEs are unpredictable and the accompanying SPE radiation can place astronauts at risk of blood cell death, contributing to a weakened immune system and increased susceptibility to infection. The doses, dose rates, and energies of the proton radiation expected to occur during a SPE have been simulated at the NASA Space Radiation Laboratory, Brookhaven National Laboratory, delivering total body doses to mice. Hematological values were evaluated at acute time points, up to 24 hrs. post-radiation exposure. PMID:25202654

  8. Acute hematological effects in mice exposed to the expected doses, dose-rates, and energies of solar particle event-like proton radiation

    Science.gov (United States)

    Sanzari, Jenine K.; Cengel, Keith A.; Steven Wan, X.; Rusek, Adam; Kennedy, Ann R.

    2014-07-01

    NASA has funded several projects that have provided evidence for the radiation risk in space. One radiation concern arises from solar particle event (SPE) radiation, which is composed of energetic electrons, protons, alpha particles and heavier particles. SPEs are unpredictable and the accompanying SPE radiation can place astronauts at risk of blood cell death, contributing to a weakened immune system and increased susceptibility to infection. The doses, dose rates, and energies of the proton radiation expected to occur during an SPE have been simulated at the NASA Space Radiation Laboratory, Brookhaven National Laboratory, delivering total body doses to mice. Hematological values were evaluated at acute time points, up to 24 hours post-radiation exposure.

  9. Melatonin Restores White Blood Cell Count, Diminishes Glycated Haemoglobin Level and Prevents Liver, Kidney and Muscle Oxidative Stress in Mice Exposed to Acute Ethanol Intoxication.

    Science.gov (United States)

    Kurhaluk, Natalia; Sliuta, Alina; Kyriienko, Svitlana; Winklewski, Pawel J

    2017-09-01

    The aim of the study was to examine the effects of melatonin impact on changes in haematological profile, biomarkers of oxidative stress (dienes conjugates, malondialdehyde (MDA), oxidatively modified protein levels, total antioxidant capacity and antioxidant enzyme activity) in liver, muscle, kidney and erythrocytes, and glycated haemoglobin (HBA1c) in mice during acute ethanol stress. Assays were carried out in quadruplicate: control, melatonin (10 mg/kg, 10 days), acute ethanol stress (0.75 g/kg/day, 10 days) and acute ethanol stress plus melatonin groups. Acute ethanol stress caused a significant increase in the total number of white blood cells (WBC), especially neutrophils in the blood, and HBA1c levels vs. control mice. The correlation between lipid peroxidation and the glycated haemoglobin level was shown (r = 0.93, P = 0.007). Ethanol reduced the antioxidant capacity by increasing reactive oxygen species (ROS) production and the level of oxidatively modified protein content, diene conjugates and MDA. Melatonin administration in animals during acute ethanol stress reduced antioxidant stress biomarkers, WBC, HBA1c levels and ROS production. Melatonin had protective effects on liver, kidney and muscle tissues by preventing the intensive lipid peroxidation processes in initial (diene conjugation production) and late stages (MDA level), and significantly reduced the level of aldehyde and ketone protein derivatives. Furthermore, melatonin restored elevated WBC count and HBA1c level and diminished ROS production. Ethanol reduces antioxidant capacity and leads to exaggerated reactive oxygen species production and consequent increases in oxidatively modified proteins. Melatonin exerts protective effects by preventing the intensive lipid peroxidation processes. Melatonin significantly reduces the level of aldehyde and ketone protein derivatives, restores glycated haemoglobin level and white blood cell count.

  10. Effects of ginsenoside Rb1 on behaviors and memory of lead-exposed mice%人参皂苷Rb1对染铅小鼠行为记忆的影响

    Institute of Scientific and Technical Information of China (English)

    刘微; 王艳春; 范红艳; 沈楠; 任旷

    2009-01-01

    AIM: To explore the effects of ginsenoside Rb1 on the blood lead levels and behaviors of lesd-exposed mice. METHODS: Lead-exposed models of mice were established with lead acetate drinking water, and different doses of ginsenoside Rb1 (100, 50, 25 mg/kg) were fed. Morris water maze test was employed to evaluate the effects of ginsenoside Rb1 on the learning and memory functions of the lead-exposed mice. The blood lead content and the activity of superoxide dismutase(SOD) and nitric oxide synthase ( NOS ) were detected. RESULTS : Morris water maze test showed that the searching distance and the latent periods were extended in lead-exposure mice. The activity of SOD decreased while the activity of NOS increased compared with those in control group (P<0.05 or P<0.01). Ginsenoside Rb1 markedly shortened the searching distance and latent periods, decreased the blood lead content, promoted the activity of SOD, and lowered the activity of NOS (P<0.05 or P<0.01). CONCLUSION: The results suggest that ginsenoside Rb1 reduces the blood lead concentration and alleviates the learning and memory obstacles of lead-expesed mice by restoring the vitality of the antioxidant system.%目的:研究人参皂苷Rb1对染铅小鼠血铅水平及行为记忆的影响.方法:以醋酸铅饮水制备染铅小鼠模型,灌胃给予100,50,25 mg/kg不同剂量的人参皂苷Rb1,采用Mor-ris水迷宫实验评价人参皂苷Rb1对小鼠学习记忆的影响,并测定小鼠血中铅含量、脑组织中超氧化物歧化酶(SOD)活性和一氧化氮合酶(NOS)活性.结果:染铅可导致小鼠水迷宫实验搜索路程及潜伏期延长;SOD活性降低及NOS活性升高,与空白对照组相比较差异显著(P<0.05或P<0.01).给予人参皂苷Rb1后,染铅小鼠水迷宫实验搜索路程及潜伏期缩短;血铅含量降低;SOD活性升高;NOS活性降低,与染铅模型组相比较差异显著(P<0.05或P<0.01).结论:人参皂苷Rb1能明显降低血铅浓度;通过提高染铅小鼠体内

  11. Morphofunctional evaluation of human skin preserved in glycerol and exposed to gamma radiation: a study in athymic mice; Avaliacao morfofuncional de pele humana conservada em glicerol e submetida a radiacao gama: estudo em camundongos atimicos

    Energy Technology Data Exchange (ETDEWEB)

    Bringel, Fabiana de Andrade

    2011-07-01

    Extensive skin lesions expose the body to damaging agents, which makes spontaneous regeneration difficult and, in many cases, leads patient to death. In such cases, if there are no donating areas for autograft, allografts can be used. In this type of graft, tissue is processed in tissue banks, where it can be subjected to radiosterilization. According to in vitro studies, gamma radiation, in doses higher than 25 kGy, induces alterations in skin preserved in glycerol at 85%, reducing the tensile strength of irradiated tissue. Clinical observation also suggests faster integration of such graft with the receptors tissue. In order to assess if the alterations observed in vitro, would compromise in vivo use, transplants of human tissue, irradiated or not, were performed in Nude mice. The skin of the mice was subjected to macroscopic analysis, optical coherence tomography imaging, histological and biomechanical assays. It was possible to conclude that grafts irradiated with 25 kGy promoted greater initial contraction, without alteration of the final dimensions of the repair area, also displaying a faster closing of the wound. Moreover, the use of irradiated grafts (25 and 50 kGy) enabled the formation of a more organized healing process without significant effects on biomechanical properties. (author)

  12. Preventive effects of physical exercise on the inhibition of creatine kinase in the cerebral cortex of mice exposed to cigarette smoke. DOI: 10.5007/1980-0037.2011v13n2p106

    Directory of Open Access Journals (Sweden)

    Daiane Bittencourt Fraga

    2011-03-01

    Full Text Available Recent studies have shown the health benefits of physical exercise, increasing the oxidative response of muscle. However, the effects of exercise on the brain are poorly understood and contradictory. The inhibition of creatine kinase (CK activity has been associated with the pathogenesis of a large number of diseases, especially in the brain. The objective of this study was to determine the preventive effects of physical exercise in the hippocampus and cerebral cortex of mice after chronic cigarette smoke exposure. Eight to 10-week-old male mice (C57BL-6 were divided into four groups and submitted to an exercise program (swimming, 5 times a week, for 8 weeks. After this period, the animals were passively exposed to cigarette smoke for 60 consecutive days, 3 times a day (4 Marlboro red cigarettes per session, for a total of 12 cigarettes. CK activity was measured in cerebral cortex and hippocampal homogenates. Enzyme activity was inhibited in the cerebral cortex of animals submitted to the inhalation of cigarette smoke. However, exercise prevented this inhibition. In contrast, CK activity remained unchanged in the hippocampus. This inhibition of CK by inhalation of cigarette smoke might be related to the process of cell death. Physical exercise played a preventive role in the inhibition of CK activity caused by exposure to cigarette smoke.

  13. Induction of p53-mediated apoptosis in splenocytes and thymocytes of C57BL/6 mice exposed to perfluorooctane sulfonate (PFOS)

    Energy Technology Data Exchange (ETDEWEB)

    Dong, Guang-Hui, E-mail: ghdong@mail.cmu.edu.cn [School of Public Health, China Medical University, Shenyang 110001 (China); Wang, Jing [Department of Biostatistics, School of Public Health, Saint Louis University, Saint Louis, MO 63104 (United States); Zhang, Ying-Hua; Liu, Miao-Miao; Wang, Da [School of Public Health, China Medical University, Shenyang 110001 (China); Zheng, Li [Department of Immunology, College of Basic Medical Science, China Medical University, Shenyang 110001 (China); Jin, Yi-He [School of Public Health, China Medical University, Shenyang 110001 (China); School of Environmental Science and Technology, Dalian University of Technology, Key Laboratory of Industrial Ecology and Environmental Engineering, Ministry of Education, Dalian 116024 (China)

    2012-10-15

    Perfluorooctane sulfonate (PFOS) is a persistent environmental contaminant found in human and wildlife tissues. It has been reported that PFOS can cause atrophy of the immune organs and apoptosis of immunocytes in rodents. However, the mechanism behind such cause is still unclear. To understand the model of cell death and its mechanism on lymphoid cells in vivo, we conducted a dose/response experiment in which 4 groups of male adult C57BL/6 mice (12 mice per group) were dosed daily by oral gavage with PFOS at 0, 0.0167, 0.0833, or 0.8333 mg/kg/day, yielding targeted Total Administered Dose (TAD) of 0, 1, 5, or 50 mg PFOS/kg, respectively, over 60 days. The results showed that spleen and thymus weight were significantly reduced in the highest PFOS-dose-group (TAD 50 mg PFOS/kg) compared to the control group, whereas liver weight was significantly increased. We analyzed the cell death via apoptosis with an annexin-V/propidium iodide assay by flow cytometry, and observed that both the percentage of apoptosis and the expression of the pro-apoptotic proteins p53 in splenocytes and thymocytes increased in a dose-related manner after PFOS treatment. We also observed that PFOS induced p53-dependent apoptosis through the cooperation between the Bcl-xl down regulation without changing the Bcl-2 and Bax expression. The down regulation of Bcl-xl was strongly indicating mitochondrial involvement in apoptosis. It is confirmed by the release of cytochrome c and activation of caspase-3. All of these findings establish an important role of p53 and mitochondrial function in PFOS induced toxic environment in the host. -- Highlights: ► PFOS immunotoxicity is caused by induction of apoptosis via the p53 activation. ► PFOS exposure can induce down regulation of Bcl-xl. ► Mitochondria are involved in PFOS-induced apoptosis. ► PFOS exposure can cause the release of cytochrome c and activation of caspase-3.

  14. Gene expression profiling in brain of mice exposed to the marine neurotoxin ciguatoxin reveals an acute anti-inflammatory, neuroprotective response

    Directory of Open Access Journals (Sweden)

    Ryan James C

    2010-08-01

    Full Text Available Abstract Background Ciguatoxins (CTXs are polyether marine neurotoxins and potent activators of voltage-gated sodium channels. This toxin is carried by multiple reef-fish species and human consumption of ciguatoxins can result in an explosive gastrointestinal/neurologic illness. This study characterizes the global transcriptional response in mouse brain to a symptomatic dose of the highly toxic Pacific ciguatoxin P-CTX-1 and additionally compares this data to transcriptional profiles from liver and whole blood examined previously. Adult male C57/BL6 mice were injected with 0.26 ng/g P-CTX-1 while controls received only vehicle. Animals were sacrificed at 1, 4 and 24 hrs and transcriptional profiling was performed on brain RNA with Agilent whole genome microarrays. RT-PCR was used to independently validate gene expression and the web tool DAVID was used to analyze gene ontology (GO and molecular pathway enrichment of the gene expression data. Results A pronounced 4°C hypothermic response was recorded in these mice, reaching a minimum at 1 hr and lasting for 8 hrs post toxin exposure. Ratio expression data were filtered by intensity, fold change and p-value, with the resulting data used for time course analysis, K-means clustering, ontology classification and KEGG pathway enrichment. Top GO hits for this gene set included acute phase response and mono-oxygenase activity. Molecular pathway analysis showed enrichment for complement/coagulation cascades and metabolism of xenobiotics. Many immediate early genes such as Fos, Jun and Early Growth Response isoforms were down-regulated although others associated with stress such as glucocorticoid responsive genes were up-regulated. Real time PCR confirmation was performed on 22 differentially expressed genes with a correlation of 0.9 (Spearman's Rho, p Conclusions Many of the genes differentially expressed in this study, in parallel with the hypothermia, figure prominently in protection against

  15. 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

  16. Examining the potential benefits of (--epicatechin, (+-catechin, and rutin on maternal and offspring cardiovascular outcomes in LDLr-/-mice exposed to an atherogenic environment during early development

    Directory of Open Access Journals (Sweden)

    Mary N. R. Lesser

    2016-04-01

    Full Text Available Background: Maternal nutritional status can impact numerous early developmental processes. In certain cases, these effects can influence the risk their off spring can have for select chronic diseases later in life. Consequently, in this article were port on the effects of maternal consumption of high levels of certain flavonoids on the development of coronary artery disease (CAD in an atherosclerosis-prone mutant mouse model.Methods:LDLr -/-mutant mice were fed a control fat (CF, high fat (HF, or the HFdiet supplemented with epicatechin and catechin (HFEC or rutin (HFRU, prior to pregnancy and during lactation, in order to explore whether the flavonoids influenced markers of vascular health in the lactating dams (lactation day (LD 21. Post-weaning (postnatal day(PND22, offspring were challenged with an atherogenic environment (HF diet in the absence of flavonoids and vascular health markers were assessed in the adult offspring (PND 60. Results:Dams fed the HF diet had elevated markers of atherosclerosisonLD 21whencompared to the dams fed with the control diet. Flavonoid consumption prior to pregnancy and during lactation had inconsistent effects on maternal markers of atherosclerosis (plasma cholesterol, aortic lipid accumulation, and oxidative stress biomarkers at LD21 compared to dams fed the HF diet without flavonoids.At PND 60, there were no differences in vascular health markers among the groups of LDLr -/-offspring whose mothers consumed the CF or the HF diet with or without flavonoids during lactation. Conclusions: Maternal consumption of the flavonoid-supplemented HF diets had modest effects on maternal markers of atherosclerosis. The exposure of offspring to the flavonoid-supplemented HF diets during early lactation had little effect on the cardiovascular parameters assessed in the adult offspring.

  17. 碧萝芷对辐射所致小鼠各脏器中自由基的清除作用%Scavenging Effect of Pycnogenol on Free Radicals in Radiation Exposed Mice Organs

    Institute of Scientific and Technical Information of China (English)

    丁翔; 强亦忠; 王利利; 程跃进; 江家贵; 崔凤梅

    2011-01-01

    目的 观察碧萝芷对60Coγ射线整体照射所致小鼠主要脏器中超氧化物歧化酶( superoxide dismutase,SOD)活力、丙二醛(malondialdehyde,MDA)含量、抗超氧阴离子自由基能力和抑制羟自由基能力的影响.方法 小鼠随机分成3组:正常对照组,辐照对照组及碧萝芷实验组.辐照对照组及碧萝芷实验组各接受1次γ射线照射,同时碧萝芷实验组用碧萝芷灌胃,连续7d.处死后取肝、脾、肾和睾丸组织,测定SOD活力、MDA含量、抑制羟自由基能力和抗超氧阴离子自由基能力.结果 碧萝芷对受照小鼠脏器中SOD活力影响不大,可降低脏器中MDA含量;能增加肝脏、肾脏和睾丸组织中抗超氧阴离子自由基能力和抑制羟自由基能力,增加脾脏抑制羟自由基能力.结论 碧萝芷具有一定的抗辐射损伤作用,其通过直接中和超氧阴离子自由基和羟自由基而发挥抗氧化功能,并不增加组织中的抗氧化酶含量.%Objective To observe the effects of pycnogenol on contents of SOD and MDA, and the inhibition of superoxide anion and hydroxyl radical in '"Co y-ray exposed mice organs. Methods The mice were randomly divided into 3 groups I. E. The normal control, irradiation control and pycnogenol experiment groups. The irradiation control and pycnogenol experiment groups were exposed to 60Co y- ray, and the mice of pycnogenol experiment group were given pycnogenol for 7 days after radiation. The tissues were obtained after being sacrificed, in which the vitality of SOD, the content of MDA and the inhibition of superoxide anion and hydroxyl radical were detected. Results Results showed that after the mice were irradiated pycnogenol had no effect on SOD; however, the content of MDA could be reduced in organs. Pycnogenol could increase the inhibition of superoxide anion and hydroxyl radical in kidney, liver and testicular and could increase the inhibition of hydroxyl radical in spleen. Conclusions Pycnogenol shows

  18. S-Nitrosylation in Organs of Mice Exposed to Low or High Doses of γ-Rays: The Modulating Effect of Iodine Contrast Agent at a Low Radiation Dose

    Directory of Open Access Journals (Sweden)

    Fadia Nicolas

    2015-04-01

    Full Text Available The covalent addition of nitric oxide (NO• onto cysteine thiols, or S-nitrosylation, modulates the activity of key signaling proteins. The dysregulation of normal S-nitrosylation contributes to degenerative conditions and to cancer. To gain insight into the biochemical changes induced by low-dose ionizing radiation, we determined global S-nitrosylation by the “biotin switch” assay coupled with mass spectrometry analyses in organs of C57BL/6J mice exposed to acute 0.1 Gy of 137Cs γ-rays. The dose of radiation was delivered to the whole body in the presence or absence of iopamidol, an iodinated contrast agent used during radiological examinations. To investigate whether similar or distinct nitrosylation patterns are induced following high-dose irradiation, mice were exposed in parallel to acute 4 Gy of 137Cs g rays. Analysis of modulated S-nitrosothiols (SNO-proteins in freshly-harvested organs of animals sacrificed 13 days after irradiation revealed radiation dose- and contrast agent-dependent changes. The major results were as follows: (i iopamidol alone had significant effects on S-nitrosylation in brain, lung and liver; (ii relative to the control, exposure to 0.1 Gy without iopamidol resulted in statistically-significant SNO changes in proteins that differ in molecular weight in liver, lung, brain and blood plasma; (iii iopamidol enhanced the decrease in S-nitrosylation induced by 0.1 Gy in brain; (iv whereas a decrease in S-nitrosylation occurred at 0.1 Gy for proteins of ~50 kDa in brain and for proteins of ~37 kDa in liver, an increase was detected at 4 Gy in both organs; (v mass spectrometry analyses of nitrosylated proteins in brain revealed differential modulation of SNO proteins (e.g., sodium/potassium-transporting ATPase subunit beta-1; beta tubulins; ADP-ribosylation factor 5 by low- and high-dose irradiation; and (vi ingenuity pathway analysis identified major signaling networks to be modulated, in particular the neuronal

  19. S-Nitrosylation in Organs of Mice Exposed to Low or High Doses of γ-Rays: The Modulating Effect of Iodine Contrast Agent at a Low Radiation Dose.

    Science.gov (United States)

    Nicolas, Fadia; Wu, Changgong; Bukhari, Salwa; de Toledo, Sonia M; Li, Hong; Shibata, Masayuki; Azzam, Edouard I

    2015-04-28

    The covalent addition of nitric oxide (NO(•)) onto cysteine thiols, or S-nitrosylation, modulates the activity of key signaling proteins. The dysregulation of normal S-nitrosylation contributes to degenerative conditions and to cancer. To gain insight into the biochemical changes induced by low-dose ionizing radiation, we determined global S-nitrosylation by the "biotin switch" assay coupled with mass spectrometry analyses in organs of C57BL/6J mice exposed to acute 0.1 Gy of (137)Cs γ-rays. The dose of radiation was delivered to the whole body in the presence or absence of iopamidol, an iodinated contrast agent used during radiological examinations. To investigate whether similar or distinct nitrosylation patterns are induced following high-dose irradiation, mice were exposed in parallel to acute 4 Gy of (137)Cs γ rays. Analysis of modulated S-nitrosothiols (SNO-proteins) in freshly-harvested organs of animals sacrificed 13 days after irradiation revealed radiation dose- and contrast agent-dependent changes. The major results were as follows: (i) iopamidol alone had significant effects on S-nitrosylation in brain, lung and liver; (ii) relative to the control, exposure to 0.1 Gy without iopamidol resulted in statistically-significant SNO changes in proteins that differ in molecular weight in liver, lung, brain and blood plasma; (iii) iopamidol enhanced the decrease in S-nitrosylation induced by 0.1 Gy in brain; (iv) whereas a decrease in S-nitrosylation occurred at 0.1 Gy for proteins of ~50 kDa in brain and for proteins of ~37 kDa in liver, an increase was detected at 4 Gy in both organs; (v) mass spectrometry analyses of nitrosylated proteins in brain revealed differential modulation of SNO proteins (e.g., sodium/potassium-transporting ATPase subunit beta-1; beta tubulins; ADP-ribosylation factor 5) by low- and high-dose irradiation; and (vi) ingenuity pathway analysis identified major signaling networks to be modulated, in particular the neuronal nitric

  20. Estudo imunohistoquímico do remodelamento pulmonar em camundongos expostos à fumaça de cigarro Immunohistochemical study of lung remodeling in mice exposed to cigarette smoke

    Directory of Open Access Journals (Sweden)

    Samuel Santos Valença

    2008-10-01

    metalloproteinases is associated with cytokines, and evidence suggests that the matrix metalloproteinase-12 (MMP-12 plays an important role. Our objective was to investigate tissue inhibitor of metalloproteinase-2 (TIMP-2, tumor necrosis factor-alpha (TNF-α and interleukin-6 (IL-6 detection by immunohistochemical methods in mouse lung. METHODS: Male C57BL/6 mice were exposed 3 times a day to smoke of 3 cigarettes over a period of 10, 20, 30 or 60 days in an inhalation chamber (groups CS10, CS20, CS30 and CS60, respectively. Controls were exposed to the same conditions in room air. RESULTS: A progressive increase in the number of alveolar macrophages was observed in the bronchoalveolar lavage fluid of the exposed mice. The mean linear intercept, an indicator of alveolar destruction, was greater in all exposed groups when compared to control group. In the CS10, CS20 and CS30 mice, the immunohistochemical index (II for MMP-12 increased in parallel with a decrease in II for TIMP-2 in the CS10, CS20 and CS30 mice. The II for the cytokines TNF-α and IL-6 was greater in all exposed groups than in the control group. Emphysema, with changes in volume density of collagen and elastic fibers, was observed in the CS60 group. CONCLUSIONS: These findings suggest that cigarette smoke induces emphysema with major participation of TNF-α and IL-6 without participation of neutrophils.

  1. Comparison of the D2 Receptor Regulation and Neurotoxicant Susceptibility of Nigrostriatal Dopamine Neurons in Wild-Type and CB1/CB2 Receptor Knockout Mice

    OpenAIRE

    Simkins, Tyrell J.; Janis, Kelly L.; McClure, Alison K.; Behrouz, Bahareh; Pappas, Samuel S.; Lehner, Andreas; Kaminski, Norbert E.; Goudreau, John L.; Lookingland, Keith J.; Kaplan, Barbara L. F.

    2012-01-01

    Motor dysfunctions of Parkinson Disease (PD) are due to the progressive loss of midbrain nigrostriatal dopamine (NSDA) neurons. Evidence suggests a role for cannabinoid receptors in the neurodegeneration of these neurons following neurotoxicant-induced injury. This work evaluates NSDA neurons in CB1/CB2 knockout (KO) mice and tests the hypothesis that CB1/CB2 KO mice are more susceptible to neurotoxicant exposure. NSDA neuronal indices were assessed using unbiased stereological cell counting,...

  2. The study of susceptibility to carbon tetrachloride and benzene in offspring of expanded simple tandem repeats mutation mice exposed to formaldehyde%甲醛致扩张性简单串联重复序列突变小鼠子代对四氯化碳和苯暴露易感性研究

    Institute of Scientific and Technical Information of China (English)

    王超; 刘云儒; 周印; 李爱萍; 周建伟

    2011-01-01

    为5.88‰±4.55‰,F10代为8.25‰±2.06‰;C组1000 mg/kg苯染毒组:F5代为7.50‰±6.99‰,F10代为10.67‰±1.16‰;H组500 mg/kg苯染毒组:F5代为7.88‰±3.09‰,F10代为9.20‰±1.30‰;H组1000 mg/kg苯染毒组:F5代为9.63‰±4.34‰,F10代为13.33‰±2.08‰)随苯剂量的增加而增加,与溶剂对照组(C组F5代为1.13‰±0.35‰,F10代为1.20‰±0.82‰;H组F5代为1.25‰±0.46‰,F10代为1.33‰±1.03‰)的差异均有统计学意义(P<0.05,P<0.01).结论 甲醛暴露引起的基因组ESTR突变可改变子代小鼠对CCl4和苯的易感性.ESTR突变可能是影响机体对化学物易感性的生物学标志,其分子机制有待进一步阐明.%Objective To investigate the susceptibility to carbon tetrachloride and benzene in offspring of expanded simple tandem repeats (ESTR) mutation mice exposed to formaldehyde (FA). Methods F5 and F10 offspring (200 mg/m3 ×2 hours) served as H group and ICR mice were used as control group(group C). The F5 and F10 offspring were exposed to 10 ml/kg carbon tetrachloride at the doses of 0.05%, 0.50% or 5.00% for 24 hours, respectively or 500 or 1000 mg/kg benzene for 24 hours, respectively by intraperitoneal injection. Serum alanine transaminase (ALT), aspartate transaminase (AST) and the hepatic superoxide dismutase (SOD) or malondialdehyde (MDA) were detected; also the hepatic pathological changes were observed under light microscope; the micronucleus in sternum bone marrow cells as the biomarker of benzene blood toxicity were measured. Results ALT and AST activities in group C of F5 mice exposed to 0.50% and 5.00% CCl4, ALT in groups C and H of F10 mice exposed to 0.05%, 0.50%, 5.00% CCl4, AST in groups C and H of F10 mice exposed to 0.50% and 5.00% CCl4 were significantly higher than those in controls, respectively (P<0.05); as compared to the control, hepatic SOD activities in group C of F5 and F10 mice exposed to 0.50% and 5.00% CCl4, in group H of F5 mice exposed to 0.50% and 5.00% CCl4, and

  3. PCBs暴露ApoE-/-小鼠肝脏的microRNA和mRNA调控网络研究%MicroRNA-mRNa interaction network in the liver of ApoE-/-mice exposed to PCBs

    Institute of Scientific and Technical Information of China (English)

    黄风尘; 单秋丽; 王静; 杜宇国

    2014-01-01

    microRNAs ( miRNAs ) are powerful negative regulators of mRNA expression, and therefore, are responsible for the modulation of important mRNA networks. Polychlorinated biphenyls ( PCBs) , among the important family numbers of persistent organic pollutants ( POPs) , are known to induce the development of atherosclerosis, probably through the alteration of gene expression. The present study was aimed to investigate the changes of miRNA-mRNA networks and their associations with the genotoxocity of PCBs, the potential molecular mechanisms involved in the atherosclerosis. Male ApoE-/- mice of 8 weeks were exposed to Aroclor1254 ( a representative mixture of PCBs, 55 mg·kg-1 body weight) by intraperitoneal injection four times over six weeks of duration. The total RNA was isolated from the liver of ApoE-/-mice with or without exposure to Aroclor1254. cDNA and the RNA with specific staining after dephosphorylation were used in gene arrays with Affymetrix GeneChip� Mouse Genome 430 2. 0 gene chip and Agilent Mouse microRNA array, respectively. Then IPA software, combined with the platform of Affymetrix mRNA gene array was used to analyze the alterations of mRNAs and miRNAs. The results were furthermore used to evaluate the effects of Aroclor1254 on the gene regulation network and the related cell signaling pathways. Our results showed that 18 miRNAs regulated 110 mRNAs after Aroclor1254 exposure, both of them could modulate the common biological functions, such as glucose metabolism, lipid metabolism, cell death and survival and cell transport. Further investigation showed that miRNA-22, let-7 family, miRNA-15a/b and the target genes of PPARα, PPARγ-coactivator1α and Foxo1 play important roles on the metabolism of glucose and lipid, which are closely related with the development of atherosclerosis.%本研究通过microRNA-mRNA相互作用考察PCBs的基因毒性,探讨PCBs致动脉粥样硬化可能的分子机制.研究使用8周龄ApoE-/-小

  4. The Effect of Dose on 2,3,7,8-TCDD Tissue Distribution, Metabolism and Elimination in CYP1A2 (-/-) Knockout and C57BL/6N Parental Strains of Mice

    Science.gov (United States)

    Numerous metabolism studies have demonstrated that the highly toxic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is poorly metabolized. A hallmark feature of TCDD exposure is induction of hepatic CYP1A2 and subsequent sequestration leading to high liver to fat concentration ratios. This study was in...

  5. The effect of dose on 2,3,7,8-TCDD tissue distribution, metabolism and elimination in CYP1A2(-/_) knockout and C57BL/6N parental strains of mice

    Science.gov (United States)

    Numerous metabolism studies have demonstrated that the toxic contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is poorly metabolized. A hallmark feature of TCDD exposure is induction of hepatic CYP1A2 and subsequent sequestration leading to high liver-to-fat concentration ra...

  6. THC Prevents MDMA Neurotoxicity in Mice.

    Directory of Open Access Journals (Sweden)

    Clara Touriño

    Full Text Available The majority of MDMA (ecstasy recreational users also consume cannabis. Despite the rewarding effects that both drugs have, they induce several opposite pharmacological responses. MDMA causes hyperthermia, oxidative stress and neuronal damage, especially at warm ambient temperature. However, THC, the main psychoactive compound of cannabis, produces hypothermic, anti-inflammatory and antioxidant effects. Therefore, THC may have a neuroprotective effect against MDMA-induced neurotoxicity. Mice receiving a neurotoxic regimen of MDMA (20 mg/kg x 4 were pretreated with THC (3 mg/kg x 4 at room (21 degrees C and at warm (26 degrees C temperature, and body temperature, striatal glial activation and DA terminal loss were assessed. To find out the mechanisms by which THC may prevent MDMA hyperthermia and neurotoxicity, the same procedure was carried out in animals pretreated with the CB(1 receptor antagonist AM251 and the CB(2 receptor antagonist AM630, as well as in CB(1, CB(2 and CB(1/CB(2 deficient mice. THC prevented MDMA-induced-hyperthermia and glial activation in animals housed at both room and warm temperature. Surprisingly, MDMA-induced DA terminal loss was only observed in animals housed at warm but not at room temperature, and this neurotoxic effect was reversed by THC administration. However, THC did not prevent MDMA-induced hyperthermia, glial activation, and DA terminal loss in animals treated with the CB(1 receptor antagonist AM251, neither in CB(1 and CB(1/CB(2 knockout mice. On the other hand, THC prevented MDMA-induced hyperthermia and DA terminal loss, but only partially suppressed glial activation in animals treated with the CB(2 cannabinoid antagonist and in CB(2 knockout animals. Our results indicate that THC protects against MDMA neurotoxicity, and suggest that these neuroprotective actions are primarily mediated by the reduction of hyperthermia through the activation of CB(1 receptor, although CB(2 receptors may also contribute to

  7. Characterizing a Rat Brca2 Knockout Model

    Science.gov (United States)

    2007-05-01

    this treatment (Figure 2b). Aspermatogenesis Meiosis in Brca2/ rats proceeds normally through leptotene and early zygotene (Figure 3a) with 40...Zygotene Late Zygotene Scp3Scp3 Scp3 Scp3 Scp1 CREST CRESTCREST Merge a b Figure 3 (a) Meiosis in Brca2/ spermatocytes does not progress beyond late...control of noncrossover and crossover recombination during meiosis . Cell 106: 47–57. Barlow C, Liyanage M, Moens PB, Tarsounas M, Nagashima K, Brown K

  8. Rapid doubling of Alzheimer’s amyloid-β40 and 42 levels in brains of mice exposed to a nickel nanoparticle model of air pollution [v1; ref status: indexed, http://f1000r.es/T5Rxeo

    Directory of Open Access Journals (Sweden)

    Soong Ho Kim

    2012-12-01

    Full Text Available Background: Over 20 genetic risk factors have been confirmed to associate with elevated risk for Alzheimer’s disease (AD, but the identification of environmental and/or acquired risk factors has been more elusive. At present, recognized acquired risks for AD include traumatic brain injury, hypercholesterolemia, obesity, hypertension, and type 2 diabetes. Methods: Based on reports associating various inhalants with AD pathology, we investigated the possibility that air pollution might contribute to AD risk by exposing wild-type mice to a standard air pollution modeling system employing nickel nanoparticle-enriched atmosphere for 3 hr. Results: Mice exposed to air pollution showed 72-129% increases in brain levels of both amyloid-β peptides Aβ40 and Aβ42, as well as Aβ42/40 (p <0.01. Conclusions: These effects on elevation of brain Aβ exceed those associated with trisomy 21, a known risk for early onset AD pathology, raising the possibility that clinical importance might be attached. Further work is required to establish the molecular and physiological basis for these phenomena. The rapid, dramatic effect, if verified, would suggest that inhalant exposures should be evaluated for their possible roles in contributing to the environmental risk for common forms of AD.

  9. Acrylamide-induced carcinogenicity in mouse lung involves mutagenicity: cII gene mutations in the lung of big blue mice exposed to acrylamide and glycidamide for up to 4 weeks.

    Science.gov (United States)

    Manjanatha, Mugimane G; Guo, Li-Wu; Shelton, Sharon D; Doerge, Daniel R

    2015-06-01

    Potential health risks for humans from exposure to acrylamide (AA) and its epoxide metabolite glycidamide (GA) have garnered much attention lately because substantial amounts of AA are present in a variety of fried and baked starchy foods. AA is tumorigenic in rodents, and a large number of in vitro and in vivo studies indicate that AA is genotoxic. A recent cancer bioassay on AA demonstrated that the lung was one of the target organs for tumor induction in mice; however, the mutagenicity of AA in this tissue is unclear. Therefore, to investigate whether or not gene mutation is involved in the etiology of AA- or GA-induced mouse lung carcinogenicity, we screened for cII mutant frequency (MF) in lungs from male and female Big Blue (BB) mice administered 0, 1.4, and 7.0 mM AA or GA in drinking water for up to 4 weeks (19-111 mg/kg bw/days). Both doses of AA and GA produced significant increases in cII MFs, with the high doses producing responses 2.7-5.6-fold higher than the corresponding controls (P ≤ 0.05; control MFs = 17.2 ± 2.2 and 15.8 ± 3.5 × 10(-6) in males and females, respectively). Molecular analysis of the mutants from high doses indicated that AA and GA produced similar mutation spectra and that these spectra were significantly different from the spectra in control mice (P ≤ 0.01). The predominant types of mutations in the lung cII gene from AA- and GA-treated mice were A:T → T:A, and G:C → C:G transversions, and -1/+1 frameshifts at a homopolymeric run of Gs. The MFs and types of mutations induced by AA and GA in the lung are consistent with AA exerting its genotoxicity via metabolism to GA. These results suggest that AA is a mutagenic carcinogen in mouse lungs and therefore further studies on its potential health risk to humans are warranted. Environ. Mol. Mutagen. 56:446-456, 2015. © 2015 Wiley Periodicals, Inc.

  10. Gene expression analysis of livers from female B6C3F1 mice exposed to carcinogenic and non-carcinogenic doses of furan, with or without bromodeoxyuridine (BrdU treatment

    Directory of Open Access Journals (Sweden)

    Anna Francina Webster

    2014-12-01

    Full Text Available Standard methodology for identifying chemical carcinogens is both time-consuming and resource intensive. Researchers are actively investigating how new technologies can be used to identify chemical carcinogens in a more rapid and cost-effective manner. Here we performed a toxicogenomic case study of the liver carcinogen furan. Full study and mode of action details were previously published in the Journal of Toxicology and Applied Pharmacology. Female B6C3F1 mice were sub-chronically treated with two non-carcinogenic (1 and 2 mg/kg bw and two carcinogenic (4 and 8 mg/kg bw doses of furan for 21 days. Half of the mice in each dose group were also treated with 0.02% bromodeoxyuridine (BrdU for five days prior to sacrifice [13]. Agilent gene expression microarrays were used to measure changes in liver gene and long non-coding RNA expression (published in Toxicological Sciences. Here we describe the experimental and quality control details for the microarray data. We also provide the R code used to analyze the raw data files, produce fold change and false discovery rate (FDR adjusted p values for each gene, and construct hierarchical clustering between datasets.

  11. Gene expression analysis of livers from female B6C3F1 mice exposed to carcinogenic and non-carcinogenic doses of furan, with or without bromodeoxyuridine (BrdU) treatment.

    Science.gov (United States)

    Webster, Anna Francina; Williams, Andrew; Recio, Leslie; Yauk, Carole L

    2014-12-01

    Standard methodology for identifying chemical carcinogens is both time-consuming and resource intensive. Researchers are actively investigating how new technologies can be used to identify chemical carcinogens in a more rapid and cost-effective manner. Here we performed a toxicogenomic case study of the liver carcinogen furan. Full study and mode of action details were previously published in the Journal of Toxicology and Applied Pharmacology. Female B6C3F1 mice were sub-chronically treated with two non-carcinogenic (1 and 2 mg/kg bw) and two carcinogenic (4 and 8 mg/kg bw) doses of furan for 21 days. Half of the mice in each dose group were also treated with 0.02% bromodeoxyuridine (BrdU) for five days prior to sacrifice [13]. Agilent gene expression microarrays were used to measure changes in liver gene and long non-coding RNA expression (published in Toxicological Sciences). Here we describe the experimental and quality control details for the microarray data. We also provide the R code used to analyze the raw data files, produce fold change and false discovery rate (FDR) adjusted p values for each gene, and construct hierarchical clustering between datasets.

  12. Determination of arsenic in liver and kidney of mice exposed in realgar by HG-FAAS%HG-FAAS 法测定雄黄染毒小鼠肝及肾脏中的砷含量

    Institute of Scientific and Technical Information of China (English)

    苑洁; 霍韬光; 王艳蕾; 郭婧潭; 焦雪鑫; 张颖花; 袁媛; 高岚岳; 姜泓

    2015-01-01

    A novel hydride generation‐flame atomic absorption spectrometry (HG‐FAAS ) method was established for the determination of arsenic in liver and kidney of mice after realgar exposure .The results showed that the method was accurate ,sensitive ,reliable and low detec‐tion limit .The distribution levels of arsenic in liver ,kidney of realgar infected mice were fairly with the liver and kidney content .Meanwhile hydride generation conditions were optimized .%建立了氢化物发生‐火焰原子吸收法(HG‐FAAS)测定雄黄染毒小鼠肝及肾脏中砷含量的方法。结果表明,该方法准确、灵敏、可靠、检出限低。雄黄染毒小鼠肝、肾脏中砷的分布水平相当。同时对氢化物发生条件进行了优化。

  13. Hematotoxicity and genotoxicity evaluations in Swiss mice intraperitoneally exposed to Bacillus thuringiensis (var kurstaki) spore crystals genetically modified to express individually Cry1Aa, Cry1Ab, Cry1Ac, or Cry2Aa.

    Science.gov (United States)

    Mezzomo, Bélin Poletto; Miranda-Vilela, Ana Luisa; Barbosa, Lilian Carla Pereira; Albernaz, Vanessa Lima; Grisolia, Cesar Koppe

    2016-08-01

    Bacillus thuringiensis (Bt) has been widely used in foliar sprays as part of integrated pest management strategies against insect pests of agricultural crops. Since the advent of genetically modified plants expressing Bt δ-endotoxins, the bioavailability of Cry proteins has increased, and therefore for biosafety reasons their adverse effects should be studied, mainly for nontarget organisms. We evaluated, in Swiss mice, the hematotoxicity and genotoxicity of the genetically modified strains of Bt spore crystals Cry1Aa, 1Ab, 1Ac, or 2Aa at 27 mg/kg, and Cry1Aa, 1Ab and 2Aa also at 136 and 270 mg/kg, administered with a single intraperitoneal injection 24 h before euthanasia. Controls received filtered water or cyclophosphamide. Blood samples collected by cardiac puncture were used to perform hemogram, and bone marrow was extracted for the micronucleus test. Bt spore crystals presented toxicity for lymphocytes when in higher doses, which varied according to the type of spore crystal studied, besides promoting cytotoxic and genotoxic effects for the erythroid lineage of bone marrow, mainly at highest doses. Although the profile of such adverse side effects can be related to their high level of exposure, which is not commonly found in the environment, results indicated that these Bt spore crystals were not harmless to mice. This suggests that a more specific approach should be taken to increase knowledge about their toxicological properties and to establish the toxicological risks to nontarget organisms. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 970-978, 2016.

  14. Quantitative, functional and biochemical alterations in the peritoneal cells of mice exposed to whole-body gamma-irradiation. 1. Changes in cellular protein, adherence properties and enzymatic activities associated with platelet-activating factor formation and inactivation

    Energy Technology Data Exchange (ETDEWEB)

    Steel, L.K.; Hughes, H.N.; Walden, T.L. Jr.

    1988-06-01

    Changes in total number, differentials, cell protein, adherence properties, acetyl-CoA transferase and acetylhydrolase activities, prostaglandin E/sub 2/ and leukotriene C/sub 4/ production, as well as Ca/sup 2+/ ionophore A23187 stimulation were examined in resident peritoneal cells isolated from mice 2 h to 10 days postexposure to a single dose (7, 10 or 12 Gy) of gamma-radiation. Radiation dose-related reductions in macrophage and lymphocyte numbers and increases in cellular protein and capacity to adhere to plastic surfaces were evident. In vivo irradiation also elevated the activities of acetyltransferase and acetyl-CoA hydrolase (catalysing platelet-activating factor biosynthesis and inactivation, respectively) in adherent and nonadherent peritoneal cells, particularly 3-4 days postexposure. Blood plasma from irradiated animals did not reflect the increased cellular acetyl-hydrolase activity. Prostaglandin E/sub 2/ and leukotriene C/sub 4/ synthesis were elevated postexposure, suggesting increased substrate (arachidonate) availability and increased cyclooxygenase and lipoxygenase activities. Ionophore stimulation of enzyme activities and eicosanoid release also differed in irradiated peritoneal cells.

  15. Fire exposed aluminium structures

    NARCIS (Netherlands)

    Maljaars, J.; Fellinger, J.H.H.; Soetens, F.

    2006-01-01

    Material properties and mechanical response models for fire design of steel structures are based on extensive research and experience. Contrarily, the behaviour of aluminium load bearing structures exposed to fire is relatively unexplored. This article gives an overview of physical and mechanical pr

  16. Fire exposed aluminium structures

    NARCIS (Netherlands)

    Maljaars, J.; Fellinger, J.H.H.; Soetens, F.

    2006-01-01

    Material properties and mechanical response models for fire design of steel structures are based on extensive research and experience. Contrarily, the behaviour of aluminium load bearing structures exposed to fire is relatively unexplored. This article gives an overview of physical and mechanical

  17. 牛磺酸锌对慢性染汞大鼠、小鼠学习记忆的影响%Study on the Effects of Learning and Memory Ability for Rats and Mice Exposed to Chronic Mercury

    Institute of Scientific and Technical Information of China (English)

    赵文涛; 张顺三; 高洁; 李积胜

    2009-01-01

    Objective:To study the different dosages of taurine-zinc coordination compound(TZC)on resisting the impairment of mercury(Hg)induced CNS damage.Methods:The chosen rats and mice were divided into control group,Hg group,Hg+TZC group.The effected differences for learning memory ability were observed with the Y maze test and shuttle before and after experiment.Results:Mercury can lead to decrease of leaning and memory ability(P< 0.05),each zinc-supplement group can mitigate the damage induced by mercury in different degree(P<0.05).Conclusions:The resistance effect of TZC on the toxic of Hg is related to the form of zinc-compound and the dosage of TZC.%目的:探讨牛磺酸锌(TZC)拮抗汞对神经系统的损害作用.方法:选用健康Wistar大鼠64只,昆明种小鼠60只分别随机分组,对照组、染汞组、汞+TZC组,大鼠采用Y迷宫,小鼠采用穿梭实验,观察染汞组和不同浓度TZC组的鼠学习记忆能力的变化.结果:汞可导致大鼠学习记忆能力下降(P<0.05),不同浓度的TZC均可缓解汞致大鼠学习记忆能力下降(P<0.05).结论:TZC在一定程度上能拮抗汞对神经系统毒性作用.

  18. Opiorphin-dependent up-regulation of CD73 (a key enzyme in the adenosine signaling pathway) in corporal smooth muscle cells exposed to hypoxic conditions and in corporal tissue in pre-priapic sickle cell mice

    Science.gov (United States)

    Fu, Shibo; Davies, Kelvin P.

    2015-01-01

    The precise molecular mechanisms underlying priapism associated with sickle cell disease remain to be defined. However, there is increasing evidence that up-regulated activity of the opiorphin and adenosine pathways in corporal tissue, resulting in heighted relaxation of smooth muscle, play an important role in development of priapism. A key enzyme in the adenosine pathway is CD73, an ecto-5-prime-nucleotidase (5-prime-ribonucleotide phosphohydrolase; EC 3.1.3.5) which catalyzes the conversion of adenosine mononucleotides to adenosine. In the present study we investigated how sickle cell disease and hypoxia regulate the interplay between opiorphin and CD73. In the corpora of sickle cell mice we observed significantly elevated expression of both the mouse opiorphin homologue mSmr3a (14-fold) and CD73 (2.2-fold) relative to non-sickle cell controls at a life-stage prior to the exhibition of priapism. Sickle cell disease has a pronounced hypoxic component, therefore we determined if CD73 was also modulated in in vitro corporal smooth muscle (CSM) models of hypoxia. Hypoxia significantly increased CD73 protein and mRNA expression by 1.5-fold and 2-fold, respectively. We previously demonstrated that expression of another component of the adenosine signaling pathway, the adensosine 2B receptor, can be regulated by sialorphin (the rat opiorphin homolologue), and we demonstrate that sialorphin also regulates CD73 expression in a dose and time dependent fashion. Using siRNA to knock-down sialorphin mRNA expression in CSM cells in vitro, we demonstrate that the hypoxic up-regulation of CD73 is dependent on the up-regulation of sialorphin. Overall our data provides further evidence to support a role for opiorphin in CSM in regulating the cellular response regulating response to hypoxia or sickle cell disease by activating smooth muscle relaxant pathways. PMID:25833166

  19. Mice deficient in the ALS2 gene exhibit lymphopenia and abnormal hematopietic function

    OpenAIRE

    2006-01-01

    One form of juvenile onset autosomal recessive amyotrophic lateral sclerosis (ALS2) has been linked to the dysfunction of the ALS2 gene. The ALS2 gene is expressed in lymphoblasts, however, whether ALS2-deficiency affects periphery blood is unclear. Here we report that ALS2 knockout (ALS2−/−) mice developed peripheral lymphopenia but had higher proportions of hematopoietic stem and progenitor cells in which the stem cell factor-induced cell proliferation was up-regulated. Our findings reveal ...

  20. Mice deficient in the ALS2 gene exhibit lymphopenia and abnormal hematopietic function.

    Science.gov (United States)

    Erie, Elizabeth A; Shim, Hoon; Smith, Aleah L; Lin, Xian; Keyvanfar, Keyvan; Xie, Chengsong; Chen, Jichun; Cai, Huaibin

    2007-01-01

    One form of juvenile onset autosomal recessive amyotrophic lateral sclerosis (ALS2) has been linked to the dysfunction of the ALS2 gene. The ALS2 gene is expressed in lymphoblasts, however, whether ALS2-deficiency affects periphery blood is unclear. Here we report that ALS2 knockout (ALS2(-/-)) mice developed peripheral lymphopenia but had higher proportions of hematopoietic stem and progenitor cells in which the stem cell factor-induced cell proliferation was up-regulated. Our findings reveal a novel function of the ALS2 gene in the lymphopoiesis and hematopoiesis, suggesting that the immune system is involved in the pathogenesis of ALS2.

  1. Inactivation of cyclin E1 inhibits chemically induced hepatocarcinogenesis in mice

    OpenAIRE

    Moro, Nives

    2011-01-01

    E-type cyclins (CcnE) control the transition of quiescent cells into the cell cycle. Two E-type cyclins, CcnE1 and CcnE2 have been described. A variety of human cancers, including hepatocellular carcinoma (HCC), overexpress CcnE and this is frequently associated with reduced patient survival. The aim of the present study was to dissect the role of CcnE1 and CcnE2 for hepatocarcinogenesis induced by the carcinogen diethylnitrosamine (DEN) using CcnE1 and CcnE2 knockout mice. The central questi...

  2. 米邦塔仙人掌果胶对慢性不可预知温和应激小鼠绝望症状的改善作用%Study on the improvement of milpa alta cactus pectin on desperate symptoms in mice exposed to chronic unpreditc able mild stress

    Institute of Scientific and Technical Information of China (English)

    肖同楚; 黄朝明; 杨兴娥; 湛进进; 郭莲军

    2015-01-01

    目的:研究米邦塔仙人掌果胶( MCP)对慢性不可预知温和应激( CUMS)小鼠绝望症状的改善作用。方法雄性昆明种小鼠随机分为空白对照组、模型组、MCP低剂量组(50 mg/kg)、MCP中剂量组(100 mg/kg)、MCP高剂量组(200 mg/kg)。除空白对照组不进行任何应激处理外,其余组均进行CUMS,各MCP组均在进行CUMS期间每天灌胃相应剂量MCP。造模结束24 h后进行悬尾实验,48 h后进行强迫游泳实验。结果模型组悬尾实验潜伏期显著短于空白对照组(P<0.01),累计不动时间显著长于空白对照组(P<0.01);MCP高剂量组潜伏期显著长于模型组(P<0.05),MCP中、高剂量组累计不动时间显著短于模型组(P均<0.01)。模型组强迫游泳实验潜伏期显著短于空白对照组(P<0.01),累计不动时间显著长于空白对照组(P<0.01);MCP各给药组潜伏期与空白对照组比较差异均无统计学意义(P均>0.05),而MCP高剂量组累计不动时间显著短于模型组(P<0.05)。结论 MCP能较好地缓解CMS小鼠的行为绝望症状。%Objetc ive It is to investigate the effect of milpa alta cactus pectin ( MCP) on desperate symptoms in mice ex-posed to chronic unpredictable mild stress ( CUMS) .Methods The male Kunming mice were randomly divided into 5 groups such as control group, CUMS+Vehicle group, CUMS+MCP 50 mg/kg group, CUMS+MCP 100 mg/kg group, and CUMS+MCP 200 mg/kg group.Except the control group, the other groups were exposed to CUMS for 6 weeks.And during this peri-od, the animals were treated with corresponding drug by intragastric administration.While the ends of the model, the tail sus-pension test ( TST) was carried out after 24 hours, and the forced swimming test ( FST) were conducted after 48 hours.Re-sults In TST, the latency of the CUMS+Vehicle group was significantly shorter (P0.05), and the immobility time of the

  3. Nrf2-mediated haeme oxygenase-1 up-regulation induced by cobalt protoporphyrin has antinociceptive effects against inflammatory pain in the formalin test in mice.

    Science.gov (United States)

    Rosa, Angelo O; Egea, Javier; Lorrio, Silvia; Rojo, Ana I; Cuadrado, Antonio; López, Manuela G

    2008-07-15

    This study investigated the effect of haeme oxygenase-1 (HO-1) in nociception induced by formalin injection in the mice hind paw. Intraperitoneal (i.p.) administration of cobalt protoporphyrin (CoPP, an HO-1 inducer, 5mg/kg) 24h before the test, inhibited the nociceptive response during the second phase, but not during the first phase of the formalin test. The effect of CoPP was prevented by treatment with tin protoporphyrin (SnPP, an inhibitor of HO-1 activity) administered either by i.p. (25mg/kg, 30 min before the test) or intraplantar (400 nmol/paw, 5 min before the test) routes. Human embryonic kidney (HEK) 293T cells treated with 10 microM CoPP expressed 20-fold higher HO-1 levels when compared to controls; this effect was suppressed by transfection with the dominant negative for the nuclear factor-erythroid 2-related factor 2 (Nrf2). Western blot analysis also revealed that CoPP treatment induced a similar 20-fold increase in HO-1 expression in the paw; this effect was attenuated in knockout mice for Nrf2. CoPP treatment of wild-type, but not in Nrf2 knockout mice, resulted in a striking increase of HO-1 stained cells surrounding the muscular tissues of the hind limbs. HO-1 positive cells were scarce in wild-type and in Nrf2 knockout untreated mice. CoPP-induced HO-1 expression in Nrf2 knockout mice was lost and correlated with the loss of antinociceptive effects. In conclusion, Nrf2-mediated HO-1 expression induced an antinociceptive effect at peripheral sites. These results suggest that HO-1 modulates the inflammatory pain pathways. Hence, the development of drugs that could raise peripheral HO-1 could be relevant in inflammatory pain treatment.

  4. Contextual fear conditioning is enhanced in mice lacking functional sphingosine kinase 2.

    Science.gov (United States)

    Lei, Mona; Shafique, Adeena; Shang, Kani; Couttas, Timothy A; Zhao, Hua; Don, Anthony S; Karl, Tim

    2017-08-30

    The lipid sphingosine 1-phosphate (S1P) is a potent neuroprotective signalling molecule that signals through its own family of five G-protein coupled receptors. S1P signalling enhances presynaptic glutamate release and is essential for neural development. S1P is synthesized by the enzymes sphingosine kinases 1 and 2 (SPHK1 and SPHK2), of which SPHK2 mRNA and activity is more abundant in the brain. In this study we investigated the consequences of global SphK2 knockout (SphK2(-/-)) on basic motor capabilities, anxiety, learning, and memory in mice, using a range of tests including the elevated plus maze, the cheeseboard, contextual and cued fear conditioning, and fear extinction. Loss of SphK2 resulted in an 85-90% reduction in brain S1P levels, and was associated with a notably higher freezing response in a novel context. SphK2 knockout mice also exhibited increased contextual fear conditioning but the extinction of contextual fear memory was similar to control mice. SphK2(-/-) mice, contrary to their control littermates, did not respond to cue presentation with increased freezing. Anxiety measures in the elevated plus maze were not different between SphK2(-/-) mice and control littermates. Also, knockout mice showed no deficits in neurological reflexes or motor functions, and performed as well as their control littermates in the spatial memory test. Our findings demonstrate that SphK2 is responsible for the vast majority of S1P synthesis in the mouse brain, and plays a role in freezing responses as evaluated in the fear conditioning paradigm. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Immature mice are more susceptible than adult mice to acetaminophen-induced acute liver injury

    Science.gov (United States)

    Lu, Yan; Zhang, Cheng; Chen, Yuan-Hua; Wang, Hua; Zhang, Zhi-Hui; Chen, Xi; Xu, De-Xiang

    2017-01-01

    Acetaminophen (APAP) overdose induces acute liver injury. The aim of the present study was to analyze the difference of susceptibility between immature and adult mice to APAP-induced acute liver injury. Weanling immature and adult mice were injected with APAP (300 mg/kg). As expected, immature mice were more susceptible than adult mice to APAP-induced acute liver injury. APAP-evoked hepatic c-Jun N-terminal kinase phosphorylation was stronger in immature mice than in adult mice. Hepatic receptor-interacting protein (RIP)1 was obviously activated at APAP-exposed immature and adult mice. Interestingly, hepatic RIP3 activation was more obvious in APAP-treated immature mice than adult mice. Although there was no difference on hepatic GSH metabolic enzymes between immature and adult mice, immature mice were more susceptible than adult mice to APAP-induced hepatic GSH depletion. Of interest, immature mice expressed a much higher level of hepatic Cyp2e1 and Cyp3a11 mRNAs than adult mice. Correspondingly, immature mice expressed a higher level of hepatic CYP2E1, the key drug metabolic enzyme that metabolized APAP into the reactive metabolite NAPQI. These results suggest that a higher level of hepatic drug metabolic enzymes in immature mice than adult mice might contribute to the difference of susceptibility to APAP-induced acute liver injury. PMID:28205631

  6. Hematological and biochemical parameters in pollution-exposed mice

    Energy Technology Data Exchange (ETDEWEB)

    Borras, M.; Llacuna, S.; Gorriz, A.; Nadal, J. [Barcelona Univ. (Spain). Dept. of Animal Biology

    1998-12-31

    Current research in this field has mainly focused on the exposure of laboratory rodents to artificially generated atmospheres under controlled conditions. As part of a comprehensive study of the impact of a coal-fired power plant in Cercs (Catalonia, northeast Spain), we have assessed the effects of air pollutants (nitric and sulphur oxides and particulate material, considered as a complex mixture, submitted to chemical interactions and to the influence of climatic conditions) on animals captured in the wild in the contamined area compared with animals captured in a matched, clean one. These animals included rodents passerine birds. This is a realistic approach, but it does not allow any control on sex, age, health status or genetic characteristics of the study subjects, nor on the real time of exposure or a possible selective pressure of predators. In that context we considered it as an interesting alternative to undertake an intermediate approach, placing caged homogeneus, controlled laboratory rodents under field conditions into both the polluted and the control zones. (orig.)

  7. Regulatory T-Cell Augmentation or Interleukin-17 Inhibition Prevents Calcineurin Inhibitor-Induced Hypertension in Mice.

    Science.gov (United States)

    Chiasson, Valorie L; Pakanati, Abhinandan R; Hernandez, Marcos; Young, Kristina J; Bounds, Kelsey R; Mitchell, Brett M

    2017-07-01

    The immunosuppressive calcineurin inhibitors cyclosporine A and tacrolimus alter T-cell subsets and can cause hypertension, vascular dysfunction, and renal toxicity. We and others have reported that cyclosporine A and tacrolimus decrease anti-inflammatory regulatory T cells and increase proinflammatory interleukin-17-producing T cells; therefore, we hypothesized that inhibition of these effects using noncellular therapies would prevent the hypertension, endothelial dysfunction, and renal glomerular injury induced by calcineurin inhibitor therapy. Daily treatment of mice with cyclosporine A or tacrolimus for 1 week significantly decreased CD4(+)/FoxP3(+) regulatory T cells in the spleen and lymph nodes, as well as induced hypertension, vascular injury and dysfunction, and glomerular mesangial expansion in mice. Daily cotreatment with all-trans retinoic acid reported to increase regulatory T cells and decrease interleukin-17-producing T cells, prevented all of the detrimental effects of cyclosporine A and tacrolimus. All-trans retinoic acid also increased regulatory T cells and prevented the hypertension, endothelial dysfunction, and glomerular injury in genetically modified mice that phenocopy calcineurin inhibitor-treated mice (FKBP12-Tie2 knockout). Treatment with an interleukin-17-neutralizing antibody also increased regulatory T-cell levels and prevented the hypertension, endothelial dysfunction, and glomerular injury in cyclosporine A-treated and tacrolimus-treated mice and FKBP12-Tie2 knockout mice, whereas an isotype control had no effect. Augmenting regulatory T cells and inhibiting interleukin-17 signaling using noncellular therapies prevents the cardiovascular and renal toxicity of calcineurin inhibitors in mice. © 2017 American Heart Association, Inc.

  8. Analysis of PFOA in Dosed CD-1 Mice Part 2: Disposition of PFOA in Tissues and fluids from pregnant and lactating mice and their pups

    Science.gov (United States)

    Previous studies in mice with multiple gestational exposures to perfluorooctanoic acid (PFOA) demonstrate numerous dose dependent growth and developmental effects which appeared to worsen if offspring exposed in utero nursed from PFOA-exposed dams. To evaluate the disposition of ...

  9. Gene expression deregulation in postnatal skeletal muscle of TK2 deficient mice reveals a lower pool of proliferating myogenic progenitor cells.

    Directory of Open Access Journals (Sweden)

    João A Paredes

    Full Text Available Loss of thymidine kinase 2 (TK2 causes a heterogeneous myopathic form of mitochondrial DNA (mtDNA depletion syndrome (MDS in humans that predominantly affects skeletal muscle tissue. In mice, TK2 deficiency also affects several tissues in addition to skeletal muscle, including brain, heart, adipose tissue, kidneys and causes death about 3 weeks after birth. We analysed skeletal muscle and heart muscle tissues of Tk2 knockout mice at postnatal development phase and observed that TK2 deficient pups grew slower and their skeletal muscles appeared significantly underdeveloped, whereas heart was close to normal in size. Both tissues showed mtDNA depletion and mitochondria with altered ultrastructure, as revealed by transmission electron microscopy. Gene expression microarray analysis showed a strong down-regulation of genes involved in cell cycle and cell proliferation in both tissues, suggesting a lower pool of undifferentiated proliferating cells. Analysis of isolated primary myoblasts from Tk2 knockout mice showed slow proliferation, less ability to differentiate and signs of premature senescence, even in absence of mtDNA depletion. Our data demonstrate that TK2 deficiency disturbs myogenic progenitor cells function in postnatal skeletal muscle and we propose this as one of the causes of underdeveloped phenotype and myopathic characteristic of the TK2 deficient mice, in addition to the progressive mtDNA depletion, mitochondrial damage and respiratory chain deficiency in post-mitotic differentiated tissue.

  10. Toxicity and teratogenicity evaluation of fenproporex in mice fetuses descending from parents that were exposed to this drug during intrauterine life Avaliação da toxicidade e da teratogenicidade do femproporex em fetos de camundongos provenientes de pais expostos à droga durante a vida intra-uterina

    Directory of Open Access Journals (Sweden)

    Camila Queiroz Moreira

    2007-10-01

    Full Text Available Fenproporex is an anorectic drug that is transformed into amphetamine in the organism. The use of amphetaminic compounds during pregnancy increases the risk of exencephaly, cleft palate and cardiac malformations. The aim of this study was to evaluate embryo-fetal development, embryotoxicity and possible teratogenic effects in mice fetuses descending from parents that were exposed to fenproporex duringintra-uterine development. Pregnant females were treated daily, by gavage, with 15 mg/kg of fenproporex during all the gestation. When the off springs reached the adult age, they were mated with integral mice, obtaining the2nd generation. On the 18th gestational day, female mice were killed. It was observed that fenproporex did not alter significantly placent weight, fetuses length, rate of postimplantation loss, visceral and skeletal analysis. This may have occurred due to the decrease of the amphetamine effects on the 2nd generation. However, there was statistically significant difference in relation to the fetuses weight. The reduction of fetal weight is used as parameter to evidence toxic effects of asubstance. Therefore, the results suggest that fenproporex presented fetaltoxicity in the tested experimental conditions. Femproporex é um anorexígeno que se transforma em anfetamina no organismo. O uso de compostos anfetamínicos durante a gravidez aumenta o risco de exencefalia, de fenda palatina e de malformações cardíacas. O objetivo deste estudo foi avaliar o desenvolvimento embriofetal, a embriotoxicidade e possíveis efeitos teratogênicos em fetos de camundongos provenientes de pais que foram expostos ao femproporex durante o desenvolvimento intra-uterino. As fêmeas prenhes foram tratadas diariamente, via gavage, com 15 mg/kg de femproporex, durante toda a gestação. Quando as progênies atingiram a idade adulta, foram acasaladas com camundongos íntegros, obtendo-se a 2ª geração. No 18º dia de prenhez, as fêmeas foram mortas

  11. Increased sensitivity to kindling in mice lacking TSP1.

    Science.gov (United States)

    Mendus, D; Rankin-Gee, E K; Mustapha, M; Porter, B E

    2015-10-01

    The development of a hyperexcitable neuronal network is thought to be a critical event in epilepsy. Thrombospondins (TSPs) regulate synaptogenesis by binding the neuronal α2δ subunit of the voltage-gated calcium channel. TSPs regulate synapse formation during development and in the mature brain following injury. It is unclear if TSPs are involved in hyperexcitability that contributes to the development of epilepsy. Here we explore the development of epilepsy using a pentylenetetrazole (PTZ) kindling model in mice lacking TSP1 and TSP2. Unexpectedly, we found increased sensitivity to PTZ kindling in mice lacking TSP1, while mice lacking TSP2 kindled similar to wild-type. We found that the increased seizure susceptibility in the TSP1 knockout (KO) mice was not due to a compensatory increase in TSP2 mRNA as TSP1/2 KO mice were sensitive to PTZ, similar to the TSP1 KO mice. Furthermore, there were similar levels of TGF-B signal activation during kindling in the TSP1 KO mice compared to wild-type. We observed decreased expression of voltage-dependent calcium channel subunit CACNA2D1 mRNA in TSP1, TSP2, and TSP1/2 KO mice. Decreased CACNA2D2 mRNA was only detected in mice that lacked TSP1 and α2δ-1/2 protein levels in the cortex were lower in the TSP 1/2 KO mice. CACNA2D2 knockout mice have spontaneous seizures and increased PTZ seizure susceptibility. Here we report similar findings, TSP1, and TSP1/2 KO mice have low levels of CACNA2D2 mRNA expression and α2δ-1/2 receptor level in the cortex, and are more susceptible to seizures. CACNA2D2 mutations in mice and humans can cause epilepsy. Our data suggest TSP1 in particular may control CACNA2D2 levels and could be a modifier of seizure susceptibility.

  12. Attenuated inflammatory response in triggering receptor expressed on myeloid cells 2 (TREM2 knock-out mice following stroke.

    Directory of Open Access Journals (Sweden)

    Matthias W Sieber

    Full Text Available BACKGROUND: Triggering receptor expressed on myeloid cells-2 (TREM2 is a microglial surface receptor involved in phagocytosis. Clearance of apoptotic debris after stroke represents an important mechanism to re-attain tissue homeostasis and thereby ensure functional recovery. The role of TREM2 following stroke is currently unclear. METHODS AND RESULTS: As an experimental stroke model, the middle cerebral artery of mice was occluded for 30 minutes with a range of reperfusion times (duration of reperfusion: 6 h/12 h/24 h/2 d/7 d/28 d. Quantitative PCR (qPCR revealed a greatly increased transcription of TREM2 after stroke. We subsequently analyzed the expression of pro-inflammatory cytokines, chemokines and their receptors in TREM2-knockout (TREM2-KO mice via qPCR. Microglial activation (CD68, Iba1 and CD3-positive T-cell invasion were analyzed via qPCR and immunohistochemistry. Functional consequences of TREM2 knockout were assessed by infarct volumetry. The acute inflammatory response (12 h reperfusion was very similar between TREM2-KO mice and their littermate controls. However, in the sub-acute phase (7 d reperfusion following stroke, TREM2-KO mice showed a decreased transcription of pro-inflammatory cytokines TNFα, IL-1α and IL-1β, associated with a reduced microglial activity (CD68, Iba1. Furthermore, TREM2-KO mice showed a reduced transcription of chemokines CCL2 (MCP1, CCL3 (MIP1α and the chemokine receptor CX3CR1, followed by a diminished invasion of CD3-positive T-cells. No effect on the lesion size was observed. CONCLUSIONS: Although we initially expected an exaggerated pro-inflammatory response following ablation of TREM2, our data support a contradictory scenario that the sub-acute inflammatory reaction after stroke is attenuated in TREM2-KO mice. We therefore conclude that TREM2 appears to sustain a distinct inflammatory response after stroke.

  13. Attenuated Inflammatory Response in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Knock-Out Mice following Stroke

    Science.gov (United States)

    Brehm, Martin; Guenther, Madlen; Linnartz-Gerlach, Bettina; Neumann, Harald; Witte, Otto W.; Frahm, Christiane

    2013-01-01

    Background Triggering receptor expressed on myeloid cells-2 (TREM2) is a microglial surface receptor involved in phagocytosis. Clearance of apoptotic debris after stroke represents an important mechanism to re-attain tissue homeostasis and thereby ensure functional recovery. The role of TREM2 following stroke is currently unclear. Methods and Results As an experimental stroke model, the middle cerebral artery of mice was occluded for 30 minutes with a range of reperfusion times (duration of reperfusion: 6 h/12 h/24 h/2 d/7 d/28 d). Quantitative PCR (qPCR) revealed a greatly increased transcription of TREM2 after stroke. We subsequently analyzed the expression of pro-inflammatory cytokines, chemokines and their receptors in TREM2-knockout (TREM2-KO) mice via qPCR. Microglial activation (CD68, Iba1) and CD3-positive T-cell invasion were analyzed via qPCR and immunohistochemistry. Functional consequences of TREM2 knockout were assessed by infarct volumetry. The acute inflammatory response (12 h reperfusion) was very similar between TREM2-KO mice and their littermate controls. However, in the sub-acute phase (7 d reperfusion) following stroke, TREM2-KO mice showed a decreased transcription of pro-inflammatory cytokines TNFα, IL-1α and IL-1β, associated with a reduced microglial activity (CD68, Iba1). Furthermore, TREM2-KO mice showed a reduced transcription of chemokines CCL2 (MCP1), CCL3 (MIP1α) and the chemokine receptor CX3CR1, followed by a diminished invasion of CD3-positive T-cells. No effect on the lesion size was observed. Conclusions Although we initially expected an exaggerated pro-inflammatory response following ablation of TREM2, our data support a contradictory scenario that the sub-acute inflammatory reaction after stroke is attenuated in TREM2-KO mice. We therefore conclude that TREM2 appears to sustain a distinct inflammatory response after stroke. PMID:23301011

  14. Behavioral and neurobiological changes in C57BL/6 mouse exposed to cuprizone: effects of antipsychotics

    Directory of Open Access Journals (Sweden)

    Haiyun Xu

    2010-03-01

    Full Text Available Recent human studies suggest a role for altered oligodendrocytes in the pathophysiology of schizophrenia. Our recent animal study has reported some schizophrenia-like behaviors in mice exposed to cuprizone (Xu et al., 2009, a copper chelator that has been shown to selectively damage the white matter. This study was to explore mechanisms underlying the behavioral changes in cuprizone-exposed mice and to examine effects of the antipsychotics haloperidol, clozapine and quetiapine on the changes in the mice. Mice given cuprizone for 14 days showed a deficit in the prepulse inhibition of acoustic startle response and higher dopamine in the prefrontal cortex (PFC, which changes were not seen in mice given cuprizone plus antipsychotics. Mice given cuprizone for 21 days showed lower spontaneous alternations in Y-maze, which was not seen in mice treated with the antipsychotics. Mice given cuprizone for 28 days displayed less social interactions, which was not seen in mice given cuprizone plus clozapine/quetiapine, but was seen in mice given cuprizone plus haloperidol. Mice given cuprizone for 42 days showed myelin sheath loss and lower myelin basic protein in PFC, caudate putamen, and hippocampus. The white matter damage in PFC was attenuated in mice given cuprizone plus clozapine/haloperidol. But the white matter damage in caudate putamen and hippocampus was only attenuated by clozapine and quetiapine, not by haloperidol. These results help us to understand the behavioral changes and provide experimental evidence for the protective effects of antipsychotics on white matter damage in cuprizone-exposed mice.

  15. Anaplerotic triheptanoin diet enhances mitochondrial substrate use to remodel the metabolome and improve lifespan, motor function, and sociability in MeCP2-null mice.

    Directory of Open Access Journals (Sweden)

    Min Jung Park

    Full Text Available Rett syndrome (RTT is an autism spectrum disorder (ASD caused by mutations in the X-linked MECP2 gene that encodes methyl-CpG binding protein 2 (MeCP2. Symptoms range in severity and include psychomotor disabilities, seizures, ataxia, and intellectual disability. Symptom onset is between 6-18 months of age, a critical period of brain development that is highly energy-dependent. Notably, patients with RTT have evidence of mitochondrial dysfunction, as well as abnormal levels of the adipokines leptin and adiponectin, suggesting overall metabolic imbalance. We hypothesized that one contributor to RTT symptoms is energy deficiency due to defective nutrient substrate utilization by the TCA cycle. This energy deficit would lead to a metabolic imbalance, but would be treatable by providing anaplerotic substrates to the TCA cycle to enhance energy production. We show that dietary therapy with triheptanoin significantly increased longevity and improved motor function and social interaction in male mice hemizygous for Mecp2 knockout. Anaplerotic therapy in Mecp2 knockout mice also improved indicators of impaired substrate utilization, decreased adiposity, increased glucose tolerance and insulin sensitivity, decreased serum leptin and insulin, and improved mitochondrial morphology in skeletal muscle. Untargeted metabolomics of liver and skeletal muscle revealed increases in levels of TCA cycle intermediates with triheptanoin diet, as well as normalizations of glucose and fatty acid biochemical pathways consistent with the improved metabolic phenotype in Mecp2 knockout mice on triheptanoin. These results suggest that an approach using dietary supplementation with anaplerotic substrate is effective in improving symptoms and metabolic health in RTT.

  16. Effect of aging and radiation in mice of different genotypes

    Energy Technology Data Exchange (ETDEWEB)

    Storer, J.B.

    1976-01-01

    Data are presented on the life span of nine inbred strains and five hybrid strains of mice based on 400 mice of each sex for inbred and 200 mice of each sex for hybrid. Some of these mice were exposed when 120 days old to 250 R or 450 R of x radiation delivered at a dose rate of 60 R/min. Data on strain, sample size, and mean survival times are presented in tables.

  17. Mycotoxicosis Caused by Aerosolized T-2 Toxin Administered to Female Mice

    Science.gov (United States)

    1988-11-01

    light cycle was 12 hours. The mice female mice exposed to aerosolized T-2 mycotoxin were were acclimated (1 week) before the study was begun. examined at...then, 10 ml of scintillation fluid was Mice - Female , 6-week-old Swiss ICR mice, weighing 15 to 20 added, and the PH] on the filter was quantitated 24

  18. 补充维生素B2对急性低氧暴露小鼠血浆代谢组的影响%Effect of vitamin B2 supplementation on plasma metabonome in the mice exposed to acute hypoxia

    Institute of Scientific and Technical Information of China (English)

    王宇平; 郭长江; 杨继军; 韦京豫; 吴健全; 高蔚娜

    2010-01-01

    目的 观察补充维生素B2对急性低氧暴露小鼠外周血代谢组的影响.方法 采用随机数字表法将35只雄性昆明小鼠随机分为:正常对照组,低氧对照组,2倍、4倍及8倍维生素B2补充组,每组7只.以相应饲料(维生素B2含量分别为6 mg/kg、12 mg/kg、24 mg/kg和48 mg/kg)喂养2周后,除正常对照组外,其它各组均在模拟6000 m高度停留8 h,采集血浆,以核磁共振的方法分析其代谢组变化.结果 急性低氧暴露后,各组动物血浆代谢组在得分图中呈聚类型分布,且有先分离后同归的代谢模式变化轨迹,显示出补充不同剂量维生素B2后小鼠血浆代谢组逐渐恢复的趋势.代谢模式产生差别的原因是脂类、乳酸、丙氨酸、N-乙酰糖蛋白、谷氨酸、胆碱、牛磺酸、糖、肉碱、甘氨酸和肌酐等物质的水平发生了变化,表明相关的代谢途径发生了变化.结论 补充维生素B2使急性低氧暴露机体碳水化合物、脂肪、蛋白质代谢发生改变,而维生素B2可以改善碳水化合物代谢,并可能通过肉碱间接调节了脂肪代谢;同时还发现一些氨基酸代谢发生显著变化.%Objective To observe the effects of vitamin B2 supplementation on plasma metabonome of the mice which exposed to acute hypoxia. Methods Thirty-five male Kunming mice were randomly and averagely divided into 5 groups, among which the control and hypoxia control groups were fed the fodder containing 6, 12, 24, 48 mg/kg vitamin B2 respectively. All groups were exposed to simulated hypoxia environment (equivalent to 6000 meters above sea level) for 8 hours except control group. Nuclear magnetic resonance spectrometer was used to test the change of metabonome from collected plasma. Results After acute hypoxia exposure, the metabonome pattern in all groups showed clustering distribution in scores plot and the metabonome changes were along the trail from segregation to regression. These indicated a gradual recover

  19. Disposition of Perfluorooctanoic Acid (PFOA) in Pregnant and Lactating CD-1 Mice and Their Pups

    Science.gov (United States)

    Previous studies in mice prenatally-exposed to PFOA demonstrate growth and developmental effects, including impaired body weight gain and mammary gland development, delayed eye opening, and increased mortality. Those dose dependent effects appeared to worsen if offspring exposed ...

  20. Cyclooxygenase-2 suppresses the anabolic response to PTH infusion in mice.

    Directory of Open Access Journals (Sweden)

    Shilpa Choudhary

    Full Text Available We previously reported that the ability of continuously elevated PTH to stimulate osteoblastic differentiation in bone marrow stromal cell cultures was abrogated by an osteoclastic factor secreted in response to cyclooxygenase-2 (Cox2-produced prostaglandin E2. We now examine the impact of Cox2 (Ptgs2 knockout (KO on the anabolic response to continuously elevated PTH in vivo. PTH (40 μg/kg/d or vehicle was infused for 12 or 21 days in 3-mo-old male wild type (WT and KO mice in the outbred CD-1 background. Changes in bone phenotype were assessed by bone mineral density (BMD, μCT and histomorphometry. PTH infusion for both 12 and 21 days increased femoral BMD in Cox2 KO mice and decreased BMD in WT mice. Femoral and vertebral trabecular bone volume fractions were increased in KO mice, but not in WT mice, by PTH infusion. In the femoral diaphysis, PTH infusion increased cortical area in Cox2 KO, but not WT, femurs. PTH infusion markedly increased trabecular bone formation rate in the femur, serum markers of bone formation, and expression of bone formation-related genes, growth factors, and Wnt target genes in KO mice relative to WT mice, and decreased gene expression of Wnt antagonists only in KO mice. In contrast to the differential effects of PTH on anabolic factors in WT and KO mice, PTH infusion increased serum markers of resorption, expression of resorption-related genes, and the percent bone surface covered by osteoclasts similarly in both WT and KO mice. We conclude that Cox2 inhibits the anabolic, but not the catabolic, effects of continuous PTH. These data suggest that the bone loss with continuously infused PTH in mice is due largely to suppression of bone formation and that this suppression is mediated by Cox2.

  1. Epimorphic regeneration in mice is p53-independent.

    Science.gov (United States)

    Arthur, L Matthew; Demarest, Renee M; Clark, Lise; Gourevitch, Dmitri; Bedelbaeva, Kamila; Anderson, Rhonda; Snyder, Andrew; Capobianco, Anthony J; Lieberman, Paul; Feigenbaum, Lionel; Heber-Katz, E

    2010-09-15

    The process of regeneration is most readily studied in species of sponge, hydra, planarian and salamander (i.e., newt and axolotl). The closure of MRL mouse ear pinna through-and-through holes provides a mammalian model of unusual wound healing/regeneration in which a blastema-like structure closes the ear hole and cartilage and hair follicles are replaced. Recent studies, based on a broad level of DNA damage and a cell cycle pattern of G₂/M "arrest," showed that p21(Cip1/Waf1) was missing from the MRL mouse ear and that a p21-null mouse could close its ear holes. Given the p53/p21 axis of control of DNA damage, cell cycle arrest, apoptosis and senescence, we tested the role of p53 in the ear hole regenerative response. Using backcross mice, we found that loss of p53 in MRL mice did not show reduced healing. Furthermore, cross sections of MRL. p53(-/-) mouse ears at 6 weeks post-injury showed an increased level of adipocytes and chondrocytes in the region of healing whereas MRL or p21(-/-) mice showed chondrogenesis alone in this same region, though at later time points. In addition, we also investigated other cell cycle-related mutant mice to determine how p21 was being regulated. We demonstrate that p16 and Gadd45 null mice show little healing capacity. Interestingly, a partial healing phenotype in mice with a dual Tgfβ/Rag2 knockout mutation was seen. These data demonstrate an independence of p53 signaling for mouse appendage regeneration and suggest that the role of p21 in this process is possibly through the abrogation of the Tgfβ/Smad pathway.

  2. Mice with ablated adult brain neurogenesis are not impaired in antidepressant response to chronic fluoxetine.

    Science.gov (United States)

    Jedynak, Paulina; Kos, Tomasz; Sandi, Carmen; Kaczmarek, Leszek; Filipkowski, Robert K

    2014-09-01

    The neurogenesis hypothesis of major depression has two main facets. One states that the illness results from decreased neurogenesis while the other claims that the very functioning of antidepressants depends on increased neurogenesis. In order to verify the latter, we have used cyclin D2 knockout mice (cD2 KO mice), known to have virtually no adult brain neurogenesis, and we demonstrate that these mice successfully respond to chronic fluoxetine. After unpredictable chronic mild stress, mutant mice showed depression-like behavior in forced swim test, which was eliminated with chronic fluoxetine treatment, despite its lack of impact on adult hippocampal neurogenesis in cD2 KO mice. Our results suggest that new neurons are not indispensable for the action of antidepressants such as fluoxetine. Using forced swim test and tail suspension test, we also did not observe depression-like behavior in control cD2 KO mice, which argues against the link between decreased adult brain neurogenesis and major depression.

  3. Akt2 Deficiency is Associated with Anxiety and Depressive Behavior in Mice

    Directory of Open Access Journals (Sweden)

    Christina Leibrock

    2013-09-01

    Full Text Available Background: The economic burden associated with major depressive disorder and anxiety disorders render both disorders the most common and debilitating psychiatric illnesses. To date, the exact cellular and molecular mechanisms underlying the pathophysiology, successful treatment and prevention of these highly associated disorders have not been identified. Akt2 is a key protein in the phosphatidylinositide-3 (PI3K / glycogen synthase 3 kinase (GSK3 signaling pathway, which in turn is involved in brain-derived neurotrophic factor (BDNF effects on fear memory, mood stabilisation and action of several antidepressant drugs. The present study thus explored the impact of Akt2 on behaviour of mice. Methods: Behavioural studies (Open-Field, Light-Dark box, O-Maze, Forced Swimming Test, Emergence Test, Object Exploration Test, Morris Water Maze, Radial Maze have been performed with Akt2 knockout mice (akt-/- and corresponding wild type mice (akt+/+. Results: Anxiety and depressive behavior was significantly higher in akt-/- than in akt+/+ mice. The akt-/- mice were cognitively unimpaired but displayed increased anxiety in several behavioral tests (O-Maze test, Light-Dark box, Open Field test. Moreover, akt-/- mice spent more time floating in the Forced Swimming test, which is a classical feature of experimental depression. Conclusion: Akt2 might be a key factor in the pathophysiology of depression and anxiety.

  4. 染矽尘小鼠早期肺组织bFGF与FGFR-1的表达及意义%Expression and Significance of Basic Fibroblast Growth Factor and Fibroblast Growth Factor Receptor-1 in Early Stage Lung Tissues of Silica Exposed Mice

    Institute of Scientific and Technical Information of China (English)

    李丹; 向军俭; 王宏; 陶俊; 邓宁; 钟雪云

    2011-01-01

    Objective To investigate the expression of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 (FGPR-1) in early stage lung tissues of silica exposed mice and to probe into the significance of bFGF in occurrence of silicosis. Methods The mice were instilled with silicon dioxide through trachea to establish modeling (0.2 g/kg). Samples of lung tissue were collected at the 7 th, 14 th, 21 st and 28 th day after injection.RT-PCR was used to detect the gene transcription of bFGF. Immunohistochemistry was used to analyze the expression of bFGF and FGFR-1 in lung tissue from silicotic and control mice. Results The results of RT-PCR showed that the gray scales of bFGF gene transcription in the silicotic group were 32.08% ± 0.05 % ~ 49.07 % ±14.37%, and in the control group were 34.79% ± 15.50%. The immunohistochemistry result showed the protein expression of bFGF was mainly in vascular smooth muscle cell, macrophage and bronchial epithelial cells and the expression had no difference between the silicotic group and the control group at the 7th, 14th and 21st day after injection of silicon dioxide (P>0.05). Nodular lesions in the lungs began to express small mount of bFGF at the 28th day after injection. The expression of FGFR-1 was significantly elevated from the 7th day to 28th day (IOD:16157.63 ± 359.13 vs. 45 873. 24±359. 13~145 030.70±577.49,P<0.05). And it was expressed by vascular smooth muscle cell, macrophage and mesenchymal cell. Conclusions No increase in the expression of bFGF is seen at the early stage of silicosis in mice, but FGFR-1 is highly expressed in a variety of lung cells. The results show that bFGF might play a role in early infection of silicosis through highly expressed FGFR-1, or play no role in silicosis.%目的 观察染矽尘小鼠早期肺组织碱性成纤维细胞生长因子(basic fibroblast growth factor,bFGF)及成纤维细胞生长因子受体-1(fibroblast growth factor receptor-1,FGFR-1

  5. Exacerbated cardiac fibrosis induced by β-adrenergic activation in old mice due to decreased AMPK activity.

    Science.gov (United States)

    Wang, Jingjing; Song, Yao; Li, Hao; Shen, Qiang; Shen, Jing; An, Xiangbo; Wu, Jimin; Zhang, Jianshu; Wu, Yunong; Xiao, Han; Zhang, Youyi

    2016-11-01

    Senescent hearts exhibit defective responses to β-adrenergic receptor (β-AR) over-activation upon stress, leading to more severe pathological cardiac remodelling. However, the underlying mechanisms remain unclear. Here, we investigated the role of adenosine monophosphate-activated protein kinase (AMPK) in protecting against ageing-associated cardiac remodelling in mice upon β-AR over-activation. 10-week-old (young) and 18-month-old (old) mice were subcutaneously injected with the β-AR agonist isoproterenol (ISO; 5 mg/kg). More extensive cardiac fibrosis was found in old mice upon ISO exposure than in young mice. Meanwhile, ISO treatment decreased AMPK activity and increased β-arrestin 1, but not β-arrestin 2, expression, and the effects of ISO on AMPK and β-arrestin 1 were greater in old mice than in young mice. Similarly, young AMPKα2-knockout (KO) mice showed more extensive cardiac fibrosis upon ISO exposure than that was observed in age-matched wild-type (WT) littermates. The extent of cardiac fibrosis in WT old mice was similar to that in young KO mice. Additionally, AMPK activities were decreased and β-arrestin 1 expression increased in KO mice. In contrast, the AMPK activator metformin decreased β-arrestin 1 expression and attenuated cardiac fibrosis in both young and old mice upon ISO exposure. In conclusion, more severe cardiac fibrosis is induced by ISO in old mice than in young mice. A decrease in AMPK activity, which further increases β-arrestin 1 expression, is the central mechanism underlying the ageing-related cardiac fibrosis induced by ISO. The AMPK activator metformin is a promising therapeutic agent for treating ageing-related cardiac remodelling upon β-AR over-activation.

  6. β-Lactotensin derived from bovine β-lactoglobulin exhibits anxiolytic-like activity as an agonist for neurotensin NTS(2) receptor via activation of dopamine D(1) receptor in mice.

    Science.gov (United States)

    Hou, I-Ching; Suzuki, Chihiro; Kanegawa, Norimasa; Oda, Ayako; Yamada, Ayako; Yoshikawa, Masaaki; Yamada, Daisuke; Sekiguchi, Masayuki; Wada, Etsuko; Wada, Keiji; Ohinata, Kousaku

    2011-11-01

    β-Lactotensin (His-Ile-Arg-Leu) is a bioactive peptide derived from bovine milk β-lactoglobulin, acting as a natural agonist for neurotensin receptors. We found that β-lactotensin exhibited anxiolytic-like activity in an elevated plus-maze test after its intraperitoneal (i.p.) administration in mice. β-Lactotensin was also orally active. The anxiolytic-like activity of β-lactotensin after i.p. administration was blocked by levocabastine, an antagonist for the neurotensin NTS(2) receptor. β-Lactotensin had anxiolytic-like activity in wild-type but not Ntsr2-knockout mice. β-Lactotensin increased intracellular Ca(2+) flux in glial cells derived from wild-type mice but not Ntsr2 knockout mice. These results suggest that β-lactotensin acts as an NTS(2) receptor agonist having anxiolytic-like activity. The anxiolytic-like activity of β-lactotensin was also blocked by SCH23390 and SKF83566, antagonists for dopamine D(1) receptor, but not by raclopride, an antagonist for D(2) receptor. Taken together, β-lactotensin may exhibit anxiolytic-like activity via NTS(2) receptor followed by D(1) receptor.

  7. Experimental oral and nasal transmission of rabies virus in mice.

    Science.gov (United States)

    Charlton, K M; Casey, G A

    1979-01-01

    Weanling female white Swiss mice were exposed to challenge virus standard rabies virus and street virus isolates from various domestic and wild animals. Virus was given free choice as suspension or as infected mouse brain by stomach tube, by single injection of suspension into the oral cavity of unanesthetized mice, by repeated injection into the oral cavity of anesthetized mice and by single application to the external nares of anesthetized mice. Challenge virus standard virus in mouse brain suspension and a suspension of skunk salivary glands infected with street virus (titers greater than or equal to 10(6)MICLD50/0.03 ml) consistently produced high rates of infection in mice exposed intranasally, low to high rates of infection in mice exposed by forced feeding and other artificial methods of oral exposure and very low rates of infection when given free choice. Street virus isolates passaged intracerebrally in mice had titers less than or equal to 10(4.5) MICLD50/0.03 ml and rarely caused rabies in mice exposed orally or nasally by any method. The results indicate that with the isolates used, virus of high titer (greater than or equal to 10(6)MICLD50/0.03 ml) is required to consistently produce infection in mice by the nasal route and that the mucosa of the nasal cavity probably is the chief route of infection even after oral administration.

  8. Studying the lipid peroxidation index, morphology and apoptosis in testis of male BALB/c mice exposed to polybrominated diphenyl ether (BDE-209)%十溴联苯醚(BDE-209)染毒对雄性BALB/c小鼠睾丸毒性作用

    Institute of Scientific and Technical Information of China (English)

    翟金霞; 王兴华; 张照祥; 邹立巍; 丁书姝

    2011-01-01

    exposure group (500 mg/kg BDE-209), the low exposure group (200 mg/kg BDE-20) and control group (normal saline). The mice were exposed by gavage one time a day for 6weeks, then were sacrificed. Body weight, testis weight, malonyldialdehyde (MDA),total supemxide dismutase (T-SOD) and glutathione (GSH) in testis were examined. the morphological alteration of testis was observed. TUNEL assay was used to detect the apoptosis in testicular cells. Results Body weight and testis weight in high and low exposure groups were (21.6140 ± 2.3550)g, (20.8000 ±1.7630)g and (0.1859±0.0349) g, (0.1718±0.0266) g, respectively, which were significantly lower than those (27.7570±1.2880) g and (0.2302±0.0335)g in the control group (P<0.05); the testis coefficient in high exposure group was (0.8640%±0.1706%), which was significantly higher than that (0.8329±0. 1386%) in the control group (P<0.05). The GSH level and SOD activities of testis in 2 BDE-209 groups were 0.044±0.006,0.039±0.005 nmol/mg prot, and 0.735±0.179, 0.907±0.198 U/mg prot, respectively, which were significantly lower than those (0.052±0.067) mol/mg and (1.161 ±0. 188) U/mg in the control group (P<0.05). The levels of MDA in 2 BDE-209 groups were (2.365±0.339) and (1.752±0.366) nmol/mg prot, which were significantly higher than that (1.173±0.232 nmol/mg prot) in control group (P<0.05). there were significant differences of SOD and MDA levels between high exposure group and low exposure group (P <0.05). Histological examination showed that the number of spermatogenic cells and layer were decreased significantly in 2 exposure groups as compared with control group. TUNEL assay showed that apoptosis cells appeared in 2 exposure groups. Conclusion BDE-209 changed lipid peroxidation in male BALB / c mice testis and caused toxic effects on the testis.

  9. Suv39h2 deficiency ameliorates diet-induced steatosis in mice.

    Science.gov (United States)

    Shao, Jing; Li, Luyang; Xu, Huihui; Yang, Lili; Bian, Yaoyao; Fang, Mingming; Xu, Yong

    2017-02-20

    Steatosis is a prototypical metabolic disorder characterized by accumulation of lipid droplets in the liver, extensive hepatic inflammation, and, in advanced stages, accelerated liver fibrogenesis. The molecular mechanism underlying steatosis is not completely understood. In the present study we investigated the involvement of the histone methyltransferase Suv39h2 in the pathogenesis of steatosis. Expression of Suv39h2 was up-regulated in the liver in two different mouse models of steatosis. Suv39h2 knockout (KO) mice developed a less severe form of steatosis fed on a methione-and-choline (MCD) deficient diet, compared to wild type (WT) littermates, as evidenced reduced levels of plasma ALT, down-regulated expression levels of inflammatory mediators, and decreased infiltration of macrophages. In addition, Masson's trichrome staining as well as qPCR measurements of fibrogenic genes suggested that liver fibrosis was attenuated in MCD diet-fed KO mice compared to WT mice. Further analysis found that Suv39h2 represses SIRT1 expression in the liver by stimulating histone H3K9 trimethylation surrounding the SIRT1 promoter and that Suv39h2 deficiency alleviated SIRT1 expression in MCD mice. Therefore, our data support a role of Suv39h2 in promoting steatosis in mice likely contributing to SIRT1 trans-reperssion.

  10. Profound obesity secondary to hyperphagia in mice lacking kinase suppressor of ras 2.

    Science.gov (United States)

    Revelli, Jean-Pierre; Smith, Deon; Allen, Jason; Jeter-Jones, Sabrina; Shadoan, Melanie K; Desai, Urvi; Schneider, Matthias; van Sligtenhorst, Isaac; Kirkpatrick, Laura; Platt, Kenneth A; Suwanichkul, Adisak; Savelieva, Katerina; Gerhardt, Brenda; Mitchell, Jay; Syrewicz, James; Zambrowicz, Brian; Hamman, Brian D; Vogel, Peter; Powell, David R

    2011-05-01

    The kinase suppressor of ras 2 (KSR2) gene resides at human chromosome 12q24, a region linked to obesity and type 2 diabetes (T2D). While knocking out and phenotypically screening mouse orthologs of thousands of druggable human genes, we found KSR2 knockout (KSR2(-/-)) mice to be more obese and glucose intolerant than melanocortin 4 receptor(-/-) (MC4R(-/-)) mice. The obesity and T2D of KSR2(-/-) mice resulted from hyperphagia which was unresponsive to leptin and did not originate downstream of MC4R. The kinases AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are each linked to food intake regulation, but only mTOR had increased activity in KSR2(-/-) mouse brain, and the ability of rapamycin to inhibit food intake in KSR2(-/-) mice further implicated mTOR in this process. The metabolic phenotype of KSR2 heterozygous (KSR2(+/minus;)) and KSR2(-/-) mice suggests that human KSR2 variants may contribute to a similar phenotype linked to human chromosome 12q24.

  11. Direct stimulation of bone mass by increased GH signalling in the osteoblasts of Socs2-/- mice.

    Science.gov (United States)

    Dobie, R; MacRae, V E; Huesa, C; van't Hof, R; Ahmed, S F; Farquharson, C

    2014-10-01

    The suppressor of cytokine signalling (Socs2(-/-))-knockout mouse is characterised by an overgrowth phenotype due to enhanced GH signalling. The objective of this study was to define the Socs2(-/-) bone phenotype and determine whether GH promotes bone mass via IGF1-dependent mechanisms. Despite no elevation in systemic IGF1 levels, increased body weight in 4-week-old Socs2(-/-) mice following GH treatment was associated with increased cortical bone area (Ct.Ar) (PGH. Indeed, male Socs2(-/-) mice had increased Ct.Ar (PGH action. Mechanistic studies showed that in osteoblasts and bone of Socs2(-/-) mice, STAT5 phosphorylation was significantly increased in response to GH. Conversely, overexpression of SOCS2 decreased GH-induced STAT5 signalling. Although an increase in Igf1 expression was observed in Socs2(-/-) osteoblasts following GH, it was not evident in vivo. Igf1 expression levels were not elevated in response to GH in 4-week-old mice and no alterations in expression was observed in bone samples of 6-week-old Socs2(-/-) mice. These studies emphasise the critical role of SOCS2 in controlling the local GH anabolic bone effects. We provide compelling evidence implicating SOCS2 in the regulation of GH osteoblast signalling and ultimately bone accrual, which maybe via mechanisms that are independent of IGF1 production in vivo.

  12. Inflammation-induced hepatocellular carcinoma is dependent on CCR5 in mice.

    Science.gov (United States)

    Barashi, Neta; Weiss, Ido D; Wald, Ori; Wald, Hanna; Beider, Katia; Abraham, Michal; Klein, Shiri; Goldenberg, Daniel; Axelrod, Jonathan; Pikarsky, Eli; Abramovitch, Rinat; Zeira, Evelyne; Galun, Eithan; Peled, Amnon

    2013-09-01

    Human hepatocellular carcinoma (HCC) is an inflammation-induced cancer, which is the third-leading cause of cancer mortality worldwide. We investigated the role of the chemokine receptors, CCR5 and CCR1, in regulating inflammation and tumorigenesis in an inflammation-induced HCC model in mice. Multidrug resistance 2 gene (Mdr2)-knockout (Mdr2-KO) mice spontaneously develop chronic cholestatic hepatitis and fibrosis that is eventually followed by HCC. We generated two new strains from the Mdr2-KO mouse, the Mdr2:CCR5 and the Mdr2:CCR1 double knockouts (DKOs), and set out to compare inflammation and tumorigenesis among these strains. We found that in Mdr2-KO mice lacking the chemokine receptor, CCR5 (Mdr2:CCR5 DKO mice), but not CCR1 (Mdr2:CCR1 DKO), macrophage recruitment and trafficking to the liver was significantly reduced. Furthermore, in the absence of CCR5, reduced inflammation was also associated with reduced periductal accumulation of CD24(+) oval cells and abrogation of fibrosis. DKO mice for Mdr2 and CCR5 exhibited a significant decrease in tumor incidence and size. Our results indicate that CCR5 has a critical role in both the development and progression of liver cancer. Therefore, we propose that a CCR5 antagonist can serve for HCC cancer prevention and treatment. © 2013 by the American Association for the Study of Liver Diseases.

  13. Generation of Immunodeficient Mice Bearing Human Immune Systems by the Engraftment of Hematopoietic Stem Cells.

    Science.gov (United States)

    Hasgur, Suheyla; Aryee, Ken Edwin; Shultz, Leonard D; Greiner, Dale L; Brehm, Michael A

    2016-01-01

    Immunodeficient mice are being used as recipients of human hematopoietic stem cells (HSC) for in vivo analyses of human immune system development and function. The development of several stocks of immunodeficient Prkdc (scid) (scid), or recombination activating 1 or 2 gene (Rag1 or Rag2) knockout mice bearing a targeted mutation in the gene encoding the IL2 receptor gamma chain (IL2rγ), has greatly facilitated the engraftment of human HSC and enhanced the development of functional human immune systems. These "humanized" mice are being used to study human hematopoiesis, human-specific immune therapies, human-specific pathogens, and human immune system homeostasis and function. The establishment of these model systems is technically challenging, and levels of human immune system development reported in the literature are variable between laboratories. The use of standard protocols for optimal engraftment of HSC and for monitoring the development of the human immune systems would enable more direct comparisons between humanized mice generated in different laboratories. Here we describe a standard protocol for the engraftment of human HSC into 21-day-old NOD-scid IL2rγ (NSG) mice using an intravenous injection approach. The multiparameter flow cytometry used to monitor human immune system development and the kinetics of development are described.

  14. Toll-like receptor 2 mediates ischemia-reperfusion injury of the small intestine in adult mice.

    Directory of Open Access Journals (Sweden)

    Toshio Watanabe

    Full Text Available Toll-like receptor 2 (TLR2 recognizes conserved molecular patterns associated with both gram-negative and gram-positive bacteria, and detects some endogenous ligands. Previous studies demonstrated that in ischemia-reperfusion (I/R injury of the small intestine, the TLR2-dependent signaling exerted preventive effects on the damage in young mice, but did not have a significant effect in neonatal mice. We investigated the role of TLR2 in adult ischemia-reperfusion injury in the small intestine. Wild-type and TLR2 knockout mice at 16 weeks of age were subjected to intestinal I/R injury. Some wild-type mice received anti-Ly-6G antibodies to deplete circulating neutrophils. In wild-type mice, I/R induced severe small intestinal injury characterized by infiltration by inflammatory cells, disruption of the mucosal epithelium, and mucosal bleeding. Compared to wild-type mice, TLR2 knockout mice exhibited less severe mucosal injury induced by I/R, with a 35%, 33%, and 43% reduction in histological grading score and luminal concentration of hemoglobin, and the numbers of apoptotic epithelial cells, respectively. The I/R increased the activity of myeloperoxidase (MPO, a marker of neutrophil infiltration, and the levels of mRNA expression of tumor necrosis factor-α (TNF-α, intercellular adhesion molecule-1 (ICAM-1, and cyclooxygenase-2 (COX-2 in the small intestine of the wild-type mice by 3.3-, 3.2-, and 13.0-fold, respectively. TLR2 deficiency significantly inhibited the I/R-induced increase in MPO activity and the expression of mRNAs for TNF-α and ICAM-1, but did not affect the expression of COX-2 mRNA. I/R also enhanced TLR2 mRNA expression by 2.9-fold. TLR2 proteins were found to be expressed in the epithelial cells, inflammatory cells, and endothelial cells. Neutrophil depletion prevented intestinal I/R injury in wild-type mice. These findings suggest that TLR2 may mediate I/R injury of the small intestine in adult mice via induction of inflammatory

  15. Alterations in Brain Inflammation, Synaptic Proteins, and Adult Hippocampal Neurogenesis during Epileptogenesis in Mice Lacking Synapsin2.

    Directory of Open Access Journals (Sweden)

    Deepti Chugh

    Full Text Available Synapsins are pre-synaptic vesicle-associated proteins linked to the pathogenesis of epilepsy through genetic association studies in humans. Deletion of synapsins causes an excitatory/inhibitory imbalance, exemplified by the epileptic phenotype of synapsin knockout mice. These mice develop handling-induced tonic-clonic seizures starting at the age of about 3 months. Hence, they provide an opportunity to study epileptogenic alterations in a temporally controlled manner. Here, we evaluated brain inflammation, synaptic protein expression, and adult hippocampal neurogenesis in the epileptogenic (1 and 2 months of age and tonic-clonic (3.5-4 months phase of synapsin 2 knockout mice using immunohistochemical and biochemical assays. In the epileptogenic phase, region-specific microglial activation was evident, accompanied by an increase in the chemokine receptor CX3CR1, interleukin-6, and tumor necrosis factor-α, and a decrease in chemokine keratinocyte chemoattractant/ growth-related oncogene. Both post-synaptic density-95 and gephyrin, scaffolding proteins at excitatory and inhibitory synapses, respectively, showed a significant up-regulation primarily in the cortex. Furthermore, we observed an increase in the inhibitory adhesion molecules neuroligin-2 and neurofascin and potassium chloride co-transporter KCC2. Decreased expression of γ-aminobutyric acid receptor-δ subunit and cholecystokinin was also evident. Surprisingly, hippocampal neurogenesis was reduced in the epileptogenic phase. Taken together, we report molecular alterations in brain inflammation and excitatory/inhibitory balance that could serve as potential targets for therapeutics and diagnostic biomarkers. In addition, the regional differences in brain inflammation and synaptic protein expression indicate an epileptogenic zone from where the generalized seizures in synapsin 2 knockout mice may be initiated or spread.

  16. Subchronic exposure of mice to Love Canal soil contaminants.

    Science.gov (United States)

    Silkworth, J B; McMartin, D N; Rej, R; Narang, R S; Stein, V B; Briggs, R G; Kaminsky, L S

    1984-04-01

    The health hazard potential of soil collected from the surface of the Love Canal chemical dump site in Niagara Falls, New York, was assessed in 90-day exposure studies. Female CD-1 mice were exposed to two concentrations of the volatile components of 1 kg of soil with and without direct soil contact. Control mice were identically housed but without soil. The soil was replaced weekly and 87 compounds were detected in the air in the cages above fresh and 7-day-old soil as analyzed by gas chromatography/mass spectrometry. The concentration of many of these compounds decreased during the 7-day exposure cycle. Histopathologic, hematologic, and serum enzyme studies followed necropsy of all mice. There was no mortality of mice exposed for up to 90 days under any condition. Thymus and spleen weights relative to body weight were increased after 4 weeks of exposure by inhalation but not after 8 or 12 weeks of exposure. alpha-, beta-, and delta- Benzenehexachlorides , pentachlorobenzene, and hexachlorobenzene were detected in liver tissue from these animals. Mice exposed to 5- to 10-fold elevated concentration of volatiles had increased body and relative kidney weights. There was no chemically induced lesion in any animal exposed only to the volatile soil contaminants. Mice exposed by direct contact with the soil without elevated volatile exposure had increased body (10%) and relative liver weights (169%). Centrolobular hepatocyte hypertrophy, which involved 40 to 70% of the lobules, was observed in all mice in this group.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. 35GHz毫米波急性辐照小鼠诱发丘脑-垂体-肾上腺皮质轴功能改变和Th1/Th2失衡%Functional changes of HPA axis and Th1/Th2 imbalance in mice acutely exposed to 35 GHz millimeter-wave

    Institute of Scientific and Technical Information of China (English)

    杜丽; 孙嵘; 马琼; 李志慧; 蔡金玲; 杨晓云; 满其航; 崔玉芳

    2013-01-01

    目的 观察35 GHz毫米波诱发的急性应激反应中重要细胞因子及下丘脑-垂体-肾上腺皮质(HPA)轴相关激素的表达规律,旨在探索神经·内分泌·免疫系统之间内在的关联.方法 以420 mW/cm2功率密度的35 GHz毫米波源急性辐照BALB/c小鼠60 s.于照后不同时间,用ELISA方法检测血清中IFN-γ、IL-4等细胞因子的表达水平,并用RT-PCR和免疫组织化学方法检测下丘脑促肾上腺皮质素释放激素(CRH)和海马区糖皮质激素受体(GR)的变化.结果 Th1和Th2型细胞因子IFN-γ和IL-4在照后3d均升高至峰值(t=-6.59、-2.28,P<0.05),至照后7d仍明显高于对照组;其比值在照后1和3d明显增高,即发生了明显的Th1/Th2平衡向Th1免疫反应漂移的现象.毫米波急性辐照后下丘脑CRH mRNA含量出现持续性升高,至7d升高至峰值(t=-7.03,P <0.05);而海马GR mRNA含量在3d达到峰值后迅速降低至对照组水平.下丘脑CRH和海马GR蛋白表达的趋势与其mRNA水平变化基本一致.结论 小鼠经35 GHz毫米波急性辐照后,Th1/Th2平衡向Th1方向偏移;同时应激增加的下丘脑CRH和海马GR对IFN-γ等因子的反馈抑制,使向Th1偏移的免疫失衡现象得以改善,可缓解过度应激造成的免疫损伤.%Objective To investigate the expression pattern of cytokines and HPA axis hormones in acute stress reaction induced by 35 GHz millimeter-wave (MMW) radiation,and to explore the intrinsic association among the nerve-endocrine-immune system.Methods BALB/c mice were exposed to 35 GHz MMW with an average power density of 420 mW/cm2 for 60 s.The contents of IFN-γ and IL-4 in serum were measured and the expression level of hypothalamic corticotropin releasing hormone (CRH) and hippocampus glucocorticoid receptor (GR) in brain were analyzed at different time points after MMW exposure.Results The levels of IFN-γ and IL-4 and the cytokines of Thl and Th2 increased to peak levels (t =-6.59,-2.28,P < 0.05) at 3

  18. Glucoraphanin Ameliorates Obesity and Insulin Resistance Through Adipose Tissue Browning and Reduction of Metabolic Endotoxemia in Mice.

    Science.gov (United States)

    Nagata, Naoto; Xu, Liang; Kohno, Susumu; Ushida, Yusuke; Aoki, Yudai; Umeda, Ryohei; Fuke, Nobuo; Zhuge, Fen; Ni, Yinhua; Nagashimada, Mayumi; Takahashi, Chiaki; Suganuma, Hiroyuki; Kaneko, Shuichi; Ota, Tsuguhito

    2017-05-01

    Low-grade sustained inflammation links obesity to insulin resistance and nonalcoholic fatty liver disease (NAFLD). However, therapeutic approaches to improve systemic energy balance and chronic inflammation in obesity are limited. Pharmacological activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) alleviates obesity and insulin resistance in mice; however, Nrf2 inducers are not clinically available owing to safety concerns. Thus, we examined whether dietary glucoraphanin, a stable precursor of the Nrf2 inducer sulforaphane, ameliorates systemic energy balance, chronic inflammation, insulin resistance, and NAFLD in high-fat diet (HFD)-fed mice. Glucoraphanin supplementation attenuated weight gain, decreased hepatic steatosis, and improved glucose tolerance and insulin sensitivity in HFD-fed wild-type mice but not in HFD-fed Nrf2 knockout mice. Compared with vehicle-treated controls, glucoraphanin-treated HFD-fed mice had lower plasma lipopolysaccharide levels and decreased relative abundance of the gram-negative bacteria family Desulfovibrionaceae in their gut microbiomes. In HFD-fed mice, glucoraphanin increased energy expenditure and the protein expression of uncoupling protein 1 (Ucp1) in inguinal and epididymal adipose depots. Additionally, in this group, glucoraphanin attenuated hepatic lipogenic gene expression, lipid peroxidation, classically activated M1-like macrophage accumulation, and inflammatory signaling pathways. By promoting fat browning, limiting metabolic endotoxemia-related chronic inflammation, and modulating redox stress, glucoraphanin may mitigate obesity, insulin resistance, and NAFLD. © 2017 by the American Diabetes Association.

  19. Nucleotide-Binding Oligomerization Domain-1 and -2 Play No Role in Controlling Brucella abortus Infection in Mice

    Directory of Open Access Journals (Sweden)

    Fernanda S. Oliveira

    2012-01-01

    Full Text Available Nucleotide-binding oligomerization domain proteins (NODs are modular cytoplasmic proteins implicated in the recognition of peptidoglycan-derived molecules. Further, several in vivo studies have demonstrated a role for Nod1 and Nod2 in host defense against bacterial pathogens. Here, we demonstrated that macrophages from NOD1-, NOD2-, and Rip2-deficient mice produced lower levels of TNF-α following infection with live Brucella abortus compared to wild-type mice. Similar reduction on cytokine synthesis was not observed for IL-12 and IL-6. However, NOD1, NOD2, and Rip2 knockout mice were no more susceptible to infection with virulent B. abortus than wild-type mice. Additionally, spleen cells from NOD1-, NOD2-, and Rip2-deficient mice showed unaltered production of IFN-γ compared to C57BL/6 mice. Taken together, this study demonstrates that NOD1, NOD2 and Rip2 are dispensable for the control of B. abortus during in vivo infection.

  20. Chrysophanol attenuates lead exposure-induced injury to hippocampal neurons in neonatal mice

    Institute of Scientific and Technical Information of China (English)

    Ji Zhang; Chunlin Yan; Shu Wang; Yong Hou; Guiping Xue; Li Zhang

    2014-01-01

    Previous studies have shown that chrysophanol protects against learning and memory impairments in lead-exposed adult mice. In the present study, we investigated whether chrys-ophanol can alleviate learning and memory dysfunction and hippocampal neuronal injury in lead-exposed neonatal mice. At the end of lactation, chrysophanol (0.1, 1.0, 10.0 mg/kg) was administered to the neonatal mice by intraperitoneal injection for 15 days. Chrysophanol signifi-cantly alleviated injury to hippocampal neurons and improved learning and memory abilities in the lead-poisoned neonatal mice. Chrysophanol also significantly decreased lead content in blood, brain, heart, spleen, liver and kidney in the lead-exposed neonatal mice. The levels of malondialdehyde in the brain, liver and kidney were significantly reduced, and superoxide dismutase and glutathione peroxidase activities were significantly increased after chrysophanol treatment. Collectively, these findings indicate that chrysophanol can significantly reduce damage to hippocampal neurons in lead-exposed neonatal mice.

  1. Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal

    Science.gov (United States)

    Abu-Elheiga, Lutfi; Matzuk, Martin M.; Kordari, Parichher; Oh, WonKeun; Shaikenov, Tattym; Gu, Ziwei; Wakil, Salih J.

    2005-01-01

    Acetyl-CoA carboxylases (ACC1 and ACC2) catalyze the carboxylation of acetyl-CoA to form malonyl-CoA, an intermediate metabolite that plays a pivotal role in the regulation of fatty acid metabolism. We previously reported that ACC2 null mice are viable, and that ACC2 plays an important role in the regulation of fatty acid oxidation through the inhibition of carnitine palmitoyltransferase I, a mitochondrial component of the fatty-acyl shuttle system. Herein, we used gene targeting to knock out the ACC1 gene. The heterozygous mutant mice (Acc1+/–) had normal fertility and lifespans and maintained a similar body weight to that of their wild-type cohorts. The mRNA level of ACC1 in the tissues of Acc1+/– mice was half that of the wild type; however, the protein level of ACC1 and the total malonyl-CoA level were similar. In addition, there was no difference in the acetate incorporation into fatty acids nor in the fatty acid oxidation between the hepatocytes of Acc1+/– mice and those of the wild type. In contrast to Acc2–/– mice, Acc1–/– mice were not detected after mating. Timed pregnancies of heterozygotes revealed that Acc–/– embryos are already undeveloped at embryonic day (E)7.5, they die by E8.5, and are completely resorbed at E11.5. Our previous results of the ACC2 knockout mice and current studies of ACC1 knockout mice further confirm our hypotheses that malonyl-CoA exists in two independent pools, and that ACC1 and ACC2 have distinct roles in fatty acid metabolism. PMID:16103361

  2. Disabled-2 Determines Commitment of a Pre-adipocyte Population in Juvenile Mice

    Science.gov (United States)

    Tao, Wensi; Moore, Robert; Meng, Yue; Yeasky, Toni M.; Smith, Elizabeth R.; Xu, Xiang-Xi

    2016-01-01

    Disabled-2 (Dab2) is a widely expressed clathrin binding endocytic adaptor protein and known for the endocytosis of the low-density lipoprotein (LDL) family receptors. Dab2 also modulates endosomal Ras/MAPK (Erk1/2) activity by regulating the disassembly of Grb2/Sos1 complexes associated with clathrin-coated vesicles. We found that the most prominent phenotype of Dab2 knockout mice was their striking lean body composition under a high fat and high caloric diet, although the weight of the mutant mice was indistinguishable from wild-type littermates on a regular chow. The remarkable difference in resistance to high caloric diet-induced weight gain of the dab2-deleted mice was presented only in juvenile but not in mature mice. Investigation using Dab2-deficient embryonic fibroblasts and mesenchymal stromal cells indicated that Dab2 promoted adipogenic differentiation by modulation of MAPK (Erk1/2) activity, which otherwise suppresses adipogenesis through the phosphorylation of PPARγ. The results suggest that Dab2 is required for the excessive calorie-induced differentiation of an adipocyte progenitor cell population that is present in juvenile but depleted in mature animals. The finding provides evidence for a limited pre-adipocyte population in juvenile mammals and the requirement of Dab2 in the regulation of Ras/MAPK signal in the commitment of the precursor cells to adipose tissues. PMID:27779214

  3. Development of a reactive stroma associated with prostatic intraepithelial neoplasia in EAF2 deficient mice.

    Directory of Open Access Journals (Sweden)

    Laura E Pascal

    Full Text Available ELL-associated factor 2 (EAF2 is an androgen-responsive tumor suppressor frequently deleted in advanced prostate cancer that functions as a transcription elongation factor of RNA Pol II through interaction with the ELL family proteins. EAF2 knockout mice on a 129P2/OLA-C57BL/6J background developed late-onset lung adenocarcinoma, hepatocellular carcinoma, B-cell lymphoma and high-grade prostatic intraepithelial neoplasia. In order to further characterize the role of EAF2 in the development of prostatic defects, the effects of EAF2 loss were compared in different murine strains. In the current study, aged EAF2(-/- mice on both the C57BL/6J and FVB/NJ backgrounds exhibited mPIN lesions as previously reported on a 129P2/OLA-C57BL/6J background. In contrast to the 129P2/OLA-C57BL/6J mixed genetic background, the mPIN lesions in C57BL/6J and FVB/NJ EAF2(-/- mice were associated with stromal defects characteristic of a reactive stroma and a statistically significant increase in prostate microvessel density. Stromal inflammation and increased microvessel density was evident in EAF2-deficient mice on a pure C57BL/6J background at an early age and preceded the development of the histologic epithelial hyperplasia and neoplasia found in the prostates of older EAF2(-/- animals. Mice deficient in EAF2 had an increased recovery rate and a decreased overall response to the effects of androgen deprivation. EAF2 expression in human cancer was significantly down-regulated and microvessel density was significantly increased compared to matched normal prostate tissue; furthermore EAF2 expression was negatively correlated with microvessel density. These results suggest that the EAF2 knockout mouse on the C57BL/6J and FVB/NJ genetic backgrounds provides a model of PIN lesions associated with an altered prostate microvasculature and reactive stromal compartment corresponding to that reported in human prostate tumors.

  4. Euthanasia of neonatal mice with carbon dioxide

    Science.gov (United States)

    Pritchett, K.; Corrow, D.; Stockwell, J.; Smith, A.

    2005-01-01

    Exposure to carbon dioxide (CO2) is the most prevalent method used to euthanize rodents in biomedical research. The purpose of this study was to determine the time of CO2 exposure required to euthanize neonatal mice (0 to 10 days old). Multiple groups of mice were exposed to 100% CO 2 for time periods between 5 and 60 min. Mice were placed in room air for 10 or 20 min after CO2 exposure, to allow for the chance of recovery. If mice recovered at one time point, a longer exposure was examined. Inbred and outbred mice were compared. Results of the study indicated that time to death varied with the age of the animals and could be as long as 50 min on the day of birth and differed between inbred and outbred mice. Institutions euthanizing neonatal mice with CO2 may wish to adjust their CO 2 exposure time periods according the age of the mice and their genetic background. Copyright 2005 by the American Association for Laboratory Animal Science.

  5. Diet-induced glucose intolerance in mice with decreased beta-cell ATP-sensitive K+ channels.

    Science.gov (United States)

    Remedi, Maria S; Koster, Joseph C; Markova, Kamelia; Seino, Susumu; Miki, Takashi; Patton, Brian L; McDaniel, Michael L; Nichols, Colin G

    2004-12-01

    ATP-sensitive K+ channels (K(ATP) channels) control electrical activity in beta-cells and therefore are key players in excitation-secretion coupling. Partial suppression of beta-cell K(ATP) channels in transgenic (AAA) mice causes hypersecretion of insulin and enhanced glucose tolerance, whereas complete suppression of these channels in Kir6.2 knockout (KO) mice leads to hyperexcitability, but mild glucose intolerance. To test the interplay of hyperexcitability and dietary stress, we subjected AAA and KO mice to a high-fat diet. After 3 months on the diet, both AAA and KO mice converted to an undersecreting and markedly glucose-intolerant phenotype. Although Kir6.2 is expressed in multiple tissues, its primary functional consequence in both AAA and KO mice is enhanced beta-cell electrical activity. The results of our study provide evidence that, when combined with dietary stress, this hyperexcitability is a causal diabetic factor. We propose an "inverse U" model for the response to enhanced beta-cell excitability: the expected initial hypersecretion can progress to undersecretion and glucose-intolerance, either spontaneously or in response to dietary stress.

  6. Antioxidants Improve the Phenotypes of Dilated Cardiomyopathy and Muscle Fatigue in Mitochondrial Superoxide Dismutase-Deficient Mice

    Directory of Open Access Journals (Sweden)

    Takahiko Shimizu

    2013-01-01

    Full Text Available Redox imbalance elevates the reactive oxygen species (ROS level in cells and promotes age-related diseases. Superoxide dismutases (SODs are antioxidative enzymes that catalyze the degradation of ROS. There are three SOD isoforms: SOD1/CuZn-SOD, SOD2/Mn-SOD, and SOD3/EC-SOD. SOD2, which is localized in the mitochondria, is an essential enzyme required for mouse survival, and systemic knockout causes neonatal lethality in mice. To investigate the physiological function of SOD2 in adult mice, we generated a conditional Sod2 knockout mouse using a Cre-loxP system. When Sod2 was specifically deleted in the heart and muscle, all mice exhibited dilated cardiomyopathy (DCM and died by six months of age. On the other hand, when Sod2 was specifically deleted in the skeletal muscle, mice showed severe exercise disturbance without morphological abnormalities. These provide useful model of DCM and muscle fatigue. In this review, we summarize the impact of antioxidants, which were able to regulate mitochondrial superoxide generation and improve the phenotypes of the DCM and the muscle fatigue in mice.

  7. Impact of chronic low to moderate alcohol consumption on blood lipid and heart energy profile in acetaldehyde dehydrogenase 2-deficient mice.

    Science.gov (United States)

    Fan, Fan; Cao, Quan; Wang, Cong; Ma, Xin; Shen, Cheng; Liu, Xiang-wei; Bu, Li-ping; Zou, Yun-zeng; Hu, Kai; Sun, Ai-jun; Ge, Jun-bo

    2014-08-01

    To investigate the roles of acetaldehyde dehydrogenase 2 (ALDH2), the key enzyme of ethanol metabolism, in chronic low to moderate alcohol consumption-induced heart protective effects in mice. Twenty-one male wild-type (WT) or ALDH2-knockout (KO) mice were used in this study. In each genotype, 14 animals received alcohol (2.5%, 5% and 10% in week 1-3, respectively, and 18% in week 4-7), and 7 received water for 7 weeks. After the treatments, survival rate and general characteristics of the animals were evaluated. Serum ethanol and acetaldehyde levels and blood lipids were measured. Metabolomics was used to characterize the heart and serum metabolism profiles. Chronic alcohol intake decreased the survival rate of KO mice by 50%, and significantly decreased their body weight, but did not affect those of WT mice. Chronic alcohol intake significantly increased the serum ethanol levels in both WT and KO mice, but KO mice had significantly higher serum acetaldehyde levels than WT mice. Chronic alcohol intake significantly increased the serum HDL cholesterol levels in WT mice, and did not change the serum HDL cholesterol levels in KO mice. After chronic alcohol intake, WT and KO mice showed differential heart and serum metabolism profiles, including the 3 main energy substrate types (lipids, glucose and amino acids) and three carboxylic acid cycles. Low to moderate alcohol consumption increases HDL cholesterol levels and improves heart energy metabolism profile in WT mice but not in ALDH2-KO mice. Thus, preserved ALDH2 function is essential for the protective effect of low to moderate alcohol on the cardiovascular system.

  8. Keratinocyte-targeted expression of human laminin γ2 rescues skin blistering and early lethality of laminin γ2 deficient mice.

    Directory of Open Access Journals (Sweden)

    Tracy L Adair-Kirk

    Full Text Available Laminin-332 is a heterotrimeric basement membrane component comprised of the α3, ß3, and γ2 laminin chains. Laminin-332 modulates epithelial cell processes, such as adhesion, migration, and differentiation and is prominent in many embryonic and adult tissues. In skin, laminin-332 is secreted by keratinocytes and is a key component of hemidesmosomes connecting the keratinocytes to the underlying dermis. In mice, lack of expression of any of the three Laminin-332 chains result in impaired anchorage and detachment of the epidermis, similar to that seen in human junctional epidermolysis bullosa, and death occurs within a few days after birth. To bypass the early lethality of laminin-332 deficiency caused by the knockout of the mouse laminin γ2 chain, we expressed a dox-controllable human laminin γ2 transgene under a keratinocyte-specific promoter on the laminin γ2 (Lamc2 knockout background. These mice appear similar to their wild-type littermates, do not develop skin blisters, are fertile, and survive >1.5 years. Immunofluorescence analyses of the skin showed that human laminin γ2 colocalized with mouse laminin α3 and ß3 in the basement membrane zone underlying the epidermis. Furthermore, the presence of "humanized" laminin-332 in the epidermal basement membrane zone rescued the alterations in the deposition of hemidesmosomal components, such as plectin, collagen type XVII/BP180, and integrin α6 and ß4 chains, seen in conventional Lamc2 knockout mice, leading to restored formation of hemidesmosomes. These mice will be a valuable tool for studies of organs deficient in laminin-332 and the role of laminin-332 in skin, including wound healing.

  9. Quenched Reinforcement Exposed to Fire

    DEFF Research Database (Denmark)

    Hertz, Kristian Dahl

    2006-01-01

    Idealized data are derived for the tensile strength of quenched and tempered prestressing steel and of quenched and self-tempered reinforcing bars for fire safety design. 0.2% stresses are derived as a function of the maximum temperature and in addition, 2.0% stresses are provided. A strain of 2.......0% is seldom found in “slack” (not prestressed) reinforcement, but 2.0% stresses might be relevant for reinforcement in T shaped cross sections and for prestressed structures, where large strains can be applied. All data are provided in a “HOT” condition during a fire and in a “COLD” condition after a fire....... The COLD condition is relevant for analyses of residual load bearing capacity of a structure after a fire exposure. It is also relevant for analyses of concrete structures exposed to fully developed fire courses. The reason is that compression zones of concrete are always the weakest in the cooling phase...

  10. Advances in treating exposed fractures.

    Science.gov (United States)

    Nogueira Giglio, Pedro; Fogaça Cristante, Alexandre; Ricardo Pécora, José; Partezani Helito, Camilo; Lei Munhoz Lima, Ana Lucia; Dos Santos Silva, Jorge

    2015-01-01

    The management of exposed fractures has been discussed since ancient times and remains of great interest to present-day orthopedics and traumatology. These injuries are still a challenge. Infection and nonunion are feared complications. Aspects of the diagnosis, classification and initial management are discussed here. Early administration of antibiotics, surgical cleaning and meticulous debridement are essential. The systemic conditions of patients with multiple trauma and the local conditions of the limb affected need to be taken into consideration. Early skeletal stabilization is necessary. Definitive fixation should be considered when possible and provisional fixation methods should be used when necessary. Early closure should be the aim, and flaps can be used for this purpose.

  11. Quenched Reinforcement Exposed to Fire

    DEFF Research Database (Denmark)

    Hertz, Kristian Dahl

    2006-01-01

    Idealized data are derived for the tensile strength of quenched and tempered prestressing steel and of quenched and self-tempered reinforcing bars for fire safety design. 0.2% stresses are derived as a function of the maximum temperature and in addition, 2.0% stresses are provided. A strain of 2.......0% is seldom found in “slack” (not prestressed) reinforcement, but 2.0% stresses might be relevant for reinforcement in T shaped cross sections and for prestressed structures, where large strains can be applied. All data are provided in a “HOT” condition during a fire and in a “COLD” condition after a fire....... The COLD condition is relevant for analyses of residual load bearing capacity of a structure after a fire exposure. It is also relevant for analyses of concrete structures exposed to fully developed fire courses. The reason is that compression zones of concrete are always the weakest in the cooling phase...

  12. Chronic exposure to low frequency noise at moderate levels causes impaired balance in mice.

    Directory of Open Access Journals (Sweden)

    Haruka Tamura

    Full Text Available We are routinely exposed to low frequency noise (LFN; below 0.5 kHz at moderate levels of 60-70 dB sound pressure level (SPL generated from various sources in occupational and daily environments. LFN has been reported to affect balance in humans. However, there is limited information about the influence of chronic exposure to LFN at moderate levels for balance. In this study, we investigated whether chronic exposure to LFN at a moderate level of 70 dB SPL affects the vestibule, which is one of the organs responsible for balance in mice. Wild-type ICR mice were exposed for 1 month to LFN (0.1 kHz and high frequency noise (HFN; 16 kHz at 70 dB SPL at a distance of approximately 10-20 cm. Behavior analyses including rotarod, beam-crossing and footprint analyses showed impairments of balance in LFN-exposed mice but not in non-exposed mice or HFN-exposed mice. Immunohistochemical analysis showed a decreased number of vestibular hair cells and increased levels of oxidative stress in LFN-exposed mice compared to those in non-exposed mice. Our results suggest that chronic exposure to LFN at moderate levels causes impaired balance involving morphological impairments of the vestibule with enhanced levels of oxidative stress. Thus, the results of this study indicate the importance of considering the risk of chronic exposure to LFN at a moderate level for imbalance.

  13. Motor Neurons Exhibit Sustained Loss of Atrophy Reversal in Immunodeficent Mice.

    Science.gov (United States)

    Huang, Zhi; Petitto, John M

    2013-01-01

    Our lab showed previously that whereas a substantial portion of chronically resected facial motor neurons reside in an atrophied state that can be reversed at 14 days following reinjury in wild-type (WT) mice, atrophy reversal was altered in immunodeficient mice. It was unclear, however, if the abnormal response at day 14 post-reinjury in immunodeficient mice might be due to differences in the kinetics of the reversal response or impaired regeneration. We sought to address this question, and test our working hypothesis that the normal regeneration of atrophied motor neurons is dependent on normal adaptive immunity, by comparing WT and immunodeficient recombination activating gene-2 knockout (RAG2-KO) mice that lack a mature T and B lymphocytes, at 3 and 28 days following reinjury. In WT mice, facial motor neurons that were resected for 10 weeks and subsequently reinjured for 3 days were able to regain fully an apparent 40% loss of countable neurons, and nearly 45% of that robust increase in neurons was sustained at 28 days post-reinjury in the WT mice. By contrast, at both 3 and 28 days post-reinjury RAG2-KO mice failed to show any increase in neuronal number. Size measurements showed that the surviving neurons of WT and RAG2-KO mice exhibited substantial motor neuron hypertrophy at 3 days post-reinjury, and similar levels of normal size motor neurons by 28 days post-reinjury. Among the WT mice, small numbers of T lymphocytes where found in the reinjured facial motor nucleus (FMN), and were significantly higher at 3 days, but not 28 days, in the reinjury compared to sham-reinjury groups. No differences were seen between the WT and RAG2-KO mice in overall microglial cell activity using CD11b expression following reinjury. These data suggest that many resected motor neurons did not survive the initial resection in RAG2-KO mice, whereas in WT mice they atrophied and could be restimulated by reinjury to regenerate their phenotype. Moreover, they indicate that normal T

  14. Effects of the light--dark cycle on a water tank social interaction test in mice.

    Science.gov (United States)

    Nejdi, A; Guastavino, J M; Lalonde, R

    1996-01-01

    Mice were exposed to a water tank interaction test in which food could be obtained either by wading in the water or by attacking littermates. A tank with progressively rising water levels caused mice in groups of four to differentiate into those willing to wade (carrier mice) from those unwilling to wade (noncarrier mice). Noncarrier mice could only obtain food by stealing it from carrier mice or from other noncarrier mice. It was found that mice during the dark period of the light--dark cycle were more willing to wade in the search for food rather than attempt to steal food from other mice. Because mice are generally more active during the dark period, this result suggests that higher activity levels increase the willingness to share the work load, a form of altruism, rather than promote parasitic behavior and aggression.

  15. Murine tribbles homolog 2 deficiency affects erythroid progenitor development and confers macrocytic anemia on mice.

    Science.gov (United States)

    Lin, Kou-Ray; Yang-Yen, Hsin-Fang; Lien, Huang-Wei; Liao, Wei-Hao; Huang, Chang-Jen; Lin, Liang-In; Li, Chung-Leung; Yen, Jeffrey Jong-Young

    2016-08-23

    Tribbles homolog 2 (Trib2) is a member of Tribbles protein pseudokinases and involves in apoptosis, autoimmunity, cancer, leukemia and erythropoiesis, however, the physiological function of Trib2 in hematopoietic system remains to be elucidated. Here, we report that Trib2 knockout (KO) mice manifest macrocytic anemia and increase of T lymphocytes. Although Trib2 deficient RBCs have similar half-life as the control RBCs, Trib2 KO mice are highly vulnerable to oxidant-induced hemolysis. Endogenous Trib2 mRNA is expressed in early hematopoietic progenitors, erythroid precursors, and lymphoid lineages, but not in mature RBCs, myeloid progenitors and granulocytes. Consistently, flow cytometric analysis and in vitro colony forming assay revealed that deletion of Trib2 mainly affected erythroid lineage development, and had no effect on either granulocyte or megakaryocyte lineages in bone marrow. Furthermore, a genetic approach using double knockout of Trib2 and C/ebpα genes in mice suggested that Trib2 promotes erythropoiesis independent of C/ebpα proteins in vivo. Finally, ectopic expression of human Trib2 in zebrafish embryos resulted in increased expression of erythropoiesis-related genes and of hemoglobin. Taking all data together, our results suggest that Trib2 positively promotes early erythrocyte differentiation and is essential for tolerance to hemolysis.

  16. Ultrastructural analyses of platelets and fibrin networks in BALB/c mice after inhalation of spherical and rod-shaped titanium nanoparticles

    CSIR Research Space (South Africa)

    Oosthuizen, MA

    2010-10-01

    Full Text Available and fibrin ultrastructure. Mice were divided into five experimental groups comprising of a control group, high and low concentration groups exposed to the sphericalshaped particles, as well as high and low concentration groups exposed to the rod...

  17. Lycopene attenuated hepatic tumorigenesis via differential mechanisms depending on carotenoid cleavage enzyme in mice.

    Science.gov (United States)

    Ip, Blanche C; Liu, Chun; Ausman, Lynne M; von Lintig, Johannes; Wang, Xiang-Dong

    2014-12-01

    Obesity is associated with increased liver cancer risks and mortality. We recently showed that apo-10'-lycopenoic acid, a lycopene metabolite generated by beta-carotene-9',10'-oxygenase (BCO2), inhibited carcinogen-initiated, high-fat diet (HFD)-promoted liver inflammation, and hepatic tumorigenesis development. The present investigation examined the outstanding question of whether lycopene could suppress HFD-promoted hepatocellular carcinoma (HCC) progression, and if BCO2 expression is important using BCO2-knockout (BCO2-KO) and wild-type male mice. Results showed that lycopene supplementation (100 mg/kg diet) for 24 weeks resulted in comparable accumulation of hepatic lycopene (19.4 vs. 18.2 nmol/g) and had similar effects on suppressing HFD-promoted HCC incidence (19% vs. 20%) and multiplicity (58% vs. 62%) in wild-type and BCO2-KO mice, respectively. Intriguingly, lycopene chemopreventive effects in wild-type mice were associated with reduced hepatic proinflammatory signaling (phosphorylation of NK-κB p65 and STAT3; IL6 protein) and inflammatory foci. In contrast, the protective effects of lycopene in BCO2-KO but not in wild-type mice were associated with reduced hepatic endoplasmic reticulum stress-mediated unfolded protein response (ER(UPR)), through decreasing ER(UPR)-mediated protein kinase RNA-activated like kinase-eukaryotic initiation factor 2α activation, and inositol requiring 1α-X-box-binding protein 1 signaling. Lycopene supplementation in BCO2-KO mice suppressed oncogenic signals, including Met mRNA, β-catenin protein, and mTOR complex 1 activation, which was associated with increased hepatic microRNA (miR)-199a/b and miR214 levels. These results provided novel experimental evidence that dietary lycopene can prevent HFD-promoted HCC incidence and multiplicity in mice, and may elicit different mechanisms depending on BCO2 expression. ©2014 American Association for Cancer Research.

  18. Control for occupationally exposed personnels

    Energy Technology Data Exchange (ETDEWEB)

    Murakami, Hiroyuki [Japan Atomic Energy Research Inst., Tokai, Ibaraki (Japan). Tokai Research Establishment; Momose, Takuma

    1999-03-01

    The present status of the technology for the measurement of personnel exposure dose was reviewed based on the basic concept of ICRP Recommendation on new assessment of exposure dose. The personnel dosimeter which has been mostly used by occupationally exposed personnels in Japan is film badge or thermoluminescence dosimeter. Now, photoluminescent glass dosimeter has been paid attention because pulse excitation method by UV laser has been developed. Measurement at an accuracy of 0.1 mSv or more became possible by using this dosimeter at present. In addition, characteristic studies for practical application of electronic, photostimulated luminescence and neutron dosimeters are progressing now. Revision of kinetic model of in vivo metabolism of radioactive substances is progressing based on the recent findings since ICRP Recommendation in 1990. Monitoring an individual internal exposure is made by two methods; direct measurement of the radiation emitted from the body and indirect one by radioanalysis of excretes etc. The latter is inferior to the former in respect of the accuracy of dose assessment, but the direct method is more suitable to detect a little amount of radioactive substance incorporated because of its high sensitivity. In future, it is needed to provide a considerable number of whole body counters against a large-scale nuclear accident. (M.N.)

  19. Neuropeptide Y-Y2 receptor knockout mice: influence of genetic background on anxiety-related behaviors.

    Science.gov (United States)

    Zambello, E; Zanetti, L; Hédou, G F; Angelici, O; Arban, R; Tasan, R O; Sperk, G; Caberlotto, L

    2011-03-10

    Neuropeptide Y (NPY) has been extensively studied in relation to anxiety and depression but of the seven NPY receptors known to date, it is not yet clear which one is mainly involved in mediating its effects in emotional behavior. Mice lacking the NPY-Y2 receptors were previously shown to be less anxious due to their improved ability to cope with stressful situations. In the present study, the behavioral phenotype including the response to challenges was analyzed in NPY-Y2 knockout (KO) mice backcrossed in to congenic C57BL/6 background. In the elevated plus-maze (EPM) and the forced swim test (FST), the anxiolytic-like or antidepressant-like phenotype of the NPY-Y2 KO mice could not be confirmed, although this study differs from the previous one only with regard to the genetic background of the mice. In addition, no differences in response to acute stress or to the antidepressant desipramine in the FST were detected between wild type (WT) and NPY-Y2 KO animals. These results suggest that the genetic background of the animals appears to have a strong influence on the behavioral phenotype of NPY-Y2 KO mice. Additionally, to further characterize the animals by their biochemical response to a challenge, the neurochemical changes induced by the anxiogenic compound yohimbine were measured in the medial prefrontal cortex (mPFC) of NPY-Y2 KO and compared to WT mice. Dopamine (DA) levels were significantly increased by yohimbine in the WT but unaffected in the KO mice, suggesting that NPY-Y2 receptor exerts a direct control over both the tonic and phasic release of DA and that, although the anxiety-like behavior of these NPY-Y2 KO mice is unaltered, there are clear modifications of DA dynamics. However, yohimbine led to a significant increase in noradrenaline (NA) concentration and a slight reduction in serotonin concentration that were identical for both phenotypes.

  20. Protective Effect of Total Flavonoids from Alpinia officinarum Hance on Brain and Kidney Oxidative Stress in Mice Exposed to Lead Acetate%高良姜总黄酮对铅中毒致小鼠脑、肾氧化应激的保护作用研究

    Institute of Scientific and Technical Information of China (English)

    夏道宗; 金相国; 陆超; 徐丽萍; 孙瑶婷

    2013-01-01

    [目的]探讨高良姜总黄酮(Total flavonoids from Alpinia officinarum Hance,TFAO)对铅中毒小鼠脑、肾脏氧化应激的保护作用。[方法]60只小鼠分为正常组,模型组,阳性组,TFAO低、中、高剂量组。通过腹腔注射醋酸铅建立铅中毒模型,灌胃给予受试物。实验结束后,测定小鼠体重、脏器指数,血液及组织铅浓度,脑、肾氧化应激参数,如还原型谷胱甘肽(glutathione,GSH)、丙二醛(malondialdehyde,MDA)、谷胱甘肽过氧化物酶(glutathione peroxidase,GSH-Px)、超氧化物歧化酶(superoxide dismutase,SOD)、过氧化氢酶(catalase,CAT)等指标。[结果]高浓度TFAO对小鼠血液及组织中铅含量有明显降低作用,且未造成其他必需元素如锌的流失。与模型组相比较,TFAO可显著增加小鼠脑、肾GSH含量和抗氧化酶活性,并能显著降低MDA水平。[结论] TFAO可通过提高铅中毒小鼠组织中抗氧化酶的活性,改善脂质过氧化,从而发挥其对铅诱导的脑、肾氧化应激的保护效应。%[Objective] To investigate the protective effect of total flavonoids from Alpinia officinarum Hance(TFAO) on lead acetate induced oxidative stress in brain and kidney of mice. [Methods] Al 60 mice were randomly divided into 6 groups:normal control group, lead group, positive control group, lead+TFAO(100, 300, 500 mg·kg-1) groups. Mice except normal control group received intraperitoneal injections of lead acetate every other day, and dif-ferent test substances were administrated to mice oral y once a day. After the last dose was administrated, the body weight, viscera index, lead and zinc con-tents in blood, brain and kidney, oxidative stress parameters such as glutathione(GSH), glutathione peroxidase(GSH-Px), superoxide dismutase(SOD), cata-lase(CAT) and malondialdehyde (MDA) in brain and kidney were determined. [Results] TFAO in high dose (500 mg·kg-1 could lower the lead

  1. EXPOSE-R2, the 3rd successful EXPOSE mission – a mission and mission ground reference overview

    OpenAIRE

    2016-01-01

    For nearly 2 years the 3rd ESA EXPOSE mission, the 2nd on the Russian Zvezda module of the ISS, exposed a variety of astrobiological samples to space and simulated Mars environmental conditions. Various chemical compounds and organisms like bacteria, archaea, fungi, plant seeds, lychens, mosses and animal eggs and larvae from the international experiments BIOMEX, BOSS, P.S.S. and the IBMP-experiment were exposed to space vacuums dryness, extraterrestrial short wavelength UV, radiation and tem...

  2. Short report: Exposing laboratory-reared fleas to soil and wild flea feces increases transmission of Yersinia pestis.

    Science.gov (United States)

    Jones, Ryan T; Vetter, Sara M; Gage, Kenneth L

    2013-10-01

    Laboratory-reared Oropsylla montana were exposed to soil and wild-caught Oropsylla montana feces for 1 week. Fleas from these two treatments and a control group of laboratory-reared fleas were infected with Yersinia pestis, the etiological agent of plague. Fleas exposed to soil transmitted Y. pestis to mice at a significantly greater rate (50.0% of mice were infected) than control fleas (23.3% of mice were infected). Although the concentration of Y. pestis in fleas did not differ among treatments, the minimum transmission efficiency of fleas from the soil and wild flea feces treatments (6.9% and 7.6%, respectively) were more than three times higher than in control fleas (2.2%). Our results suggest that exposing laboratory-reared fleas to diverse microbes alters transmission of Y. pestis.

  3. Interleukin-12 is not essential for silicosis in mice

    Directory of Open Access Journals (Sweden)

    Hemenway David R

    2006-01-01

    Full Text Available Abstract Background Silicosis features foci of inflammation where macrophages and lymphocytes precede and accompany fibroblast proliferation, alveolar epithelial hyperplasia, and increased deposition of connective tissue matrix material. In the mouse following silica inhalation there is recruitment of natural killer-, B-, and CD4+ and CD8+ lymphocytes to the alveolar spaces, enlargement of bronchial-associated lymphoid tissues (BALT, and aggregation of lymphocytes surrounding small airways and blood vessels. A substantial fraction of the recruited lung lymphocytes produce interferon-γ (IFN-γ, and IFN-γ gene-deleted mice develop less silicosis than wild-type mice. Interleukin-12 (IL-12 is an important pathway for driving the adaptive immune response towards a TH1-like phenotype. We hypothesized that IL-12 might stimulate lymphocyte activation and the up-regulation of IFN-γ, and consequently be an essential mediator for silicosis. Results C57Bl/6 wild-type (WT and IL-12 deficient (IL-12 KO mice were exposed to sham-air or crystobalite silica (61 mg/m3 by inhalation for 5 hours/day for 12 days and then studied from 1 to 112 days after exposure. Mice exposed to sham-air had normal lung histology at all time points. WT mice exposed to titanium dioxide (72 mg/m3 showed pulmonary macrophage recruitment but no increase in lung collagen. Both WT and IL-12 KO mice exposed to silica showed similar progressive lung pathology, increased wet lung weight and increased total lung collagen (hydroxyproline. IL-12 p35 mRNA was not increased in either strain after silica exposure; IL-12 p40 mRNA was up-regulated after silica in WT mice and constitutively absent in the IL-12 KO mice. IL-18 mRNA was not increased after silica exposure. The expression of IL-15 (an important driver for innate immunity, Natural Killer cell activation, and IFN-γ production was abundant in air-exposed mice and was increased slightly in the lungs of mice with silicosis. Conclusion The

  4. Effects of G6pc2 deletion on body weight and cholesterol in mice.

    Science.gov (United States)

    Boortz, Kayla A; Syring, Kristen E; Pound, Lynley D; Mo, Huan; Bastarache, Lisa; Oeser, James K; McGuinness, Owen P; Denny, Joshua C; O'Brien, Richard M

    2017-04-01

    Genome-wide association study (GWAS) data have linked the G6PC2 gene to variations in fasting blood glucose (FBG). G6PC2 encodes an islet-specific glucose-6-phosphatase catalytic subunit that forms a substrate cycle with the beta cell glucose sensor glucokinase. This cycle modulates the glucose sensitivity of insulin secretion and hence FBG. GWAS data have not linked G6PC2 to variations in body weight but we previously reported that female C57BL/6J G6pc2-knockout (KO) mice were lighter than wild-type littermates on both a chow and high-fat diet. The purpose of this study was to compare the effects of G6pc2 deletion on FBG and body weight in both chow-fed and high-fat-fed mice on two other genetic backgrounds. FBG was reduced in G6pc2 KO mice largely independent of gender, genetic background or diet. In contrast, the effect of G6pc2 deletion on body weight was markedly influenced by these variables. Deletion of G6pc2 conferred a marked protection against diet-induced obesity in male mixed genetic background mice, whereas in 129SvEv mice deletion of G6pc2 had no effect on body weight. G6pc2 deletion also reduced plasma cholesterol levels in a manner dependent on gender, genetic background and diet. An association between G6PC2 and plasma cholesterol was also observed in humans through electronic health record-derived phenotype analyses. These observations suggest that the action of G6PC2 on FBG is largely independent of the influences of environment, modifier genes or epigenetic events, whereas the action of G6PC2 on body weight and cholesterol are influenced by unknown variables. © 2017 Society for Endocrinology.

  5. Chronic Endurance Exercise Impairs Cardiac Structure and Function in Middle-Aged Mice with Impaired Nrf2 Signaling

    Directory of Open Access Journals (Sweden)

    Gobinath Shanmugam

    2017-05-01

    fractional shortening, pronounced ST segment, and J wave elevation upon CEE compared to age-matched WT littermates. In conclusion, our findings indicate that while the aged WT and Nrf2 knockout animals both exhibit hypertrophy after CEE, the older Nrf2 knockouts showed ventricular remodeling coupled with profound cardiac functional abnormalities and diastolic dysfunction.

  6. Thermal latency studies in opiate-treated mice

    OpenAIRE

    Noam Schildhaus; Eliana Trink; Chirs Polson; Louis DeTolla; Tyler, Betty M.; Jallo, George I.; Sino Tok; Michael Guarnieri

    2014-01-01

    Background: The change in the reaction time of a tail or paw exposed to a thermal stimulus is a measure of nociceptive activity in laboratory animals. Tail-flick and plantar thermal sensitivity (Hargreaves) tests are non-invasive, minimize stress, and can be used to screen animals for phenotype and drug activity. Objective: Hargreaves testing has been widely used in rats. We investigated its use to measure the activity of opiate analgesia in mice. Methods: Mice were used in thermal stimulus s...

  7. Benzene inhalation effects upon tetanus antitoxin. Responses and leukemogenesis in mice

    Energy Technology Data Exchange (ETDEWEB)

    Stoner, R D; Drew, R T; Bernstein, D M

    1980-01-01

    The effects of inhaled benzene on primary and secondary antibody responses and the incidence of leukemia in mice are reported. Young adult mice were given 5, 12, or 22 exposures to 400 ppM benzene for 6 hrs/day 5 days/week. After the exposure periods, the mice were immunized with absorbed tetanus toxoid (APTT) and/or fluid tetanus toxid (FTT). Exposure to benzene increasingly suppressed primary antibody responses to both antigens. Secondary antibody responses to FTT were nearly normal in animals given 10, 15, or 20 exposures to 400 ppM benzene. Other groups of mice were exposed to either 200 ppM or 50 ppM benzene. Primary antibody responses elicited with FTT and/or APTT were nearly normal in all mice exposed to 50 ppM benzene and in mice exposed to 200 ppM benzene for 5 days. However, 10 and 20 exposures to 200 ppM benzene inhibited antibody production. The effects of chronically inhaled 300 ppM benzene on the time of onset and incidence of leukemia in 400 7-month-old female HRS/J mice were also studied. Two genotypes were used; the (hr/hr) hairless mice are leukemia-prone, whereas the (hr/+) haired mice are more resistant to leukemia. The exposure continued for a period of 6 months. Lymphoid, myeloid, and mixed (lymphoid and myeloid) leukemias were observed. Ninety percent of the (hr/hr) mice exposed to benzene died from leukemia as compared with 91% for the (hr/hr) air control group. Eighty-five percent of the (hr/+) mice exposed to benzene died from leukemia as compared with 81% for the (hr/+) air control group. Exposures to 300 ppM benzene did not alter the time of onset or the incidence of leukemia commonly expected in HRS/J mice.

  8. CCR2 elimination in mice results in larger and stronger tibial bones but bone loss is not attenuated following ovariectomy or muscle denervation.

    Science.gov (United States)

    Mader, Tara L; Novotny, Susan A; Lin, Angela S; Guldberg, Robert E; Lowe, Dawn A; Warren, Gordon L

    2014-11-01

    Bone loss due to age and disuse contributes to osteoporosis and increases fracture risk. It has been hypothesized that such bone loss can be attenuated by modulation of the C-C chemokine receptor 2 (CCR2) and/or its ligands. The objectives of this study were to examine the effects of genetic elimination of CCR2 on cortical and trabecular bones in the mouse tibia and how bone loss was impacted following disuse and estrogen loss. Female CCR2 knockout (CCR2(-/-)) and wildtype mice underwent ovariectomy (OVX) or denervation of musculature adjacent to the tibia (DEN) to induce bone loss. Cortical and trabecular structural properties as well as mechanical properties (i.e., strength) of tibial bones were measured. Compared to wildtype mice, CCR2(-/-) mice had tibiae that were up to 9% larger and stronger; these differences could be explained mainly by the 17% greater body mass (P bone loss per se. These findings indicate that while CCR2(-/-) mice do have larger and stronger bones than do wildtype mice, there is minimal evidence that CCR2 elimination provides protection against bone loss during disuse and estrogen loss.

  9. Loss of Endogenous Interleukin-12 Activates Survival Signals in Ultraviolet-Exposed Mouse Skin and Skin Tumors

    Directory of Open Access Journals (Sweden)

    Syed M. Meeran

    2009-09-01

    Full Text Available Interleukin-12 (IL-12-deficiency promotes photocarcinogenesis in mice; however, the molecular mechanisms underlying this effect have not been fully elucidated. Here, we report that long-term exposure to ultraviolet (UV radiation resulted in enhancement of the levels of cell survival kinases, such as phosphatidylinositol 3-kinase (PI3K, Akt (Ser473, p-ERK1/2, and p-p38 in the skin of IL-12p40 knockout (IL-12 KO mice compared with the skin of wild-type mice. UV-induced activation of nuclear factor-κB (NF-κB/p65 in the skin of IL-12 KO mice was also more prominent. The levels of NF-κB-targeted proteins, such as proliferating cell nuclear antigen (PCNA, cyclooxygenase-2, cyclin D1, and inducible nitric oxide synthase, were higher in the UV-exposed skin of IL-12 KO mice than the UV-exposed skin of wild types. In short-term UV irradiation experiments, subcutaneous treatment of IL-12 KO mice with recombinant IL-12 (rIL-12 or topical treatment with oridonin, an inhibitor of NF-κB, resulted in the inhibition of UV-induced increases in the levels of PCNA, cyclin D1, and NF-κB compared with non-rIL-12- or non-oridonin-treated IL-12 KO mice. UV-induced skin tumors of IL-12 KO mice had higher levels of PI3K, p-Akt (Ser473, p-ERK1/2, p-p38, NF-κB, and PCNA and fewer apoptotic cells than skin tumors of wild types. Together, these data suggest that the loss of endogenous IL-12 activates survival signals in UV-exposed skin and that may lead to the enhanced photocarcinogenesis in mice.

  10. Suspended animation-like state protects mice from lethal hypoxia.

    Science.gov (United States)

    Blackstone, Eric; Roth, Mark B

    2007-04-01

    Joseph Priestley observed the high burn rate of candles in pure oxygen and wondered if people would "live out too fast" if we were in the same environment. We hypothesize that sulfide, a natural reducer of oxygen that is made in many cell types, acts as a buffer to prevent unrestricted oxygen consumption. To test this, we administered sulfide in the form of hydrogen sulfide (H2S) to mice (Mus musculus). As we have previously shown, H2S decreases the metabolic rate of mice by approximately 90% and induces a suspended animation-like state. Mice cannot survive for longer than 20 min when exposed to 5% oxygen. However, if mice are first put into a suspended animation-like state by a 20-min pretreatment with H2S and then are exposed to low oxygen, they can survive for more than 6.5 h in 5% oxygen with no apparent detrimental effects. In addition, if mice are exposed to a 20-min pretreatment with H2S followed by 1 h at 5% oxygen, they can then survive for several hours at oxygen tensions as low as 3%. We hypothesize that prior exposure to H2S reduces oxygen demand, therefore making it possible for the mice to survive with low oxygen supply. These results suggest that H2S may be useful to prevent damage associated with hypoxia.

  11. Neonatal SSRI Exposure Programs a Hypermetabolic State in Adult Mice

    Directory of Open Access Journals (Sweden)

    Gary J. Kummet

    2012-01-01

    Full Text Available Background. Selective serotonin reuptake inhibitor (SSRI therapy complicates up to 10% of pregnancies. During therapy, SSRIs exert pleiotropic antidepressant, anorexigenic, and neurotrophic effects. Intrauterine SSRI exposure has been modeled by neonatal administration to developmentally immature rodents, and it has paradoxically elicited features of adult depression. We hypothesized neonatal SSRI exposure likewise programs a rebound hypermetabolic state in adult mice. Methods. C57BL/6 pups were randomized to saline or sertraline (5 mg/kg/d from P1–P14. Because estrogen increases tryptophan hydroxylase 2 (TPH2 expression, a subset of female mice underwent sham surgery or bilateral ovariectomy (OVX. Metabolic rate was determined by indirect calorimetry. Results. In both male and female mice, neonatal SSRI exposure increased adult caloric intake and metabolic rate. SSRI-exposed female mice had significantly decreased adult weight with a relative increase in brain weight and melatonin excretion, independent of ovarian status. Cerebral cortex TPH2 expression was increased in SSRI-exposed male mice but decreased in OVX SSRI-exposed female mice. Conclusions. SSRI exposure during a critical neurodevelopmental window increases adult caloric intake and metabolic rate. Ovarian status modulated central TPH2 expression, but not adult energy balance, suggesting programmed neural connectivity or enhanced melatonin production may play a more important role in the post-SSRI hypermetabolic syndrome.

  12. Quantitative, functional, and biochemical alterations in the peritoneal cells of mice exposed to whole-body gamma irradiation. 1. Changes in cellular protein, adherence properties, and enzymatic activities associated with platelet-activating factor formation and inactivation, and arachidonate metabolism. Scientific report

    Energy Technology Data Exchange (ETDEWEB)

    Steel, L.K.; Hughes, H.N.; Walden, T.L.

    1988-01-01

    Changes in total number, differentials, cell protein, adherence properties, acetyltransferase and acetylhydrolase activities, prostaglandin E2 and leukotriene C4 production, as well as calcium (2+) ionophore A23187 stimulation were examined in resident peritoneal cells isolated from mice 2h to 10 days postexposure to a single dose (7,10 or 12 Gy) of gamma radiation. Radiation dose-related reductions in macrophage and lymphocyte numbers and increases in cellular protein and capacity to adhere to plastic surfaces were evident. In-vitro irradiation also elevated the activities of acetyltransferase and acetylhydrolase (catalyzing platelet-activating factor biosynthesis and inactivation, respectively) in adherent and nonadherent peritoneal cells, particularly 3-4 days postexposure. Blood plasma from irradiated animals did not reflect the increased cellular acetylhydrolase activity. Prostaglandin E2 and leukotriene C4 synthesis were elevated postexposure, suggesting increased substrate (arachidonate) availability and increased cyclooxygenase and lipoxygenase activities. Ionospheric stimulation of enzyme activities and eicosanoid release also differed in irradiated peritoneal cells. While the properties of adherence, platelet-activating factor synthesis/inactivation-associated enzyme activities, and eicosanoid production are generally characterized as those of macrophages, lymphocytes or their products may influence or contribute to the observed radiation-induced changes.

  13. Chronic Co-species Housing Mice and Rats Increased the Competitiveness of Male Mice.

    Science.gov (United States)

    Liu, Ying-Juan; Li, Lai-Fu; Zhang, Yao-Hua; Guo, Hui-Fen; Xia, Min; Zhang, Meng-Wei; Jing, Xiao-Yuan; Zhang, Jing-Hua; Zhang, Jian-Xu

    2017-03-01

    Rats are predators of mice in nature. Nevertheless, it is a common practice to house mice and rats in a same room in some laboratories. In this study, we investigated the behavioral and physiological responsively of mice in long-term co-species housing conditions. Twenty-four male mice were randomly assigned to their original raising room (control) or a rat room (co-species-housed) for more than 6 weeks. In the open-field and light-dark box tests, the behaviors of the co-species-housed mice and controls were not different. In a 2-choice test of paired urine odors [rabbit urine (as a novel odor) vs. rat urine, cat urine (as a natural predator-scent) vs. rabbit urine, and cat urine vs. rat urine], the co-species-housed mice were more ready to investigate the rat urine odor compared with the controls and may have adapted to it. In an encounter test, the rat-room-exposed mice exhibited increased aggression levels, and their urines were more attractive to females. Correspondingly, the levels of major urinary proteins were increased in the co-species-housed mouse urine, along with some volatile pheromones. The serum testosterone levels were also enhanced in the co-species-housed mice, whereas the corticosterone levels were not different. The norepinephrine, dopamine, and 5-HT levels in the right hippocampus and striatum were not different between the 2. Our findings indicate that chronic co-species housing results in adaptation in male mice; furthermore, it appears that long-term rat-odor stimuli enhance the competitiveness of mice, which suggests that appropriate predator-odor stimuli may be important to the fitness of prey animals. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  14. Neonatal periostin knockout mice are protected from hyperoxia-induced alveolar simplication.

    Directory of Open Access Journals (Sweden)

    Paul D Bozyk

    Full Text Available In bronchopulmonary dysplasia (BPD, alveolar septae are thickened with collagen and α-smooth muscle actin, transforming growth factor (TGF-β-positive myofibroblasts. Periostin, a secreted extracellular matrix protein, is involved in TGF-β-mediated fibrosis and myofibroblast differentiation. We hypothesized that periostin expression is required for hypoalveolarization and interstitial fibrosis in hyperoxia-exposed neonatal mice, an animal model for this disease. We also examined periostin expression in neonatal lung mesenchymal stromal cells and lung tissue of hyperoxia-exposed neonatal mice and human infants with BPD. Two-to-three day-old wild-type and periostin null mice were exposed to air or 75% oxygen for 14 days. Mesenchymal stromal cells were isolated from tracheal aspirates of premature infants. Hyperoxic exposure of neonatal mice increased alveolar wall periostin expression, particularly in areas of interstitial thickening. Periostin co-localized with α-smooth muscle actin, suggesting synthesis by myofibroblasts. A similar pattern was found in lung sections of infants dying of BPD. Unlike wild-type mice, hyperoxia-exposed periostin null mice did not show larger air spaces or α-smooth muscle-positive myofibroblasts. Compared to hyperoxia-exposed wild-type mice, hyperoxia-exposed periostin null mice also showed reduced lung mRNA expression of α-smooth muscle actin, elastin, CXCL1, CXCL2 and CCL4. TGF-β treatment increased mesenchymal stromal cell periostin expression, and periostin treatment increased TGF-β-mediated DNA synthesis and myofibroblast differentiation. We conclude that periostin expression is increased in the lungs of hyperoxia-exposed neonatal mice and infants with BPD, and is required for hyperoxia-induced hypoalveolarization and interstitial fibrosis.

  15. 3 EXPOSE Missions - overview and lessons learned

    Science.gov (United States)

    Rabbow, E.; Willnekcer, R.; Reitz, G.; Aman, A.; Bman, B.; Cman, C.

    2011-10-01

    The International Space Station ISS provides a variety of external research platforms for experiments aiming at the utilization of space parameters like vacuum, temperature oscillation and in particular extraterrestrial short wavelength UV and ionizing radiation which cannot be simulated accurately in the laboratory. Three Missions, two past and one upcoming, will be presented. A family of astrobiological experimental ESA facilities called "EXPOSE" were and will be accommodated on these outside exposure platforms: on one of the external balconies of the European Columbus Module (EXPOSE-E) and on the URM-D platform on the Russian Zvezda Module (EXPOSE-R and EXPOSE-R2). Exobiological and radiation experiments, exposing chemical, biological and dosimetric samples to the harsh space environment are - and will be - accommodated on these facilities to increase our knowledge on the origin, evolution and distribution of life, on Earth and possibly beyond. The biological experiments investigate resistance and adaptation of organisms like bacteria, Achaea, fungi, lichens, plant seeds and small animals like mosquito larvae to extreme environmental conditions and underlying mechanisms like DNA repair. The organic chemical experiments analyse chemical reactions triggered by the extraterrestrial environment, especially short wavelength UV radiation, to better understand prebiotic chemistry. The facility is optimized to allow exposure of biological specimen and material samples under a variety of conditions, using optical filter systems. Environmental parameters like temperature and radiation are regularly recorded and down linked by telemetry. Two long term missions named according to their facility - EXPOSE-E and EXPOSE-R - are completed and a third mission is planned and currently prepared. Operations of all three missions including sample accommodation are performed by DLR. An overview of the two completed missions will be given including lessons learned as well as an outlook

  16. Teratogenic effects of noise in mice

    Science.gov (United States)

    Murata, M.; Takigawa, H.

    1989-07-01

    This study was undertaken to assess the hazardous effects of noise on embryonic development. The experiment was composed of two parts; one was the observation of the effect due to noise alone, and the other was the observation of the combined effect of noise and known teratogens. ICR mice were exposed to a wide octave-band noise at 100 dB(C) for 6 hours a day in three ways: the first group was exposed to a continuous noise only on day 7 of pregnancy (group "N"), the second was exposed to an intermittent noise (15 min ON/15 min OFF) only on day 7 of pregnancy (group "IN"), and the third was exposed daily to a continuous noise during days 7-12 of pregnancy (group "RN"). Cadmium sulfate or trypan blue was applied as a teratogen, and was administered intraperitoneously on day 7 of pregnancy. On day 18 of pregnancy, mice were sacrificed and the developmental status and external malformations of their fetuses were examined. Each type of noise exposure did not significantly induce embryolethality and fetal growth retardation. However, teratogenicity was observed in groups "N" and "IN". Combined effects of teratogen and noise did not show clear-cut interactions.

  17. Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice.

    Science.gov (United States)

    Deppermann, Carsten; Cherpokova, Deya; Nurden, Paquita; Schulz, Jan-Niklas; Thielmann, Ina; Kraft, Peter; Vögtle, Timo; Kleinschnitz, Christoph; Dütting, Sebastian; Krohne, Georg; Eming, Sabine A; Nurden, Alan T; Eckes, Beate; Stoll, Guido; Stegner, David; Nieswandt, Bernhard

    2013-07-01

    Platelets are anuclear organelle-rich cell fragments derived from bone marrow megakaryocytes (MKs) that safeguard vascular integrity. The major platelet organelles, α-granules, release proteins that participate in thrombus formation and hemostasis. Proteins stored in α-granules are also thought to play a role in inflammation and wound healing, but their functional significance in vivo is unknown. Mutations in NBEAL2 have been linked to gray platelet syndrome (GPS), a rare bleeding disorder characterized by macrothrombocytopenia, with platelets lacking α-granules. Here we show that Nbeal2-knockout mice display the characteristics of human GPS, with defective α-granule biogenesis in MKs and their absence from platelets. Nbeal2 deficiency did not affect MK differentiation and proplatelet formation in vitro or platelet life span in vivo. Nbeal2-deficient platelets displayed impaired adhesion, aggregation, and coagulant activity ex vivo that translated into defective arterial thrombus formation and protection from thrombo-inflammatory brain infarction following focal cerebral ischemia. In a model of excisional skin wound repair, Nbeal2-deficient mice exhibited impaired development of functional granulation tissue due to severely reduced differentiation of myofibroblasts in the absence of α-granule secretion. This study demonstrates that platelet α-granule constituents are critically required not only for hemostasis but also thrombosis, acute thrombo-inflammatory disease states, and tissue reconstitution after injury.

  18. AMIGO2 modulates T cell functions and its deficiency in mice ameliorates experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Li, Zhilin; Khan, Mohd Moin; Kuja-Panula, Juha; Wang, Hongyun; Chen, Yu; Guo, Deyin; Chen, Zhi Jane; Lahesmaa, Riitta; Rauvala, Heikki; Tian, Li

    2017-05-01

    The immune function of AMIGO2 is currently unknown. Here, we revealed novel roles of AMIGO2 in modulating T-cell functions and EAE using Amigo2-knockout (AMG2KO) mice. Amigo2 was abundantly expressed by murine T helper (Th) cells. Its deficiency impaired transplanted T-cell infiltration into the secondary lymphoid organs and dampened Th-cell activation, but promoted splenic Th-cell proliferation and abundancy therein. AMG2KO Th cells had respectively elevated T-bet in Th1- and GATA-3 in Th2-lineage during early Th-cell differentiation, accompanied with increased IFN-γ and IL-10 but decreased IL-17A production. AMG2KO mice exhibited ameliorated EAE, dampened spinal T-cell accumulation, decreased serum IL-17A levels and enhanced splenic IL-10 production. Adoptive transfer of encephalitogenic AMG2KO T cells induced milder EAE and dampened spinal Th-cell accumulation and Tnf expression. Mechanistically, Amigo2-overexpression in 293T cells dampened NF-kB transcriptional activity, while Amigo2-deficiency enhanced Akt but suppressed GSK-3β phosphorylation and promoted nuclear translocations of NF-kB and NFAT1 in Th-cells. Collectively, our data demonstrate that AMIGO2 is important in regulating T-cell functions and EAE, and may be harnessed as a potential therapeutic target for multiple sclerosis.

  19. Prenatal alcohol exposure inducing the apoptosis of mossy cells in hippocampus of SMS2-/- mice.

    Science.gov (United States)

    Wang, Lai; Wu, Lin; Wang, Xiaoqing; Deng, Jiexin; Ma, Zhanyou; Fan, Wenjuan; He, Weiya; Deng, Jinbo

    2015-11-01

    In order to understand the mechanisms of alcohol-induced neuroapoptosis through the ceramide pathway, sphingomyelin synthase 2 knockout (SMS2-/-) mice were used to make the prenatal alcohol exposure model, and the role of ceramide regulation on alcohol-induced neuroapoptosis was studied in the offspring. Initially the levels of serum sphingomyelin (SM) were detected with enzymatic method in P0 pups after alcohol exposure in parents. Then the apoptosis of mossy cells in the offspring hippocampus was investigated after prenatal alcohol exposure with immunohistochemistry and TUNEL assay. Finally the expression of activated Caspase 8 and activated Caspase 3 in the offspring hippocampus was detected with Western blot analysis. Our results showed that SM levels were down-regulated in a dose-dependent manner (palcohol exposure in wild-type (WT) and SMS2-/- pups. However, SM levels of serum in SMS2-/- pups were significantly lower than that in WT pups (palcohol-induced neuroapoptosis. In both WT pups and SMS2-/- pups, the number of apoptotic mossy cells in the hippocampus increased after prenatal alcohol exposure in a dose dependent manner (palcohol exposure, consistent with results from TUNEL assay and immunocytochemistry. Our study suggests that mossy cells may be the easily attacked cells for fetal alcohol spectrum disorder (FASD), and ceramide is involved in the alcohol-induced neural apoptosis. The mechanism probably lies in the accumulated ceramide in SMS2 mice, and the increase of activated Caspase 8 and Caspase 3 promotes alcohol-induced neuroapoptosis.

  20. Dissociated fear and spatial learning in mice with deficiency of ataxin-2.

    Directory of Open Access Journals (Sweden)

    Duong P Huynh

    Full Text Available Mouse models with physiological and behavioral differences attributable to differential plasticity of hippocampal and amygdalar neuronal networks are rare. We previously generated ataxin-2 (Atxn2 knockout mice and demonstrated that these animals lacked obvious anatomical abnormalities of the CNS, but showed marked obesity and reduced fertility. We now report on behavioral changes as a consequence of Atxn2-deficiency. Atxn2-deficiency was associated with impaired long-term potentiation (LTP in the amygdala, but normal LTP in the hippocampus. Intact hippocampal plasticity was associated behaviorally with normal Morris Water maze testing. Impaired amygdala plasticity was associated with reduced cued and contextual fear conditioning. Conditioned taste aversion, however, was normal. In addition, knockout mice showed decreased innate fear in several tests and motor hyperactivity in open cage testing. Our results suggest that Atxn2-deficiency results in a specific set of behavioral and cellular disturbances that include motor hyperactivity and abnormal fear-related behaviors, but intact hippocampal function. This animal model may be useful for the study of anxiety disorders and should encourage studies of anxiety in patients with spinocerebellar ataxia type 2 (SCA2.

  1. Metabolic characteristics of long-lived mice

    Directory of Open Access Journals (Sweden)

    Andrzej eBartke

    2012-12-01

    Full Text Available Genetic suppression of insulin/insulin-like growth factor signaling (IIS can extend longevity in worms, insects, and mammals. In laboratory mice, mutations with the greatest, most consistent, and best documented positive impact on lifespan are those that disrupt growth hormone (GH release or actions. These mutations lead to major alterations in IIS but also have a variety of effects that are not directly related to the actions of insulin or insulin-like growth factor (IGF-1. Long-lived GH-resistant GHRKO mice with targeted disruption of the GH receptor gene, as well as Ames dwarf (Prop1df and Snell dwarf (Pit1dw mice lacking GH (along with prolactin and TSH, are diminutive in size and have major alterations in body composition and metabolic parameters including increased subcutaneous adiposity, increased relative brain weight, small liver, hypoinsulinemia, mild hypoglycemia, increased adiponectin levels and insulin sensitivity, and reduced serum lipids. Body temperature is reduced in Ames, Snell, and female GHRKO mice. Indirect calorimetry revealed that both Ames dwarf and GHRKO mice utilize more oxygen per gram (g of body weight than sex- and age-matched normal animals from the same strain. They also have reduced respiratory quotient (RQ, implying greater reliance on fats, as opposed to carbohydrates, as an energy source. Differences in oxygen consumption (VO2 were seen in animals fed or fasted during the measurements as well as in animals that had been exposed to 30% calorie restriction or every-other-day feeding. However, at the thermoneutral temperature of 30°C, VO2 did not differ between GHRKO and normal mice. Thus, the increased metabolic rate of the GHRKO mice, at a standard animal room temperature of 23°C, is apparently related to increased energy demands for thermoregulation in these diminutive animals. We suspect that increased oxidative metabolism combined with enhanced fatty acid oxidation contribute to the extended longevity of

  2. Eryptosis in lead-exposed workers

    Energy Technology Data Exchange (ETDEWEB)

    Aguilar-Dorado, Itzel-Citlalli [Biochemistry Department, Centro de Investigación y Estudios Avanzados IPN, México, DF (Mexico); Hernández, Gerardo [Section of Methodology of Science, Centro de Investigación y Estudios Avanzados IPN, México, DF (Mexico); Quintanar-Escorza, Martha-Angelica [Faculty of Medicine, UJED, Durango, DGO (Mexico); Maldonado-Vega, María [CIATEC, León, GTO (Mexico); Rosas-Flores, Margarita [Biochemistry Department, Centro de Investigación y Estudios Avanzados IPN, México, DF (Mexico); Calderón-Salinas, José-Víctor, E-mail: jcalder@cinvestav.mx [Biochemistry Department, Centro de Investigación y Estudios Avanzados IPN, México, DF (Mexico)

    2014-12-01

    Eryptosis is a physiological phenomenon in which old and damaged erythrocytes are removed from circulation. Erythrocytes incubated with lead have exhibited major eryptosis. In the present work we found evidence of high levels of eryptosis in lead exposed workers possibly via oxidation. Blood samples were taken from 40 male workers exposed to lead (mean blood lead concentration 64.8 μg/dl) and non-exposed workers (4.2 μg/dl). The exposure to lead produced an intoxication characterized by 88.3% less δ-aminolevulinic acid dehydratase (δALAD) activity in lead exposed workers with respect to non-lead exposed workers. An increment of oxidation in lead exposed workers was characterized by 2.4 times higher thiobarbituric acid-reactive substance (TBARS) concentration and 32.8% lower reduced/oxidized glutathione (GSH/GSSG) ratio. Oxidative stress in erythrocytes of lead exposed workers is expressed in 192% higher free calcium concentration [Ca{sup 2+}]{sub i} and 1.6 times higher μ-calpain activity with respect to non-lead exposed workers. The adenosine triphosphate (ATP) concentration was not significantly different between the two worker groups. No externalization of phosphatidylserine (PS) was found in non-lead exposed workers (< 0.1%), but lead exposed workers showed 2.82% externalization. Lead intoxication induces eryptosis possibly through a molecular pathway that includes oxidation, depletion of reduced glutathione (GSH), increment of [Ca{sup 2+}], μ-calpain activation and externalization of PS in erythrocytes. Identifying molecular signals that induce eryptosis in lead intoxication is necessary to understand its physiopathology and chronic complications. - Graphical abstract: Fig. 1. (A) Blood lead concentration (PbB) and (B) phosphatidylserine externalization on erythrocyte membranes of non-lead exposed (□) and lead exposed workers (■). Values are mean ± SD. *Significantly different (P < 0.001). - Highlights: • Erythrocytes of lead exposed workers

  3. Adaptive Response in Animals Exposed to Non-Ionizing Radiofrequency Fields: Some Underlying Mechanisms

    Directory of Open Access Journals (Sweden)

    Yi Cao

    2014-04-01

    Full Text Available During the last few years, our research group has been investigating the phenomenon of adaptive response in animals exposed to non-ionizing radiofrequency fields. The results from several separate studies indicated a significant increase in survival, decreases in genetic damage as well as oxidative damage and, alterations in several cellular processes in mice pre-exposed to radiofrequency fields and subsequently subjected to sub-lethal or lethal doses of γ-radiation or injected with bleomycin, a radiomimetic chemical mutagen. These observations indicated the induction of adaptive response providing the animals the ability to resist subsequent damage. Similar studies conducted by independent researchers in mice and rats have supported our observation on increased survival. In this paper, we have presented a brief review of all of our own and other independent investigations on radiofrequency fields-induced adaptive response and some underlying mechanisms discussed.

  4. B cells exposed to enterobacterial components suppress development of experimental colitis

    DEFF Research Database (Denmark)

    Schmidt, Esben Gjerløff Wedebye; Larsen, Hjalte List; Kristensen, Nanna Ny

    2012-01-01

    BACKGROUND: B cells positively contribute to immunity by antigen presentation to CD4(+) T cells, cytokine production, and differentiation into antibody secreting plasma cells. Accumulating evidence implies that B cells also possess immunoregulatory functions closely linked to their capability of IL......-10 secretion. METHODS: Colitis development was followed in CD4(+) CD25(-) T cell transplanted SCID mice co-transferred with B cells exposed to an enterobacterial extract (ebx-B cells). B and T cell cytokine expression was measured by flow cytometry and enzyme-linked immunosorbent assay (ELISA......). RESULTS: We demonstrate that splenic B cells exposed to ebx produce large amounts of IL-10 in vitro and express CD1d and CD5 previously known to be associated with regulatory B cells. In SCID mice transplanted with colitogenic CD4(+) CD25(-) T cells, co-transfer of ebx-B cells significantly suppressed...

  5. Effects of exposure of newborn patched1 heterozygous mice to GSM, 900 MHz.

    Science.gov (United States)

    Saran, A; Pazzaglia, S; Mancuso, M; Rebessi, S; Di Majo, V; Tanori, M; Lovisolo, G A; Pinto, R; Marino, C

    2007-12-01

    Patched1 heterozygous knockout mice (Ptc1+/-), an animal model of multiorgan tumorigenesis in which ionizing radiation dramatically accelerates tumor development, were used to study the potential tumorigenic effects of electromagnetic fields (EMFs) on neonatal mice. Two hundred Ptc1+/- mice and their wild-type siblings were enrolled in this study. Newborn mice were exposed to 900 MHz radiofrequency radiation (average SAR: 0.4 W/kg for 5 days, 0.5 h twice a day) or were sham exposed. We found that RF EMFs simulating the Global System for Mobile Communications (GSM) did not affect the survival of the mice, because no statistically significant differences in survival were found between exposed and sham-exposed animals. Also, no effects attributable to radiofrequency radiation were observed on the incidence and histology of Ptc1-associated cerebellar tumors. Moreover, the skin phenotype was analyzed to look for proliferative effects of RF EMFs on the epidermal basal layer and for acceleration of preneoplastic lesions typical of the basal cell carcinoma phenotype of this model. We found no evidence of proliferative or promotional effects in the skin from neonatal exposure to radiofrequency radiation. Furthermore, no difference in Ptc1-associated rhabdomyosarcomas was detected between sham-exposed and exposed mice. Thus, under the experimental conditions tested, there was no evidence of life shortening or tumorigenic effects of neonatal exposure to GSM RF radiation in a highly tumor-susceptible mouse model.

  6. Early physical and motor development of mouse offspring exposed to valproic acid throughout intrauterine development.

    Science.gov (United States)

    Podgorac, Jelena; Pešić, Vesna; Pavković, Željko; Martać, Ljiljana; Kanazir, Selma; Filipović, Ljupka; Sekulić, Slobodan

    2016-09-15

    Clinical research has identified developmental delay and physical malformations in children prenatally exposed to the antiepileptic drug (AED) valproic acid (VPA). However, the early signs of neurodevelopmental deficits, their evolution during postnatal development and growth, and the dose effects of VPA are not well understood. The present study aimed to examine the influence of maternal exposure to a wide dose range (50, 100, 200 and 400mg/kg/day) of VPA during breeding and gestation on early physical and neuromotor development in mice offspring. Body weight gain, eye opening, the surface righting reflex (SRR) and tail suspension test (TST) were examined in the offspring at postnatal days 5, 10 and 15. We observed that: (1) all tested doses of VPA reduced the body weight of the offspring and the timing of eye opening; (2) offspring exposed to VPA displayed immature forms of righting and required more time to complete the SRR; (3) latency for the first immobilization in the TST is shorter in offspring exposed to higher doses of VPA; however, mice in all groups exposed to VPA exhibited atypical changes in this parameter during the examined period of maturation; (4) irregularities in swinging and curling activities were observed in animals exposed to higher doses of VPA. This study points to delayed somatic development and postponed maturation of the motor system in all of the offspring prenatally exposed to VPA, with stronger effects observed at higher doses. The results implicate that the strategy of continuous monitoring of general health and achievements in motor milestones during the early postnatal development in prenatally VPA-exposed offspring, irrespectively of the dose applied, could help to recognize early developmental irregularities.

  7. Mice expressing aberrant sperm-specific protein PMIS2 produce normal-looking but fertilization-incompetent spermatozoa.

    Science.gov (United States)

    Yamaguchi, Ryo; Fujihara, Yoshitaka; Ikawa, Masahito; Okabe, Masaru

    2012-07-01

    Eight kinds of gene-disrupted mice (Clgn, Calr3, Pdilt, Tpst2, Ace, Adam1a, Adam2, and Adam3) show impaired sperm transition into the oviducts and defective sperm binding to the zona pellucida. All of these knockout strains are reported to lack or show aberrant expression of a disintegrin and metallopeptidase domain 3 (ADAM3) on the sperm membrane. We performed proteomic analyses of the proteins of these infertile spermatozoa to clarify whether the abnormal function is caused exclusively by a deficiency in ADAM3 expression. Two proteins, named PMIS1 and PMIS2, were missing in spermatozoa from Clgn-disrupted mice. To study their roles, we generated two gene-disrupted mouse lines. Pmis1-knockout mice were fertile, but Pmis2-knockout males were sterile because of a failure of sperm transport into the oviducts. Pmis2-deficient spermatozoa also failed to bind to the zona pellucida. However, they showed normal fertilizing ability when eggs surrounded with cumulus cells were used for in vitro fertilization. Further analysis revealed that these spermatozoa lacked the ADAM3 protein, but the amount of PMIS2 was also severely reduced in Adam3-deficient spermatozoa. These results suggest that PMIS2 might function both as the ultimate factor regulating sperm transport into the oviducts and in modulating sperm-zona binding.

  8. SLAP/SLAP2 prevent excessive platelet (hem)ITAM signaling in thrombosis and ischemic stroke in mice.

    Science.gov (United States)

    Cherpokova, Deya; Bender, Markus; Morowski, Martina; Kraft, Peter; Schuhmann, Michael K; Akbar, Sarah M; Sultan, Cheryl S; Hughes, Craig E; Kleinschnitz, Christoph; Stoll, Guido; Dragone, Leonard L; Watson, Steve P; Tomlinson, Michael G; Nieswandt, Bernhard

    2015-01-01

    Glycoprotein VI and C-type lectin-like receptor 2 are essential platelet activating receptors in hemostasis and thrombo-inflammatory disease, which signal through a (hem)immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway. The adapter molecules Src-like adapter proteins (SLAP and SLAP2) are involved in the regulation of immune cell surface expression and signaling, but their function in platelets is unknown. In this study, we show that platelets expressed both SLAP isoforms and that overexpression of either protein in a heterologous cell line almost completely inhibited glycoprotein VI and C-type lectin-like receptor 2 signaling. In mice, single deficiency of SLAP or SLAP2 had only moderate effects on platelet function, whereas double deficiency of both adapters resulted in markedly increased signal transduction, integrin activation, granule release, aggregation, procoagulant activity, and thrombin generation in response to (hem)ITAM-coupled, but not G protein-coupled, receptor activation. In vivo, constitutive SLAP/SLAP2 knockout mice displayed accelerated occlusive arterial thrombus formation and a dramatically worsened outcome after focal cerebral ischemia. This was attributed to the absence of both adapter proteins in platelets, as demonstrated by adoptive transfer of Slap(-/-)/Slap2(-/-) platelets into wild-type mice. Our results establish SLAP and SLAP2 as critical inhibitors of platelet (hem)ITAM signaling in the setting of arterial thrombosis and ischemic stroke.

  9. Elastase-2, a Tissue Alternative Pathway for Angiotensin II Generation, Plays a Role in Circulatory Sympathovagal Balance in Mice

    Science.gov (United States)

    Becari, Christiane; Durand, Marina T.; Guimaraes, Alessander O.; Lataro, Renata M.; Prado, Cibele M.; de Oliveira, Mauro; Candido, Sarai C. O.; Pais, Paloma; Ribeiro, Mauricio S.; Bader, Michael; Pesquero, Joao B.; Salgado, Maria C. O.; Salgado, Helio C.

    2017-01-01

    In vitro and ex vivo experiments indicate that elastase-2 (ELA-2), a chymotrypsin-serine protease elastase family member 2A, is an alternative pathway for angiotensin II (Ang II) generation. However, the role played by ELA-2 in vivo is unclear. We examined ELA-2 knockout (ELA-2KO) mice compared to wild-type (WT) mice and determined whether ELA-2 played a role in hemodynamics [arterial pressure (AP) and heart rate (HR)], cardiocirculatory sympathovagal balance and baroreflex sensitivity. The variability of systolic arterial pressure (SAP) and pulse interval (PI) for evaluating autonomic modulation was examined for time and frequency domains (spectral analysis), whereas a symbolic analysis was also used to evaluate PI variability. In addition, baroreflex sensitivity was examined using the sequence method. Cardiac function was evaluated echocardiographically under anesthesia. The AP was normal whereas the HR was reduced in ELA-2KO mice (425 ± 17 vs. 512 ± 13 bpm from WT). SAP variability and baroreflex sensitivity were similar in both strains. The LF power from the PI spectrum (33.6 ± 5 vs. 51.8 ± 4.8 nu from WT) and the LF/HF ratio (0.60 ± 0.1 vs. 1.45 ± 0.3 from WT) were reduced, whereas the HF power was increased (66.4 ± 5 vs. 48.2 ± 4.8 nu from WT) in ELA-2KO mice, indicating a shift toward parasympathetic modulation of HR. Echocardiographic examination showed normal fractional shortening and an ejection fraction in ELA-2KO mice; however, the cardiac output, stroke volume, and ventricular size were reduced. These findings provide the first evidence that ELA-2 acts on the sympathovagal balance of the heart, as expressed by the reduced sympathetic modulation of HR in ELA-2KO mice. PMID:28386233

  10. 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.

    2011-01-01

    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 eithe

  11. Memory Deficits Are Associated with Impaired Ability to Modulate Neuronal Excitability in Middle-Aged Mice

    Science.gov (United States)

    Kaczorowski, Catherine C.; Disterhoft, John F.

    2009-01-01

    Normal aging disrupts hippocampal neuroplasticity and learning and memory. Aging deficits were exposed in a subset (30%) of middle-aged mice that performed below criterion on a hippocampal-dependent contextual fear conditioning task. Basal neuronal excitability was comparable in middle-aged and young mice, but learning-related modulation of the…

  12. Stressor exposure has prolonged effects on colonic microbial community structure in Citrobacter rodentium-challenged mice

    Science.gov (United States)

    Galley, Jeffrey D.; Mackos, Amy R.; Varaljay, Vanessa A.; Bailey, Michael T.

    2017-01-01

    Stressor exposure significantly affects the colonic mucosa-associated microbiota, and exacerbates Citrobacter rodentium-induced inflammation, effects that can be attenuated with probiotic Lactobacillus reuteri. This study assessed the structure of the colonic mucosa-associated microbiota in mice exposed to a social stressor (called social disruption), as well as non-stressed control mice, during challenge with the colonic pathogen C. rodentium. Mice were exposed to the social stressor or home cage control conditions for six consecutive days and all mice were challenged with C. rodentium immediately following the first exposure to the stressor. In addition, mice received probiotic L. reuteri, or vehicle as a control, via oral gavage following each stressor exposure. The stressor-exposed mice had significant differences in microbial community composition compared to non-stressed control mice. This difference was first evident following the six-cycle exposure to the stressor, on Day 6 post-C. rodentium challenge, and persisted for up to 19 days after stressor termination. Mice exposed to the stressor had different microbial community composition regardless of whether they were treated with L. reuteri or treated with vehicle as a control. These data indicate that stressor exposure affects the colonic microbiota during challenge with C. rodentium, and that these effects are long-lasting and not attenuated by probiotic L. reuteri. PMID:28344333

  13. Topical tacrolimus in combination with simulated solar radiation does not enhance photocarcinogenesis in hairless mice

    DEFF Research Database (Denmark)

    Lerche, C.M.; Philipsen, P.A.; Poulsen, T.;

    2008-01-01

    tacrolimus ointment on squamous cell carcinoma formation in hairless female C3.Cg/TifBomTac immunocompetent mice exposed to solar simulated radiation (SSR). In a first experiment, mice (n = 200) had tacrolimus applied on their dorsal skin three times weekly followed by SSR (2, 4 or 6 standard erythema doses...

  14. Pre-Exposure to Context Affects Learning Strategy Selection in Mice

    Science.gov (United States)

    Tunur, Tumay; Dohanich, Gary P.; Schrader, Laura A.

    2010-01-01

    The multiple memory systems hypothesis proposes that different types of learning strategies are mediated by distinct neural systems in the brain. Male and female mice were tested on a water plus-maze task that could be solved by either a place or response strategy. One group of mice was pre-exposed to the same context as training and testing (PTC)…

  15. 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

  16. Phase responses to light pulses in mice lacking functional per or cry genes

    NARCIS (Netherlands)

    Spoelstra, K; Albrecht, U; van der Horst, GTJ; Brauer, [No Value; Daan, S; Horst, Gijsbertus T.J. van der; Brauer, Verena

    2004-01-01

    The phase-resetting properties of the circadian system in mice with a functional deletion in mCry1, mCry2, mPer1, or mPer2 were studied in 2 experiments. In experiment 1, mCry1(-/-) and mCry2(-/-) mice as well as mPer1(Brdm1) and mPer2(Brdm1) mutant mice were exposed to 15-min light pulses during

  17. Effects of nitric oxide on resistance to bacterial infection in mice

    Energy Technology Data Exchange (ETDEWEB)

    Azoulay, E. (INSERM, Paris, France); Bouley, G.; Blayo, M.C.

    1981-06-01

    Continuous exposure to 2 ppM nitric oxide (NO) for as long as 4 wk did not reduce the resistance of male mice to infection by aerosol inoculation with Pasteurella multocida. In contrast, mortality was slightly enhanced and survival shortened in NO-exposed compared to control female mice; however, the importance of these small differences is uncertain. These results suggest only that male and famale mice did not react similarly to the infectious challenge after exposure to NO.

  18. Genetic Alterations in Pesticide Exposed Bolivian Farmers

    OpenAIRE

    J?rs, Erik; Gonz?les, Ana Rosa; Ascarrunz, Maria Eugenia; Tirado, Noemi; Takahashi, Catharina; Lafuente, Erika; dos Santos, Raquel A.; Bailon, Natalia; Cervantes, Rafael; O, Huici; B?lum, Jesper; Lander, Flemming

    2007-01-01

    Background Pesticides are of concern in Bolivia because of increasing use. Frequent intoxications have been demonstrated due to use of very toxic pesticides, insufficient control of distribution and sale and little knowledge among farmers of protective measures and hygienic procedures. Method Questionnaires were applied and blood tests taken from 81 volunteers from La Paz County, of whom 48 were pesticide exposed farmers and 33 non-exposed controls. Sixty males and 21 females participated wit...

  19. Elastase-2, an angiotensin II-generating enzyme, contributes to increased Ang II in resistance arteries of mice with myocardial infarction.

    Science.gov (United States)

    Becari, Christiane; Silva, Marcondes A B; Durand, Marina T; Prado, Cibele M; Oliveira, Eduardo B; Ribeiro, Mauricio S; Salgado, Helio C; Salgado, Maria Cristina O; Tostes, Rita C

    2017-02-21

    Angiotensin II (Ang II), whose generation largely depends on angiotensin-converting enzyme activity, mediates most of the renin-angiotensin-system effects. Elastase-2 (ELA-2), a chymotrypsin-serine protease elastase family member 2A, alternatively generates Ang II in rat arteries. Myocardial infarction (MI) leads to intense RAS activation, but mechanisms involved on Ang II-generation in resistance arteries are unknown. We hypothesized that ELA-2 contributes to vascular Ang II generation and to cardiac damage in mice submitted to MI. Concentration-effect curves to Ang I and Ang II were performed in mesenteric resistance arteries from male wild type (WT) and ELA-2 knockout (ELA-2KO) mice submitted to left anterior descending coronary artery ligation (myocardial infarction, MI). MI size was similar in WT (29.5 ± 9 %) and ELA-2KO (32 ± 4%) mice. Ejection fraction and fractional shortening after MI similarly decreased in both strains. However, MI decreased stroke volume and cardiac output in WT, but not in ELA-2KO mice. Ang I-induced contractions increased in WT mice submitted to MI (MI-WT) compared to Sham-WT mice. No differences were observed in Ang I reactivity between arteries from Sham-ELA-2KO and ELA-2KO submitted to MI (MI-ELA-2KO). Ang I contractions increased in arteries from MI-WT vs. MI-ELA-2KO mice. Chymostatin attenuated Ang I-induced vascular contractions in WT mice (P ELA-2KO arteries. These results provide the first evidence that ELA-2 contributes to increased Ang II formation in resistance arteries and modulates cardiac function after MI, implicating ELA-2 as a key player in ACE-independent dysregulation of the RAS.

  20. Increased renal renin content in mice lacking the Na+/H+ exchanger NHE2.

    Science.gov (United States)

    Hanner, Fiona; Chambrey, Régine; Bourgeois, Soline; Meer, Elliott; Mucsi, István; Rosivall, László; Shull, Gary E; Lorenz, John N; Eladari, Dominique; Peti-Peterdi, János

    2008-04-01

    Macula densa (MD) cells express the Na(+)/H(+) exchanger (NHE) isoform NHE2 at the apical membrane, which may play an important role in tubular salt sensing through the regulation of cell volume and intracellular pH. These studies aimed to determine whether NHE2 participates in the MD control of renin synthesis. Renal renin content and activity and elements of the MD signaling pathway were analyzed using wild-type (NHE2(+/+)) and NHE2 knockout (NHE2(-/-)) mice. Immunofluorescence studies indicated that NHE2(-/-) mice lack NHE3 at the MD apical membrane, so the other apical NHE isoform has not compensated for the lack of NHE2. Importantly, the number of renin-expressing cells in the afferent arteriole in NHE2(-/-) mice was increased approximately 2.5-fold using renin immunohistochemistry. Western blotting confirmed approximately 20% higher renal cortical renin content in NHE2(-/-) mice compared with wild type. No-salt diet for 1 wk significantly increased renin content and activity in NHE2(+/+) mice, but the response was blunted in NHE2(-/-) mice. Renal tissue renin activity and plasma renin concentration were elevated three- and twofold, respectively, in NHE2(-/-) mice compared with wild type. NHE2(-/-) mice also exhibited a significantly increased renal cortical cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase (mPGES) expression, indicating MD-specific mechanisms responsible for the increased renin content. Significant and chronic activation of ERK1/2 was observed in MD cells of NHE2(-/-) kidneys. Removal of salt or addition of NHE inhibitors to cultured mouse MD-derived (MMDD1) cells caused a time-dependent activation of ERK1/2. In conclusion, the NHE2 isoform appears to be important in the MD feedback control of renin secretion, and the signaling pathway likely involves MD cell shrinkage and activation of ERK1/2, COX-2, and mPGES, all well-established elements of the MD-PGE(2)-renin release pathway.

  1. The astrobiological mission EXPOSE-R on board of the International Space Station

    Science.gov (United States)

    Rabbow, Elke; Rettberg, Petra; Barczyk, Simon; Bohmeier, Maria; Parpart, Andre; Panitz, Corinna; Horneck, Gerda; Burfeindt, Jürgen; Molter, Ferdinand; Jaramillo, Esther; Pereira, Carlos; Weiß, Peter; Willnecker, Rainer; Demets, René; Dettmann, Jan

    2015-01-01

    EXPOSE-R flew as the second of the European Space Agency (ESA) EXPOSE multi-user facilities on the International Space Station. During the mission on the external URM-D platform of the Zvezda service module, samples of eight international astrobiology experiments selected by ESA and one Russian guest experiment were exposed to low Earth orbit space parameters from March 10th, 2009 to January 21st, 2011. EXPOSE-R accommodated a total of 1220 samples for exposure to selected space conditions and combinations, including space vacuum, temperature cycles through 273 K, cosmic radiation, solar electromagnetic radiation at >110, >170 or >200 nm at various fluences up to GJ m-2. Samples ranged from chemical compounds via unicellular organisms and multicellular mosquito larvae and seeds to passive radiation dosimeters. Additionally, one active radiation measurement instrument was accommodated on EXPOSE-R and commanded from ground in accordance with the facility itself. Data on ultraviolet radiation, cosmic radiation and temperature were measured every 10 s and downlinked by telemetry and data carrier every few months. The EXPOSE-R trays and samples returned to Earth on March 9th, 2011 with Shuttle flight, Space Transportation System (STS)-133/ULF 5, Discovery, after successful total mission duration of 27 months in space. The samples were analysed in the individual investigators laboratories. A parallel Mission Ground Reference experiment was performed on ground with a parallel set of hardware and samples under simulated space conditions following to the data transmitted from the flight mission.

  2. Comparison of the D2 receptor regulation and neurotoxicant susceptibility of nigrostriatal dopamine neurons in wild-type and CB1/CB2 receptor knockout mice.

    Science.gov (United States)

    Simkins, Tyrell J; Janis, Kelly L; McClure, Alison K; Behrouz, Bahareh; Pappas, Samuel S; Lehner, Andreas; Kaminski, Norbert E; Goudreau, John L; Lookingland, Keith J; Kaplan, Barbara L F

    2012-09-01

    Motor dysfunctions of Parkinson Disease (PD) are due to the progressive loss of midbrain nigrostriatal dopamine (NSDA) neurons. Evidence suggests a role for cannabinoid receptors in the neurodegeneration of these neurons following neurotoxicant-induced injury. This work evaluates NSDA neurons in CB1/CB2 knockout (KO) mice and tests the hypothesis that CB1/CB2 KO mice are more susceptible to neurotoxicant exposure. NSDA neuronal indices were assessed using unbiased stereological cell counting, high pressure liquid chromatography coupled with electrochemical detection or mass spectrometry, and Western blot. Results reveal that CB1 and CB2 cannabinoid receptor signaling is not necessary for the maintenance of a normally functioning NSDA neuronal system. Mice lacking CB1 and CB2 receptors were found to be equally susceptible to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP). These studies support the use of CB1/CB2 KO mice for investigating the cannabinoid receptor-mediated regulation of the NSDA neuronal system in models of PD.

  3. Memory Deficit Recovery after Chronic Vanadium Exposure in Mice

    Directory of Open Access Journals (Sweden)

    Oluwabusayo Folarin

    2016-01-01

    Full Text Available Vanadium is a transitional metal with an ability to generate reactive oxygen species in the biological system. This work was designed to assess memory deficits in mice chronically exposed to vanadium. A total of 132 male BALB/c mice (4 weeks old were used for the experiment and were divided into three major groups of vanadium treated, matched controls, and animals exposed to vanadium for three months and thereafter vanadium was withdrawn. Animals were tested using Morris water maze and forelimb grip test at 3, 6, 9, and 12 months of age. The results showed that animals across the groups showed no difference in learning but had significant loss in memory abilities after 3 months of vanadium exposure and this trend continued in all vanadium-exposed groups relative to the controls. Animals exposed to vanadium for three months recovered significantly only 9 months after vanadium withdrawal. There was no significant difference in latency to fall in the forelimb grip test between vanadium-exposed groups and the controls in all age groups. In conclusion, we have shown that chronic administration of vanadium in mice leads to memory deficit which is reversible but only after a long period of vanadium withdrawal.

  4. Effects of a 4.7 T static magnetic field on fetal development in ICR mice

    Energy Technology Data Exchange (ETDEWEB)

    Okazaki, Ryuji; Ootsuyama, Akira; Uchida, Soshi; Norimura, Toshiyuki [Univ. of Occupational and Environmental Health, Kitakyushu, Fukuoka (Japan). School of Medicine

    2001-09-01

    In order to determine the effects of a 4.7 T static magnetic field (SMF) on fetal development in mice, we evaluated fetal teratogenesis and endochondral ossification following exposure in utero. Pregnant ICR mice were exposed to a 4.7 T SMF from day 7.5 to 9.5 of gestation in a whole-body dose, and sacrificed on day 18.5 of gestation. We examined with incidence of prenatal death, external malformations and fetal skeletal malformations. There were no significant differences observed in the incidence of prenatal death and/or malformations between SMF-exposed mice and control mice. Further, we evaluated the immunoreactivity for the vascular endothelial growth factor (VEGF), which is implicated in angiogenesis and osteogenesis, in the sternum of fetal mice following magnetic exposure. Our studies also indicated that on day 16.5 of gestation following SMF exposure, the immunoreactivity for VEGF was increased compared to unexposed controls. However, it was decreased in the exposed group compared to the control group on day 18.5 of gestation. DNA and proteoglycan (PG) synthesis were also measured in rabbit costal growth plate chondrocytes in vitro. No significant differences were observed in DNA synthesis between the SMF exposed chondrocytes and the control chondrocytes; however, PG synthesis in SMF exposed chondrocytes increased compared to the controls. Based on these results, we suggest that while SMF exposure promoted the endochondral ossification of chondrocytes, it did not induce any harmful effects on fetal development in ICR mice. (author)

  5. The effects of electronic cigarette aerosol exposure on inflammation and lung function in mice.

    Science.gov (United States)

    Larcombe, Alexander N; Janka, Maxine A; Mullins, Benjamin J; Berry, Luke J; Bredin, Arne; Franklin, Peter J

    2017-07-01

    Electronic cigarette usage is increasing worldwide, yet there is a paucity of information on the respiratory health effects of electronic cigarette aerosol exposure. This study aimed to assess whether exposure to electronic cigarette (e-cigarette) aerosol would alter lung function and pulmonary inflammation in mice and to compare the severity of any alterations with mice exposed to mainstream tobacco smoke. Female BALB/c mice were exposed for 8 wk to tobacco smoke, medical air (control), or one of four different types of e-cigarette aerosol. E-cigarette aerosols varied depending on nicotine content (0 or 12 mg/ml) and the main excipient (propylene glycol or glycerin). Twenty-four hours after the final exposure, we measured pulmonary inflammation, lung volume, lung mechanics, and responsiveness to methacholine. Mice exposed to tobacco cigarette smoke had increased pulmonary inflammation and responsiveness to methacholine compared with air controls. Mice exposed to e-cigarette aerosol did not have increased inflammation but did display decrements in parenchymal lung function at both functional residual capacity and high transrespiratory pressures. Mice exposed to glycerin-based e-cigarette aerosols were also hyperresponsive to methacholine regardless of the presence or absence of nicotine. This study shows, for the first time, that exposure to e-cigarette aerosol during adolescence and early adulthood is not harmless to the lungs and can result in significant impairments in lung function. Copyright © 2017 the American Physiological Society.

  6. Autosomal mutants of proton-exposed kidney cells display frequent loss of heterozygosity on nonselected chromosomes.

    Science.gov (United States)

    Grygoryev, Dmytro; Dan, Cristian; Gauny, Stacey; Eckelmann, Bradley; Ohlrich, Anna P; Connolly, Marissa; Lasarev, Michael; Grossi, Gianfranco; Kronenberg, Amy; Turker, Mitchell S

    2014-05-01

    High-energy protons found in the space environment can induce mutations and cancer, which are inextricably linked. We hypothesized that some mutants isolated from proton-exposed kidneys arose through a genome-wide incident that causes loss of heterozygosity (LOH)-generating mutations on multiple chromosomes (termed here genomic LOH). To test this hypothesis, we examined 11 pairs of nonselected chromosomes for LOH events in mutant cells isolated from the kidneys of mice exposed to 4 or 5 Gy of 1 GeV protons. The mutant kidney cells were selected for loss of expression of the chromosome 8-encoded Aprt gene. Genomic LOH events were also assessed in Aprt mutants isolated from isogenic cultured kidney epithelial cells exposed to 5 Gy of protons in vitro. Control groups were spontaneous Aprt mutants and clones isolated without selection from the proton-exposed kidneys or cultures. The in vivo results showed significant increases in genomic LOH events in the Aprt mutants from proton-exposed kidneys when compared with spontaneous Aprt mutants and when compared with nonmutant (i.e., nonselected) clones from the proton-exposed kidneys. A bias for LOH events affecting chromosome 14 was observed in the proton-induced Aprt mutants, though LOH for this chromosome did not confer increased radiation resistance. Genomic LOH events were observed in Aprt mutants isolated from proton-exposed cultured kidney cells; however the incidence was fivefold lower than in Aprt mutants isolated from exposed intact kidneys, suggesting a more permissive environment in the intact organ and/or the evolution of kidney clones prior to their isolation from the tissue. We conclude that proton exposure creates a subset of viable cells with LOH events on multiple chromosomes, that these cells form and persist in vivo, and that they can be isolated from an intact tissue by selection for a mutation on a single chromosome.

  7. Genetic Alterations in Pesticide Exposed Bolivian Farmers

    DEFF Research Database (Denmark)

    Jørs, Erik; González, Ana Rosa; Ascarrunz, Maria Eugenia

    2007-01-01

    : Questionnaires were applied and blood tests taken from 81 volunteers from La Paz County, of whom 48 were pesticide exposed farmers and 33 non-exposed controls. Sixty males and 21 females participated with a mean age of 37.3 years (range 17-76). Data of exposure and possible genetic damage were collected...... and evaluated by well known statistical methods, controlling for relevant confounders. To measure genetic damage chromosomal aberrations and the comet assay analysis were performed. Results: Pesticide exposed farmers had a higher degree of genetic damage compared to the control group. The number of chromosomal...... aberrations increased with the intensity of pesticide exposure. Females had a lower number of chromosomal aberrations than males, and people living at altitudes above 2500 metres seemed to exhibit more DNA damage measured by the comet assay. Conclusions: Bolivian farmers showed signs of genotoxic damage...

  8. GABAA receptor γ2 subunit knockdown mice have enhanced anxiety-like behavior but unaltered hypnotic response to benzodiazepines

    Directory of Open Access Journals (Sweden)

    De Blas Angel L

    2005-04-01

    Full Text Available Abstract Background Gamma-aminobutyric acid type A receptors (GABAA-Rs are the major inhibitory receptors in the mammalian brain and are modulated by a number of sedative/hypnotic drugs including benzodiazepines and anesthetics. The significance of specific GABAA-Rs subunits with respect to behavior and in vivo drug responses is incompletely understood. The γ2 subunit is highly expressed throughout the brain. Global γ2 knockout mice are insensitive to the hypnotic effects of diazepam and die perinatally. Heterozygous γ2 global knockout mice are viable and have increased anxiety-like behaviors. To further investigate the role of the γ2 subunit in behavior and whole animal drug action, we used gene targeting to create a novel mouse line with attenuated γ2 expression, i.e., γ2 knockdown mice. Results Knockdown mice were created by inserting a neomycin resistance cassette into intron 8 of the γ2 gene. Knockdown mice, on average, showed a 65% reduction of γ2 subunit mRNA compared to controls; however γ2 gene expression was highly variable in these mice, ranging from 10–95% of normal. Immunohistochemical studies demonstrated that γ2 protein levels were also variably reduced. Pharmacological studies using autoradiography on frozen brain sections demonstrated that binding of the benzodiazepine site ligand Ro15-4513 was decreased in mutant mice compared to controls. Behaviorally, knockdown mice displayed enhanced anxiety-like behaviors on the elevated plus maze and forced novelty exploration tests. Surprisingly, mutant mice had an unaltered response to hypnotic doses of the benzodiazepine site ligands diazepam, midazolam and zolpidem