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Pathways identified by toxicogenomics analysis reveal the size and dose independency of silica particles-induced toxicity in mice.

ABSTRACT: Understanding the interactions of nanostructures with biological systems is essential to nanotoxicological research. Using a microarray-based toxicogenomics approach at early stage, this study investigated the relationship between particle size and toxicity of silica particles (SP) with diameters of 30, 70, and 300 nm (SP30, SP70, and SP300) as well as the mechanism of injury in mice. Two experiments with SiO2 particles of different sizes were considered in mice. One was aimed to investigate the dose-response relationship of SP70 toxicity at a dose of 10, 20, or 40 mg/kg (experiment 1), and the other set to study the size-response relationship of SP-induced toxicity using SP30, SP70, or SP300 (experiment 2). In experiment 2, two dosages each of SP30, SP70, and SP300 were performed. One was 10 mg/kg at three particle sizes, and the other was toxic doses of the three particle sizes, i.e., 10 mg/kg for SP30, 40 mg/kg for SP70, and 200 mg/kg for SP300. The toxic doses of the three particle sizes of SP were decided on the basis of the results of histopathological examinations and serum biochemical analysis in our previous study.n = 5

ORGANISM(S): Mus musculus

SUBMITTER: Xiaoyan Lu

PROVIDER: E-GEOD-30861 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Pathways identified by toxicogenomics analysis reveal the size and dose independency of silica particles-induced toxicity in mice.

Project description:Understanding the interactions of nanostructures with biological systems is essential to nanotoxicological research. Using a microarray-based toxicogenomics approach at early stage, this study investigated the relationship between particle size and toxicity of silica particles (SP) with diameters of 30, 70, and 300 nm (SP30, SP70, and SP300) as well as the mechanism of injury in mice.

2011-08-01 | GSE30861 | GEO

Effect of dietary vitamin B6 on white adipose tissue

Project description:Transcriptional profiling of mouse white adipose tissues The objective of this study is to explore the relationship between vitamin B6 activity and chronic inflammation of white adipose tissue in mice fed a high-fat diet. Twenty-four CD-1 mice were divided into two groups (n = 12) and fed either a 1 mg pyridoxine (PN) HCl /kg diet or a 35 mg PN HCl /kg diet for 8 weeks. We isolated total RNA from epididymal white adipose tissue of each group and compared gene expression profiles by DNA microarray data analysis. Noriyuki Yanaka

2013-01-12 | E-GEOD-43465 | biostudies-arrayexpress

Transcription profiling of mouse small intestine following treatment with dexamethosone and DBZ

Project description:Gamma-secretase inhibitors (GSIs), which block the activation of NOTCH receptors, are being tested in the treatment of T-cell acute lymphoblastic leukemia (T-ALL). Thus far, limited antileukemic cytotoxicity and severe gastrointestinal toxicity have restricted the clinical application of these targeted drugs. Here we show that combination therapy with GSIs plus glucocorticoids can improve the antileukemic effects of GSIs and reduce their gut toxicity in vivo. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid receptor auto-up-regulation and induced apoptotic cell death through induction of BIM expression. Additionally, cotreatment with glucocorticoids induced Ccnd2 upregulation in the gut which protected mice from the intestinal secretory metaplasia typically induced by loss of NOTCH signaling. These results support a role for glucocorticoids plus GSIs in the treatment of glucocorticoid-resistant T-ALL. Experiment Overall Design: Experiments analyzing the interacition of dexamethasone and the gamma-secretase inhibitor DBZ were carried out in 6-week-old C57/Black6 female mice (Jackson Laboratory). In these studies we treated mice with vehicle (DMSO) (n=2), dexamethasone (15 mg/kg) (n=2), DBZ (10 micromol/kg) (n=2) and dexamethasone (15 mg/kg) plus DBZ (10 micromol/kg) (n=2) daily by intraperitoneal injection for 5 days. At the end of the treatment, animals were euthanized and segments of the small intestine were collected and processed for RNA extraction, histological and immunohistochemical analysis.

2009-04-10 | E-GEOD-11184 | biostudies-arrayexpress

Quantitative proteomics of liver from methylmercury-exposed Atlantic cod

Project description:In order to investigate the underlying mechanisms of methylmecury (MeHg)-mediated toxicity to Atlantic cod (Gadus morhua), we analyzed the liver proteome of fish exposed in vivo to MeHg (0, 0.5, 2 mg/kg body weight) for 2 weeks. Label-free quantitative mass spectrometry enabled quantification of 1143 proteins, and 125 were differentially regulated between MeHg-treated samples and controls. Six proteins among the top differentially regulated (T23O, GLNA EPS8L2, APOA4, RAP1B, CZTZ) were analyzed using selected reaction monitoring (SRM). Supported by bioinformatics analyses, we conclude that MeHg disrupts mainly redox homeostasis and energy generating metabolic pathways in cod liver, the latter potentially modulated through MeHg-induced oxidative stress.

2016-08-09 | PXD004311 | Pride

Transcription profiling of mouse macrophage response to silica nanoparticles

Project description:Using a macrophage cell line, we demonstrate the ability of amorphous silica particles to stimulate inflammatory protein secretion and induce cytotoxicity. Whole genome microarray analysis of early gene expression changes induced by 10nm and 500nm particles showed that the magnitude of change for the majority of genes correlated more tightly with particle surface area than either particle mass or number. Gene expression changes that were size-specific were also identified, however the overall biological processes represented by all gene expression changes were nearly identical, irrespective of particle diameter. Our results suggest that on an equivalent nominal surface area basis, common biological modes of action are expected for nano- and supranano-sized silica particles. Experiment Overall Design: RAW 264.7 mouse macrophage cells were treated with two sizes of amorphous silica particles at three doses each for 2 hours. Cells were exposed to 10nm silica at 5 (low), 20 (mid), or 50 (high) ug/ml or 500nm silica at 250 (low), 500 (mid), or 1000 (high) ug/ml in serum-free medium.

2009-01-13 | E-GEOD-13005 | biostudies-arrayexpress

5-Day Gavage Study of Propylene glycol phenyl ether (PPH; CASRN 770-35-4) in Male Harlan Sprague Dawley Rats

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2015-12-31 | E-GEOD-75656 | biostudies-arrayexpress

Transcription profiling of rat skeletal muscle treated with cerivastatin

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2008-06-13 | E-GEOD-4418 | biostudies-arrayexpress

Characteristic molecular and proteomic signatures of drug-induced liver injury in a rat model

Project description:we assessed characteristic molecular and proteomic signatures in rat liver treated with drugs (pyrazinamide, ranitidine, enalapril, carbamazepine, and chlorpromazine) that are known to cause DILI in humans. In the present study, we assessed the characteristic gene expression signature for DILI in a rat model. Rats were administered representative drugs that are already known to induce DILI in humans and transcriptomic changes in rat liver were analyzed. The representative drugs, which induce three types (hepatocellular, mixed, and cholestatic) of DILI, that were used in this study were pyrazinamide (PZA, 150~1500 mg/kg), ranitidine (RAN, 209.5~2095 mg/kg), enalapril (ENA, 148.65~1486.5 mg/kg), carbamazepine (CBZ, 97.85~978.5 mg/kg), and chlorpromazine (CPZ, 7.1~71 mg/kg).

2013-08-16 | E-GEOD-49631 | biostudies-arrayexpress

Impacts of 2-amino-4,6-dinitrotoluene (2-ADNT) Exposure in Northern Bobwhite

Project description:Effects of 2A-DNT on global protein expression were investigated in liver tissue for both sexes and kidney in males, all at a 30 mg/kg-d dose using nLC-MS/MS.

2016-07-06 | PXD001206 | Pride

Cardiotoxicity of tubulin binders

Project description:The use of tubulin binders (TBs) in oncology indications often is associated with cardiotoxicity, the mechanism of which has not been elucidated. We observed that a single administration of TBs to rats caused an increase in the number of mitotic figures in the myocardial interstitium after 24 hours. We therefore hypothesized that interstitial cells are the primary target of TBs. To test this hypothesis, we evaluated the acute effects of a single intravenous administration of 3 reference TBs, colchicine (0.2 and 2 mg/kg), vinblastine (0.5 and 3 mg/kg), and vincristine (0.1 and 1 mg/kg) 6 and 24 hours after dosing. Mitotic arrest was identified at 24 hours in all high-dose groups based on an increase in the number of mitotic figures in the interstitium coupled with a dramatic decrease in the number of Ki67-positive interstitial cells. Analysis of the myocardial transcriptomic data further supported G2/M cell cycle arrest 6 hours after dosing with the high-dose groups of all 3 compounds. Apoptotic figures and an increase in the number of cleaved caspase 3-positive cells were identified at 6 and 24 hours at the highest dose of each compound almost exclusively in interstitial cells; a few cardiomyocytes were affected as well. Transcriptomic data further suggested that some of the affected interstitial cells were endothelial cells based on the up-regulation of genes typically associated with vascular damage and down-regulation of Endothelial Cell-Specific Molecule 1 and Apelin. Taken together, these data identify endothelial cells of the myocardium as the primary target of the cardiotoxicity of TBs and identify cell cycle arrest as the mechanism of this toxicity. Gene expression was profiled in the myocardium of rats at 6 and 24 hr after a single dose of colchicine, vinblastine or vincristine.

2010-01-01 | E-GEOD-19290 | biostudies-arrayexpress

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