Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Gene expression profiles of amiodarone, valproic acid, and tetracycline induced steatosis in C57BL/6 mice

ABSTRACT: Toxicogenomics (tgx) is used as a tool to identify mechanisms and markers of steatosis in C57BL/6 mice treated by oral gavage using amiodarone (AMD), valproic acid (VPA), and tetracycline (TET). Critical doses for tgx analysis were derived from a 25 day dose range finding study. For tgx analysis, livers of mice were collected after 1, 4, and 11 days of repeated treatment with 6.7, 20, and 60 mg/kg bw for AMD; 125, 250, and 500 mg/kg bw for VPA; and 14.8, 44, and 133 mg/kg bw for TET. For each treatment (compound and vehicle) in the toxicogenomics study samples were as follows: four at the high dose 1 and 4 day time point, and five at the low, medium, and high dose at 11 days. One set of vehicle controls were used for AMD and VPA (PBS), and TET had its own vehicle controls (milli-q water with ascorbic acid). The total number of samples was 95.

ORGANISM(S): Mus musculus

SUBMITTER: Alexa Vitins

PROVIDER: E-GEOD-48126 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Mechanisms of amiodarone and valproic acid induced liver steatosis in mouse in vivo act as a template for other hepatotoxicity models.

Vitins Alexa P AP Kienhuis Anne S AS Speksnijder Ewoud N EN Roodbergen Marianne M Luijten Mirjam M van der Ven Leo T M LT

Archives of toxicology 20140218 8

Liver injury is the leading cause of drug-induced toxicity. For the evaluation of a chemical compound to induce toxicity, in this case steatosis or fatty liver, it is imperative to identify markers reflective of mechanisms and processes induced upon exposure, as these will be the earliest changes reflective of disease. Therefore, an in vivo mouse toxicogenomics study was completed to identify common pathways, nuclear receptor (NR) binding sites, and genes regulated by three known human steatosis ...[more]

PMID: 24535564

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Project description:Microglia colonize the brain parenchyma at early stages of development and accumulate in specific regions where they actively participate in cell death, angiogenesis, neurogenesis and synapse elimination. A recurring feature of embryonic microglial distribution is their association with developing axon tracts which, together with in vitro data, supports the idea of a physiological role for microglia in neurite development. Yet the demonstration of this role of microglia is still lacking. Here, we have studied the consequences of microglial dysfunction on the formation of the corpus callosum, the largest connective structure in the mammalian brain, which shows consistent microglial accumulation during development. We studied two models of microglial dysfunction: the loss-of-function of DAP12, a key microglial-specific signaling molecule, and a model of maternal inflammation by peritoneal injection of LPS at E15.5. We performed transcriptional profiling of maternally inflamed and Dap12-mutant microglia at E17.5. We found that both treatments principally down-regulated genes involved in nervous system development and function, particularly in neurite formation. We then analyzed the functional consequences of these microglial dysfunctions on the formation of the corpus callosum. We also took advantage of the Pu.1-/- mouse line, which is devoid of microglia. We now show that all three models of altered microglial activity resulted in the same defasciculation phenotype. Our study demonstrates that microglia are actively involved in the fasciculation of corpus callosum axons. To investigate possible roles for microglial during brain development, we challenged microglial function by two complementary approaches. First, we induced maternal inflammation by peritoneal injection of LPS into pregnant dams. Next, we analyzed the consequences of a loss of function of DAP12, a signaling molecule specifically expressed in microglia that is crucial for several aspects of microglia biology (references in Wakselman et al., 2008). We compared the gene expression profiles of microglia from control, maternally-inflamed by LPS (MI), and Dap12-mutated embryos. We isolated RNA from FACS sorted maternally inflamed (by LPS) and Dap12-mutant microglia at E17.5 pooled per pregnant dam; as a control we included PBS treated and untreated (UT) microglia. We compared gene expression between maternally inflamed microlgia (PBSvsLPS) and DAP12-mutant microglia (UTvsDAP12KO).

Project description:Abstract Two major dendritic cell (DC) subsets have been described in the islets of mice: The immunogenic CD8Î±-CD11b+ DCs and the tolerogenic CD8Î±+CD103+ DCs. We have recently reported on reduced numbers of the minor population of tolerogenic CD8Î±+CD103+ DCs in the pancreas of 5 week old pre-diabetic non-obese diabetic (NOD) mice. Aim: To analyze also the larger subset of CD11c+CD8Î±- DCs isolated from the pancreas of pre-diabetic NOD mice 1) for maturation and tolerance inducing molecules found abnormally expressed on CD8Î±+CD103+ DCs, and 2) for genome-wide gene expression to further elucidate abnormalities in underlying gene expression networks. Methods: CD11c+CD8Î±- DCs were isolated from 5 week old C57BL/6 and NOD pancreas. Expression of cell surface markers including CD86, CCR5, CD11b, CD103, Clec9a, CD24 and CD200R3 were measured by FACS. Genome-wide gene expression by microarray was assessed during the steady state and after in vitro LPS stimulation. Results: The steady state pancreatic CD11c+ CD8Î±- DCs during the pre-diabetic stage showed: 1) A reduced expression of several gene networks important for the prime functions of the cell, such as for cell renewal, immune stimulation and immune tolerance induction, for migration and for the provision of growth factors for beta cell regeneration. This general deficiency state was corroborated by a reduced in vivo proliferation (BrdU incorporation) of the cells and the reduced expression in FACS analysis of CD86, CCR5, CD103, Clec9a, CD24 and CD200R3 on the cells. 2) A hyper reactivity of these cells to LPS correlated with an enhanced pro-inflammatory state characterized by altered expression of a number of classical pro-inflammatory factors and cytokines. Conclusion: The NOD CD11c+CD8Î±- DCs seem to be Janus-faced depending on the conditions: Deficient in steady state with reduced immune stimulation capabilities also for tolerance induction; over-inflammatory with a molecular profile suggesting a preferential stimulatory capacity for Th1 cells when encountering a Pathogen-Associated Molecular Pattern (PAMP) in the form of LPS. We used microarray gene expression analysis to explain the abnormal expression of several cell surface markers involved in tolerace, migration and maturation in the steady-state and to measure the effect of a PAMP such as LPS We isolated RNA from FACS sorted CD11c+CD8Î±- DCs in 10 pooled pancreases from pre-diabetic NOD and non-diabetic C57BL/6 mice at 5 weeks. In addition, we treated in another experiment the isolated pancreas DCs with LPS (and PBS), incubated for 18h and measured gene expression. We compared gene expression between strains NOD vs C57BL/6 under steady-state and after in-vitro LPS/PBS stimulation.

Dataset Information

Gene expression profiles of amiodarone, valproic acid, and tetracycline induced steatosis in C57BL/6 mice

Publications

Mechanisms of amiodarone and valproic acid induced liver steatosis in mouse in vivo act as a template for other hepatotoxicity models.

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