Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Cumulative low doses of the organic pesticide rotenone in the adult rat substantia nigra pars compacta

ABSTRACT: Adult male Sprague Dawley rats (5 month-old at the beginning of the study) were subcutaneously exposed to 0.5 mg.kg/d rotenone or the corresponding solvent (PEG/DMSO, 1/1) for 28 days. At the end of the experiment, animals were sacrificed by decapitation and brains were rapidly taken out within 30-40 s. Total RNA was prepared from laser-capture microdissected rat substantia nigra pars compacta (Snpc). Changes in transcript abundance within SNpc were analyzed on samples from solvent and rotenone-exposed groups (n = 3 per group) using CodeLinkâ¢ Rat Whole Genome bioarrays containing 34,000 transcripts and EST probes (GE Healthcare, Amersham, Saclay, France). Two groups of rats were exposed either to rotenone (CR rats) or to solvents (CS rats) in order to analyse pesticides impact on gene expression.

ORGANISM(S): Rattus norvegicus

SUBMITTER: frÃ©dÃ©ric leprÃªtre

PROVIDER: E-GEOD-22364 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The pesticide rotenone, a neurotoxin that inhibits the mitochondrial complex I, and destabilizes microtubules (MT) has been linked to Parkinson disease (PD) etiology and is often used to model this neurodegenerative disease (ND). Many of the mechanisms of action of rotenone are posited mechanisms of neurodegeneration; however, they are not fully understood. Therefore, the study of rotenone-affected functional pathways is pertinent to the understanding of NDs pathogenesis. This report describes the transcriptome analysis of a neuroblastoma (NB) cell line chronically exposed to marginally toxic and moderately toxic doses of rotenone. The results revealed a complex pleiotropic response to rotenone that impacts a variety of cellular events, including cell cycle, DNA damage response, proliferation, differentiation, senescence and cell death, which could lead to survival or neurodegeneration depending on the dose and time of exposure and cell phenotype. The response encompasses an array of physiological pathways, modulated by transcriptional and epigenetic regulatory networks, likely activated by homeostatic alterations. Pathways that incorporate the contribution of MT destabilization to rotenone toxicity are suggested to explain complex I-independent rotenone-induced alterations of metabolism and redox homeostasis. The postulated mechanisms involve the blockage of mitochondrial voltage-dependent anions channels (VDACs) by tubulin, which coupled with other rotenone-induced organelle dysfunctions may underlie many presumed neurodegeneration mechanisms associated with pathophysiological aspects of various NDs including PD, AD and their variant forms. Thus, further investigation of such pathways may help identify novel therapeutic paths for these NDs. SK-N-MC cells were grown in three different conditions: media + vehicle (EtOH), media + a sublethal dose (5 nM) of rotenone, and media + a slightly toxic dose (50 nM) of rotenone. Gene expression was examined at 1 and 4 weeks of rotenone treatment. Three experiments were performed, each lasting 1 and 4 weeks. For each experiment, 5 separate dishes of vehicle-treated, and rotenone-treated cells were harvested at 1 and 4 weeks (30 independent samples at each time point) and pooled into 3 samples (vehicle treated,and rotenone treated with 5 nM and 50 nM) at each time point for a total of 18 individual samples from all thre experiments. Total RNA isolated from each of the 18 individual samples was used to prepared labeled cRNA and hybridized to one Genechip (Affymetrix) Human Genome array HG-U133A at the UCLA microarray core facility (http://microarray.genetics.ucla.edu/). After QC check, the data was normalized and used to assess expression indexes and fold changes (FC > 2.0, compared to vehicle-treated controls) using the model-based expression indexes (MBEI) method implemented in dCHIP, ( http://biosun1.harvard.edu/complab/dchip/), and the Signifiance Analysis of Microarrays (SAM) software for multiple test corrections. Enrichment analysis was performed by the functional annotation tools implemented in DAVID ( http://david.abcc.ncifcrf.gov), to ascertain sets of rotenone DRGs that are enriched in certain biological annotations.

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Cumulative low doses of the organic pesticide rotenone in the adult rat substantia nigra pars compacta

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