Unknown,Transcriptomics,Genomics,Proteomics

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New insights into the molecular mechanisms of 1,3-dinitrobenzene-induced testicular toxicity

ABSTRACT: Several studies have shown that 1,3-dinitrobenzene (DNB) causes injury to Sertoli cells and induces apoptosis in the surrounding germinal cells in male laboratory rats ; however, the mechanisms by which DNB functions are not well understood. In this context, we have conducted studies using standard parameters and molecular tools to better understand the pathogenesis of the testicular effects produced by DNB, as well as its mode of action. Wistar rats were orally exposed to 0.1-8 mg DNB/kg/day for 4 days. Testosterone concentrations were not affected at any dose level, but marked histopathological lesions in the testes were recorded at 4 mg/kg/day. Global transcriptomic analysis of rat testes revealed cell cycle and cell death as the major biological processes affected. In particular, we identified an alteration in the expression of genes associated with cell cycle progression (mitotic roles of polo-like kinase). Dinitrobenzene was administered in suspension to rats (7 weeks old at start of treatment) by oral gavage at a daily dose of 0 (control, 0.5% methylcellulose in sterilized water), 0.1, 1, and 4 mg/kg body weight, for 4 consecutive days. Dose-related changes in gene expression were determined in the testes using whole genome oligonucleotide microarrays.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Sophie Ludwig

PROVIDER: E-GEOD-39344 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Grange2001 - PK interaction of L-dopa and benserazide A pharmacokinetics of L-dopa in rats after administration of L-dopa alone (BIOMD0000000321) or L-dopa combined with a peripheral AADC (amino-acid-decarboxylase) inhibitor (this model: BIOMD0000000320) has been studied using noncompartmental analysis. This model is described in the article: A pharmacokinetic model to predict the PK interaction of L-dopa and benserazide in rats. Grange S, Holford NH, Guentert TW Pharmaceutical Research [2001, 18(8):1174-1184] Abstract: PURPOSE: To study the PK interaction of L-dopa/benserazide in rats. METHODS: Male rats received a single oral dose of 80 mg/kg L-dopa or 20 mg/kg benserazide or 80/20 mg/kg L-dopa/benserazide. Based on plasma concentrations the kinetics of L-dopa, 3-O-methyldopa (3-OMD), benserazide, and its metabolite Ro 04-5127 were characterized by noncompartmental analysis and a compartmental model where total L-dopa clearance was the sum of the clearances mediated by amino-acid-decarboxylase (AADC), catechol-O-methyltransferase and other enzymes. In the model Ro 04-5127 inhibited competitively the L-dopa clearance by AADC. RESULTS: The coadministration of L-dopa/benserazide resulted in a major increase in systemic exposure to L-dopa and 3-OMD and a decrease in L-dopa clearance. The compartmental model allowed an adequate description of the observed L-dopa and 3-OMD concentrations in the absence and presence of benserazide. It had an advantage over noncompartmental analysis because it could describe the temporal change of inhibition and recovery of AADC. CONCLUSIONS: Our study is the first investigation where the kinetics of benserazide and Ro 04-5127 have been described by a compartmental model. The L-dopa/benserazide model allowed a mechanism-based view of the L-dopa/benserazide interaction and supports the hypothesis that Ro 04-5127 is the primary active metabolite of benserazide. The volumes and variables in this model are taken for a rat with 0.25 kg. The inital dose for L_Dopa (L_Dopa_per_kg_rat) and Benserazide (Benserazide_per_kg_rat) are to be given in umole per kg. 80 mg/kg L-Dopa correspond to 404 umol/kg, 20 mg/kg benserazide to 78 umol/kg. To change the model to a different mass of rat the compartment volumes, and the parameters rat_body_mass and Q have to changed accordingly. The model has three species (A-dopa, A_B, A_M) whose initial concentrations are calculated from a listOfInitialAssignments . While running for the first time the time-course (24hrs) for this model in COPASI (up to version 4.6, Build 33), the resulting graph displays only straight lines for all the species. Any subsequent runs should provide proper plots (i.e. without making any change to the model, just by clicking the "run" button again). The above issue is caused by some initial assignments which are not calculated when COPASI imports the file. This issue should not be present in newer releases of COPASI. This model is hosted on BioModels Database and identified by: MODEL0910130001 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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New insights into the molecular mechanisms of 1,3-dinitrobenzene-induced testicular toxicity

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