Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptional analysis of organ-specific toxicity induced by a panPPAR agonist in mice: Identification of organ-specific toxicity biomarkers


ABSTRACT: In this study, we aim to identify candidate biomarkers which may be useful as surrogate indicators of toxicity for pre-clinical development of panPPAR-agonist drug candidates. Gene expression microarray, histopathology and clinical chemistry data were generated from liver, heart, kidney and skeletal muscles of three groups of mice administered with three different dosages of an experimental pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist, PPM-201, for 14 days. The histopathology and clinical chemistry data were compared with the gene expression analysis and candidate biomarker genes were identified. Nine wild type mice (strain: C57BL/6J) were randomly divided into three groups - Group-I, II and III. PPM-201 in the vehicle base was administered daily for 14 days at 6 mg/kg body weight dose rate to each mouse in Group-II and at 20mg/kg body weight dose rate to each mouse in Group-III while the mice in Group-I received only the vehicle base. On 15th day, the mice were sacrificed to harvest blood, heart, skeletal muscle, liver and kidney tissues for clinical chemistry, microarray and histopathology analysis. In the clinical chemistry analysis, alanine aminotransferase (ALT, U/L), aspartate aminotransferase (AST, U/L), creatinine kinase (CK, U/L), blood urea nitrogen (BUN, mmol/L), creatinine (umol/L) and lactate dehydrogenase (LDH, U/L) were measured from the blood of each mouse. Two sections of liver, two sections of kidney, one or two sections of skeletal muscle, and one section of heart were prepared from each mouse, stained with hematoxylin and eosin (H&E), and examined by a veterinary pathologist. RNA was extracted and processed as per the established protocol from heart, skeletal muscle, liver and kidney tissue samples of all the 9 mice for profiling with Affymetrix Mouse Genome 430 2.0 Array and in total 36 chips were prepared. Using various quality control measures, the data was analysed for its quality. As it was found to be good in quality, the data from all the 36 chips were used for further analysis. The results from histopathology and clinical chemistry analysis were compared with the gene expression to determine if the dosages selected for the study were associated with findings in target organs.

ORGANISM(S): Mus musculus

SUBMITTER: Manikhandan Mudaliar 

PROVIDER: E-GEOD-31561 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Simultaneous non-negative matrix factorization for multiple large scale gene expression datasets in toxicology.

Lee Clare M CM   Mudaliar Manikhandan A V MA   Haggart D R DR   Wolf C Roland CR   Miele Gino G   Vass J Keith JK   Higham Desmond J DJ   Crowther Daniel D  

PloS one 20121214 12


Non-negative matrix factorization is a useful tool for reducing the dimension of large datasets. This work considers simultaneous non-negative matrix factorization of multiple sources of data. In particular, we perform the first study that involves more than two datasets. We discuss the algorithmic issues required to convert the approach into a practical computational tool and apply the technique to new gene expression data quantifying the molecular changes in four tissue types due to different  ...[more]

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