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Toxicogenomic analysis of gene expression changes in rat liver after a 28-day oral benzene exposure

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Author: Heijne, W.H.M. · Jonker, D. · Stierum, R.H. · Ommen, B. van · Groten, J.P.
Type:article
Date:2005
Institution: TNO Kwaliteit van Leven
Source:Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, 1-2, 575, 85-101
Identifier: 238643
doi: doi:10.1016/j.mrfmmm.2005.02.003
Keywords: Toxicology Biology · Toxicology and Applied Pharmacology · Benzene · cDNA microarrays · Gene expression · Hepatotoxicity · Metabolomics · Toxicogenomics · Transcriptomics · benzene · bromobenzene · paracetamol · animal experiment · animal tissue · biotransformation · blood toxicity · cholesterol metabolism · conference paper · DNA microarray · gene expression · genetic analysis · genetic toxicology · glutathione metabolism · liver necrosis · liver weight · male · nonhuman · nuclear magnetic resonance spectroscopy · nucleotide sequence · priority journal · rat · rat strain · unindexed sequence · Animals · Benzene · Blood Cell Count · Cholesterol · Fatty Acids · Gene Expression Profiling · Gene Expression Regulation · Hemoglobins · Liver · Male · Mutagens · Oligonucleotide Array Sequence Analysis · Organ Size · Rats · Rats, Inbred F344 · Spleen · Thymus Gland · Time Factors · Urinalysis · Martes pennanti

Abstract

Benzene is an industrial chemical, component of automobile exhaust and cigarette smoke. After hepatic bioactivation benzene induces bone marrow, blood and hepatic toxicity. Using a toxicogenomics approach this study analysed the effects of benzene at three dose levels on gene expression in the liver after 28 daily doses. NMR based metabolomics was used to assess benzene exposure by identification of characteristic benzene metabolite profiles in urine. The 28-day oral exposure to 200 and 800 mg/kg/day but not 10 mg/kg/day benzene-induced hematotoxicity in male Fisher rats. Additionally these upper dose levels slightly reduced body weight and increased relative liver weights. Changes in hepatic gene expression were identified with oligonucleotide microarrays at all dose levels including the 10 mg/kg/day dose level where no toxicity was detected by other methods. The benzene-induced gene expression changes were related to pathways of biotransformation, glutathione synthesis, fatty acid and cholesterol metabolism and others. Some of the effects on gene expression observed here have previously been observed after induction of acute hepatic necrosis with bromobenzene and acetaminophen. In conclusion, changes in hepatic gene expression were found after treatment with benzene both at the toxic and non-toxic doses. The results from this study show that toxicogenomics identified hepatic effects of benzene exposure possibly related to toxicity. The findings aid to interpret the relevance of hepatic gene expression changes in response to exposure to xenobiotics. In addition, the results have the potential to inform on the mechanisms of response to benzene exposure. © 2005 Elsevier B.V. All rights reserved.