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Bromobenzene-induced hepatotoxicity at the transcriptome level

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Author: Heijne, W.H.M. · Slitt, A.L. · Bladeren, P.J. van · Groten, J.P. · Klaassen, C.D. · Stierum, R.H. · Ommen, B. van
Type:article
Date:2004
Institution: TNO Voeding Centraal Instituut voor Voedingsonderzoek TNO
Source:Toxicological Sciences, 2, 79, 411-422
Identifier: 237784
doi: doi:10.1093/toxsci/kfh128
Keywords: Biology Toxicology · Physiological Sciences · Bromobenzene · cDNA microarray · Hepatotoxicity · Rat · Toxicogenomics · Transcriptomics · Bromobenzene · Cholesterol · Complementary DNA · Cytochrome P450 4A · Fatty acid · Glutathione · Messenger RNA · Metallothionein · Protein · Sterol · Acute phase response · Animal experiment · Animal model · Animal tissue · Cell communication · Cholesterol metabolism · Concentration response · Controlled study · Cytoskeleton · DNA determination · DNA microarray · DNA responsive element · Drug metabolism · Electron · Fatty acid metabolism · Gene amplification · Gene expression profiling · Gene rearrangement · Liver toxicity · Nonhuman · Nucleotide sequence · Oxidative stress · Protein depletion · Protein metabolism · Protein synthesis · Rat · Signal transduction · Transcription regulation · Animals · Bromobenzenes · Gene Expression Profiling · Gene Expression Regulation · Glutathione · Hepatitis, Toxic · Liver · Male · Microarray Analysis · Oligonucleotide Array Sequence Analysis · Rats · Rats, Inbred Strains · Time Factors · Transcription, Genetic

Abstract

Rats were exposed to three levels of bromobenzene, sampled at 6, 24, and 48 h, and liver gene expression profiles were determined to identify dose and time-related changes. Expression of many genes changed transiently, and dependent on the dose. Few changes were identified after 6 h, but many genes were differentially expressed after 24 h, while after 48 h, only the high dose elicited large effects. Differentially expressed genes were involved in drug metabolism (upregulated GSTs, mEH, NQO1, Mrps, downregulated CYPs, sulfotransferases), oxidative stress (induced HO-1, peroxiredoxin, ferritin), GSH depletion (induced GCS-1, GSTA, GSTM) the acute phase response, and in processes like cholesterol, fatty acid and protein metabolism, and intracellular signaling. Trancriptional regulation via the electrophile and sterol response elements seemed to mediate part of the response to bromobenzene. Recovery of the liver was suggested in response to BB by the altered expression of genes involved in protein synthesis and cytoskeleton rearrangement. Furthermore, after 48 h, rats in the mid dose group showed no toxicity, and gene expression patterns resembled the normal situation. For certain genes (e.g., CYP4A, metallothioneins), intraday variation in expression levels was found, regardless of the treatment. Selected cDNA microarray measurements were confirmed using the specific and sensitive branched DNA signal amplification assay. © Society of Toxicology 2004; all rights reserved.