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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Dynamic gene expression changes precede dioxin-induced liver pathogenesis in medaka fish.

Authors: Volz, David C; Hinton, David E; Law, J McHugh; Kullman, Seth W

Published In Toxicol Sci, (2006 Feb)

Abstract: A major challenge for environmental genomics is linking gene expression to cellular toxicity and morphological alteration. Herein, we address complexities related to hepatic gene expression responses after a single injection of the aryl hydrocarbon receptor (AHR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) and illustrate an initial stress response followed by cytologic and adaptive changes in the teleost fish medaka. Using a custom 175-gene array, we find that overall hepatic gene expression and histological changes are strongly dependent on dose and time. The most pronounced dioxin-induced gene expression changes occurred early and preceded morphologic alteration in the liver. Following a systematic search for putative Ah response elements (AHREs) (5'-CACGCA-3') within 2000 bp upstream of the predicted transcriptional start site, the majority (87%) of genes screened in this study did not contain an AHRE, suggesting that gene expression was not solely dependent on AHRE-mediated transcription. Moreover, in the highest dosage, we observed gene expression changes associated with adaptation that persisted for almost two weeks, including induction of a gene putatively identified as ependymin that may function in hepatic injury repair. These data suggest that the cellular response to dioxin involves both AHRE- and non-AHRE-mediated transcription, and that coupling gene expression profiling with analysis of morphologic pathogenesis is essential for establishing temporal relationships between transcriptional changes, toxicity, and adaptation to hepatic injury.

PubMed ID: 16267337 Exiting the NIEHS site

MeSH Terms: Animals; Cytochrome P-450 CYP1A1/genetics; Cytochrome P-450 CYP1A2/genetics; Dose-Response Relationship, Drug; Gene Expression Profiling; Gene Expression/drug effects*; Injections, Intraperitoneal; Liver*/drug effects; Liver*/metabolism; Liver*/pathology; Male; Oligonucleotide Array Sequence Analysis; Oryzias; Polychlorinated Dibenzodioxins/toxicity*; Receptors, Aryl Hydrocarbon/genetics*; Reverse Transcriptase Polymerase Chain Reaction; Time Factors

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