Gene expression profiling in liver and testis of rats to characterize the toxicity of triazole fungicides

Tully, Douglas Β.; Bao, Wenjun; Goetz, Amber K.; Blystone, Chad R.; Ren, Hongzu; Schmid, Judith E.; Strader, Lillian F.; Wood, Carmen R.; Best, Deborah S.; Narotsky, Michael G.; Wolf, Douglas C.; Rockett, John C.; Dix, David J.

doi:10.1016/j.taap.2006.02.015

Cited by 104 publications

(77 citation statements)

References 27 publications

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“…Similar to the present study, Tully et al (2006) found that triadimefon and propiconazole altered similar numbers of genes, with myclobutanil altering far fewer genes. It was of interest to relate toxicological findings to concurrent changes in gene expression for a series of endpoints based on high dose exposure.…”

Section: Discussionsupporting

confidence: 90%

Transcriptional Profiles in Liver from Rats Treated with Tumorigenic and Non-tumorigenic Triazole Conazole Fungicides: Propiconazole, Triadimefon, and Myclobutanil

et al. 2006

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Conazoles are a class of fungicides used as pharmaceutical and agricultural agents. In chronic bioassays in rats, triadimefon was hepatotoxic and induced follicular cell adenomas in the thyroid gland, whereas, propiconazole and myclobutanil were hepatotoxic but had no effect on the thyroid gland. These conazoles administered in the feed to male Wistar/Han rats were found to induce hepatomegaly, induce high levels of pentoxyresorufin-O-dealkylase, increase cell proliferation in the liver, increase serum cholesterol, decrease serum T3 and T4, and increase hepatic uridine diphosphoglucuronosyl transferase activity. The goal of the present study was to define pathways that explain the biologic outcomes. Male Wistar/Han rats (3 per group), were exposed to the 3 conazoles in the feed for 4, 30, or 90 days of treatment at tumorigenic and nontumorigenic doses. Hepatic gene expression was determined using high-density Affymetrix GeneChips (Rat 230 2). Differential gene expression was assessed at the probe level using Robust Multichip Average analysis. Principal component analysis by treatment and time showed within group sample similarity and that the treatment groups were distinct from each other. The number of altered genes varied by treatment, dose, and time. The greatest number of altered genes was induced by triadimefon and propiconazole after 90 days of treatment, while myclobutanil had minimal effects at that time point. Pathway level analyses revealed that after 90 days of treatment the most significant numbers of altered pathways were related to cell signaling, growth, and metabolism. Pathway level analysis for triadimefon and propiconazole resulted in 71 altered pathways common to both chemicals. These pathways controlled cholesterol metabolism, activation of nuclear receptors, and N-ras and K-ras signaling. There were 37 pathways uniquely changed by propiconazole, and triadimefon uniquely altered 34 pathways. Pathway level analysis of altered gene expression resulted in a more complete description of the associated toxicological effects that can distinguish triadimefon from propiconazole and myclobutanil.

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Section: Discussionsupporting

confidence: 90%

Transcriptional Profiles in Liver from Rats Treated with Tumorigenic and Non-tumorigenic Triazole Conazole Fungicides: Propiconazole, Triadimefon, and Myclobutanil

et al. 2006

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“…While the toxicogenomic effects of these triazoles has been studied in rats (Tully et al, 2006), profiling of low molecular weight metabolites in various tissues and biofluids from triazole-exposed rodents has not been reported. The study of metabolic responses, known as metabolomics/metabonomics provides simultaneous measurements of perturbations in a large number of tissue or biofluid metabolites induced by xenobiotics that can be used to explore the effects of toxicological insult (or pharmacological efficacy).…”

Section: Introductionmentioning

confidence: 99%

Metabolomic evaluation of rat liver and testis to characterize the toxicity of triazole fungicides

et al. 2006

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The effects of two triazole fungicides, myclobutanil and triadimefon, on endogenous rat metabolite profiles in blood serum, liver, and testis was assessed using proton nuclear magnetic resonance ( 1 H-NMR) spectroscopy. Adult male Sprague-Dawley rats were dosed daily by gavage for 14 days with myclobutanil or triadimefon, at two dose levels for each triazole. Following exposure, serum, liver, and testis were collected and processed for NMR analysis. Principal components analysis (PCA) and partial least squares discriminant analysis (PLS-DA) of the resulting spectra were used to determine changes in metabolite profiles as a result of exposure. Using this approach, responses common to both triazoles were identified, as well as responses indicative of differences in the toxicity of these two compounds. Although changes were observed in serum metabolites following exposure, none were robust enough to be considered a biomarker of exposure/effect. A number of metabolic changes were, however, observed in the liver with both triazoles, particularly in metabolites related to the methionine cycle. The testes of myclobutanil-exposed animals displayed altered levels of creatine and creatinine, consistent with testicular toxicity. Overall, the results of this study support the possible application of a metabolomics approach to assessing the toxicity of triazole fungicides and identifying biomarkers of exposure and/or effect.

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“…It is now well established that PXR is a key regulator of xenobiotic-inducible CYP3A gene expression in liver (reviewed in Goodwin et al, 2002). PXR also regulates the druginducible expression and activity of genes encoding key members of the CYP2B and CYP2C subfamily of enzymes in liver, as well as the drug-inducible expression and activity of several glutathione S-transferase, sulfotransferase, and UDP-glucuronosyltransferase enzymes in liver (Maglich et al, 2002;Sonoda et al, 2002;Wei et al, 2002;Tully et al, 2006). PXR target genes also encode key hepatic drug transporter proteins such as organic anion transporting polypeptide 2, multidrug resistance 1/P-glycoprotein, and multidrug resistance proteins 2 and 3 (Geick et al, 2001;Kast et al, 2002;Staudinger et al, 2003).…”

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“…Recent reports indicate a key role for human PXR in regulating the expression of the CES2 gene in human hepatocytes and the human hepatoma cell line Huh-7 in culture (Yang and Yan, 2007). Other reports suggest a positive role for rat PXR in regulating liver-enriched expression of CES enzymes in rodents Tully et al, 2006;Shi et al, 2008). Earlier research indicates that overexpression of constitutively active human PXR has a positive effect on the expression of mouse genes encoding Ces2 and Ces3 enzymes in mouse liver (Rosenfeld et al, 2003).…”

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Regulation of Tissue-Specific Carboxylesterase Expression by Pregnane X Receptor and Constitutive Androstane Receptor

Wang

Staudinger

2009

Drug Metab Dispos

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ABSTRACT:The liver-and intestine-enriched carboxylesterase 2 (CES2) enzyme catalyzes the hydrolysis of several clinically important anticancer agents administered as prodrugs. For example, irinotecan, a carbamate prodrug used in the treatment of colorectal cancer, is biotransformed in vivo by CES2 in intestine and liver, thereby producing a potent topoisomerase I inhibitor. Pregnane X receptor (PXR) and constitutive androstane receptor (CAR), two members of the nuclear receptor superfamily of ligand-activated transcription factors, mediate gene activation in response to xenobiotic stress. Together, these receptors comprise a protective response in mammals that coordinately regulate hepatic transport, metabolism, and elimination of numerous xenobiotic compounds. In the present study, microarray analysis was used to identify PXR target genes in duodenum in mice. Here, we show that a gene encoding a member of the CES2 subtype of liver-and intestine-enriched CES enzymes, called Ces6, is induced after treatment with pregnenolone 16␣-carbonitrile in a PXR-dependent manner in duodenum and liver in mice. Treatment of mice with the CAR activator 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene also induced expression of Ces6 in duodenum and liver in a CAR-dependent manner, whereas treatment with phenobarbital produced induction of Ces6 exclusively in liver. These data identify a key role for PXR and CAR in regulating the drug-inducible expression and activity of an important CES enzyme in vivo. Future studies should focus on determining whether these signaling pathways governing drug-inducible CES expression in intestine and liver are conserved in humans.

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Gene expression profiling in liver and testis of rats to characterize the toxicity of triazole fungicides

Cited by 104 publications

References 27 publications

Transcriptional Profiles in Liver from Rats Treated with Tumorigenic and Non-tumorigenic Triazole Conazole Fungicides: Propiconazole, Triadimefon, and Myclobutanil

Transcriptional Profiles in Liver from Rats Treated with Tumorigenic and Non-tumorigenic Triazole Conazole Fungicides: Propiconazole, Triadimefon, and Myclobutanil

Metabolomic evaluation of rat liver and testis to characterize the toxicity of triazole fungicides

Regulation of Tissue-Specific Carboxylesterase Expression by Pregnane X Receptor and Constitutive Androstane Receptor

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