Mode of Action for Reproductive and Hepatic Toxicity Inferred from a Genomic Study of Triazole Antifungals

被引:91
作者
Goetz, Amber K. [1 ,2 ]
Dix, David J. [1 ]
机构
[1] US EPA, Natl Ctr Computat Toxicol, Off Res & Dev, Res Triangle Pk, NC 27711 USA
[2] N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA
关键词
myclobutanil; propiconazole; triadimefon; toxicogenomics; steroid metabolism; PREGNANE-X-RECEPTOR; CONSTITUTIVE ANDROSTANE RECEPTOR; CONAZOLE FUNGICIDES; NUCLEAR RECEPTOR; RAT-LIVER; GENE-EXPRESSION; ACTIVE/ANDROSTANE RECEPTOR; TRANSCRIPTIONAL PROFILES; CYTOCHROME-P450; ENZYMES; NUTRITIONAL REGULATION;
D O I
10.1093/toxsci/kfp098
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
The mode of action for the reproductive toxicity of some triazole antifungals has been characterized as an increase in serum testosterone and hepatic response, and reduced insemination and fertility indices. In order to refine our mechanistic understanding of these potential modes of action, gene expression profiling was conducted on liver and testis from male Wistar Han IGS rats exposed to myclobutanil (500, 2000 ppm), propiconazole (500, 2500 ppm), or triadimefon (500, 1800 ppm) from gestation day six to postnatal day 92. Gene expression profiles indicated that all three triazoles significantly perturbed the fatty acid, steroid, and xenobiotic metabolism pathways in the male rat liver. In addition, triadimefon modulated expression of genes in the liver from the sterol biosynthesis pathway. Although expression of individual genes were affected, there were no common pathways modulated by all three triazoles in the testis. The pathways identified in the liver included numerous genes involved in phase I-III metabolism (Aldh1a1, Cyp1a1, Cyp2b2, Cyp3a1, Cyp3a2, Slco1a4, Udpgtr2), fatty acid metabolism (Cyp4a10, Pcx, Ppap2b), and steroid metabolism (Ugt1a1, Ugt2a1) for which expression was altered by the triazoles. These differentially expressed genes form part of a network involving lipid, sterol, and steroid homeostatic pathways regulated by the constitutive androstane (CAR), pregnane X (PXR), peroxisome proliferator-activated alpha, and other nuclear receptors in liver. These relatively high dose and long-term exposures to triazole antifungals appeared to perturb fatty acid and steroid metabolism in the male rat liver predominantly through the CAR and PXR signaling pathways. These toxicogenomic effects describe a plausible series of key events contributing to the disruption in steroid homeostasis and reproductive toxicity of select triazole antifungals.
引用
收藏
页码:449 / 462
页数:14
相关论文
共 59 条
[41]  
*US EPA, 1996, CARC PEER REV BAYL
[42]  
*US EPA, 2005, 109901 PC US EPA OFF
[43]  
*US EPA, 2006, TRIAD PREL HUM HLTH
[44]  
VANDENBOSSCHE H, 1990, BRIT J CLIN PRACT, V44, P41
[45]   Relationship between hepatic phenotype and changes in gene expression in cytochrome P450 reductase (POR) null mice [J].
Wang, XJ ;
Chamberlain, M ;
Vassieva, O ;
Henderson, CJ ;
Wolf, CR .
BIOCHEMICAL JOURNAL, 2005, 388 :857-867
[46]   Transcriptional profiles in liver from mice treated with hepatotumorigenic and nonhepatotumorigenic triazole conazole fungicides: Propiconazole, triadimefon, and myclobutanil [J].
Ward, William O. ;
Delker, Don A. ;
Hester, Susan D. ;
Thai, Sheau-Fung ;
Wolf, Douglas C. ;
Allen, James W. ;
Nesnow, Stephen .
TOXICOLOGIC PATHOLOGY, 2006, 34 (07) :863-878
[47]   Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response [J].
Wei P. ;
Zhang J. ;
Dowhan D.H. ;
Han Y. ;
Moore D.D. .
The Pharmacogenomics Journal, 2002, 2 (2) :117-126
[48]   The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism [J].
Wei, P ;
Zhang, J ;
Egan-Hafley, M ;
Liang, SG ;
Moore, DD .
NATURE, 2000, 407 (6806) :920-923
[49]   Toxicity profiles in rats treated with tumorigenic and nontumorigenic triazole conazole fungicides: Propiconazole, triadimefon, and myclobutanil [J].
Wolf, Douglas C. ;
Allen, James W. ;
George, Michael H. ;
Hester, Susan D. ;
Sun, Guobin ;
Moore, Tanya ;
Thai, Sheau-Fung ;
Delker, Don ;
Winkfield, Ernest ;
Leavitt, Sharon ;
Nelson, Gail ;
Roop, Barbara C. ;
Jones, Carlton ;
Thibodeaux, Julie ;
Nesnow, Stephen .
TOXICOLOGIC PATHOLOGY, 2006, 34 (07) :895-902
[50]   Regulation of rat hepatic L-pyruvate kinase promoter composition and activity by glucose, n-3 polyunsaturated fatty acids, and peroxisome proliferator-activated receptor-α agonist [J].
Xu, Jinghua ;
Christian, Barbara ;
Jump, Donald B. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (27) :18351-18362