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

Journal Article · Fri Sep 15 04:00:00 EDT 2006 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2006.02.015· OSTI ID:20850413

Tully, Douglas B ^[1]; Wenjun, Bao ^[1]; Goetz, Amber K ^[2]; Blystone, Chad R ^[2]; Ren, Hongzu ^[1]; Schmid, Judith E ^[1]; Strader, Lillian F ^[1]; Wood, Carmen R ^[1]; Best, Deborah S ^[1]; Narotsky, Michael G ^[1]; Wolf, Douglas C ^[1]; Rockett, John C ^[1]; Dix, David J ^[1]

---

1. Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (United States)
2. Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695 (United States)

Four triazole fungicides were studied using toxicogenomic techniques to identify potential mechanisms of action. Adult male Sprague-Dawley rats were dosed for 14 days by gavage with fluconazole, myclobutanil, propiconazole, or triadimefon. Following exposure, serum was collected for hormone measurements, and liver and testes were collected for histology, enzyme biochemistry, or gene expression profiling. Body and testis weights were unaffected, but liver weights were significantly increased by all four triazoles, and hepatocytes exhibited centrilobular hypertrophy. Myclobutanil exposure increased serum testosterone and decreased sperm motility, but no treatment-related testis histopathology was observed. We hypothesized that gene expression profiles would identify potential mechanisms of toxicity and used DNA microarrays and quantitative real-time PCR (qPCR) to generate profiles. Triazole fungicides are designed to inhibit fungal cytochrome P450 (CYP) 51 enzyme but can also modulate the expression and function of mammalian CYP genes and enzymes. Triazoles affected the expression of numerous CYP genes in rat liver and testis, including multiple Cyp2c and Cyp3a isoforms as well as other xenobiotic metabolizing enzyme (XME) and transporter genes. For some genes, such as Ces2 and Udpgtr2, all four triazoles had similar effects on expression, suggesting possible common mechanisms of action. Many of these CYP, XME and transporter genes are regulated by xeno-sensing nuclear receptors, and hierarchical clustering of CAR/PXR-regulated genes demonstrated the similarities of toxicogenomic responses in liver between all four triazoles and in testis between myclobutanil and triadimefon. Triazoles also affected expression of multiple genes involved in steroid hormone metabolism in the two tissues. Thus, gene expression profiles helped identify possible toxicological mechanisms of the triazole fungicides.

• OSTI ID: 20850413
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 215; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
BIOCHEMISTRY
DNA
ENZYMES
FUNGICIDES
GENES
HYPERTROPHY
LIVER
LIVER CELLS
POLYMERASE CHAIN REACTION
RATS
RECEPTORS
SPERMATOZOA
TESTES
TESTOSTERONE
TOXICITY
TRIAZOLES