Discrimination of tumorigenic triazole conazoles from phenobarbital by transcriptional analyses of mouse liver gene expression.

Abstract

Conazoles are fungicides used to control fungal growth in environmental settings and to treat humans with fungal infections. Mouse hepatotumorigenic conazoles display many of the same hepatic toxicologic responses as the mouse liver carcinogen phenobarbital (PB): constitutive androstane receptor (CAR) activation, hypertrophy, Cyp2b induction, and increased cell proliferation. The goal of this study was to apply transcriptional analyses to hepatic tissues from mice exposed to PB, propiconazole (Pro) or triadimefon (Tri) at tumorigenic exposure levels to reveal similarities and differences in response among these treatments. Mice were administered diets containing PB (850 ppm), Pro (2500 ppm), or Tri (1800 ppm) for 4 and 30 days. Targeted transcriptomic analyses were conducted at the gene level examining differentially expressed genes (DEGs), and subsets of DEGs: cell cycle genes, and transcription factors. Analyses were also conducted on function, pathway and network levels examining Ingenuity Pathway Analysis Tox Lists and Canonical Pathways, and Gene-Go MetaCore dynamic networks and their central hubs. Genes expressed by PB or the two conazoles were also compared with those genes associated with human hepatocellular cancer. The results from these analyses indicated greater differences between PB and the two conazoles than similarities. Significant commonalities between the two conazole treatments were also noted. We posit that the transcriptional profiles of tissues exposed to toxic chemicals inherently contain their mechanisms of toxicity. We conclude that although PB and these 2 conazoles induce mouse liver tumors and exhibit similar toxicological responses, their transcriptional profiles are significantly different and thus their mechanisms of tumorigenic action are likely to differ.

• Authors: Stephen Nesnow, William Ward, Tanya Moore, Hongzu Ren, Susan D Hester
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 110 Issue 1 Pg. 68-83 (Jul 2009) ISSN: 1096-0929 [Electronic] United States
• PMID: 19363144 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Carcinogens
• Fungicides, Industrial
• Transcription Factors
• Triazoles
• propiconazole
• triadimefon
• Phenobarbital

Topics

• Animals
• Carcinogens (toxicity)
• Carcinoma, Hepatocellular (genetics)
• Cell Cycle (genetics)
• Cell Proliferation (drug effects)
• Fungicides, Industrial (toxicity)
• Gene Expression (drug effects)
• Gene Expression Profiling
• Hybridization, Genetic
• Liver (drug effects, metabolism, pathology)
• Male
• Mice
• Oligonucleotide Array Sequence Analysis
• Organ Size (drug effects)
• Phenobarbital (pharmacology)
• Transcription Factors (genetics)
• Transcription, Genetic (drug effects)
• Triazoles (toxicity)