A potential microRNA signature for tumorigenic conazoles in mouse liver.
Triadimefon, propiconazole, and myclobutanil are conazoles, an important class of agricultural fungicides. Triadimefon and propiconazole are mouse liver tumorigens, while myclobutanil is not. As part of a coordinated study to understand the molecular determinants of conazole tumorigenicity, we analyzed the microRNA expression levels in control and conazole-treated mice after 90 d of administration in feed. MicroRNAs (miRNAs) are small noncoding RNAs composed of approximately 19-24 nucleotides in length, and have been shown to interact with mRNA (usually 3' UTR) to suppress its expression. MicroRNAs play a key role in diverse biological processes, including development, cell proliferation, differentiation, and apoptosis. Groups of mice were fed either control diet or diet containing 1800 ppm triadimefon, 2500 ppm propiconazole, or 2000 ppm myclobutanil. MicroRNA was isolated from livers and analyzed using Superarray whole mouse genome miRNA PCR arrays from SABioscience. Data were analyzed using the significance analysis of microarrays (SAM) procedure. We identified those miRNAs whose expression was either increased or decreased relative to untreated controls with q < or = 0.01. The tumorigenic conazoles induced many more changes in miRNA expression than the nontumorigenic conazole. A group of 19 miRNAs was identified whose expression was significantly altered in both triadimefon- and propiconazole-treated animals but not in myclobutanil-treated animals. All but one of the altered miRNAs were downregulated compared to controls. This pattern of altered miRNA expression may represent a signature for tumorigenic conazole exposure in mouse liver after 90 d of treatment.
Ross
Jeffrey A
JA
Integrated Systems Toxicology Division, NHEERL, U.S. EPA, Research Triangle Park, North Carolina, USA.
Blackman
Carl F
CF
Thai
Sheau-Fung
SF
Li
Zhiguang
Z
Kohan
Michael
M
Jones
Carlton P
CP
Chen
Tao
T
D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity; D015536:Down-Regulation; D005659:Fungicides, Industrial / Q000633:toxicity; D015972:Gene Expression Regulation, Neoplastic; D008099:Liver / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000473:pathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D035683:MicroRNAs / Q000032:analysis* / Q000302:isolation & purification / Q000378:metabolism; D008954:Models, Biological; D009010:Monte Carlo Method; D009570:Nitriles / Q000633:toxicity; D016133:Polymerase Chain Reaction; D014230:Triazoles / Q000633:toxicity*
D002273:Carcinogens; D005659:Fungicides, Industrial; D035683:MicroRNAs; C549289:Mirn135 microRNA, mouse; D009570:Nitriles; D014230:Triazoles; C045950:propiconazole; C032910:triadimefon; C446685:systhane