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

Abstract

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.

Thyroid endocrine disruption of acetochlor on zebrafish (Danio rerio) larvae

“…Furthermore, UDP‐glucuronosyltransferase and sulfotransferase also play important roles in TH homeostasis, via the major pathway for T 4 conjugation (Jugan et al , ). Previous studies have shown that T 4 was increased and ugt 1 ab was downregulated in zebrafish larvae when exposed to DE‐71 (Yu et al , ) and in rats after treatment with triazole fungicides (Hester et al , ; Wolf et al , ). In the present study, a reduction in mRNA expression of the ugt 1 ab gene after acetochlor exposure was observed, which might be associated with upregulation of the T 4 level.…”

Identification of Environmental Chemicals Associated with the Development of Toxicant-associated Fatty Liver Disease in Rodents

“…According to EPA, global annual fungicide application is nearly 500 million pounds (Reigart, 2013). Some azole antifungals including triadimefon, propiconazole and cyproconazole have been previously associated with hepatotoxicity and hepatomegaly in rats (Hester et al , 2006, Peffer et al , 2007). Interestingly, dazomet and hexaconazole were associated with fatty liver disease at relatively low LELs in multiple studies in ToxRefDB.…”

Cardiac-specific deletion of the microtubule-binding protein CENP-F causes dilated cardiomyopathy

“…Microarray images were scanned with an Affymetrix high resolution GenePix 4000B scanner in the Vanderbilt Functional Shared Resource (http://www.thefgsr.com/). Data was uploaded into Partek Genomics Suite version 6.6 (Partek Incorporated, St Louis, MO) and processed using Robust Multi-chip Average (RMA) normalization (Bolstad et al, 2003; Hansel et al, 2005; Kirwan et al, 2005; Hester et al, 2006). The normalization procedures successfully resulted in comparable hybridization signals across the entire array set, and histograms, M versus A plots and scatter plots (data not shown) demonstrated comparable hybridization signals across replicate samples.…”