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TRANSCRIPTIONAL RESPONSES IN THYROID TISSUES FROM RATS TREATED WITH A TUMORIGENIC AND A NON-TUMORIGENIC TRIAZOLE CONAZOLE FUNGICIDE
Citation:
HESTER, S. D. AND S. NESNOW. TRANSCRIPTIONAL RESPONSES IN THYROID TISSUES FROM RATS TREATED WITH A TUMORIGENIC AND A NON-TUMORIGENIC TRIAZOLE CONAZOLE FUNGICIDE . TOXICOLOGY AND APPLIED PHARMACOLOGY. Academic Press Incorporated, Orlando, FL, 227(3):357-369, (2008).
Impact/Purpose:
The goal of this study was to identify pathways and networks of genes that were associated with thyroid cancer through transcriptional analyses
Description:
What is the study?
Conazoles are triazole- or imidazole-containing fungicides that are used in agriculture and medicine. Conazoles can induce follicular cell adenomas of the thyroid in rats after chronic bioassay. The goal of this study was to identify pathways and networks of genes that were associated with thyroid cancer through transcriptional analyses. We compared transcriptional profiles from tissues of rats treated with a tumorigenic and a non tumorigenic conazole. Triadimefon, a rat thyroid tumorigen, and myclobutanil, which was not tumorigenic in rats after a 2 year bioassay, were administered in the feed to male Wistar/Han rats for 30 or 90 days similar to the treatment conditions previously used in their chronic bioassays. Thyroid gene expression was determined using high density Affymetrix GeneChips (Rat 230_2). Gene Set Expression Analyses method clearly separated the tumorigenic treatments (tumorigenic response group, TRG) from the non-tumorigenic treatments (non-tumorigenic response group, NRG). In addition, the core genes in each geneset were compared with genes known to be associated with human thyroid cancer. Among the genes that appeared in both rat and human data sets were: Acaca, Asns, Cebpg, Crem, Ddit3, Gja1, Grn, Jun, Junb, and Vegf. These genes were major contributors in the previously developed network from triadimefon-treated rat thyroids. It is postulated that triadimefon induces oxidative response genes and activates the nuclear receptor, Pparγ, initiating transcription of gene products and signaling to a series of genes involved in cell proliferation.
Why was it done?
The mode of action proposed for triadimefon in the induction of thyroid tumors in rats was suggested to be through modulation of endocrine effects, disruption of the hypothalamic-pituitary-thyroid hormonal balance. This mechanism of action had been shown to be operative with a series of thyroid carcinogens (Hill et al. 1998; Hurley et al. 1998), however subsequent experimental studies did not support this hypothesis for triadimefon (Wolf et al. 2006).
Using transcriptomic analyses of thyroid tissues from rats exposed to a pair of tumorigenic and non-tumorigenic structurally related conazoles we present new findings on thyroid gene expression of genesets associated with triadimefon exposure that are strongly related to transcriptional changes found in human thyroid neoplasms, suggesting potential human revelance. We suggest that Pparγ is a primary controlling nuclear receptor whose activation by triadimefon mediates and correlates with the observed phenotypic changes in the thyroid gland.
What is the impact to the field and the Agency?
This study defined a binary approach to model treatment groups into tumorigenic response group, TRG or non-tumorigenic subsequent statistical analysis. Using this approach we determined that Pparγ may underlie the cellular proliferation signaling which was consistent with the thyroid phenotype.
Abstract
Conazoles are triazole- or imidazole-containing fungicides that are used in agriculture and medicine. Conazoles can induce follicular cell adenomas of the thyroid in rats after chronic bioassay. The goal of this study was to identify pathways and networks of genes that were associated with thyroid cancer through transcriptional analyses. To this end we compared transcriptional profiles from tissues of rats treated with a tumorigenic and a non tumorigenic conazole. Triadimefon, a rat thyroid tumorigen, and myclobutanil, which was not tumorigenic in rats after a 2 year bioassay, were administered in the feed to male Wistar/Han rats for 30 or 90 days similar to the treatment conditions previously used in their chronic bioassays. Thyroid gene expression was determined using high density Affymetrix GeneChips (Rat 230_2). Gene expression was analyzed by the Gene Set Expression Analyses method which clearly separated the tumorigenic treatments (tumorigenic response group, TRG) from the non-tumorigenic treatments (non-tumorigenic response group). Core genes from these data sets were mapped to canonical, metabolic, and GeneGo processes and these processes compared across group and treatment time. Extensive analyses were performed on the 30d genesets as they represented the major perturbations. Genesets in the 30d TRG group had over representation of fatty acid metabolism, oxidation, and degradation processes (including PPARγ and CYP involvement), and of cell proliferation responses. Core genes from these data sets were combined into networks and found to possess signaling interactions. In addition, the core genes in each geneset were compared with genes known to be associated with human thyroid cancer. Among the genes that appeared in both rat and human data sets were: Acaca, Asns, Cebpg, Crem, Ddit3, Gja1, Grn, Jun, Junb, and Vegf. These genes were major contributors in the previously developed network from triadimefon-treated rat thyroids. It is postulated that triadimefon induces oxidative response genes and activates the nuclear receptor, Pparγ, initiating transcription of gene products and signaling to a series of genes involved in cell proliferation.
