Unknown,Transcriptomics,Genomics,Proteomics

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MicroRNAs and Their Predicted TargetMessenger RNAs are Deregulated by Exposure to a Carcinogenic Dose of Comfrey in Rat Liver

ABSTRACT: MicroRNAs (miRNAs) are small non-coding RNAs that function as regulators of gene expression to control cell growth and differentiation. MiRNA levels are substantially altered in various types of tumors and have been used as biomarkers in defining malignant status. However, studies on responses of miRNA expression to carcinogen insults in their target tissues are rare. In this study, we analyzed miRNA expression in the livers of rats treated with carcinogenic dose of comfrey (Symphytum officinale), a rat botanical carcinogen. Groups of 6 Big Blue Fisher 344 rats were fed a normal diet or a diet containing 8% comfrey root for 12 weeks. The animals were sacrificed one day after the last treatment and the livers were isolated from the control and treated rats for miRNA expression analysis. The miRNA expressions were determined using miRNA microarrays for human, mouse and rat (LC Sciences). Data were normalized using cyclic method and statistically analyzed using Ttest.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Zhiguang Li

PROVIDER: E-GEOD-22655 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Perfluorooctanesulfonate (PFOS) has been widely used in a variety of industrial and commercial applications as a surfactant and stain repellent. PFOS causes liver damage (including liver tumors) in experimental animals, primarily via interaction with PPARa and CAR/PXR. We investigated the involvement of microRNAs (miRNAs) in PFOS-induced hepatotoxicity, and mechanisms involved in abnormal TH homeostasis, in the livers of adult male rats exposed in feed to 50 mg PFOS/kg diet for 28 days. PFOS-treated rats exhibited expected histopathological and clinical chemistry changes. Global gene expression changes were consistent with the involvement of PPARα and CAR/PXR in PFOS-induced effects. Thirty-eight miRNAs were significantly altered. Three members of the miR-200 family were the most increased, while miR-122 and miR-21 were the most decreased, in PFOS-treated relative to control rats. Expression of the miR-23b/27b/24 cluster also decreased in PFOS-treated animals. Pathway analysis of miRNAs and associated gene expression changes demonstrated enrichment of transcripts involved in epithelial to mesenchymal transition (EMT), which is a primary process involved in tumor cell motility and cancer metastasis. Liver expression analysis revealed transcripts that may mediate PFOS effects on thyroid hormone (TH) homeostasis including: activation of the CAR/PXR pathway, phase II/III enzymes, and deiodinase. These changes are consistent with low serum TH due to enhanced metabolic clearance of TH. However, most TH hepatic target genes were not altered in a manner consistent with reduced TH signalling; suggesting that PFOS exposure did not induce functional hypothyroidism. Collectively, PFOS-induced miRNA perturbations were strongly associated with EMT suggesting an important role for miRNAs in PFOS-induced hepatotoxicity. The work also provides novel insights into the effects of PFOS on TH homeostasis. Total RNAs from liver samples (4 animals from each group) were labelled using the miRNA Complete Labelling and Hybridization kit (Agilent Technologies). Labelled RNA was hybridized on 8 X 15K Agilent rat miRNA microarray slides. Arrays were scanned using an Agilent G2505B scanner (5 μm resolution). Agilent Feature Extraction (version 10.7.3.1) was used to acquire the fluorescence intensity of each probe. The quality of the microarray data was evaluated using Agilent Feature Extraction quality control metrics. Data were normalized in R using cyclic-lowess (Bolstad et al., 2003). Ratio-intensity plots, boxplots and cluster analyses were used to identify potential outliers. One control sample failed the quality control tests and was eliminated for subsequent analyses. Statistically significantly altered miRNAs were identified using the methods described above for gene expression.

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MicroRNAs and Their Predicted TargetMessenger RNAs are Deregulated by Exposure to a Carcinogenic Dose of Comfrey in Rat Liver

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