Identification of potential biomarkers from gene expression profiles in rat lungs intratracheally instilled with C₆₀ fullerenes

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• 作者：Katsuhide Fujita ; Yasuo Morimoto ; Shigehisa Endoh ; Kunio Uchida ; Hiroko Fukui ; Akira Ogami ; Isamu Tanaka ; Masanori Horie ; Yasukazu Yoshida ; Hitoshi Iwahashi ; Junko Nakanishi
• 关键词：C₆₀ fullerene ; Gene expression ; Lung ; DNA microarray ; Nanoparticles ; Biomarker
• 刊名：Toxicology
• 出版年：2010
• 出版时间：July-August 2010
• 年：2010
• 卷：274
• 期：1-3
• 页码：34-41
• 全文大小：368 K

文摘

The use of C₆₀ fullerenes is expected to increase in various industrial fields. Little is known about the potential toxicological mechanism of action of water-soluble C₆₀ fullerenes. In our previous research, gene expression profiling of the rat lung was performed after whole-body inhalation exposure to C₆₀ fullerenes to gain insights into the molecular events. These DNA microarray-based data closely matched the pathological findings that C₆₀ fullerenes caused no serious adverse pulmonary effects under the inhalation exposure condition. Taking advantage of this, we attempted to characterize time-dependent changes in the gene expression profiles after intratracheal instillation with C₆₀ fullerenes at different dosages and to identify the candidate expressed genes as potential biomarkers. The hierarchical cluster analysis revealed that the up- or downregulation of genes after intratracheal instillation with 1.0 mg C₆₀ fullerene particles in rat lung tissue was significantly over-represented in the “response to stimulus” and “response to chemical stimulus” categories of biological processes and in the “extracellular space” category of the cellular component. These results were remarkable for 1 week after the instillation with C₆₀ fullerenes. In the lung tissues instilled with 1.0 mg C₆₀ fullerene particles, many representative genes involved in “inflammatory response,” such as the Cxcl2, Cxcl6, Orm1, and Spp1 genes, and in “matrix metalloproteinase activity,” such as the Mmp7 and Mmp12 genes, were upregulated for over 6 months. The expression levels of 89 and 21 genes were positively correlated with the C₆₀ fullerene dose at 1 week and 6 months after the instillation, respectively. Most of them were involved in “inflammatory response”, and the Ccl17, Ctsk, Cxcl2, Cxcl6, Lcn6, Orm1, Rnase9, Slc26a4, Spp1, Mmp7, and Mmp12 genes were overlapped. Meanwhile, the expression levels of 16 and 4 genes were negatively correlated with the C₆₀ fullerene dose at 1 week and 6 months after the instillation, respectively. Microarray-based gene expression profiling suggested that the expression of some genes is correlated with the dose of intratracheally instilled C₆₀ fullerenes. We propose that these genes are useful for identifying potential biomarkers in acute-phase or persistent responses to C₆₀ fullerenes in the lung tissue.