ToxSci Advance Access originally published online on November 12, 2007
Toxicological Sciences 2008 101(2):226-238; doi:10.1093/toxsci/kfm268
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Arsenite-Induced Thymus Atrophy is Mediated by Cell Cycle Arrest: A Characteristic Downregulation of E2F-Related Genes Revealed by a Microarray Approach
* Environmental Health Sciences Division, National Institute for Environmental Studies, Tsukuba 305-8506, Japan
Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan
1 To whom correspondence should be addressed. Fax: +81-29-850-2574. E-mail: keikon{at}nies.go.jp.
Received August 30, 2007; accepted October 22, 2007
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Abstract |
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Thymus atrophy is induced by a variety of chemicals, including environmental contaminants and is used as a sensitive index to detect their adverse effects on lymphocytes. In the present study we adopted a toxicogenomics approach to identify the pathways that mediate the atrophy induced by arsenite. We also analyzed gene expression changes observed in the course of thymus atrophy by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), dexamethasone (DEX), and estradiol (E2), to determine whether arsenite induces atrophy by activating an arsenite-specific pathway or the same pathways as other chemicals. These compounds were intraperitoneally administered to C57BL/6 mice at doses that reduce thymus weight by approximately 30% within 3 days, and gene expression changes in the thymus 24 h after the administration were analyzed by using microarrays and real-time PCR. The microarray analysis showed that arsenite specifically downregulates a variety of E2F target genes that are involved in cell cycle progression. The same genes were also downregulated when mouse B-cell lymphoma A20 cells were exposed to arsenite. Arsenite exposure of the A20 cells was confirmed to induce cell cycle arrest, mainly in the G1 phase, and reduce cell number. Cell cycle arrest in the G1 phase was also confirmed to occur in the thymocytes of the arsenite-exposed mice. These results indicate that arsenite induces thymus atrophy through E2F-dependent cell cycle arrest. The results of this study also show that analysis of gene expression in thymuses is a useful method of obtaining clues to the pathways that mediate the effects of atrophy-inducing chemicals.
Key Words: thymus atrophy; arsenite; cell cycle; E2F; microarray.