Arsenite-induced thymus atrophy is mediated by cell cycle arrest: A characteristic downregulation of E2F-Related genes revealed by a microarray approach
Arsenite-induced thymus atrophy is mediated by cell cycle arrest: A characteristic downregulation of E2F-Related genes revealed by a microarray approach
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DOI：
10.1093/toxsci/kfm268
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发表时间：
2008-02-01
影响因子：
3.8
通讯作者：
Kobayashi, Takahiro
中科院分区：
文献类型：
--
作者：
Nohara, Keiko;Ao, Kana;Kobayashi, Takahiro
胸腺萎缩是由多种化学物质，包括环境污染物引起的，并被用作检测其对淋巴细胞的不利影响的敏感指标。在本研究中，我们采用了毒理基因组学的方法来确定介导砷诱导的萎缩的途径。我们还分析了2，3，7，8-四氯二苯并-对-二恶英（TCDD），地塞米松（DEX）和雌二醇（E2）在胸腺萎缩过程中观察到的基因表达变化，以确定亚砷酸盐是否通过激活亚砷酸盐特异性途径或与其他化学物质相同的途径诱导萎缩。将这些化合物以在3天内使胸腺重量减少约30%的剂量腹膜内给予C57 BL/6小鼠，并通过使用微阵列和实时PCR分析给药后24小时胸腺中的基因表达变化。微阵列分析表明，亚砷酸盐特异性下调多种参与细胞周期进程的E2 F靶基因。当小鼠B细胞淋巴瘤A20细胞暴露于亚砷酸盐时，相同的基因也下调。砷暴露于A20细胞被证实诱导细胞周期停滞，主要在G（1）期，并减少细胞数量。细胞周期阻滞在G（1）期也被证实发生在砷暴露小鼠的胸腺细胞。这些结果表明，亚砷酸盐诱导胸腺萎缩通过E2 F依赖的细胞周期阻滞。这项研究的结果还表明，胸腺基因表达的分析是一个有用的方法，获得线索的途径，介导的萎缩诱导化学品的影响。
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 G(1) phase, and reduce cell number. Cell cycle arrest in the G(1) 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.