RIKILT-Institute of Food Safety, Wageningen University and Research Centre, Wageningen, The Netherlands.
Toxicol Appl Pharmacol. 2011 Feb 1;250(3):299-311. doi: 10.1016/j.taap.2010.11.001. Epub 2010 Nov 11.
Deoxynivalenol (DON) is a mycotoxin produced by several Fusarium species and is often detected in grains. Because of its high abundance, there has been a large interest in the effects of DON in animals and humans. DON is known to be immunosuppressive at high concentrations and immunostimulatory at low concentrations. The present study aimed to acquire insight into the modes of action of DON. For this, C57Bl6 mice were orally exposed to 5, 10, or 25mg/kg bw DON for 3, 6, or 24h and thymuses were subjected to genome-wide expression microarray analysis. Gene set enrichment analysis (GSEA) demonstrated that DON downregulated genes involved in proliferation, mitochondria, protein synthesis, and ribosomal proteins. Furthermore, GSEA showed a selective downregulation of genes highly expressed at the early precursor thymocytes stage. This indicates that early precursor thymocytes, particularly at the double-positive CD4+CD8+ stage, are more vulnerable to DON than very early or late precursor thymocytes. There was a large overlap of genes upregulated by DON with genes previously reported to be either upregulated during T cell activation or upregulated during negative selection of thymocytes that recognize "self-antigens". This indicates that DON induces cellular events that also occur after activation of the T cell receptor, for example, release of calcium from the endoplasmatic reticulum. This T cell activation in the thymus then evokes negative selection and depletion of thymocytes, which provides a plausible explanation for the high sensitivity of the thymus for DON exposure. The expression patterns of four genes indicative for some of the processes that were affected after DON treatment were confirmed using real-time PCR. Immunocytological experiments with primary mouse thymocytes demonstrated the translocation of NFAT from the cytoplasm into the nucleus upon exposure top DON, thus providing further evidence for the involvement of T cell activation.
脱氧雪腐镰刀菌烯醇（DON）是由几种镰刀菌属产生的一种真菌毒素，经常在谷物中检测到。由于其含量高，人们对 DON 在动物和人类中的作用产生了极大的兴趣。DON 已知在高浓度时具有免疫抑制作用，在低浓度时具有免疫刺激作用。本研究旨在深入了解 DON 的作用模式。为此，C57Bl6 小鼠经口暴露于 5、10 或 25mg/kg bw DON 3、6 或 24h，然后对胸腺进行全基因组表达微阵列分析。基因集富集分析（GSEA）表明，DON 下调了与增殖、线粒体、蛋白质合成和核糖体蛋白相关的基因。此外，GSEA 显示出对早期前体胸腺细胞阶段高表达基因的选择性下调。这表明，早期前体胸腺细胞，特别是双阳性 CD4+CD8+阶段，比非常早期或晚期前体胸腺细胞对 DON 更为敏感。DON 上调的基因与先前报道的 T 细胞激活过程中上调的基因或识别“自身抗原”的胸腺细胞阴性选择过程中上调的基因有很大的重叠。这表明 DON 诱导了 T 细胞受体激活后也会发生的细胞事件，例如内质网中钙的释放。这种胸腺中的 T 细胞激活随后引发了负选择和胸腺细胞耗竭，这为胸腺对 DON 暴露高度敏感提供了合理的解释。使用实时 PCR 证实了四个基因的表达模式，这些基因指示了 DON 处理后受影响的一些过程。用原代小鼠胸腺细胞进行免疫细胞化学实验表明，NFAT 在接触 DON 后从细胞质易位到细胞核，从而为 T 细胞激活的参与提供了进一步的证据。
