Arsenic Exposure Perturbs Epithelial-Mesenchymal Cell Transition and Gene Expression In a Collagen Gel Assay
Arsenic Exposure Perturbs Epithelial-Mesenchymal Cell Transition and Gene Expression In a Collagen Gel Assay
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DOI：
10.1093/toxsci/kfq086
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发表时间：
2010-07-01
影响因子：
3.8
通讯作者：
Runyan, Raymond B.
中科院分区：
文献类型：
--
作者：
Lencinas, Alejandro;Broka, Derrick M.;Runyan, Raymond B.
砷是一种天然存在的类金属和环境污染物。据报道，饮用水中的砷暴露会导致肝癌、肾癌、肺癌、膀胱癌和皮肤癌，以及出生缺陷，包括神经管、面部和血管缺陷。早期胚胎期对砷最敏感，包括各种细胞过程。一个关键的细胞过程是上皮-间充质转化（EMT），其中上皮片发育成三维结构。EMT的胚胎原型在发育中的心脏的房室（AV）管中发现，在那里内皮细胞分化形成心脏瓣膜。用胶原凝胶侵袭法（EMT）检测了砷对鸡胚房室管的影响。用12.5-500 ppb砷处理的AV管在12.5 ppb时表现出间充质的损失，并且在500 ppb时完全抑制了间充质的形成。砷处理的外植体基因表达的变化进行了研究，通过微阵列分析。在10、25和100 ppb的暴露水平下，其表达一致改变的基因被鉴定出来，结果表明25 ppb在体外特别有效。382个基因在这种暴露水平下发生了显着改变。使用鸡相互作用组的微阵列数据的Cytoscape分析基于已发表的关系和途径确定了四个改变的基因簇。该分析鉴定了细胞骨架和细胞粘附相关基因，其破坏与经历EMT的改变的能力一致。这些研究表明，EMT是敏感的砷和相互作用为基础的方法可以在确定目标是有用的。
Arsenic is a naturally occurring metalloid and environmental contaminant. Arsenic exposure in drinking water is reported to cause cancer of the liver, kidneys, lung, bladder, and skin as well as birth defects, including neural tube, facial, and vasculogenic defects. The early embryonic period most sensitive to arsenic includes a variety of cellular processes. One key cellular process is epithelial-mesenchymal transition (EMT) where epithelial sheets develop into three-dimensional structures. An embryonic prototype of EMT is found in the atrioventricular (AV) canal of the developing heart, where endothelia differentiate to form heart valves. Effects of arsenic on this cellular process were examined by collagen gel invasion assay (EMT assay) using explanted AV canals from chicken embryo hearts. AV canals treated with 12.5-500 ppb arsenic showed a loss of mesenchyme at 12.5 ppb, and mcsenchyme formation was completely inhibited at 500 ppb. Altered gene expression in arsenic-treated explants was investigated by microarray analysis. Genes whose expression was altered consistently at exposure levels of 10, 25, and 100 ppb were identified, and results showed that 25 ppb in vitro was particularly effective. Three hundred and eighty two genes were significantly altered at this exposure level. Cytoscape analysis of the microarray data using the chicken interactome identified four clusters of altered genes based on published relationships and pathways. This analysis identified cytoskeleton and cell adhesion related genes whose disruption is consistent with an altered ability to undergo EMT. These studies show that EMT is sensitive to arsenic and that an interactome-based approach can be useful in identifying targets.