The transition metal nickel is used in a wide variety of alloys and medical devices. Nickel can cause a range of toxicities from allergy in humans to tumors when implanted in animals. Several microarray studies have examined nickel toxicity, but so far none have comprehensively profiled expression over an extended period. In this work, male mice were implanted with a single nickel pellet in the muscle of the right leg with the left leg used as a control. At 3 week intervals up to 12 months, nickel concentrations in bioflulids and microarrays of surrounding tissue were used to track gene expression patterns. Pellet biocorrosion resulted in varying levels of systemic nickel over time, with peaks of 600 μg L-1 in serum, while global gene expression was cyclical in nature with immune related genes topping the list of overexpressed genes. IPA and KEGG pathway analyses was used to attribute overall biological function to changes in gene expression levels, supported by GO enrichment analysis. IPA pathways identified sirtuin, mitochondria, and oxidative phosphorylation as top pathways, based predominantly on downregulated genes, whereas immune processes were associated with upregulated genes. Top KEGG pathways identified were lysosome, osteoclast differentiation, and phasgosome. Both pathway approaches identified common immune responses, as well as hypoxia, toll like receptor, and matrix metalloproteinases. Overall, pathway analysis identified a negative impact on energy metabolism, and a positive impact on immune function, in particular the acute phase response. Inside the cell the impacts were on mitochondria and lysosome. New pathways and genes responsive to nickel were identified from the large dataset in this study which represents the first long-term analysis of the effects of chronic nickel exposure on global gene expression.

中文翻译：

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镍颗粒植入后小鼠肌肉中基因表达随时间的变化。

过渡金属镍广泛用于各种合金和医疗器械。镍在植入动物体内时会引起一系列毒性，从人类过敏到肿瘤。几项微阵列研究已经检测了镍的毒性，但迄今为止还没有一项研究能够全面分析长期的表达情况。在这项工作中，雄性小鼠在右腿肌肉中植入单个镍颗粒，并以左腿作为对照。每隔 3 周直至 12 个月，使用生物流体和周围组织微阵列中的镍浓度来追踪基因表达模式。随着时间的推移，颗粒生物腐蚀导致全身镍水平发生变化，血清中的峰值为 600 μg L-1，而整体基因表达本质上是周期性的，免疫相关基因位居过度表达基因列表之首。IPA 和 KEGG 通路分析用于将整体生物学功能归因于基因表达水平的变化，并得到 GO 富集分析的支持。IPA 途径将 Sirtuin、线粒体和氧化磷酸化确定为首要途径，主要基于下调的基因，而免疫过程则与上调的基因相关。确定的主要 KEGG 通路是溶酶体、破骨细胞分化和吞噬体。两种途径方法都确定了常见的免疫反应，以及缺氧、Toll 样受体和基质金属蛋白酶。总体而言，途径分析确定了对能量代谢的负面影响，以及对免疫功能，特别是急性期反应的积极影响。在细胞内部，影响是对线粒体和溶酶体的。本研究从大型数据集中确定了对镍敏感的新途径和基因，这是对慢性镍暴露对全球基因表达影响的首次长期分析。