U.S. Army Public Health Centre, Toxicology Directorate, 8988 Willoughby Road, Aberdeen Proving Ground, Maryland 21010, USA.
Metallomics. 2020 Apr 1;12(4):528-538. doi: 10.1039/c9mt00289h. Epub 2020 Feb 17.
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 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.
过渡金属镍被广泛应用于各种合金和医疗器械中。镍在植入动物体内时，会引起一系列毒性反应，包括人类过敏和肿瘤。已有多项微阵列研究探讨了镍毒性，但迄今为止，尚无研究全面分析过镍暴露对基因表达的长期影响。在这项研究中，雄性小鼠的右后腿肌肉中植入单个镍丸，左后腿作为对照。在 3 周的间隔内，最多持续 12 个月，通过生物流体中的镍浓度和周围组织的微阵列来跟踪基因表达模式。由于微丸生物腐蚀，体内镍水平随时间呈波动变化，血清中的峰值达到 600μg/L，而整体基因表达呈周期性变化，免疫相关基因是过表达基因中的主要部分。IPA 和 KEGG 通路分析用于根据基因表达水平的变化赋予整体生物学功能，GO 富集分析提供了支持。IPA 通路主要基于下调基因，确定了沉默信息调节因子、线粒体和氧化磷酸化是最重要的通路，而免疫过程与上调基因有关。鉴定出的顶级 KEGG 通路是溶酶体、破骨细胞分化和吞噬体。这两种途径方法都识别出了共同的免疫反应，以及缺氧、 Toll 样受体和基质金属蛋白酶。总体而言，通路分析表明镍对能量代谢有负面影响，对免疫功能有积极影响，特别是急性期反应。在细胞内，影响的是线粒体和溶酶体。本研究中的大量数据集识别出了对镍有反应的新通路和基因，这代表了首次对慢性镍暴露对整体基因表达的长期影响进行分析。
