Lombaert Noömi, Lison Dominique, Van Hummelen Paul, Kirsch-Volders Micheline
Vrije Universiteit Brussel, Laboratorium voor Cellulaire Genetica, Pleinlaan 2, B-1050 Brussel, Belgium.
Toxicol Appl Pharmacol. 2008 Mar 1;227(2):299-312. doi: 10.1016/j.taap.2007.11.002. Epub 2007 Nov 13.
Hard metals consist of tungsten carbide (WC) and metallic cobalt (Co) particles and are important industrial materials produced for their extreme hardness and high wear resistance properties. While occupational exposure to metallic Co alone is apparently not associated with an increased risk of cancer, the WC-Co particle mixture was shown to be carcinogenic in exposed workers. The in vitro mutagenic/apoptogenic potential of WC-Co in human peripheral blood mononucleated cells was previously demonstrated by us. This study aimed at obtaining a broader view of the pathways responsible for WC-Co induced carcinogenicity, and in particular genotoxicity and apoptosis. We analyzed the profile of gene expression induced in vitro by WC-Co versus control (24 h treatment) in human PBMC and monocytes using microarrays. The most significantly up-regulated pathways for WC-Co treated PBMC were apoptosis and stress/defense response; the most down-regulated was immune response. For WC-Co treated monocytes the most significantly up- and down-regulated pathways were nucleosome/chromatin assembly and immune response respectively. Quantitative RT-PCR data for a selection of the most strongly modulated genes (HMOX1, HSPA1A, HSPA1L, BNIP3, BNIP3L, ADORA2B, MT3, PLA2G7, TNFAIP6), and some additionally chosen apoptosis related genes (BCL2, BAX, FAS, FASL, TNFalpha), confirmed the microarray data after WC-Co exposure and demonstrated limited differences between the Co-containing compounds. Overall, this study provides the first analysis of gene expression induced by the WC-Co mixture showing a large profile of gene modulation and giving a preliminary indication for a hypoxia mimicking environment induced by WC-Co exposure.
硬质合金由碳化钨（WC）和金属钴（Co）颗粒组成，是因其极高的硬度和高耐磨性而生产的重要工业材料。虽然单独职业接触金属钴显然与癌症风险增加无关，但WC-Co颗粒混合物在接触工人中显示具有致癌性。我们之前已证明WC-Co在人外周血单核细胞中的体外诱变/凋亡潜力。本研究旨在更全面地了解导致WC-Co致癌性的途径，特别是遗传毒性和凋亡。我们使用微阵列分析了WC-Co与对照（24小时处理）在体外诱导的人PBMC和单核细胞中的基因表达谱。对于经WC-Co处理的PBMC，上调最显著的途径是凋亡和应激/防御反应；下调最显著的是免疫反应。对于经WC-Co处理的单核细胞，上调和下调最显著的途径分别是核小体/染色质组装和免疫反应。对一些调控最强的基因（HMOX1、HSPA1A、HSPA1L、BNIP3、BNIP3L、ADORA2B、MT3、PLA2G7、TNFAIP6）以及一些额外选择的凋亡相关基因（BCL2、BAX、FAS、FASL、TNFalpha）进行定量RT-PCR数据，证实了WC-Co暴露后的微阵列数据，并显示含钴化合物之间差异有限。总体而言，本研究首次分析了WC-Co混合物诱导的基因表达，显示出大量的基因调控谱，并初步表明WC-Co暴露诱导了类似缺氧的环境。
