Evaluation of environmental chemical toxicity by using human DNA microarray analysis

致癌是重金属的一种重要的慢性毒性，尽管其机制尚不清楚。比较重金属和模式致癌物诱导的基因表达模式，有助于深入了解它们的致癌机制。在这项研究中，我们检测了三种重金属暴露后人肝癌细胞系HepG2基因表达的变化；砷、镉、镍和三种致癌物；用8795个人类基因的DNA芯片对n -二甲基亚硝基胺（DMN）、12- o -十四烷酰基苯酚-13-乙酸酯（TPA）和四氯乙烯（TCE）进行分析。在砷、镉和镍暴露改变的基因中，31-55%与三种模型致癌物暴露的基因重叠。其中，三种重金属与TPA和TCE具有一定的共性，均显著上调细胞周期进展相关基因，这可能在重金属致癌过程中发挥核心作用。此外，砷暴露细胞中维生素C的细胞内积累抵消了这种基因表达改变的特征，而镉和镍暴露细胞中则没有。这些结果表明，砷暴露下的细胞增殖反应主要是由活性氧（ROS）引起的，而镉和镍暴露下的细胞增殖反应可能涉及其他机制。此外，根据Q-PCR结果，在阵列实验中被所有致癌化学物质上调的致癌基因PTTG1在重金属中呈剂量依赖性上调，这表明该基因可能是评估重金属致癌作用的有用生物标志物。

Carcinogenesis is an important chronic toxicity of heavy metals, although their mechanisms are still unclear. Comparison of gene expression patterns induced by heavy metals and model carcinogens would give an insight into understanding of their carcinogenic mechanisms. In this study, we examined the gene expression alteration in human hepatoma cell line, HepG2 following exposures of three heavy metals; arsenic, cadmium and nickel and three carcinogens; N-dimethylnitrosoamine (DMN), 12-O-tetradecanoylphorbol-13-acetate (TPA) and tetrachloroethylene (TCE) using DNA microarray with 8795 human genes. Of the genes altered by As, Cd and Ni exposure, 31-55% were overlapped with those by three model carcinogen exposures in our experiments. In particular, three heavy metals shared certain characteristics with TPA and TCE in remarkable up-regulations of the genes associated with progression of cell cycle, which might play a central role in heavy metal carcinogenesis.In addition, this characteristic of gene expression alteration was counteracted by intracellular accumulation of vitamine C in As-exposed cells but not in Cd- and Ni-exposed cells. These results suggest that the cell proliferative responses are caused by reactive oxygen species (ROS) mainly in As exposure, while other mechanisms would be involved in these responses in Cd and Ni exposures. Furthermore, based on the results of Q-PCR, the oncogene PTTG1, which was up-regulated by all carcinogenic chemicals in the array experiments, was up-regulated by heavy metals in a dose dependent manner, suggesting that this gene might be a useful biomarker for evaluation of carcinogenesis of heavy metals.