Evaluation of environmental chemical toxicity by using human DNA microarray analysis

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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.