Microarray technology is proving to be a useful tool to classify undefined environmental toxicants, to investigate underlying mechanisms of toxicity, and to identify candidate toxicant-specific genetic markers by examining global effects of putative toxicants on gene expression profiles. The aim of this study was to evaluate the toxicities of six heavy metals through the comparison with gene expression patterns induced by well-known chemicals. For this purpose, we first identified the genes altered specifically in HepG2 under the exposure of 2,3-dimethoxy-1,4-naphthoquinone (DMNQ), phenol, and N-nitrosodimethylamine (DMN), which were selected as the model chemicals, using DNA microarray. On the basis of the expression profiles of these genes, toxicities of six heavy metals, arsenic, cadmium, nickel, antimony, mercury, and chromium, were evaluated. The specific gene alteration and hierarchical clustering revealed that biological action of six heavy metals was clearly related to that of DMNQ which has been reported to be a reactive oxygen species (ROS) generating chemical and which induced the genes associated with cell proliferative responses. These results suggest that cell proliferative responses which are probably caused by ROS are a major apparent biological action of high-dose heavy metals, supporting the previous reports. Overall, a mechanism-based classification by DNA microarray would be an efficient method for evaluation of toxicities of environmental samples.

Carcinogenesis is an important chronic toxicity of metals and metalloids, although their mechanisms of action are still unclear. Comparison of gene expression patterns induced by carcinogenic metals, metalloids, 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, after exposing to two metals (cadmium and nickel), a metalloid (arsenic), and three model carcinogenic chemicals N-dimethylnitrosoamine (DMN), 12-O-tetradecanoylphorbol-13-acetate (TPA), and tetrachloroethylene (TCE) using DNA microarrays with 8,795 human genes. Of the genes altered by As, Cd, and Ni exposures, 31-55% were overlapped with those altered by three model carcinogenic chemical exposures in our experiments. In particular, the metals and metalloid shared certain characteristics with TPA and TCE in remarkable upregulations of the genes associated with progression of cell cycle, which might play a central role in As, Cd, and Ni carcinogenesis. This characteristic of gene expression alteration was partially counteracted by intracellular accumulation of vitamin C in Asexposed cells, whereas the number of cell-cycle associated genes was increased in Cd-and Niexposed cells. In our experimental conditions, ROS might have an accelerative effect on the cell proliferation mechanisms of As, but have an inhibitory effect on those of other two heavy metals. Furthermore, based on the results of Q-PCR, the oncogene PTTG1, which was upregulated by all carcinogenic chemical exposures in the array experiments, might be a useful biomarker for evaluation of the carcinogenesis of inorganic carcinogens. Environ. Mol. Mutagen. 50:46-59, 2009.