Chromatin Condensation and DNA Methylation During Nickel Carcinogenesis

Max Costa
Nelson Institute of Environmental Medicine; New York University

Certain nickel compounds including crystalline nickel sulfide (NiS) and subsulfide (Ni3S2) are potent human and animal carcinogens. In Chinese hamster embryo cells, an X-linked senescence gene was inactivated following nickel-induced DNA methylation. Further studies had shown that nickel induced the inactivation of the gpt reporter gene in the transgenic gpt+ Chinese hamster cell line (G12). The involvement of chromatin condensation and DNA methylation in the inactivation of the transgene was confirmed. The high incidence of gpt- variants induced by nickel in the G12 cell line, but not in another transgenic cell line, G10, suggested that the location of the transgene in G12 cells near a large and dense heterochromatin region of the genome was a preferential site for nickel activity. In order to examine if nickel can cause gene silencing independently of the process of DNA methylation, based only on the induction of changes in chromatin structure, we measured its influence on the TPE (telomeric position effect) levels in the yeast Saccharomyces cerevisiae. We showed that growth in the presence of nickel chloride repress a telomeric marker gene (URA3) and thus cause a stable epigenetic switch. This phenomenon is dependent on the number of cell doubling prior to selection and also on the distance of the marker gene from the end of the chromosome. The level of TPE induction is increased by elevation of nickel concentration. Magnesium caused inhibition of the nickel effect, but had no effect on the level of silencing by itself. In order to compare the effect of nickel to other transition metals, the level of silencing was also measured after treatment with various concentrations of cobalt, copper and cadmium. In the sublethal range, cobalt induced similar effects as nickel, while copper and cadmium did not change the basal level.