Title: Arsenite induces delayed mutagenesis and transformation in human osteosarcoma cells at extremely low concentrations.
Authors: Mure, Kanae; Uddin, Ahmed N; Lopez, Laura C; Styblo, Miroslav; Rossman, Toby G
Published In Environ Mol Mutagen, (2003)
Abstract: Arsenite is a human multisite carcinogen, but its mechanism of action is not known. We recently found that extremely low concentrations (</=0.1 microM) of arsenite transform human osteosarcoma TE85 (HOS) cells to anchorage-independence. In contrast to other carcinogens which transform these cells within days of exposure, almost 8 weeks of arsenite exposure are required for transformation. We decided to reexamine the question of arsenite mutagenicity using chronic exposure in a spontaneous mutagenesis assay we previously developed. Arsenite was able to cause a delayed increase in mutagenesis at extremely low concentrations (</=0.1 microM) in a dose-dependent manner. The increase in mutant frequency occurred after almost 20 generations of growth in arsenite. Transformation required more than 30 generations of continuous exposure. We also found that arsenite induced gene amplification of the dihydrofolate reductase (DHFR) gene in a dose-dependent manner. Since HOS cells are able to methylate arsenite at a very low rate, it was possible that active metabolites such as monomethylarsonous acid (MMA(III)) contributed to the delayed mutagenesis and transformation in these cells. However, when the assay was repeated with MMA(III), we found no significant increase in mutagenesis or transformation, suggesting that arsenite-induced delayed mutagenesis and transformation are not caused by arsenite's metabolites, but by arsenite itself. Our results suggest that long-term exposure to low concentrations of arsenite may affect signaling pathways that result in a progressive genomic instability.
PubMed ID: 12802802
MeSH Terms: Arsenites/pharmacokinetics; Arsenites/toxicity*; Bone Neoplasms/drug therapy; Bone Neoplasms/genetics*; Cell Survival/drug effects; Dose-Response Relationship, Drug; Humans; Metabolic Detoxication, Drug; Methylation; Mutagenesis/drug effects*; Mutagenicity Tests; Organometallic Compounds/metabolism; Organometallic Compounds/toxicity; Osteosarcoma/drug therapy; Osteosarcoma/genetics*; Tetrahydrofolate Dehydrogenase/drug effects; Tetrahydrofolate Dehydrogenase/genetics; Tumor Cells, Cultured