title: Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells.
abstract: Gene expression analysis has been established as a tool for the characterization of genotoxic mechanisms of chemical mutagens. It has been suggested that expression analysis is capable of distinguishing compounds that cause DNA damage from those that interfere with mitotic spindle function. Formaldehyde (FA) is known to be a DNA-reactive substance which mainly induces chromosomal damage in cultured mammalian cells. However, there has been concern that FA might also induce leukemia-specific aneuploidies, although recent cytogenetic studies excluded a relevant aneugenic potential of FA. We now investigated whether gene expression profiling can be used as a molecular tool to further characterize FA's genotoxic mode of action and to differentiate between clastogenic and aneugenic activity. TK6 cells were exposed to FA for 4 and 24 h, and changes in gene expression were analyzed using a whole-genome human microarray. Results were compared to the expression profiles of two DNA-damaging clastogens (methyl methanesulfonate and ethyl methanesulfonate) and two aneugens (colcemid and vincristine). The genotoxic activity of FA, MMS and EMS under these conditions was confirmed by comet assay experiments. The gene expression profiles indicated that clastogens and aneugens induce discriminable gene expression patterns. Exposure of TK6 cells to FA led to a discrete gene expression pattern, and all toxicogenomics analyses revealed a closer relationship of FA with clastogens than with aneugens.
authors: Institut für Humangenetik, Universität Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
authors: Stefanie
authors: S
authors: Kuehner
authors: Microarray-Core Facility, Universitätsklinikum Ulm, Helmholtzstraße 8/1, 89081, Ulm, Germany.
authors: Karlheinz
authors: K
authors: Holzmann
authors: Institut für Humangenetik, Universität Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany. guenter.speit@uni-ulm.de.|Institut für Humangenetik, Universität Ulm, 89069, Ulm, Germany. guenter.speit@uni-ulm.de.
authors: Günter
authors: G
authors: Speit
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents; D020552:Comet Assay; D003703:Demecolcine / Q000633:toxicity; D015536:Down-Regulation / Q000187:drug effects; D005020:Ethyl Methanesulfonate / Q000633:toxicity; D005557:Formaldehyde / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects*; D016158:Genes, p53 / Q000187:drug effects; D006801:Humans; D008741:Methyl Methanesulfonate / Q000633:toxicity; D046228:Microarray Analysis; D009153:Mutagens; D015854:Up-Regulation / Q000187:drug effects; D014750:Vincristine / Q000633:toxicity
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004396:Coloring Agents; D009153:Mutagens; D005557:Formaldehyde; D014750:Vincristine; D005020:Ethyl Methanesulfonate; D008741:Methyl Methanesulfonate; D003703:Demecolcine