title: Mutagenicity of metabolic oxygen radicals in mammalian cell cultures.
abstract: Reactive oxygen species produced by normal cellular metabolism have been considered to play a causative role in spontaneously occurring genomic instability and carcinogenesis. To study the genotoxic consequences of an enhanced flux of metabolically produced reactive oxygen species, cells may be exposed to hyperoxia (elevated concentrations of oxygen), a condition known to generate high levels of microscopically visible chromosomal damage. Here we assess the mutagenic potential of normobaric hyperoxia in several mammalian cells lines (CHO-K1-BH4 and AS52 Chinese hamster cells and TK6 human lymphoblastoid cells) using different target genes, including hprt, xprt and tk. Exposure of cell cultures to hyperoxia to 10-40% clonogenic cell survival, failed to induce mutations at the hprt and xprt loci. In human TK6 cells, hyperoxia failed to induce normal growing tk mutants, but efficiently induced slow growing tk mutants. The latter type of mutant is supposed to result from very large deletions or mutlilocus events. Our results suggest that elevated levels of endogenous activated oxygen species are inefficient in inducing point mutations or small deletions, but tend to generate gross rearrangements. Mammalian cells under oxidative stress thus exhibit a hyper-recombination phenotype. The carcinogenic impact of metabolic oxygen radical fluxes may thus be based on enhanced mitotic recombination rates, leading to tumor suppressor gene inactivation through 'loss of heterozygosity'.
authors.affiliation: Department of Human Genetics, Free University, Amsterdam, The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Gille
authors.forename: C G
authors.initials: CG
authors.lastname: van Berkel
authors.forename: H
authors.initials: H
authors.lastname: Joenje
mesh_terms: D000818:Animals; D016466:CHO Cells / Q000187:drug effects* / Q000378:metabolism; D006224:Cricetinae; D005796:Genes / Q000187:drug effects; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D009152:Mutagenicity Tests; D010100:Oxygen / Q000378:metabolism*; D010430:Pentosyltransferases / Q000235:genetics; D017382:Reactive Oxygen Species / Q000633:toxicity*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D011995:Recombination, Genetic / Q000187:drug effects*; D013937:Thymidine Kinase / Q000235:genetics
chemical_list: D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D010430:Pentosyltransferases; C024827:xanthine phosphoribosyltransferase; D007041:Hypoxanthine Phosphoribosyltransferase; D013937:Thymidine Kinase; D010100:Oxygen