A short low-level exposure to metavanadate during a cell cycle-specific interval of time is sufficient to permanently derange the differentiative properties of Mel cells

Mouse erythroleukemia (Mel) cells have a cell cycle-dependent high sensitiv ity to chemical and physical mutagens. This report shows that a 5 h exposur e to 0.1 or 0.01 mug/ml metavanadate during the initial period of erythroid differentiation induction was sufficient to permanently damage the ability of treated Mel cells and their progeny to undergo erythroid differentiatio n, without affecting cell viability and proliferation. Conversely, a 5 h pu lse of metavanadate at 1 or 10 mug/ml inhibited both differentiation and ce ll proliferation. The cell cycle-dependent period of mutagenesis was essent ial for fixation of damage in the cell genome and the progeny of the cells treated with 0.1 or 0.01 mug/ml metavanadate stably inherited an impaired c apacity to differentiate. The efficiency of the DNA repair synthesis machin ery during the specific period of exposure of Mel cells seemed directly inv olved in damage fixation. In fact, the mutagenic effects of a 0.1 mug/ml me tavanadate pulse was further increased in the presence of 1 mM hydroxyurea, an inhibitor of DNA repair synthesis. In contrast, 5 mug/ml vanillin, an a ntimutagenic agent that stimulates repair, completely restored the capacity of progeny of cells treated with 0.1 mug/ml metavanadate to complete diffe rentiation. Determination of [H-3]deoxythymidine in acid-insoluble DNA indi cated that incorporation was stimulated by metavanadate alone and was furth er increased by metavanadate plus vanillin; conversely, incorporation of th ymidine was reduced in the presence of hydroxyurea. The capacity of metavan adate to permanently damage Mel cell erythroid differentiation appeared to depend on the cell cycle-related efficiency of the DNA repair systems, acti vated to correct the induced alteration, rather than on a specific concentr ation.