Silver nanoparticles (Ag-NPs) have increasingly been used for coatings on various textiles and certain implants, for the treatment of wounds and burns, as a water disinfectant, and in air-freshener sprays. The wide use of Ag-NPs may have potential human health impacts. In this study, the mutagenicity of 5-nm Ag-NPs was evaluated in the mouse lymphoma assay system, and modes of action were assessed using standard alkaline and enzyme-modified Comet assays and gene expression analysis. Treatments of L5178Y/Tk(+/-) mouse lymphoma cells with 5-nm uncoated Ag-NPs resulted in a significant yield of mutants at doses between 3 and 6 μg/mL; the upper range was limited by toxicity. Loss of heterozygosity analysis of the Tk mutants revealed that treatments with uncoated Ag-NPs induced mainly chromosomal alterations spanning less than 34 megabase pairs on chromosome 11. Although no significant induction of DNA damage in Ag-NP-treated mouse lymphoma cells was observed in the standard Comet assay, the Ag-NP treatments induced a dose-responsive increase in oxidative DNA damage in the enzyme-modified Comet assay in which oxidative lesion-specific endonucleases were added. Gene expression analysis using an oxidative stress and antioxidant defense polymerase chain reaction (PCR) array showed that the expressions of 17 of the 59 genes on the arrays were altered in the cells treated with Ag-NPs. These genes are involved in production of reactive oxygen species, oxidative stress response, antioxidants, oxygen transporters, and DNA repair. These results suggest that 5 nm Ag-NPs are mutagenic in mouse lymphoma cells due to induction of oxidative stress by the Ag-NPs.
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