Nickel is a toxic metal that causes mutagenesis and promotes carcinogenesis. Its toxicological properties are partially related to the generation of reactive oxygen species (ROS) that can induce DNA damage and mutation. It also interfere redox-sensitive transcription factors, particularly p53 and hypoxia-inducible factor 1 (HIF-1), which might lead to genomic expression change. Nuclear factor erythroid-2 related factor 2 (Nrf2) is a redox factor which is responsible for control of oxidation/reduction status and consequent cytoprotection against environmental toxicants. First, we confirmed the protective effect of the Nrf2 gene under oxidative stress and DNA damage induced by 20uM nickel at sub-lethal doses in terms of gene-environment interactions. Here, we attempted to identify potential nickel and Nrf2-responsive targets and the relevant pathway via microarray, qRT-PCR, and pathway analysis. Under nickel exposure conditions, we detected significantly higher amounts of DNA damage via a comet assay, in addition to increased intracellular ROS generation, in Nrf2 lacking cells in comparison to Nrf2 wild-type cells. Additionally, gene expression data were analyzed via microarray assays for the selection of Nrf2-responsive genes under nickel treatment. In particular, altered expressions of 10 genes (CAV1, FOSL2, MICA, PIM2, RUNX1, SLC7A6, APLP1, CLSPN, PCAF, and PRAME) were verified by qRT-PCR. These genes functioned principally in a variety of biological processes, including oxidative stress response, DNA repair, necrosis, and cell survival. These findings indicate that Nrf2 is an important factor that performs a protective role in the suppression of oxidative stress-induced DNA damage by environmental nickel exposure. Furthermore, we describe the potential biomarkers regarded as molecular targets for Nrf2-related cellular protection against nickel exposure.


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  • Received: 09 May 2012
  • Accepted: 09 May 2012
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