Induction of Neoplastic Transformation, AP‐1 Signaling, PDCD4 signaling, and DNA Damage by Metal Oxide Nanoparticles Involves ROS‐Mediated MAPK Pathways in JB6 Cells

Abstract

Occupational exposures to metal oxide nanoparticles have been reported to be harmful to human health, with possible risk of cancer among workers from many sectors. Metal Oxide nanoparticles have not, to our knowledge, been extensively examined for potential carcinogenic or genotoxic effects. To investigate the mechanisms of TiO2, WC‐Co, and CuO‐induced pathogenesis, the effect of metal oxide fine and nanoparticles on AP‐1‐MAPKs and ROS generation were investigated. The results indicated that CuO, WC‐Co, andTiO2 nanoparticles caused a 2‐fold increase or more in AP‐1 activity in JB6 cells. The induction of AP‐1 activity in cultured cell lines was time and dose‐dependent. The signal transduction pathways for AP‐1 activation were also investigated. Western Blot analysis demonstrate that CuO, WC‐Co, and TiO2 nanoparticles stimulate phosphorylation of p38 MAPK and ERKs. CuO, WC‐Co, and TiO2 also generated ROS when incubated with the cells as measured by electron spin resonance (ESR). Nano‐sized CuO, WC‐Co, and TiO2 generated more ROS than the fine sized particles when incubated with the cells. COMET assay suggests that exposure of the cells to CuO resulted in DNA damage. Cells pre‐treated with ROS inhibitors sodium formate and Polyvinylpyridine‐N‐Oxide (PVPNO) before exposure to CuO and WC‐Co nanoparticles demonstrate a significant reduction in p‐38 and ERK activity, suggesting the H2O2 may have a role in the ROS mechanism. Soft agar transformation assays demonstrated that there is a significant increase in colony formation in JB6/AP‐1 cells treated with CuO, WC‐Co, and TiO2 nanoparticles as compared to the control, indicative of neoplastic transformation. Unraveling the complex mechanisms associated with these events may provide insights into the initiation and progression of metal oxide‐induced pathogenesis.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.