| Summary: | Amorphous silica nanoparticles (SiO<sub>2</sub>NPs) have been widely used in medicine including targeted drug/DNA delivery, cancer therapy, and enzyme immobilization. Nevertheless, SiO<sub>2</sub>NPs should be used with caution due to safety concerns associated with unique physical and chemical characteristics. The objective of this study was to determine the effects of SiO<sub>2</sub>NPs on genotoxic and non-genotoxic mechanisms associated with abnormal gap junctional intercellular communication (GJIC) in multistage carcinogenesis. The SiO<sub>2</sub>NPs exhibited negative responses in standard genotoxicity tests including the Ames test, chromosome aberration assay, and micronucleus assay. In contrast, the SiO<sub>2</sub>NPs significantly induced DNA breakage in comet assay. Meanwhile, SiO<sub>2</sub>NPs inhibited GJIC based on the results of scrape/loading dye transfer assay for the identification of non-genotoxic tumor-promoting potential. The reduction in expression and plasma membrane localization of Cx43 was detected following SiO<sub>2</sub>NP treatment. Particularly, SiO<sub>2</sub>NP treatment increased Cx43 phosphorylation state, which was significantly attenuated by inhibitors of extracellular signal-regulated kinases 1/2 (ERK1/2) and threonine and tyrosine kinase (MEK), but not by protein kinase C (PKC) inhibitor. Taken together, in addition to a significant increase in DNA breakage, SiO<sub>2</sub>NP treatment resulted in GJIC dysregulation involved in Cx43 phosphorylation through the activation of mitogen-activated protein kinase (MAPK) signaling. Overall findings of the genotoxic and non-genotoxic carcinogenic potential of SiO<sub>2</sub>NPs provide useful toxicological information for clinical application at an appropriate dose.
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