Nano-scaled metal oxides including nFe2O3have been widely used for various applications but with unknown healthconsequences, especially after long-term exposures. Previous studies have shown that ferric oxides have the potential to be toxic, such as induction of lunginflammation, cell death, and reactive oxygen species formation from acute in vivo and in vitro observations. However, the underlying mechanisms of disease pathogenesis are unclear. The present study was undertaken to investigate the effect of long-term/low dose exposure of small airway epithelial cells (SAECs), a major cellular target of inhaled toxicants, to nFe2O3 on cell transformation and cancer-like properties. Primary human SAECs were exposed to a sub-lethal concentration (0.625 μg/cm2) of nFe2O3 (size dXRD = 20 nm, SSA = 50 m2/g) for up to 10 weeks in culture and its effects on cell proliferation, colony formation, and cell invasion were examined.As controls, cells were similarly exposed to multi-walled carbon nanotubes (MWCNT), a known inducer of neoplastic transformation in vitro and a tumor promoter in vivo, and to nano cerium oxide (nCeO2), a similar sized metal oxide known to induce lung toxicity. Unexposed SAECs served as passage-matched controls. At 6 weeks post-exposure, nCeO2 induced cell proliferation, whereas nFe2O3 caused decreased cell viability, as determined by the metabolism-based WST-1 assay. However, at 10 weeks post-exposure, nFe2O3 stimulated cell growth and induced neoplastic transformation as determined by soft-agar colony formation and Transwell®cell invasion assays. The effect of nFe2O3 on neoplastic transformation is more pronounced than that of MWCNT, suggesting the potential carcinogenicity of nFe2O3 after prolonged exposure. nCeO2 induced cell proliferation without having the same effect on colony formation or cell invasion, even at 10 weeks post-exposure. These results indicate the differentialeffects of nano-metal oxides on human lung cells, with nFe2O3 being pro-neoplastic and nCeO2 being pro-growth. Knowledge gained from this study could aid in the design of further animal and cellular studies aimed at assessing the cancer risk of nano-metal oxides and unveiling the underlying mechanisms of action.
Keywords: metal oxides, nanoparticle, lung, epithelial cell, transformation, carcinogenesis
Citation Format: Liying Wang, Donna C. Davidson, Raymond Derk, Sudjit Luanpitpong, Georgios A. Sotiriou, Philip Demokritou, Vincent Castranova, Yon Rojanasakul, Todd A. Stueckle. Ferric oxide nanoparticles (nFe2O3) induce neoplastic transformation of primary human small airway epithelial cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2723. doi:10.1158/1538-7445.AM2015-2723