IRON HOMEOSTASIS AND BIOLOGICAL EFFECTS OF MINERAL OXIDE PARTICLES

Particle exposure is ubiquitous for all forms of life and presents significant health effects in humans. The basis for the biological effect of particles is not known. We tested the postulate that mineral oxide particles complex endogenous iron resulting in both an oxidative stress and biological effect. Cells were exposed to either media or SiO2 (Minusil-5). SiO2 exposure increased cell iron import measured as non-heme iron by inductively couple plasma (ICP) optical emission spectroscopy; co-exposure to SiO2 and ferric ammonium citrate (FAC) further increased cell iron concentrations relative to incubations with FAC alone. Complexation of mitochondrial iron by SiO2 was studied using cells grown in flasks and exposed to 57Fe FAC. Incubation with SiO2 resulted in diminished mitochondrial 57Fe concentrations (by ICP mass spectroscopy) in the particle-exposed cells as the silica complexed host metal from the organelle. Pre-incubation of cells with FAC increased nuclear and mitochondrial metal concentrations and prevented significant iron loss from mitochondria exposed to SiO2. Cell oxidant generation increased with various doses of SiO2 exposure. However, pre-exposure of the cells to FAC diminished oxidant generation. Finally, cell exposure to SiO2 increased expression of pro-inflammatory transcription factors and mediators; this elevation was also inhibited by pre-treatment with FAC. We conclude that oxidative stress and biological response (here inflammation) following exposure to silica is associated with complexation of host mitochondrial iron; increasing available iron in the cell diminished both oxidative stress and biological response to SiO2. The initiating event in the toxicity of mineral oxides relates to their capacity for surface complexation and cation exchange. Development of replacement materials and nanoparticles must consider and minimize the surface capacity to complex endogenous iron requisite to cells.