Crucial role of chelatable iron in silver nanoparticles induced DNA damage and cytotoxicity

Damage to mitochondria and subsequent ROS leakage is a commonly accepted mechanism of nanoparticle toxicity. However, malfunction of mitochondria results in generation of superoxide anion radical (O-2(center dot)-), which due to the relatively low chemical reactivity is rather unlikely to cause harmful effects triggered by nano-particles. We show that treatment of HepG2 cells with silver nanoparticles (AgNPs) resulted in generation of H2O2 instead of O-2(center dot)-, as measured by ROS specific mitochondrial probes. Moreover, addition of a selective iron chelator diminished AgNPs toxicity. Altogether these results suggest that O-2(center dot)- generated during NPs induced mitochondrial collapse is rapidly dismutated to H2O2, which in the presence of iron ions undergoes a Fenton reaction to produce an extremely reactive hydroxyl radical ((OH)-O-center dot). Clarification of the mechanism of NPs-dependent generation of OH and demonstration of the crucial role of iron ions in NPs toxicity will facilitate our understanding of NPs toxicity and the design of safe nanomaterials.