Molecular toxicity mechanism of nanosilver

Abstract

Silver is an ancient antibiotic that has found many new uses due to its unique properties on the nanoscale. Due to its presence in many consumer products, the toxicity of nanosilver has become a hot topic. This review summarizes recent advances, particularly the molecular mechanism of nanosilver toxicity. The surface of nanosilver can easily be oxidized by O(2) and other molecules in the environmental and biological systems leading to the release of Ag(+), a known toxic ion. Therefore, nanosilver toxicity is closely related to the release of Ag(+). In fact, it is difficult to determine what portion of the toxicity is from the nano-form and what is from the ionic form. The surface oxidation rate is closely related to the nanosilver surface coating, coexisting molecules, especially thiol-containing compounds, lighting conditions, and the interaction of nanosilver with nucleic acids, lipid molecules, and proteins in a biological system. Nanosilver has been shown to penetrate the cell and become internalized. Thus, nanosilver often acts as a source of Ag(+) inside the cell. One of the main mechanisms of toxicity is that it causes oxidative stress through the generation of reactive oxygen species and causes damage to cellular components including DNA damage, activation of antioxidant enzymes, depletion of antioxidant molecules (e.g., glutathione), binding and disabling of proteins, and damage to the cell membrane. Several major questions remain to be answered: (1) the toxic contribution from the ionic form versus the nano-form; (2) key enzymes and signaling pathways responsible for the toxicity; and (3) effect of coexisting molecules on the toxicity and its relationship to surface coating.

Keywords: Nanosilver; Silver nanoparticle; Toxicity mechanism.

Fig. 1

Fate and toxicity of nanosilver in biological and environmental media.

Fig. 2

Proposed mechanism of environmental transformation of nanosilver. Note. From “Environmental transformations of silver nanoparticles: impact on stability and toxicity,” by C. Levard, E.M. Hotze, G.V. Lowry, et al, 2012, Environ Sci Technol, 46, p. 6900–14. Copyright 2012, American Chemical Society. Reproduced with permission.

Fig. 3

Proposed mechanism of nanosilver toxicity. Note. From “Anti-proliferative activity of silver nanoparticles,” by P. AshaRani, M.P. Hande, and S. Valiyaveettil, 2009, BMC Cell Biol, 10, p.65. Copyright 2009, BMC Central. Reproduced with permission.

Fig. 4

Uptake of nanosilver by skin keratinocytes. (A) 60 nm × 30 nm nanorod. (B) 60 nm nanosphere. (C) uptake related to incubation time. Note. From “Effect of surface coating on the toxicity of silver nanomaterials on human skin keratinocytes,” by W. Lu, D. Senapati, S. Wang, et al, 2010, Chem Phys Lett, 487, p. 92–6. Copyright 2010. Elsevier B.V. Reproduced with permission.

Fig. 5

Schematic representation of nanoparticle surface induced unfolding of the interacting protein molecule and consequences. Note. From “Interaction of nanoparticles with proteins: relation to bio-reactivity of the nanoparticle,” by S.R. Saptarshi, L. Duschl, and A.L. Lopata, 2013, J Nanobiotech, 11, p. 26. Copyright 2013, BMC Central. Reproduced with permission.

Fig. 6

Effect of nanosilver on 8-oxoG levels. Note. From “Silver nanoparticles down-regulate Nrf2-mediated 8-oxoguanine DNA glycosylase 1 through inactivation of extracellular regulated kinase and protein kinase B in human Chang liver cells,” by M.J. Piao, K.C. Kim, J.-Y. Choi et al, 2011, Toxicol Lett, 207, p. 143–9. Copyright 2011, Elsevier Ireland Ltd. Reproduced with permission.

Fig. 7

Direct (A) and oxidative (B) DNA damage and repair of HaCaT cells exposed to nanosilver after 30 minutes, 4 hours, 8 hours, and 24 hours of incubation.