Academic journal article Environmental Health Perspectives

Silver Nanoparticles Compromise Neurodevelopment in PC12 Cells: Critical Contributions of Silver Ion, Particle Size, Coating, and Composition

Academic journal article Environmental Health Perspectives

Silver Nanoparticles Compromise Neurodevelopment in PC12 Cells: Critical Contributions of Silver Ion, Particle Size, Coating, and Composition

Article excerpt

BACKGROUND: Silver exposures are rising because of the increased use of silver nanoparticles (AgNPs) in consumer products. The monovalent silver ion ([Ag.sup.+]) impairs neurodevelopment in PC12 cells and zebrafish.

OBJECTIVES AND METHODS: We compared the effects of AgNPs with [Ag.sup.+] in PC12 cells for neurodevelopmental end points including cell replication, oxidative stress, cell viability, and differentiation. First, we compared citrate-coated AgNPs (AgNP-Cs) with [Ag.sup.+], and then we assessed the roles of particle size, coating, and composition by comparing AgNP-C with two different sizes of polyvinylpyrrolidone-coated AgNPs (AgNP-PVPs) or silica nanoparticles.

RESULTS: In undifferentiated cells, AgNP-C impaired DNA synthesis, but to a lesser extent than an equivalent nominal concentration of [Ag.sup.+], whereas AgNP-C and [Ag.sup.+] were equally effective against protein synthesis; there was little or no oxidative stress or loss of viability due to AgNP-C. In contrast, in differentiating cells, AgNP-C evoked robust oxidative stress and impaired differentiation into the acetylcholine phenotype. Although the effects of AgNP-PVP showed similarities to those of AgNP-C, we also found significant differences in potencies and differentiation outcomes that depended both on particle size and coating. None of the effects reflected simple physical attributes of nanoparticles, separate from composition or coating, as equivalent concentrations of silica nanoparticles had no detectable effects.

CONCLUSIONS: AgNP exposure impairs neurodevelopment in PC12 cells. Further, AgNP effects are distinct from those of [Ag.sup.+] alone and depend on size and coating, indicating that AgNP effects are not due simply to the release of [Ag.sup.+] into the surrounding environment.

KEY WORDS: acetylcholine, developmental neurotoxicity, dopamine, in vitro, metal neurotoxicity, nanoparticles, PC12 cells, silver. Environ Health Perspect 119:37-44 (2011). doi:10.1289/ehp.1002337 [Online 14 September 2010]

The rapid growth in the commercial use of silver nanoparticles (AgNPs) is increasing silver exposure in the general population (Wijnhoven et al. 2009). AgNPs are incorporated into products primarily as an antimicrobial, reflecting their release of monovalent silver ion ([Ag.sup.+]) (Wijnhoven et al. 2009). However, the same mechanisms that make [Ag.sup.+] an antimicrobial also render it a potential developmental neurotoxicant. Silver crosses the placenta and concentrates in the human fetus, achieving higher concentrations than in the mother (Lyon et al. 2002). Animal studies show accumulation in the developing brain, developmental dysmorphology, and behavioral changes in exposed adults (Rungby 1990). Importantly, AgNP exposure via either inhalation or oral routes also leads to Ag accumulation in the adult rodent brain (Wijnhoven et al. 2009), altering the expression of genes involved in neuronal function (Rahman et al. 2009). We recently showed that in PC12 cells, a well-established model of neuronal development, [Ag.sup.+] disrupts key mechanisms involved in cell replication and neurodifferentiation (Powers et al. 2010a); we then demonstrated that nervous system development is disrupted in developing zebrafish exposed to [Ag.sup.+] (Powers et al. 2010b). Unlike primary neuronal cultures, PC12 cells provide a homogeneous population that continues to divide until differentiation is triggered by addition of nerve growth factor. Accordingly, this model allows direct study of effects on DNA synthesis associated with cell replication, an important target of neurotoxicants; the cells then differentiate into distinct acetylcholine (ACh) and dopamine (DA) phenotypes.

It is thus critical to assess the extent to which AgNPs can elicit the same or different types of neurodevelopmental outcomes as [Ag.sup.+]. In the same PC12 model, high concentrations of AgNPs disrupt the cell membrane and impair mitochondrial function (Hussain et al. …

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