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ToxSci Advance Access originally published online on May 19, 2006
Toxicological Sciences 2006 92(2):456-463; doi:10.1093/toxsci/kfl020
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The Interaction of Manganese Nanoparticles with PC-12 Cells Induces Dopamine Depletion

Saber M. Hussain*,1, Amanda K. Javorina*, Amanda M. Schrand{dagger}, Helen M. Duhart{ddagger}, Syed F. Ali{ddagger} and John J. Schlager*

* Applied Biotechnology Branch, Human Effectiveness Directorate, Air Force Research Laboratory, Wright-Patterson AFB, Ohio 45431; {dagger} Department of Chemical and Materials Engineering, University of Dayton, Dayton, Ohio 45469; and {ddagger} Neurochemistry Laboratory, Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, Arkansas 72079

Received February 5, 2006; accepted March 25, 2006

This investigation was designed to determine whether nano-sized manganese oxide (Mn-40nm) particles would induce dopamine (DA) depletion in a cultured neuronal phenotype, PC-12 cells, similar to free ionic manganese (Mn2+). Cells were exposed to Mn-40nm, Mn2+ (acetate), or known cytotoxic silver nanoparticles (Ag-15nm) for 24 h. Phase-contrast microscopy studies show that Mn-40nm or Mn2+ exposure did not greatly change morphology of PC-12 cells. However, Ag-15nm and AgNO3 produce cell shrinkage and irregular membrane borders compared to control cells. Further microscopic studies at higher resolution demonstrated that Mn-40nm nanoparticles and agglomerates were effectively internalized by PC-12 cells. Mitochondrial reduction activity, a sensitive measure of particle and metal cytotoxicity, showed only moderate toxicity for Mn-40nm compared to similar Ag-15nm and Mn2+ doses. Mn-40nm and Mn2+ dose dependently depleted DA and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), while Ag-15nm only significantly reduced DA and DOPAC at concentrations of 50 µg/ml. Therefore, the DA depletion of Mn-40nm was most similar to Mn2+, which is known to induce concentration-dependent DA depletion. There was a significant increase (> 10-fold) in reactive oxygen species (ROS) with Mn-40nm exposure, suggesting that increased ROS levels may participate in DA depletion. These results clearly demonstrate that nanoscale manganese can deplete DA, DOPAC, and HVA in a dose-dependent manner. Further study is required to evaluate the specific intracellular distribution of Mn-40nm nanoparticles, metal dissolution rates in cells and cellular matrices, if DA depletion is induced in vivo, and the propensity of Mn nanoparticles to cross the blood-brain barrier or be selectively uptaken by nasal epithelium.

Key Words: nanoparticles; manganese; in vitro toxicity; PC-12 cells; dopamine.


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