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ToxSci Advance Access published online on May 19, 2006
Toxicological Sciences, 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
Received February 5, 2006
Accepted March 25, 2006

In Vitro Toxicology

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

S M Hussain 1 *, A Javorina 1, A M Schrand 2, H Duhart 3, S F Ali 3, and J J Schlager 1

1 Applied Biotechnology Branch, Human Effectiveness Directorate, Air Force Research Laboratory, Wright-Patterson AFB, OH
2 Department of Chemical and Materials Engineering, University of Dayton, Dayton, OH
3 Neurochemistry Laboratory, Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR

* To whom correspondence should be addressed.
S M Hussain, E-mail: saber.hussain{at}wpafb.af.mil


  Abstract

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 hours. 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 are 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 dopamine (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 dopamine depletion of Mn-40nm was most similar to Mn2+, which is known to induce concentration-dependent dopamine depletion. There was a significant increase (>10-fold) in reactive oxygen species (ROS) with Mn-40 nm exposure suggesting that increased ROS levels may participate in dopamine depletion. These results clearly demonstrate that nanoscale manganese can deplete dopamine, 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 dopamine depletion is induced in vivo, and the propensity of Mn nanoparticles to cross the blood brain barrier or be selectively uptaken by nasal epithelium.

Keywords: Nanoparticles; manganese; in vitro toxicity; PC12 cells; dopamine.
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