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ToxSci Advance Access published online on June 1, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl028
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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 March 21, 2006
Accepted May 27, 2006

Neurotoxicology

Brain Accumulation and Toxicity of Mn(II) and Mn(III) Exposures

Stephen H. Reaney 1 *, Graham Bench 2, and Donald R. Smith 3

1 Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA
2 Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA
3 Department of Environmental Toxicology, University of California, Santa Cruz, CA 95064, USA

* To whom correspondence should be addressed.
Stephen H. Reaney, E-mail: stevereaney{at}hotmail.com


  Abstract

Concern over the neurotoxic effects of chronic moderate exposures to manganese has arisen due to increased awareness of occupational exposures and to the use of methylcyclopentadienyl tricarbonyl (MMT) a manganese containing gasoline anti-knock additive. Little data exists on how the oxidation state of manganese exposure affects toxicity. The objective of this study was to better understand how the oxidation state of manganese exposure affects accumulation and subsequent toxicity of manganese. This study utilized a rat model of manganese neurotoxicity to investigate how i.p. exposure to Mn(II)-chloride or Mn(III)-pyrophosphate at total cumulative doses of 0, 30 or 90 mg Mn/kg body weight affected the brain region distribution and neurotoxicity of manganese. Results indicate that Mn(III) exposures produced significantly higher blood manganese levels than equimolar exposures to Mn(II). Brain manganese concentrations increased in a dose-dependent manner, with Mn(III) exposures producing significantly higher (>25%) levels than exposures to Mn(II), but with no measurable differences in the accumulation of manganese across different brain regions. GABA concentrations were increased globus pallidus with manganese exposure. Dopamine levels were altered in the globus pallidus, with the highest Mn(II) and Mn(III) exposures producing significantly different dopamine levels. In addition, transferrin receptor and H-ferritin protein expression increased in the globus pallidus with manganese exposure. These data substantiate the heightened susceptibility of the globus pallidus to manganese, and they indicate that the oxidation state of manganese exposure may be an important determinant of tissue toxicodynamics and subsequent neurotoxicity.

Keywords: GABA; Dopamine; Oxidation State; Neurotoxicity; PIXE; Brain Region.
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