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ToxSci Advance Access originally published online on November 12, 2008
Toxicological Sciences 2009 107(1):182-193; doi:10.1093/toxsci/kfn231
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Ceruloplasmin Alters the Tissue Disposition and Neurotoxicity of Manganese, but not its Loading onto Transferrin

Thomas Jursa and Donald R. Smith1

Department of Environmental Toxicology, University of California, Santa Cruz, California 95064

1 To whom correspondence should be addressed at Dept. of Environmental Toxicology, UCSC, Santa Cruz, CA 95064. Fax: (831) 459-3524. E-mail: smith{at}etox.ucsc.edu.

Received August 21, 2008; accepted October 18, 2008


  Abstract

Manganese (Mn) is a redox-active element, and whereas its uptake, disposition, and toxicity in mammals may depend in part on its oxidation state, the proteins affecting manganese oxidation state and speciation in vivo are not well known. Studies have suggested that the oxidase protein ceruloplasmin (Cp) mediates iron and manganese oxidation and loading onto plasma transferrin (Tf), as well as cellular iron efflux. We hypothesized that ceruloplasmin may also affect the tissue distribution and eventual neurotoxicity of manganese. To test this, aceruloplasminemic versus wild-type mice were treated with a single i.p. 54Mn tracer dose, or elevated levels of manganese subchronically (0, 7.5, or 15 mg Mn/kg s.c., three doses per week for 4 weeks), and evaluated for transferrin-bound manganese, blood manganese partitioning, tissue manganese disposition, and levels of brain glutathione, thiobarbituric acid reactive substances (TBARS), and protein carbonyls as measures of oxidative stress, and open arena activity. Results show that ceruloplasmin does not play a role in the loading of manganese onto plasma transferrin in vivo, or in the partitioning of manganese between the plasma and cellular fractions of whole blood. Ceruloplasmin did, however, affect the retention of manganese in blood and its distribution to tissues, most notably kidney and to a lesser extent brain and lung. Results also indicate that ceruloplasmin interacted with chronic elevated manganese exposures to produce greater levels of brain oxidative stress. These results provide evidence that metal oxidase proteins play an important role in altering neurotoxicity arising from elevated manganese exposures.

Key Words: manganese; ceruloplasmin; transferrin; oxidation state; neurotoxicity.


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