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ToxSci Advance Access published online on April 25, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj209
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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 November 23, 2005
Accepted April 3, 2006

Neurotoxicology

Correlation of Brain Magnetic Resonance Imaging Changes with Pallidal Manganese Concentrations in Rhesus Monkeys Following Subchronic Manganese Inhalation

David C. Dorman 1 *, Melanie F. Struve 1, Brian A. Wong 1, Janice A. Dye 2 1, and Ian D. Robertson 3

1 CIIT Centers for Health Research (CIIT), 6 Davis Drive, P.O. Box 12137, Research Triangle Park, NC 27709-2137, USA
2 U.S. Environmental Protection Agency, ORD, National Health and Environmental Effects Research Laboratory, Experimental Toxicology Division, Research Triangle Park, North Carolina 27709, USA
3 North Carolina State University, College of Veterinary Medicine, Department of Biomedical Science, Raleigh, NC, 27606 USA

* To whom correspondence should be addressed.
David C. Dorman, E-mail: dorman{at}ciit.org


  Abstract

High dose manganese exposure is associated with parkinsonism. Because manganese is paramagnetic, its relative distribution within the brain can be examined using magnetic resonance imaging (MRI). Herein, we present the first comprehensive study to use MRI, pallidal index (PI), and T1 relaxation rate (R1) in concert with chemical analysis to establish a direct association between MRI changes and pallidal manganese concentration in rhesus monkeys following subchronic inhalation of manganese sulfate (MnSO4). Monkeys exposed to MnSO4 at ≥ 0.06 mg Mn/m3 developed increased manganese concentrations in the globus pallidus, putamen, olfactory epithelium, olfactory bulb, and cerebellum. Manganese concentrations within the olfactory system of the MnSO4-exposed monkeys demonstrated a decreasing rostral-caudal concentration gradient, a finding consistent with olfactory transport of inhaled manganese. Marked MRI signal hyperintensities were seen within the olfactory bulb and the globus pallidus, however, comparable changes could not be discerned in the intervening tissue. The R1 and PI were correlated with the pallidal manganese concentration. However, increases in white matter manganese concentrations in MnSO4-exposed monkeys confounded the PI measurement and may lead to underestimation of pallidal manganese accumulation. Our results indicate that the R1 can be used to estimate regional brain manganese concentrations, and may be a reliable biomarker of occupational manganese exposure. To our knowledge, this study is the first to provide evidence of direct olfactory transport of an inhaled metal in a nonhuman primate. Pallidal delivery of manganese, however, likely arises primarily from systemic delivery and not directly from olfactory transport.

Keywords: Parkinson Disease, Secondary; Manganese Poisoning; Pharmacokinetics; Inhalation Exposure; Macaca mulatta; Magnetic Resonance Imaging.

1Disclaimer footnote: The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency and approved for publication. Approval does not signify that the contents necessarily reflect the views and the policies of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use.


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