Manganese Neurotoxicity: Lessons Learned from Longitudinal Studies in Non-Human Primates

Manganese Neurotoxicity: Lessons Learned from

Longitudinal Studies in Non-Human Primates

http://www.ehponline.org/docs/2008/0800035/abstract.pdf

Neal C. Burton and Tomás R. Guilarte

doi: 10.1289/ehp.0800035 (available at http://dx.doi.org/)

Online 3 October 2008

Abstract

Background: Exposure to excess levels of the essential trace element

manganese (Mn) produces cognitive, psychiatric, and motor abnormalities. The

understanding of Mn neurotoxicology is heavily governed by pathological and

neurochemical observations derived from rodent studies that often employ acute

Mn exposures. The comparatively sparse studies incorporating in vivo

neuroimaging in non-human primates provide invaluable insights on the effects of

Mn on brain chemistry.

Objectives: The purpose of this review is to discuss important aspects of Mn

neurotoxicology and to synthesize recent findings from one of the largest cohorts

of non-human primates used to study the neurological effects of chronic Mn

exposure.

Discussion: We review our recent in vivo and ex vivo studies that have

significantly advanced the understanding of Mn-induced neurotoxicity. We

administered weekly doses of 3.3-5.0 (n=4), 5.0-6.7 (n=5) or 8.3-10.0 mg Mn/kg

(n=3) for 7-59 weeks to Cynomolgus macaque monkeys. Animals expressed

subtle deficits in cognition and motor function and decreases in the Nacetylaspartate

to creatine ratio in the parietal cortex measured by MRS

reflective of neuronal dysfunction. Impaired striatal dopamine release measured

by PET was observed in the absence of changes in markers of dopamine neuron

degeneration. Neuropathology indicated decreased glutamine synthetase

expression in the globus pallidus with otherwise normal markers of glutamatergic

and GABAergic neurotransmission. Increased APLP1 gene expression with

multiple markers of neurodegeneration and glial cell activation was observed in

the frontal cortex.

Conclusions: These findings provide new information on mechanisms by which

Mn affects behavior, neurotransmitter function and neuropathology in non-human

primates.