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.
