Manganese Neurotoxicity: Lessons Learned from Longitudinal Studies in Nonhuman Primates

By Burton, Neal C.; Guilarte, Tomas R. | Environmental Health Perspectives, March 2009 | Go to article overview

Manganese Neurotoxicity: Lessons Learned from Longitudinal Studies in Nonhuman Primates


Burton, Neal C., Guilarte, Tomas R., Environmental Health Perspectives


BACKGROUND: Exposure to excess levels of the essential trace element manganese produces cognitive, psychiatric, and motor abnormalities. The understanding of Mn neurotoxicology is heavily governed by pathologic and neurochemical observations derived from rodent studies that often employ acute Mn exposures. The comparatively sparse studies incorporating in vivo neuroimaging in nonhuman 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 nonhuman primates used to study the neurologic effects of chronic Mn exposure.

DISCUSSION: We reviewed our recent in vivo and ex vivo studies that have significantly advanced the understanding of Mn-induced neurotoxicity. In those studies, 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 N-acetylaspartate-to-creatine ratio in the parietal cortex measured by magnetic resonance spectroscopy reflective of neuronal dysfunction. Impaired striatal dopamine release measured by position emission tomography 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 amyloid beta (A4) precursor-like protein 1 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 nonhuman primates.

KEYWORDS: cognitive function, dopamine, manganese, neurodegeneration, neurotoxicity, nonhuman primates, Parkinson disease, positron emission tomography. Environ Health Perspect 117:325-332 (2009). doi:10.1289/ehp.0800035 available via http//dx..doi.org/ [Online 3 October 2008]

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Biological role of manganese. Manganese is an essential micronutrient that has a broad role in macromolecular metabolism. Mn plays a role in immune response, blood sugar homeostasis, adenosine triphosphate (ATP) regulation, reproduction, digestion, and bone growth (Aschner and Aschner 2005). It is a necessary component of metalloenzymes such as Mn superoxide dismutase, arginase, phosphoenolpyruvate decarboxylase, and glutamine synthetase (GS) (Aschner and Aschner 2005). GS, an enzyme that converts glutamate into glutamine, is thought to be associated with up to 80% of brain Mn (Prohaska 1987). Mn has a heterogeneous distribution throughout the brain. In the normal human brain, Mn is most concentrated in the globus pallidus, caudate, and putamen and is less concentrated in cortical areas (Larsen et al. 1979). Intraneuronal axonal transport (Sloot and Gramsbergen 1994; Takeda et al. 1998b) and potassium-evoked (54) Mn release in rat amygdala (Takeda et al. 1998a) demonstrate that Mn may participate in neuronal function and neurotransmission. Mn can also enter neuronal terminals through calcium channels (Narita et al. 1990). The consumption of a Mn-deficient diet produced seizures in rats, demonstrating the importance of Mn in neuronal function (Hurley et al. 1963). Mn deficiency, although rare, can cause developmental defects including malformation of bones, altered macro-molecular metabolism, and reduced fertility (Aschner and Aschner 2005).

Sources of human exposure. Mn is ubiquitous in the environment. It is present at 0.1% in the earth's crust, and it is also a constituent of soil, ranging in concentrations from 40 to 900 mg/kg (Cooper 1984). It is released into the environment as a product of industrial activities, the use of the Mn-containing pesticide maneb, and through the use of methylcyclopentadienyl manganese tricarbonyl (MMT) as a gasoline antiknock agent (Agency for Toxic Substances and Disease Registry 2000). …

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