Manganese toxicity: Accumulation in bone, effect on brain neurochemistry, and impact on adult neurogenesis

Manganese (Mn) exposure is a growing public health concern as new evidence continues to show that high level exposure to this essential metal is toxic. Chiefly toxic to the central nervous system, it produces signs and symptoms resembling, but not identical to idiopathic Parkinson's disease. The hypothesis tested in this dissertation is that Mn accumulation in body tissues produces subclinical changes in the central nervous system altering neuronal repair mechanisms and leading to neurodegenerative damage. The studies in this dissertation evaluated the extent of these changes in the central nervous system. Changes in the toxicokinetic properties of Mn in bone affecting the parameters of accumulation, distribution, and elimination were also identified. Importantly, the half-life of Mn in bone was estimated to be approximately 8.6 years in humans, a finding which will be essential in developing a biomonitoring system for Mn exposure. Significant accumulation of Mn in brain and body tissues was observed along with significant metal dyshomeostasis following Mn exposure. Several brain regions had altered neurochemistry, and as a consequence, impaired motor function was observed. The subventricular zone (SVZ), one of two neurogenic niches in the adult brain, had the largest magnitude of change. Therefore, effects of Mn exposure on cell proliferation and differentiation in this region were investigated further. The processes involved in adult neurogenesis were significantly altered following Mn exposure, particularly with regard to cell proliferation. The full extent of the consequences resulting from Mn exposure in the pathology of neurodegenerative disease remains unknown, but the results of these studies demonstrate that although Mn exposure undoubtedly leads to several changes observed early in neurodegenerative disease pathology, no overt neurodegeneration was observed. The results of this work will help researchers studying the effect of metal exposure on adult neurogenesis and will also help researchers studying neurodegenerative disease and other disorders of the central nervous system.