The organic or methylated form of mercury (Hg), consisting of one methyl groupbound to each atom of Hg, (methylmercury; MeHg), accounts for most of the Hg towhich humans are exposed. MeHg, by virtue of its lipophilicity is highly neurotoxic toboth the developing and mature central nervous system (CNS). Historically, MeHg hasbeen implicated in high morbidity and mortality rates over the last 40 years in Japan,Iraq, Pakistan and Guatemala. The most common symptom exhibited in these exposureepisodes was cerebellar ataxia. Recent in vitro studies using cultured granule cellsshowed that MeHg alters intracellular calcium ion ([Ca2+]i) homeostasis, potentiatesreactive oxygen species (ROS) generation and loss of mitochondrial membrane potentialleading to apoptotic death of cerebellar granule neurons. To better understand theneurotoxic mechanisms of MeHg on cerebellum, changes with respect to biochemicalprocesses in cerebellar granule cells and associated behavior changes were investigated.The aims of this dissertation were: (1) to assess mercury concentrations in mousebrain using different routes of administration and different tissue preparations, (2) todetermine the behavior effects of in vivo MeHg exposure in young adult mice. (3) to understand specific biochemical processes leading to granule cell death/dysfunction dueto in vivo MeHg toxicity in mice, and (4) to determine the toxic effects of in vivo MeHgexposure on mice aged between 16-20 months.The present results showed that repeated oral exposure to MeHg results in greateraccumulation of Hg in brain tissue when compared to single oral or subcutaneousexposures at the same concentration of MeHg. Behavior analysis revealed that MeHg atthe concentrations used in this study had profound effects on motor coordination andbalance in young adult and aged mice. Investigation of biochemical processes incerebellar granule cells of mice exposed to MeHg showed an increase in ROSgeneration, alteration of ([Ca2+]i (in young adult mice) and loss of MMP in young adultand aged mice. However, these changes did not lead to apoptotic cell death of granulecells at the concentrations of MeHg used and at the specific time point it wasinvestigated in young adult mice.
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