Neurotoxic mechanisms of methylmercury: cellular and behavior changes
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The organic or methylated form of mercury (Hg), consisting of one methyl group bound to each atom of Hg, (methylmercury; MeHg), accounts for most of the Hg to which humans are exposed. MeHg, by virtue of its lipophilicity is highly neurotoxic to both the developing and mature central nervous system (CNS). Historically, MeHg has been 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 exposure episodes was cerebellar ataxia. Recent in vitro studies using cultured granule cells showed that MeHg alters intracellular calcium ion ([Ca2+]i) homeostasis, potentiates reactive oxygen species (ROS) generation and loss of mitochondrial membrane potential leading to apoptotic death of cerebellar granule neurons. To better understand the neurotoxic mechanisms of MeHg on cerebellum, changes with respect to biochemical processes in cerebellar granule cells and associated behavior changes were investigated. The aims of this dissertation were: (1) to assess mercury concentrations in mouse brain using different routes of administration and different tissue preparations, (2) to determine the behavior effects of in vivo MeHg exposure in young adult mice. (3) to understand specific biochemical processes leading to granule cell death/dysfunction due to in vivo MeHg toxicity in mice, and (4) to determine the toxic effects of in vivo MeHg exposure on mice aged between 16-20 months. The present results showed that repeated oral exposure to MeHg results in greater accumulation of Hg in brain tissue when compared to single oral or subcutaneous exposures at the same concentration of MeHg. Behavior analysis revealed that MeHg at the concentrations used in this study had profound effects on motor coordination and balance in young adult and aged mice. Investigation of biochemical processes in cerebellar granule cells of mice exposed to MeHg showed an increase in ROS generation, alteration of ([Ca2+]i (in young adult mice) and loss of MMP in young adult and aged mice. However, these changes did not lead to apoptotic cell death of granule cells at the concentrations of MeHg used and at the specific time point it was investigated in young adult mice.
Bellum, Sairam (2005). Neurotoxic mechanisms of methylmercury: cellular and behavior changes. Doctoral dissertation, Texas A&M University. Texas A&M University. Available electronically from