Mechanism of Manganese-Induced NeurotoxicityEPA Grant Number: R826248
Title: Mechanism of Manganese-Induced Neurotoxicity
Institution: The State University of New York at Buffalo
EPA Project Officer: Chung, Serena
Project Period: October 1, 1997 through September 30, 2000
Project Amount: $355,000
RFA: Ambient Air Quality (1997) RFA Text | Recipients Lists
Research Category: Air Quality and Air Toxics , Air
Description:Atmospheric levels of manganese (Mn) have significantly increased in urban cities since its introduction as a fuel additive. This is particularly relevant based on recent studies indicating that people with compromised liver function may be at considerably greater risk than the normal population to the toxic actions of Mn. Mn is a potent neurotoxin which is capable of producing a variety of neurological symptoms characterized by severe extrapyramidal dysfunction resembling the dystonic movements associated with Parkinson's disease. With the realization of increased environmental exposure to Mn, it becomes necessary to delineate the fundamental biochemical and molecular mechanisms responsible for its selective neurotoxic actions in order to prevent and identify individuals with Mn toxicity.
Approach:Dopaminergic neurons in the striatum have been proposed to be one of the primary target for the toxic actions of Mn. We have utilized rat pheochromocytoma cells (PC12) grown in culture as a model system to study Mn toxicity since these cells contain the complete biological machinery for synthesis, storage, release and metabolism of dopamine. Our initial findings demonstrate that Mn is capable of not only provoking the expected toxic response in PC12 cells, as seen in the dopaminergic neurons, but is also capable of inducing neuronal differentiation similar to that observed with nerve growth factor (NGF). Preliminary evidence suggests that Mn-induced cell toxicity and differentiation may be linked to a common signal transduction pathway which may lead to altered gene expression and apoptitic cell death. We propose to determine the mechanism and signal transduction pathways by which Mn promotes PC12 cell death.
- Determine the role of oxidative stress and altered mitochondrial function in influencing Mn toxicity
- Determine intracellular concentrations of Mn inducing PC12 cell death
- Assess Mn effect on oxidative stress and other related metabolic processes
- Assess the effects of Mn on changes in DNA structure associated with apoptosis in PC12 cells
- Assess effects of Mn on DNA and nuclear changes
- Examine effects of Mn on signal transduction systems known to promote apoptosis ( MAP kinase RAS, p38 protein, JNK protein, c-jun levels