Pesticide-Mediated Generation of a Toxic Neurotransmitter Metabolite

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PROJECT SUMMARY Exposure to the organochlorine dieldrin predisposes individuals to Parkinson's Disease (PD); however, the mechanisms linking exposure to disease and selective loss of dopaminergic cells are unknown. In addition, dieldrin alone may be insufficient for loss of dopamine (DA) neurons, and neurodegeneration may require an additional “hit”, such as from genetics. Several animal models have demonstrated that altering DA metabolism and/or trafficking yields progressive loss of DA neurons; therefore, a genetic variation modifying DA metabolism may be an additional “hit” that has toxic synergy with pesticide exposure. Cell types other than DA neurons are thought to be involved in PD, such as glia, and toxic factors released via glial activation are realized as a critical contributors to disease progression. Both DA neurons and glial cells (e.g., astrocytes) metabolize DA and other neurotransmitters and generate toxic intermediates such as ROS and aldehydes (3,4-dihydroxyphenylacetaldehyde, DOPAL), via monoamine oxidase. Based on literature precedent and preliminary data, we propose DA metabolism and trafficking as a mechanistic target for the pesticide dieldrin that can produce a build-up of reactive and toxic intermediates such as DOPAL and neuroinflammation. While the role of DA and its quinone have been explored as a mechanism for neurotoxicity, very little is known about DOPAL and the role of aldehyde metabolism. DOPAL generation is proposed as a mechanism unifying pesticide exposure, neuroinflammation and loss of catecholaminergic cells. The goal of this work is to elucidate mechanisms underlying environmental risk factors for neurodegenerative disease, specifically focusing on the interaction of the pesticide dieldrin with DArgic and glia and resulting injury to dopaminergic neurons via reactive intermediates such as DOPAL. In addition, the gene-environment interaction will be explored as dieldrin alone may be insufficient to cause loss of DA neurons. The central hypothesis is that pesticides such as dieldrin target DA metabolism and/or trafficking in neurons and glia, yielding reactive aldehyde metabolites that damage DA neurons and promote neuroinflammatory activation of glial cells. Three Aims will be completed: 1) Determine the effects of pesticide exposure on the nigro-striatal DA system in transgenic mice with altered DA metabolism. 2) Determine the contribution of glial-derived reactive DA intermediates to pesticide-mediated neuronal injury. 3) Identify cellular and molecular targets of reactive intermediates. An innovative and encompassing approach in vivo and in vitro will be used with a robust genetic strategy of mice that are deficient or have overexpression of enzymes key to DA metabolism. These Specific Aims will build upon previous work to address key mechanistic questions regarding critical cellular interactions between astrocytes and neurons that potentiate dysfunction caused by exposure to pesticides.