Aberrant Dopamine Homeostasis as a Focal Point in the Mechanism of Environmental Contaminant-Induced Dopaminergic Dysfunction

Abstract

Exposure to several environmental contaminants, including pesticides and herbicides, has been implicated as a significant risk factor for Parkinson’s Disease (PD); however, the adverse outcome pathways linking cellular interaction of such toxic compounds with adverse outcomes (e.g., PD) are lacking. In addition, there is no clear and consistent toxicophore relating the pesticide or herbicide structure with the proposed activity, raising questions about a common mechanistic target. Recent work has shown that interference with DA homeostasis is a shared toxic property of many environmental agents linked to neurodegenerative disease. Numerous studies have demonstrated the critical importance for proper dopamine (DA) signaling, metabolism, and trafficking for the health of catecholaminergic neurons, which has implications for neurodevelopment and later neurodegenerative disease (i.e., PD). Interference with DA homeostasis produces elevated levels of reactive oxygen species, and endogenous, toxic DA-related products, specifically, the DA-quinone and the monoamine oxidase metabolite, 3,4-dihydroxyphenylacetaldehyde (DOPAL). These reactive DA-related species modify proteins, inhibit cellular function and disturb proteostasis, thereby, compromising the health of DA neurons and potentially glial cells. Mitigating the production of toxic DA-metabolites is predicted to subvert initiating and/or key events related to adverse outcomes, such as neuro- degenerative or developmental disease. In addition, accurate and sensitive means to measure downstream products of reactive DA metabolites (e.g., protein adducts or DOPAL-conjugates) could reveal novel biomarkers of impaired dopamine homeostasis and pathogenic mechanisms indicative of later disease.KeywordsPolychlorinated biphenylsDieldrinParkinson's diseaseDopaminePyrethroidsOrganophosphatesPesticidesHerbicidesInsecticides3,4,dihydroxyphenylacetaldehyde