Gene-Environment Interactions in Neurodegenerative Disease

项目总结/文摘

Project Summary/Abstract In conjunction with the Mission Statement of the National Institute of Environmental Health Sciences (NIEHS), the long-term goal of this research is to determine whether toxicity associated with the widely-used class of fungicides containing Mn/Zn-ethylene-bis-dithiocarbamate (Mn/Zn-EBDC) is exacerbated in people with mutations associated with genes responsible for cellular antioxidant defense systems and mitochondrial homeostasis. Increased amounts of reactive oxygen species (ROS) and mitochondrial inhibition are implicated in many neurodegenerative diseases. Additionally, epidemiology studies indicate that occupational pesticide exposure increases a person’s risk for many diseases associated with the brain, although exposure alone is often insufficient to cause the disease phenotype. On the other hand, specific gene mutations play a role in the etiology of about 20% of the neurodegenerative cases (Parkinson’s disease, Alzheimer’s disease, etc.). Thus, it is likely that the vast majority of patients suffering from these devastating diseases had a genetic background that resulted in a greater vulnerability to a toxic insult (gene-environment interaction). Therefore, the overarching hypothesis of this application is that multiple, low-dose exposures to Mn/Zn-EBDC-containing fungicides, such as mancozeb, may lead to increased neurodegeneration in populations with mutations in LRRK2 (an antioxidant defense system gene), parkin, or PIKN1 (both of which are associated with mitochondrial mitophagy or homeostasis). In order to address our hypothesis, two specific aims will guide the research. The first aim will determine if multiple exposures of Caenorhabditis elegans (C. elegans) to various pesticide concentrations used for fungal control leads to neurodegeneration similar to that observed in single exposure studies published by this lab. The second aim will assess whether exposure to a Mn/Zn-EBDC fungicide leads to greater toxicity in organisms with modified genetic backgrounds. These studies will be completed by treating various strains of C. elegans with environmentally-relevant concentrations of mancozeb. The goal is to characterize the potential increases in lethality, neuronal degeneration, oxidative stress, and mitophagy. These studies are timely and highly relevant to the goals of the NIEHS because they address the potential neurotoxicity of high-use pesticides to which members of the public are routinely exposed (Strategic Plan Theme 2), the interaction of agrochemicals with genes or proteins known to be involved in neurodegneration (Strategic Plan Themes 2 & 3), and to provide education and training to the next generation of scientists and science professionals (Strategic Plan Theme 5).