| Numerous epidemiological studies have reported an association between pesticide exposure and an increased risk of developing Parkinson's disease (PD). However, to date, the specific compounds responsible for this association have yet to be identified. The goals of this dissertation were to analyze the effects of specific environmental toxicants in both in vitro and in vivo systems, and identify potential mechanisms responsible for the deleterious effects of these compounds in the nigrostriatal dopaminergic system affected in PD. Additionally, using advanced GC-MS techniques, the goal was to identify specific environmental compounds associated with PD and other neurodegenerative disease diagnoses in post-mortem human brain tissue.; Based on studies in the literature, dieldrin and DDE, the major metabolite of DDT, were chosen as potential candidates. Initial studies in vitro indicated that DDT, and its two major metabolites, DDD and DDE, were capable of disrupting dopamine handling via inhibition of the vesicular monoamine transporter (VMAT2) and the plasma membrane dopamine transporter (DAT). Dieldrin also inhibited DAT and induced intracellular oxidative stress in vitro.; Based on these data, to determine if these effects occurred in vivo studies were performed by exposing mice to dieldrin, DDT, or DDE. Dieldrin exposure led to oxidative damage specific to the nigrostriatal dopamine system, including increased evidence of oxidative damage and decreased antioxidant levels. The expression of alpha-synuclein, a key protein in Lewy bodies, was elevated only in the striatum and the striatal expression of DAT was reduced. Exposure of mice to DDE or DDT did not result in any detectable neurotoxicological outcomes including nigrostriatal dysfunction or alterations in behavior. This suggests that dieldrin, and potentially other similarly-acting compounds may contribute to the vulnerability of dopaminergic neurons and lead to an acceleration of their death. DDT and its metabolites, however, do not appear to cause neurotoxic effects in mice and are not likely to induce PD-related pathology.; In order to identify specific compounds present in the brain that correlated with PD diagnosis, post-mortem brain samples were collected from the Emory University Brain Bank and included control cases as well as those with pathologically confirmed PD, Alzheimer's disease (AD), Huntington's disease, or other tauopathies. Analysis of brain tissue revealed that concentrations of the organochlorine pesticide, endrin (a cyclodiene) were elevated in cases with PD neuropathology. Furthermore, PD cases exhibited significantly elevated levels of the summed group of cyclodiene pesticides. A combination of four DDT-like compounds did not reveal any association with any neurodegenerative disease examined.; The data presented in this thesis represent the first study to show that brain concentrations of specific pesticides are correlated to PD diagnosis in a U.S. population. The persistence of organochlorines in the environment and in the brain provides the temporal and toxicokinetic features for chronically-acting neurotoxicants. Furthermore, the deleterious effects seen in mice following dieldrin exposure provide plausible biological mechanisms by which these cyclodienes may cause nigrostriatal damage. Given the theory that PD develops over the course of decades, these persistent neurotoxicants are well-positioned to be lead candidates for the link between environmental exposure and PD. |
