Substantial evidence suggests an important role for environmental factors in the development of Parkinson's disease (PD). Specifically, numerous studies indicate that agricultural/industrial chemicals, particularly pesticides, can damage dopamine (DA) neurons of the substantia nigra pars compacta, leading to DA deficits and motor impairment. Within the present thesis, we assessed the neurodegenerative and functional effects of the herbicide, paraquat, and determined if its effects would be augmented in the presence of another environmental toxin, namely the fungicide, maneb. To this end PQ + MB did additively provoke neurodegeneration of nigrostriatal DA neurons and motor disturbances, as indicated by reduced open field exploration. Interestingly, however, these behavioral and neurological consequences were observed in mice obtained from Charles River but not identical animals from Jackson laboratories.

Given the mounting data suggesting that neuroinflammatory factors mediate neuronal loss in PD, a second component of this study assessed the potential contribution of the cytokines, interleukin-10 (EL-10) and interleukin-6 (IL-6) to paraquat induced neurodegeneration. To this end, mice genetically deficient of IL-6 were greatly resistant to the neurotoxic effects of paraquat. However, central administration of either IL-6 or EL-10 also attenuated the neurodegenerative, as well as the neuroinflammatory (as indicated by diminished microglial density), consequences of both PQ + MB. Thus, EL-6 and IL-10 administration appears to have neuroprotective effects against pesticide toxins. Yet, the fact that inhibition of the cytokine from birth (at least in the case of EL-6) was also neuroprotective, raises the possibility that protective compensatory changes might occur in the absence of the cytokine at developmentally critical times. Taken together, these data further our understanding of how the complex interplay between environmental insult exposure, early life history (e.g. place of breeding) and presence of inflammatory factors (e.g. cytokines) might shape the evolution of PD.