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by Brian K. Barlow B.S./B.A., 2002 University of Rochester Thesis Advisor: Mona Thiruchelvam, PhD Graduate Program of Neuroscience Robert Wood Johnson Medical School Research Tower Room V-10 Piscataway, NJ Friday, April 9, 2010 9:00 am Abstract The Fetal Basis of Adult Disease (FeBAD) hypothesis suggests that adverse events in early life can cause a vulnerability to later development of chronic disease. Support for this hypothesis has derived from metabolic and endocrine disorders, cardiovascular disease, cancer, and recently, mental health and neurodegenerative conditions. Idiopathic Parkinson’s disease (PD) is a neurodegenerative disorder that is thought to begin years or even decades before the late-in-life onset of clinically-characteristic motor disturbances. Motor symptoms result from the loss of dopamine and dopaminergic neurons within the nigrostriatal system. Exposure to pesticides has consistently been reported as a risk factor for PD in human populations. Two such widely-used pesticides are the herbicide paraquat and the fungicide maneb, and animal models incorporating exposure to these agents reproduce features of PD. In a “multiple hit” mouse model, the current work hypothesized that prenatal exposure to maneb would alter neurodevelopment and result in enhanced vulnerability to degeneration, and that risk for the PD phenotype would be increased upon subsequent adulthood paraquat exposure. Specific aims provide evidence of: 1) a sensitive neurodevelopmental window for exposure; 2) fetal exposure to maneb following maternal systemic exposure; 3) specificity of effects of maneb and other structurally similar fungicides; 4) modification of neurotoxic effects by gender; and 5) enhanced nigrostriatal dopamine system disruption with prenatal + adulthood exposures. Ultimately, with a cohort-design study, we describe a gender-specific, late-onset, persistent motor phenotype implicating prenatal maneb + adulthood paraquat exposures in nigrostriatal system degeneration. These aims successfully address several key criteria for the FeBAD hypothesis, including environmentally-based disruption, sensitive timing of exposure, agent specificity, and phenotypically normal offspring that harbor a latent vulnerability for the disease state. Further, the multiple hit exposure paradigm reproduces important features of PD, including late-onset motor disturbances, nigrostriatal dopamine system damage, and increased severity in males. Together, in an experimental model of PD, this work presents compelling evidence for studying the FeBAD hypothesis in relation to progressive neurodegenerative disease. |
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