PrincipalInvestigator/Program Director (Last, First, Middle): Thiruchelvam, Mona J. ABSTRACT The Parkinson's disease (PD) phenotype is a complex disease trait resulting from the interaction of an unknown number of risk factors including genetic background, life-long environmental exposures, diet, life- style, and aging. Increasing evidence implicates environmental risk factors as contributory to the etiology of the PDP, a disorder resulting from the death of nigrostriatal dopaminergic (DA) neurons. Although typically onset is later in life, it has been suggested that insults incurred developmentally could underlie PD. Data from our laboratory now supports this assertion, implicating a role for developmental neurotoxicant exposure in the induction of neurodegenerative disorders such as PD. PD is a progressive neurodegenerative disorder that is characterized by loss of the nigrostriatal dopaminergic system. Thus, an ideal animal of PD should recapitulate this essential characteristic of the disease phenotype. Our model actually provides compelling support for such a possibility. Combined exposure from postnatal day (PND) 7-19 to the pesticides paraquat(PQ) + maneb (MB) produces permanent and selective nigrostriatal DA neurotoxicity, and markedly enhances vulnerability to subsequent pesticide exposures later in adulthood, with strikingly greater losses of nigrostriatal DA neurons than occurs in response to postnatal or adult only exposures. More recent findings suggest that the model produces a significant progressive loss of nigral DA neurons, striatal DA and locomotor activity as currently evaluated over the period from 2 to 22 months of age following postnatal exposure to PQ+MB. Additionally, the progressive decline in DA function is only gender specific, with males more affected than females. Our preliminary data indicate that this progressive decline in DA function may be attributed to sustained elevation of oxidative stress and proteasomal dysfunction, both implicated in the pathogenesis of PD. Although a developmental basis for PD has been proposed, it remains largely unexplored and thus is the focus of this proposal. Specific Aim One will fully characterize the progressive degeneration of the DA system in this model, as it pertains to aging by evaluating various symptoms seen in humans with PD. To be able to be predictive of the human condition, an animal model needs to recapitulate as many symptoms seen in humans as possible. Specific Aim Two will address the mechanism(s) of neurotoxicity associated with either compound alone or in combination in both male and female mice, in particular focusing on dopamine maintenance and survival factors, oxidative stress and proteasomal function. Specific Aim Three will examine the hypotheses that females are protected against the neurotoxicity of PQ and MB due to the ability of estrogen to prevent or decrease oxidative stress induced by these toxicants and there by provent dopaminergic cell death. The experiments proposed here will further validate this developmental PQ+MB model as a novel progressive degeneration model of PD. These experiments will greatly enhance our understanding of how nigrostriatal DA damage occurring developmentally can result in the PD phenotype and its progressive nature. Progressive models offer especially significant opportunities for exploring neuroprotective and therapeutic approaches to PD. Additionally, markers of early dysfunction may emerge from the host of endpoints proposed to be examined in this proposal. Thus, if early markers of dopaminergic dysfunction can be identified, it will could lead to the identification of potential biomarkers of the disease in addition to neuroprotective strategies. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page PrincipalInvestigator/Program Director (Last, First, Middle): Thiruchelvam, Mona J. PROJECT NARRATIVE Sporadic Parkinson's disease (PD) is an aging neurodegenerative disorder that typically onsets after the 5th decade of life. It results from progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta and a corresponding decrease in striatal dopamine (DA) levels and accompanied by the presence of Lewy neurites and Lewy bodies. Although PD is an aging disorder, the timing of the insult(s) that lead to the disease remains unknown. Despite previous suggestions about a developmental basis, the consequences of developmental exposures to neurotoxicants targeting the nigrostriatal DA system remain a relatively unexplored hypothesis. This proposal seeks to characterize the progressive nature of what appears to be a novel developmental model of the disease, and to examine the pathological and neurochemical hallmarks of PD associated with the progressive decline in dopaminergic function. Given that PD is a progressive neurodegenerative disorder, it is essential to have an animal model that mimics this phenomenon. Developmental exposure to PQ+MB results in progression of both behavior and DA dysfunction with age and an increase in vulnerability to subsequent insults. A model that can produce a progressive decline in dopaminergic dysfunction would be critical for establishing neuroprotective strategies. These experiments will greatly enhance our understanding of how nigrostriatal DA damage occurring developmentally can modulate the PD phenotype, and provide a progressive animal model that can be used for exploring potential neuroprotective and therapeutic approaches for PD. These studies will also enhance our understanding of the mechanisms of gender-related differences in the incidence of PD. Moreover, these findings will have implications for the derivation of biomarkers and therapeutic strategies for PD. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page