Submitted in response to PAR-02-105, this project will explore the fetal basis of dopaminergic (DA) neurodegeneration in idiopathic Parkinson's diseases (PD) by testing the Barker hypothesis as applied to the nigro-striatal system. Currently, the 'double hit' model for the disease progression of sporadic PD predicts that an initial early physiological insult (1st hit) produces either acute subsymptomatic cell loss, compromised physiological conditions or altered cell death gene expression that results in an augmented clinical susceptibility to a 2nd hit, such as normal aging or environmental toxin exposure. Etiological studies strongly suggest that exposure to environmental toxins including pesticides are risk factors in sporadic PD. However, the progression of sporadic PD remains quite elusive. Thus, based on DA cell death mechanistic studies including ours, we would like to test the hypothesis that prenatally-generated susceptibility during the critical window of nigro-striatal system development contributes to the disease progression later in life. In our previous studies we have already identified (i) PD-related pesticides generate cellular stresses including oxidative stress, which result in the significantly altered genes expression including functional proteins of which physiological dysfunctions have been implicated in PD, and (ii) disturbances during the embryonic nigro-striatal innervation period are harmful to the survival of DA neurons. This proposal will test the Barker hypothesis by characterizing altered gene expression profiles and augmented toxin/age-dependent susceptibility initially employing the specific PD-related pesticide, paraquat, as a model and subsequently other toxins.