Organochlorine-Mediated Generation of a Dopamine Derived Neurotoxin

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DESCRIPTION (provided by applicant): Exposure to environmental chemicals is a risk factor for Parkinson's Disease (PD). Specifically, pesticides used in agriculture, such as the organochlorine dieldrin, are associated with PD incidence; however, the link between exposure and disease is not known, and the underlying mechanisms remain to be determined. A potential pathway involves oxidative stress. Dieldrin, which is associated with PD incidence, has been shown to induce this injurious condition. However, it is not known how general oxidative stress, resulting from environmental exposure, can translate into specific dopaminergic toxicity. A proposed mechanism to account for this involves 3,4-dihydroxyphenylacetaldehyde (DOPAL), a dopamine (DA) derived neurotoxin. DA is metabolized to the toxic intermediate, DOPAL, which is oxidized via mitochondrial aldehyde dehydrogenase (mALDH) to 3,4-dihydroxyphenyl acetic acid (DOPAC) using the cofactor NAD. Aldehydes generated via oxidative stress, e.g., 4-hydroxynonenal (4HNE), are potent inhibitors of mALDH; therefore, cellular stress resulting from environmental agents may inhibit DOPAL metabolism yielding high levels of the DA-derived aldehyde. Furthermore, impairment of complex I, responsible for generation of mitochondrial NAD, has been observed for pesticides, and such an insult would also decrease the ability of mALDH to metabolize DOPAL. Preliminary data presented in this application demonstrate that both the oxidative stress product 4HNE and dieldrin yield inhibition of mitochondrial metabolism of DOPAL; furthermore, the DA-derived aldehyde is highly reactive toward proteins. Based on previous studies and preliminary data presented in this application, it is hypothesized that the organochlorine dieldrin inhibits cellular metabolism of DOPAL, yielding aberrant levels of this endogenous aldehyde neurotoxin and subsequent protein modification. To test the hypothesis, three specific aims will be completed. Specific Aim 1 will examine the ability of dieldrin to impair DOPAL metabolism in dopaminergic cells and elucidate the mechanism of inhibition. Specific Aim 2 will demonstrate protein adduction by the DA-derived aldehyde in cells treated with dieldrin. Specific Aim 3 will determine the extent of protein modification by DOPAL in vivo in a mouse model of chronic dieldrin dosing. The work proposed in this application is significant and innovative and will serve as a foundation for future research aimed at determining the role of environmetal exposure in PD pathogenesis.