Endotoxin Exposure and Risk of Parkinsonism

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DESCRIPTION (provided by applicant): This application is to establish a Virtual Consortium for Translational/Transdisciplinary Research (ViCTER) of three research groups engaged in epidemiological, translational and basic science research into environmental causes of parkinsonism (PS), including Parkinson disease (PD). The Consortium's efforts will expand an ongoing epidemiological study of PS among women textile workers in Shanghai exposed to endotoxin (lipopolysaccharide [LPS]). LPS is a widespread environmental inflammagen and very potent experimental inducer of nigrostriatal cell injury and death. In fact, a convincing experimental rodent model of LPS-induced PS recapitulates the pathological features and motor effects seen in humans. Neuroinflammation via indirect microglial activation by pro-inflammatory mediators is the presumed major pathogenesis mechanism of LPS- induced PS. Gram-negative bacteria is the source of LPS, and substantial LPS exposures in the study cohort derive from cotton handling and processing. The investigators have previously quantified LPS exposures among cohort members for ongoing studies of PS and cancer. The aims of the parent project (R01E5017462), directed by Dr. Checkoway, are to estimate dose-response relations of quantified occupational LPS exposures with risk, severity, and progression of clinically validated PS. The new components of the project will be incorporation of peripheral protein and genetic biomarkers that may serve as indicators of risk, further characterization of the LPS mechanistic pathway, and identification of genetic susceptibility factors relevant to the LPS-PS pathway. The aims of this application are to: 1) characterize plasma and saliva biomarkers pertinent to neuroinflammation and oxidative/nitrosative (redox) stress, including cytokines/chemokines, complement 3 (C3), factor H (FH), 1-synuclein, DJ-1 (PARK7), protein disulfide isomerase (PDI), PTEN induced putative kinase 1 (PINK1), ubiquitin carboxyl-terminal esterase L1 (UCHL1), and parkin (PARK2), and to relate those with PS, and seek to identify additional biomarkers of PS; 2) identify S-nitrosylated plasma adducts on these and other proteins involved in nigrostriatal cell injury and death via inflammation, oxidative stress, and accelerated apoptosis; 3) perform targeted genotyping related to LPS uptake and toxicity and these same PS pathogenesis pathways (neuroinflammation, oxidative stress, and apoptosis) and protein S-nitrosylation or further oxidation. Ultimately, this research has excellent potential to elucidate further PS mechanisms potentially attributable to a well-defined common environmental toxicant. Identification of PS biomarkers offers good promise for disease prevention and early detection, which have clear translational implications. Moreover, development of a consortium among the three research groups should lay the groundwork for future transdisciplinary research into environmental causes of PS and other neurodegenerative disorders. PUBLIC HEALTH RELEVANCE: Endotoxin/LPS is a highly plausible cause of human PS, based on accepted animal models. By incorporating biomarker and genotyping components into the parent epidemiological study of PS in Shanghai textile workers exposed to LPS, the investigators will have an excellent opportunity to elucidate further pathogenesis mechanisms and potentially identify high risk persons. Successful completion of this research would have substantial implications for prevention of this relatively common, but highly debilitating condition.