Epidemiological evidence suggests that pesticides and other environmental exposures may have a role in the etiology of idiopathic Parkinson's disease (PD). However, there is little human data on risk associated with specific pesticide products, including organic pesticides such as rotenone with PD. Using a case-control design, this study examined self-reports of exposure to pesticide products, organic pesticides such as rotenone, and other occupational and environmental exposures on the risk of PD in an East Texas population. The findings demonstrated significantly increased risk of PD with use of organic pesticides such as rotenone in the past year in gardening (OR = 10.9; 95% CI = 2.5-48.0) and any rotenone use in the past (OR = 10.0; 95% CI = 2.9-34.3). Use of chlorpyrifos products (OR = 2.0; 95% CI = 1.02-3.8), past work in an electronics plant (OR = 5.1; 95% CI = 1.1-23.6), and exposure to fluorides (OR = 3.3; 95% CI = 1.03-10.3) were also associated with significantly increased risk. A trend of increased PD risk was observed with work history in paper/lumber mill (OR = 6.35; 95% CI = 0.7-51.8), exposure to cadmium (OR = 5.3; 95% CI = 0.6-44.9), exposure to paraquat (OR = 3.5; 95% CI = 0.4-31.6), and insecticide applications to farm animals/animal areas and agricultural processes (OR = 4.4; 95% CI = 0.5-38.1). Cigarette smoking, alcohol use, and fish intake were associated with reduced risk. In summary, this study demonstrates an increased risk of PD associated with organic pesticides such as rotenone and certain other pesticides and environmental exposures in this population.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. The pathogenesis of interstitial lung diseases, including its most common form, IPF, remains poorly understood. Alveolar epithelial cell (AEC) apoptosis, proliferation, and accumulation of myofibroblasts and extracellular matrix deposition results in progressive loss of lung function in IPF. We found induction of tumor suppressor protein, p53, and apoptosis with suppression of urokinase-type plasminogen activator (uPA) and the uPA receptor in AECs from the lungs of IPF patients, and in mice with bleomycin, cigarette smoke, silica, or sepsis-induced lung injury. Treatment with the caveolin-1 scaffolding domain peptide (CSP) reversed these effects. Consistent with induction of p53, AECs from IPF lungs or mice with diverse types of lung injuries showed increased p53 acetylation and miR-34a expression with reduction in Sirt1. This was significantly reduced after treatment of wild-type mice with CSP, and uPA-deficient mice were unresponsive. Bleomycin failed to induce miR-34a in p53- or plasminogen activator inhibitor-1 (PAI-1)-deficient mice. CSP-mediated inhibition of miR-34a restored Sirt1, suppressed p53 acetylation and apoptosis in injured AECs, and prevented pulmonary fibrosis (PF). AEC-specific suppression of miR-34a inhibited bleomycin-induced p53, PAI-1, and apoptosis and prevented PF, whereas overexpression of precursor-miR-34a increased p53, PAI-1, and apoptosis in AECs of mice unexposed to bleomycin. Our study validates p53-miR-34a feedback as a potential therapeutic target in PF.

The data presented argue that asbestos fibers of all lengths induce pathological responses and that caution should be exerted when attempting to exclude any population of inhaled fibers, based on their length, from being contributors to the potential for development of asbestos-related diseases.

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