Endotoxin Exposure and Risk of Parkinsonism

描述（由首席研究员提供）：帕金森病（PS）是一种使人衰弱的神经退行性疾病，影响着全世界数百万人。原发性（特发性）PS的病因在很大程度上是未知的，尽管有越来越多的实验和流行病学证据表明环境毒物在病因学中起重要作用。内毒素（脂多糖）是革兰氏阴性菌细胞壁外膜的一种成分，当细菌裂解时释放。人类暴露于内毒素在许多环境中都会发生，特别是在棉纺织制造业中发现的内毒素水平很高，这是本研究的重点。值得注意的是，内毒素已被建立为诱导多巴胺能神经元在体内和体外选择性死亡的模型实验剂。尽管有令人信服的实验支持内毒素在PS中可能的致病作用，但以前没有流行病学研究明确测试这种关联。因此，我们建议在中国上海的纺织女工中进行一项流行病学研究，我们之前已经研究了癌症危险因素。我们之前的研究已经产生了内毒素累积剂量的定量估计。我们将对600名曾在棉纺织工厂工作并暴露于内毒素的退休妇女和300名从未在棉纺织工厂工作或从事潜在内毒素暴露工作的退休纺织女工进行标准化的神经学检查，以确定帕金森病主要症状和症状的患病率和严重程度。我们还将对项目第1年和第2年发现的PS病例进行为期3年的临床随访，以确定疾病进展。我们的分析将产生内毒素暴露与PS风险、严重程度和进展关系的定量剂量反应趋势，并根据年龄、吸烟、生育史和其他职业暴露的潜在混淆因素进行调整。这个项目的发现有很大的希望进一步阐明神经炎症在人类帕金森病发病机制中的作用，这将最终对预防这种疾病很重要。本研究旨在对上海市纺织女工临床帕金森病（PS）发病风险、严重程度及进展与职业性内毒素暴露的关系进行流行病学研究。内毒素是一种广泛存在的环境暴露，已被证明可诱发动物多发性硬化。因此，研究结果可能具有重要的疾病预防意义。公共卫生相关性：这项新应用旨在对上海纺织女工帕金森病（PS）的风险、严重程度和进展进行流行病学研究。要测试的主要假设是，棉尘中的内毒素暴露是患PS的一个危险因素。该研究将对600名接触棉尘的工人和300名从未接触过棉尘的纺织工人进行比较。

DESCRIPTION (provided by principal investigator): Parkinsonism (PS) is a debilitating neurodegenerative disorder that affects millions of people worldwide. The causes of primary (idiopathic) PS are largely unknown, although there is growing experimental and epidemiologic evidence that environmental toxicants play important etiologic roles. Endotoxin (lipopolysaccharide) is a component of the outer membranes of Gram-negative bacteria cell walls that is released when bacteria lyse. Human exposure to endotoxin occurs in numerous environmental settings, with especially high levels found in cotton textile manufacturing, which is the focus of this proposed research. It is noteworthy that endotoxin has been established as a model experimental agent that induces selective death of dopaminergic neurons in vitro and in vivo. Despite convincing experimental support for a plausible pathogenic role of endotoxin in PS, there have been no previous epidemiologic studies that have explicitly tested this association. Accordingly, we are proposing to conduct an epidemiological study of PS among a well- characterized cohort of women textile workers in Shanghai, China that we have studied previously for cancer risk factors. Our previous research has generated quantitative estimates of cumulative doses of endotoxin. We will conduct standardized neurological examinations to determine the prevalence and severity of the cardinal signs and symptoms of parkinsonism among 600 retired women previously employed in cotton textile factories who were exposed to endotoxin and an age-matched non-exposed group composed of 300 retired women textile workers who had never worked in cotton factories or in jobs with potential endotoxin exposure. We will also perform a 3-year clinical follow-up among PS cases identified in years 1 and 2 of the project to determine disease progression. Our analyses will generate quantitative dose-response trends for relations of endotoxin exposure with PS risk, severity, and progression that are adjusted for potential confounding by age, smoking, reproductive history, and other occupational exposures. The findings from this project have great promise to clarify further the role of neuroinflammation in the pathogenesis of human parkinsonism, which will ultimately be important for prevention of this disorder. This new application is for an epidemiological study of the risks, severity, and progression of clinical parkinsonism (PS) among women textile workers in Shanghai in relation to occupational endotoxin exposure. Endotoxin, which has been shown to induce PS in animals, is a widespread environmental exposure. Thus, the results of the research could have important disease prevention implications. PUBLIC HEALTH RELEVANCE: This new application is for an epidemiological study of the risks, severity, and progression of clinical parkinsonism (PS) among women textile workers in Shanghai. The primary hypothesis to be tested is that endotoxin exposure from cotton dust is a risk factor for PS. The study will compare 600 workers exposed to cotton dust with 300 textile workers who never worked with cotton dust.