Endotoxin Exposure and Risk of Parkinsonism

描述（由首席研究员提供）：帕金森症 (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。尽管越来越多的实验和流行病学证据表明环境毒物起着重要的病因作用，但原发性（特发性）PS 的病因在很大程度上尚不清楚。内毒素（脂多糖）是革兰氏阴性细菌细胞壁外膜的一种成分，在细菌裂解时释放。人类在许多环境环境中都会接触内毒素，其中在棉纺织品制造中发现的内毒素含量尤其高，这是本拟议研究的重点。值得注意的是，内毒素已被确立为一种模型实验剂，可在体外和体内诱导多巴胺能神经元选择性死亡。尽管有令人信服的实验支持内毒素在 PS 中的合理致病作用，但之前还没有流行病学研究明确检验过这种关联。因此，我们建议在中国上海的一组特征明确的纺织女工中进行 PS 流行病学研究，我们之前已经研究过这些女性的癌症危险因素。我们之前的研究已经对内毒素的累积剂量进行了定量估计。我们将对600名曾经在棉纺织厂工作过、接触过内毒素的退休女工和由300名从未在棉纺织厂工作或从事过可能接触内毒素的工作的退休女纺织工人组成的年龄匹配的非暴露组进行标准化的神经系统检查，以确定帕金森氏症主要体征和症状的患病率和严重程度。我们还将对项目第一年和第二年发现的 PS 病例进行为期 3 年的临床随访，以确定疾病进展。我们的分析将生成内毒素暴露与 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杂因素进行调整。该项目的研究结果有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，这最终对于预防这种疾病非常重要。这项新申请旨在对上海女纺织工人中与职业内毒素暴露相关的临床帕金森病 (PS) 的风险、严重程度和进展进行流行病学研究。内毒素是一种广泛存在的环境接触物，已被证明可在动物中诱导 PS。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女纺织工人中临床帕金森病 (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 PS 的危险因素。该研究将比较 600 名接触棉尘的工人和 300 名从未接触过棉尘的纺织工人。

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.