Mapping the ALS Exposome to Gain New Insights into Disease Risk and Pathogenesis

摘要 肌萎缩侧索硬化症（amyotrophiclateralsclerosis，ALS）是一种进行性、致死性神经退行性疾病，其发病机制尚不清楚.最近的证据支持基因-时间-环境假说，即环境暴露叠加在遗传风险特征上时会引发神经退行性变。支持这一前提，长期不利的环境暴露与ALS风险和进展有关;我们已经表明，测量和报告的农药暴露强烈增加ALS风险，高水平的持久性有机污染物（POP）降低了密歇根州ALS受试者的ALS生存率。因此，有必要描述“ALS危险组”，定义为导致ALS风险的环境暴露的寿命。在这项提案中，我们的目标是通过提高对与ALS遗传风险相关的污染物混合物的洞察力，确定暴露的敏感期，将易于评估的生物流体中的毒素测量与流行病学数据相关联，并确定这些环境毒素是否被吸收到中枢神经系统（CNS）中，以提高对基因-时间-ALS的环境假说我们的中心假设是，识别生物流体和中枢神经系统组织中的环境污染物将推进ALS发病机制的模型。在目标1中，我们将通过测量从密歇根大学ALS患者库和密歇根州年龄和性别匹配对照的ALS受试者中纵向获得的生物样本中的环境毒素来更好地表征ALS疾病组，以深入了解有助于疾病风险和生存的污染物混合物，通过多基因风险评分解释遗传易感性。在目标2中，我们将评估居住和职业史与ALS风险和生存率的相关性，同时还将暴露史与目标1中的毒素措施相关联，以全面了解ALS关键的暴露混合物和时间窗 风险最后，在目标3中，我们将定量ALS和对照CNS组织中的环境毒素和重金属，并将外周改变与ALS CNS组织和关键暴露窗口中观察到的变化联系起来，从而确定可能导致ALS发病的环境风险因素。总体而言，成功完成这些目标将通过识别与职业和环境暴露相关的ALS疾病风险因素，同时考虑遗传易感性，产生重要的积极转化影响。因此，这项提案将扩大我们对ALS基因组遗传风险的理解，确定构成公共卫生风险的毒素，确定与暴露有关的职业，并建立一个框架来测试其他神经退行性疾病中的这些暴露。这种对ALS疾病组的理解将支持急需的公共卫生干预措施，以针对这一领域中可改变的疾病风险因素。 致命的紊乱

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease with complex unknown pathogenesis. Recent evidence supports a gene-time-environment hypothesis whereby environmental exposures trigger neurodegeneration when superimposed on a genetic risk profile. Supporting this premise, long-term adverse environmental exposures are linked to ALS risk and progression; we have shown that measured and reported pesticide exposures strongly increase ALS risk and that high levels of persistent organic pollutants (POPs) decrease ALS survival in ALS subjects in Michigan. Therefore, there is a need to delineate the “ALS exposome,” defined as the lifetime of environmental exposures that contributes to ALS risk. In this proposal, our objectives are to improve our ALS exposome model by enhancing insight into pollutant mixtures associated with ALS accounting for genetic risk, identifying periods of susceptibility to exposures, correlating toxin measurements in easily assessable biofluids with epidemiologic data, and identifying whether these environmental toxins are absorbed into the central nervous system (CNS) in order to improve insight into the gene-time-environment hypothesis in ALS. Our central hypothesis is that identifying environmental pollutants in biofluids and CNS tissues will advance models of ALS pathogenesis. In Aim 1, we will better characterize the ALS exposome by measuring environmental toxins in biological samples obtained longitudinally from ALS subjects from the University of Michigan ALS Patient Repository and age- and sex-matched controls across the State of Michigan to yield insight into the pollutant mixtures that contribute to disease risk and survival, accounting for genetic susceptibility via polygenic risk scores. In Aim 2, we will evaluate residential and occupational histories for association with ALS risk and survival, while also correlating exposure histories to toxin measures from Aim 1, to gain comprehensive insight into exposure mixtures and time windows critical for ALS risk. Finally, in Aim 3, we will quantitate environmental toxins and heavy metals in ALS and control CNS tissues, and link peripheral alterations with observed changes in ALS CNS tissue and critical exposure windows to thereby ascertain environmental risk factors that potentially contribute to ALS pathogenesis. Overall, successful completion of these aims will have an important positive translational impact by identifying ALS disease risk factors associated with occupational and environmental exposures, while accounting for genetic susceptibility. This proposal will therefore expand our understanding of the ALS exposome in the context of genetic risk, identify toxins that pose a public health risk, identify occupations linked to exposures, and establish a framework to test for these exposures in other neurodegenerative diseases. This understanding of the ALS exposome will support much-needed public health interventions to target modifiable disease risk factors in this lethal disorder.