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

摘要 肌萎缩侧索硬化症(ALS)是一种进行性和致死性神经退行性疾病，发病机制复杂。最近的证据支持基因-时间-环境假说，即当环境暴露叠加在遗传风险谱上时，会触发神经退化。支持这一前提的是，长期的不良环境暴露与ALS的风险和进展有关；我们已经证明，在密歇根州ALS受试者中，测量和报告的农药暴露强烈增加了ALS的风险，高水平的持久性有机污染物(POP)降低了ALS的存活率。因此，有必要描述“肌萎缩侧索硬化症暴露组”，定义为导致肌萎缩侧索硬化症风险的环境暴露的终生时间。在这项建议中，我们的目标是通过提高对与ALS相关的污染物混合物的洞察力来改进ALS暴露组模型，以考虑遗传风险，识别暴露的敏感期，将易于评估的生物液中的毒素测量与流行病学数据相关联，并识别这些环境毒素是否被吸收到中枢神经系统(CNS)，以便更好地洞察ALS的基因-时间-环境假说。我们的中心假设是，在生物液和中枢神经系统组织中识别环境污染物将推动ALS发病模型的发展。在目标1中，我们将通过测量从密歇根大学ALS患者资料库和密歇根州各地年龄和性别匹配的对照组获得的ALS受试者纵向生物样本中的环境毒素，更好地表征ALS暴露组，以洞察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，我们将评估居住史和职业史与肌萎缩侧索硬化症风险和存活率的关系，同时也将暴露史与目标1中的毒素指标相关联，以全面了解暴露的混合物和对肌萎缩侧索硬化症至关重要的时间窗口。 风险。最后，在目标3中，我们将量化ALS中的环境毒素和重金属，并控制CNS组织，并将外周变化与观察到的ALS CNS组织和关键暴露窗口的变化联系起来，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确定与职业和环境暴露相关的ALS疾病风险因素，同时考虑到遗传易感性，产生重要的积极转化影响。因此，这项建议将扩大我们在遗传风险背景下对ALS暴露组的理解，识别构成公共健康风险的毒素，识别与暴露相关的职业，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。对ALS暴露的这种理解将支持急需的公共卫生干预措施，以针对可改变的疾病风险因素 致命性障碍。

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.