Project 4: Using Adductomic Signatures to Evaluate Risks of Superfund Chemicals

项目4：摘要/摘要 尽管活性亲电体是人类健康和疾病状态的重要贡献者，但这些 在暴露研究中，分子通常被忽视。例如，许多亲电体是 天生有毒和致癌，因为它们可以修饰人类的DNA和蛋白质，但活性太强，不能 用血液来衡量。调查接触反应性亲电物质的一种方法是测量 与血液蛋白质反应形成的加合物。人血清白蛋白(HSA)含有一种亲核试剂 热点(Cys34)，它是进入的活性氧和其他亲电性物质的主要清除剂 血液由吸入、摄取和新陈代谢产生。我们实验室已经研制出一种非靶向检测方法。 (‘adductomics’)用于分析HSA-Cys34加合物，并编制了一个包含100多个此类加合物的文库 在人类血液中检测到。有趣的是，一些加合物是特定暴露的(例如，苯氧化物 来自苯)，而其他更普遍地与氧化应激和代谢途径失调有关 (例如，Cys34氧化产物和循环硫醇的二硫化物)。我们假设这一组合 血液中的化学特异性和氧化应激加合物建立了加合物的模式或特征，这些加合物可以 与受试者暴露于超级基金污染物及其与环境的相互作用有关 压力源。通过对严重接触艾滋病的人群进行横断面研究，对血液中的HSA加合物进行分析 三种超级基金化学物质(苯、多环芳烃和砷)，我们建议找到它们的吸合特征。然后, 通过在存档的血清中定位这些内收特征，这项研究是由 上海国家癌症研究所中国教授，我们将调查苯暴露对患癌症风险的贡献 淋巴癌和髓系癌以及多环芳烃和砷暴露对肺癌风险的影响。 项目4将通过检查过多的 与暴露于超级基金化学品和环境应激源有关的加合物。由于项目4将 探索在癌症前瞻性研究中将内收征作为过去暴露的生物标记物的使用，它 还直接解决了问题2。项目4将向项目3提供有关蛋白质修饰的见解 和生物激活途径，到关于砷在人类中致癌机制的项目1， 单独或与心理-社会压力和肥胖相结合，以及项目2和项目5关于 活性中间体对毒性和降解的贡献。

PROJECT 4: SUMMARY/ABSTRACT Although reactive electrophiles are important contributors to states of human health and disease, these molecules are generally overlooked in exposomic investigations. For example, many electrophiles are inherently toxic and carcinogenic because they modify human DNA and proteins, but are too reactive to be measured in blood. One approach for investigating exposures to reactive electrophiles involves measurement of adducts formed from reactions with blood proteins. Human serum albumin (HSA) contains a nucleophilic hotspot (Cys34), which is the major scavenger of reactive oxygen species and other electrophiles that enter the blood from inhalation, ingestion and metabolism. Our laboratory has developed an untargeted assay (`adductomics') for profiling HSA-Cys34 adducts and has compiled a library of over a hundred such adducts detected in human blood. Interestingly, some adducts are specific to particular exposures (e.g., benzene oxide from benzene) while others relate more generally to oxidative stress and dysregulation of metabolic pathways (e.g. Cys34 oxidation products and disulfides of circulating thiols). We hypothesize that this combination of chemical-specific and oxidative-stress adducts in blood establishes patterns or `signatures' of adducts that can be related to subjects' exposures to Superfund contaminants and their interactions with environmental stressors. By profiling HSA adducts in blood from cross sectional studies of populations heavily exposed to three Superfund chemicals (benzene, PAHs & arsenic), we propose to find their adductomic signatures. Then, by targeting these adductomic signatures in archived serum from a large cohort study being conducted by the National Cancer Institute in Shanghai, China, we will investigate contributions of benzene exposure on risks of lymphoid and myeloid cancers and of PAH and arsenic exposures on risks of lung cancer. Project 4 will directly address Problems 3 & 4 on mixtures/complexity by examining a plethora of adducts associated with exposures to Superfund chemicals and environmental stressors. Since Project 4 will explore the use of adductomic signatures as biomarkers of past exposure in prospective studies of cancers, it also directly addresses Problem 2. Project 4 will provide insights to Project 3 regarding protein modifications and bioactivation pathways, to Project 1 regarding mechanisms by which arsenic causes cancer in humans, either alone or in conjunction with psycho-social stress and obesity, and to Projects 2 and 5 regarding contributions of reactive intermediates to toxicity and degradation.