Project 3: Mapping Proteome-Wide Reactivity of Superfund Chemicals Using Chemoproteomic Platforms

项目3：摘要/摘要 超级基金网站上的许多危险化学品都与有害的健康影响有关，但他们的 毒理学机制仍然知之甚少。 该项目将应用创新的分析技术 剖析和简化与分析相关毒理学机制相关的复杂性 暴露在化学混合物和Exposome中。我们开发了一种化学蛋白质组学技术 称为基于反应性的蛋白质图谱(RBPP)，它使得能够绘制 在复杂的生物系统中以蛋白质为靶标的反应性SRP化学品。这是一部新奇而又非常 创新技术，能够全面评估化学品与特定物质的相互作用 直接在复杂的哺乳动物生理中的分子靶标，进而告知下游的类型 可能因接触化学品而产生的生化和病理影响。这项技术和 使用它所揭示的信息将极大地扩展我们的知识：1)新的毒理学机制 单独的SRP化学物质；2)可能成为多个SRP化学物质靶标的公共途径；以及3) 暴露在化学混合物和其他因素中可能产生的毒理学机制 曝光体。我们假设，解剖出化学物质和测绘的个别目标 针对多种化学物质的共同途径将使我们能够识别特定的 与接触复杂的化学混合物有关的重要毒理学机制。我们一直在 使用RBPP来描述许多广泛使用的令人关注的环境化学品的直接蛋白质靶标。我们有 发现参与脂肪酸降解、新陈代谢和类固醇生成的几个蛋白质靶点是 直接和通常被数量惊人的活性环境化学品所抑制。这些 共同的靶向通路可能会导致不良的健康影响，因为抑制脂肪燃烧将 导致脂肪在组织中积聚，抑制类固醇激素的降解会导致脂肪在组织中积聚 这两种激素，如睾酮和皮质醇，都可能具有促进行为和肿瘤的作用。我们 假设累积接触这些反应性SRP化学物质和抑制蛋白质靶标 参与脂肪和类固醇代谢将直接影响小鼠和人类体内的脂类和类固醇水平。 我们建议应用创新的分析平台来绘制反应性SRP的蛋白质组靶标 揭示新的毒理学机制的化学品，重点是了解 暴露在SRP化学混合物中可能会协同作用影响脂肪和类固醇代谢。这个项目 将直接解决问题1、3和4，解决以下问题：1)混合物，2)复杂性 通过独特和重叠的机制运作的化学品，以及3)确定与以下方面相关的风险 通过使用我们创新的RBPP方法简化我们的 了解化学混合物潜在的毒理学机制。

PROJECT 3: SUMMARY/ABSTRACT Many hazardous chemicals at Superfund sites have been linked to adverse health effects, but their toxicological mechanisms remain poorly understood. This project will apply innovative analytical technologies to dissect and simplify the complexities associated with analyzing the toxicological mechanisms associated with exposure to chemical mixtures and the Exposome. We have developed a chemical proteomic technology termed reactivity-based protein profiling (RBPP) that enables the mapping of direct interactions of reactive SRP chemicals with protein targets in complex biological systems. This is a novel and very innovative technology that enables a comprehensive assessment of how chemicals interact with specific molecular targets directly in complex mammalian physiology, which in-turn informs the types of downstream biochemical and pathological effects that may result from chemical exposure. This technology and the information revealed from using it will vastly expand our knowledge of: 1) novel toxicological mechanisms of individual SRP chemicals; 2) common pathways that may be targeted by multiple SRP chemicals; and 3) toxicological mechanisms that may arise from exposure to chemical mixtures and other factors in the Exposome. We hypothesize that dissecting out the individual targets of chemicals and mapping common pathways that are targeted across multiple chemicals will enable us to identify particularly important toxicological mechanisms associated exposure to complex chemical mixtures. We have been using RBPP to profile direct protein targets of many widely used environmental chemicals of concern. We have found that several protein targets involved in fatty acid degradation, metabolism, and steroidogenesis are directly and commonly inhibited by a strikingly large number of reactive environmental chemicals. These commonly targeted pathways are likely to result in adverse health effects since inhibiting the burning of fat will lead to accumulation of fat in tissues and inhibiting steroid hormone degradation will lead to accumulation in both hormones like testosterone and cortisol which may have behavioral and tumor promoting effects. We hypothesize that cumulative exposure to these reactive SRP chemicals and the inhibition of protein targets involved in fat and steroid metabolism will directly impact lipid and steroid levels in vivo in mice and humans. We propose to apply innovative analytical platforms to map proteome-wide targets of reactive SRP chemicals to reveal novel toxicological mechanisms with a particular focus on understanding how exposure to SRP chemical mixtures may synergize to impact fat and steroid metabolism. This project will directly address Problems 1, 3, and 4 on addressing the problem of: 1) mixtures, 2) complexities of chemicals operating through unique and overlapping mechanisms, and 3) identifying risks associated with chemical exposure in vulnerable populations, through using our innovative RBPP methods to simplify our understanding of toxicological mechanisms underlying chemical mixtures.