Project 4: Measurement and Engineering Solutions to Detect and Prevent N-Nitrosamine Exposure

项目 4：检测和防止 N-亚硝胺暴露的测量和工程解决方案

• 批准号: 10351935
• 负责人: Desiree Plata
• 金额: $ 24.96万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10351935
• 关键词: Address; Air; Biological; Biological Assay; Bioreactors; Biotechnology; Cancer Etiology; Carbon; Carbon Nanotubes; Carcinogens; Cells; Chemicals; Chromatography; Collaborations; Collection; Complex Mixtures; DNA Damage; Data; Data Analyses; Detection; Development; Devices; Dimensions; Disease; Disinfection; Encapsulated; Engineering; Ensure; Environment; Environment and Public Health; Environmental Exposure; Enzymes; Equilibrium; Exposure to; Family; Filtration; Flame Ionization; Food; Gas Chromatography; Genetic Engineering; Genetically Engineered Mouse; Goals; Hazardous Chemicals; Hazardous Substances; Health; Home; Human; In Situ; Ion Exchange; Knowledge; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Measures; Methods; Microbe; Mission; Modeling; Molecular; Municipalities; Mutagens; Nanotechnology; Nitrosamines; Nitroso Compounds; Octanols; Performance; Persons; Pharmaceutical Preparations; Phase; Plant Resins; Polymers; Prevention; Process; Property; Public Health; Research; Research Support; Risk; Safety; Solid; Source; Structure; Superfund; System; Techniques; Technology; Testing; Training; Translational Research; Tribes; United States Environmental Protection Agency; Water; Work; analytical method; base; community engagement; contaminated water; data management; detector; drinking water; experience; exposed human population; genotoxicity; improved; iterative design; molecular recognition; new technology; novel; novel strategies; prevent; programs; remediation; safety testing; scaffold; sensor; superfund chemical; superfund site; therapy design; toxicant; treatment strategy; water sampling; water treatment

PROJECT SUMMARY/ABSTRACT – PROJECT 4 N-nitroso (-N-N=O) compounds include some of the most powerful chemical mutagens known and encompass a family of chemicals with hundreds of different structures. However, only a handful of N-nitrosamines are routinely measured via EPA Standard Methods, and these methods are not effective at the low levels anticipated to cause health impacts. To overcome this challenge and reduce human exposure, Project 4 seeks to measure and destroy a suite of N-nitrosamines at the point of use in homes, where they are needed most to protect public health and the environment. First, Specific Aim 1 is to develop methods to detect a suite of established and novel N-nitrosamines using multi-dimensional gas chromatography paired with both mass spectrometry (for identification) and flame ionization detection (for quantification with authentic standards or via an effective carbon number concept when authentic standards can be neither synthesized nor purchased). This technique enables estimation of nearly a dozen critical environmental parameters, such that novel molecules detected in complex mixtures will have at-the-ready physicochemical metrics to feed environmental fate models and predict exposure. Water samples will be collected in collaboration with the Community Engagement Core using traditional collection methods as well as novel Recognition-Solid Phase Extraction (R-SPEs) materials that concentrate N- nitrosamines (to be developed in Project 3), and fractions of extracts will be provided to Project 2 for mutagenicity assessment. Knowledge about the levels of NDMA will inform Project 1 so that environmentally relevant levels can be studied for their biological impacts using novel genetically engineered mice that are sensitized to NDMA. In addition, the Data Management and Analysis Core will integrate data for “what” and “how much” with data on biological impact to inform risk. Armed with knowledge of environmental levels of N-nitrosamines, Specific Aim 2 is to develop novel in-home water filtration technologies based on electrochemical processes and molecular recognition with enzymatic destruction. The latter relies on genetically engineered microbes that act as non-living scaffolds for enzymes; as such, it overcomes many classical challenges faced by bioreactors and opens up vast possibilities to leverage advances in biotechnology for long-awaited revolutions in water treatment. Specific Aim 3 will test the degradation products to ensure that they are no longer genotoxic by collaborating with Project 1 to use “Chem-Sense” cells that act as animate detectors of DNA damage. Trainees will drive the research and will be supported by the Research Experience and Training Coordination Core to ensure optimal professional development. In addition, Project 4 will benefit from activities organized by the Administrative Core that ensure close collaborations with other Projects and with the Cores, as well as opportunities for research translation to stakeholders, including people living near the Olin Chemical Superfund Site and the Passamaquoddy Tribe. Via a Systems Approach of interactions and interdependencies, Project 4 will contribute to the protection of human health from hazardous substances.

项目总结/摘要-项目4 N-亚硝基（-N-N=O）化合物包括一些已知的最强大的化学诱变剂， 一系列化学物质有数百种不同的结构然而，只有少数N-亚硝胺是 通过EPA标准方法进行常规测量，这些方法在预期的低水平下无效 造成健康影响。为了克服这一挑战并减少人类接触，项目4寻求测量 并在家庭使用点销毁一套N-亚硝胺，在那里他们最需要保护公众 健康和环境。首先，具体目标1是开发方法来检测一套既定的和 新的N-亚硝胺使用多维气相色谱法与两个质谱法配对（用于 鉴定）和火焰离子化检测（用于用真实标准品或通过有效碳 数字概念，当真实标准品既不能合成也不能购买时）。该技术使得能够 估计了近12个关键的环境参数，这样，在复杂的环境中检测到的新分子， 混合物将具有现成的物理化学指标，可用于环境转归模型和预测接触。 水样将与社区参与核心合作，使用传统的 收集方法以及新型的浓缩N- 亚硝胺（将在项目3中开发）和提取物馏分将提供给项目2进行致突变性研究 考核关于NDMA水平的知识将为项目1提供信息， 可以使用对NDMA致敏的新型基因工程小鼠研究其生物学影响。 此外，数据管理和分析核心将整合“什么”和“多少”的数据， 生物影响，以告知风险。掌握了N-亚硝胺的环境水平知识， 2是开发基于电化学过程的新型家庭水过滤技术， 分子识别和酶促破坏。后者依赖于基因工程微生物， 作为酶的非生命支架;因此，它克服了生物反应器面临的许多经典挑战 并为利用生物技术的进步实现期待已久的水革命开辟了巨大的可能性 治疗具体目标3将检测降解产物，以确保其不再具有遗传毒性 通过与项目1合作，使用“化学传感”细胞作为DNA损伤的活体检测器。 学员将推动研究，并将得到研究经验和培训协调的支持 核心，以确保最佳的专业发展。此外，项目4将受益于联合国环境规划署组织的活动， 确保与其他项目和核心密切合作的行政核心，以及 为利益相关者提供研究翻译的机会，包括居住在奥林化学超级基金附近的人们 地点和帕萨马科迪部落。通过相互作用和相互依存的系统方法，项目4 将有助于保护人类健康免受有害物质的危害。