Sequencing the exposome: developing an integrated approach using nontargeted mass spectrometry and computational chemistry

暴露组测序：使用非靶向质谱和计算化学开发综合方法

• 批准号: RGPIN-2020-06628
• 负责人: Jobst, Karl
• 金额: $ 2.99万
• 依托单位: Memorial University of Newfoundland
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=747929
• 关键词: Sequencing; exposome; developing; integrated; approach

The exposome encompasses the totality of environmental exposures during a lifetime. In chemistry and chemical biology, these exposures manifest as endogenous and exogenous chemicals that result from diet, lifestyle, radiation, stress, and exposure to environmental pollutants. Unlike the genome, the exposome is variable and thus requires frequent, cost-effective and reliable measurements of exposures that evolve over time, most appropriately by sampling small quantities of blood (e.g. dried-blood spots). Such measurements will be vital in order to identify the causes of most chronic diseases, but the obstacles to further progress are formidable: c. 90% of unknown pollutants in a drop of blood are not detectable using existing analytical platforms; and the identities of most environmental toxicants and their role in causing chronic disease are unknown! My group's research will address these challenges through the development of innovative mass spectrometry (MS) techniques, viz. flow modulated multidimensional gas chromatography-atmospheric pressure ionization (GCxGC-API), complemented by state-of-the-art computational tools. The proposed analytical platform affords unparalleled separation and significantly improves detection limits when coupled with an API source that is resilient to high flows. Despite its promise, this has not been previously attempted! The development of this approach will enable: the identification of unknown pollutants with 3-50 microliters of blood (1 PhD, 1 BSc), a remarkable improvement over existing methodologies that require pooled sampling and excessive blood volumes >300uL; and innovative hyphenation of ionization (1 MSc) and activation (1 PhD, 1 BSc) techniques that will provide new information critically needed to identify unknown toxicants. Nontargeted screening (NTS) is the term-of-art for qualitative experiments aimed at identifying unknown organic compounds using MS. The prevailing thought is that a compound's structure must be elucidated prior to assessing environmental significance, but this approach is impractical considering sample complexity. We suggest that that the environmental significance of an unknown chemical may be inferred from its behavior (and reactivity) in the mass spectrometer without a priori knowledge of its structure. Trainees in my lab will: develop automated software that accelerates pollutant discovery (1 PhD, 1 BSc); investigate and exploit the rich chemistry occurring in the mass spectrometer that mirrors in vivo metabolism and can be used to differentiate toxic from non-toxic chemicals (1 PhD, 1 BSc); and finally, conduct reconnaissance studies (3 MSc, 1 BSc) aimed at answering the question: What risk do these newfound pollutants pose to the environment and health? It is anticipated that the results from this research program will help guide the creation of effective environmental regulation; and guide industry on the development of safer, more sustainable chemicals.

该展览组包括一生中的全部环境暴露。在化学和化学生物学中，这些暴露表现为饮食，生活方式，辐射，压力和暴露于环境污染物的内源性和外源化学物质。与基因组不同，该杂志是可变的，因此需要频繁，成本效益且可靠的测量，这些暴露会随着时间的流逝而演变而来，这是通过对少量的血液（例如干血点）进行采样而适当地进行的。这样的测量对于确定大多数慢性疾病的原因至关重要，但是进一步进步的障碍是巨大的：c。使用现有的分析平台无法检测到一滴血液中90％的未知污染物；大多数环境有毒物质及其在引起慢性疾病中的作用的身份尚不清楚！我小组的研究将通过开发创新的质谱法（MS）技术来解决这些挑战，即。流量调制多维气相色谱 - 大气压力电离（GCXGC-API），并由最先进的计算工具补充。提出的分析平台可提供无与伦比的分离，并与API源相结合，可显着提高检测极限，该API源可抵御高流量。尽管有希望，但此前尚未尝试过！这种方法的发展将实现：鉴定出3-50个微量流血（1 Phd，1 BSC）的未知污染物，这是对需要合并抽样和过量血量> 300ul的现有方法的显着改善；电离（1 MSC）和激活（1 phd，1 BSC）技术的创新连字符，这些技术将为识别未知的毒物提供至关重要的新信息。非目标筛选（NTS）是旨在使用MS鉴定未知有机化合物的定性实验的术语。普遍的想法是，必须在评估环境意义之前阐明化合物的结构，但是考虑样品复杂性，这种方法是不切实际的。我们建议，未知化学物质的环境意义可能是从质谱仪中其行为（和反应性）中推断出的，而没有对其结构的先验知识。我的实验室的受训者将：开发自动化软件，以加速污染物发现（1 PhD，1 BSC）；研究并利用在质谱仪中发生的丰富化学反应，以反映体内代谢，可用于区分毒性与无毒化学物质（1 Phd，1 BSC）；最后，进行侦察研究（3 MSC，1 BSC）旨在回答以下问题：这些新发现的污染物对环境和健康构成什么风险？预计该研究计划的结果将有助于指导创建有效的环境调节；并指导行业开发更安全，更可持续的化学物质。