Non-target analysis of maternal and cord blood samples: Advancing computational tools and discovering novel chemicals

项目摘要/摘要 非目标分析(NTA)提供了一种分析环境和生物的综合方法 几乎所有存在的化学物质的样本。尽管最近在NTA方面取得了进展，但确认的人数 与检测到的特征数量相比，具有分析标准的化学品仍然相当少。那里 因此，需要进一步开发计算工具，以推导出更多的化学结构并充分利用 人力资源管理系统的潜力。提高我们派生更多化学结构的能力将使我们能够发现新的 人类接触到的工业化学品，特别是在关键的发展窗口，如 怀孕了。它还将使发现内源性产生的代谢物可能与 重要的生物学结果，如早产。我的提议的目的是发展小说 显著提高我们分析和解释非目标分析数据的能力的计算方法 从高分辨率质谱仪(HRMS)中提取数据，并将其应用于产前接触工业的研究 北加州一大群孕妇体内的化学物质和内源性代谢物。我的 该提案基于我在分析和环境化学方面的专业知识，以及我目前的博士后 在计算化学和人体暴露应用方面的经验。我寻求额外的培训，以 开发和应用创新的计算方法，以更好地表征人体曝光组和 特别是对早产的揭露。我的建议将有两方面的贡献：(1)发展小说 基于MS数据和物理化学的HRMS数据集计算结构预测算法 性质(有机溶剂和水之间的平衡分配比，例如，辛醇/水， 氯苯/水、乙醚/水等)(目标1)，并应用它们来推导潜在的结构 从340名孕妇和340名匹配的脐带血样本中检测到的HRMS数据集中的化学特征 补充通过MS/MS和分析标准确定的有限数量的化学品(目标2)；以及 (2)利用分子相互作用研究早产暴露组和代谢组之间的相互作用 可视化和比较工业化学品和内源化学品之间的分子相互作用的网络 早产和足月分娩的代谢物不同(目标3)。K99培训将扩展我之前的研究 通过课程学习、研究实习和有指导的阅读获得经验，具体培训如下：(1) 高级分析技能，包括组学数据分析、机器学习和生物统计学；(2)流行病学， 风险评估，人类暴露于化学应激源；以及(3)人类怀孕和发育。这个 在这个奖项中获得的技能对我的长期目标至关重要，我的目标是将计算方法改进到更好的 分析和解释非目标分析数据，以支持更好地描述人类暴露组的工作。 这项工作将产生新的科学知识，极大地促进对 环境暴露会导致不良的健康后果，特别是早产。

PROJECT SUMMARY/ABSTRACT Non-targeted analysis (NTA) provides a comprehensive approach to analyze environmental and biological samples for nearly all chemicals present. Despite the recent advancements in NTA, the number of confirmed chemicals with analytical standards remains fairly small compared to the number of detected features. There is, thus, a need to further develop computational tools to derive more chemical structures and leverage the full potential of HRMS. Enhancing our ability to derive more chemical structures will enable the discovery of new industrial chemicals that humans are exposed to, especially in critical windows of development, such as pregnancy. It will also enable the discovery of endogenously produced metabolites that may be related to biological outcomes of importance, such as preterm birth. The objective of my proposal is to develop novel computational methods to significantly advance our ability to analyze and interpret non-targeted analysis data from high-resolution mass spectrometry (HRMS) and apply them to study prenatal exposures to industrial chemicals and endogenous metabolites in a large cohort of pregnant women from Northern California. My proposal builds on my expertise in analytical and environmental chemistry and my current postdoctoral experience in computational chemistry and applications in human exposure. I seek additional training to develop and apply innovative computational methods to better characterize the human exposome and in particular the exposome of preterm birth. The contribution of my proposal will be two-fold: (1) developing novel computational structure-prediction algorithms for HRMS datasets based on MS data and physicochemical properties (equilibrium partition ratios between organic solvents and water, e.g., octanol/water, chlorobenzene/water, diethyl ether/water etc.) (Aim 1) and apply them to derive potential structures for chemical features detected in a HRMS dataset from 340 maternal and 340 matched cord blood samples to complement the limited number of chemicals identified through MS/MS and analytical standards (Aim 2); and (2) study the interplay between the exposome and the metabolome in preterm birth using molecular interaction networks to visualize and compare how molecular interactions between industrial chemicals and endogenous metabolites differ between preterm and full-term birth (Aim 3). The K99 training will expand my prior research experience through coursework, research apprenticeship, and mentored reading, with specific training in: (1) advanced analytical skills including -omics data analysis, machine learning, and biostatistics; (2) epidemiology, risk assessment, human exposure to chemical stressors; and (3) human pregnancy and development. The skills acquired during this award are critical to my long-term goal to advance computational methods to better analyze and interpret non-targeted analysis data to support efforts to better characterize the human exposome. This work will produce new scientific knowledge to greatly advance the understanding of the influence of environmental exposures in the development of adverse health outcomes and in particular, preterm birth.