Protein Adducts as Measures of Exposure Throughout Childhood Development

 描述（由申请人提供）：胎儿、婴儿和儿童早期发育时期对环境危害非常敏感，在这些敏感的关键窗口期间暴露于有毒化学品与儿童期和整个生命周期的疾病、残疾和不良健康有关。因此，在调查疾病的环境原因时，生命早期暴露的时间是一个关键因素。作为对人类基因组的补充，染色体组的概念-代表从受孕开始发生的人类暴露的总体-在环境健康科学领域中越来越突出，用于调查疾病病因。虽然目前不可能使用单一实验测量血液样本中的所有化学品（类似于用于测量基因的全基因关联研究），但可以在开发的关键时期研究重要类别的化学品。其中一类重要的化学物质是亲电体，它们是高度反应性的化合物，与绝大多数癌症和慢性疾病有关。亲电体既具有外源性（例如，环境污染物和饮食）和内源性（例如，氧化应激和炎症）来源，并因此反映了跨越整个疾病连续体的广泛的重要分子。然而，由于亲电体在体内的寿命往往很短，因此通常不能直接在血液样品中测量它们。这促使使用蛋白质加成产物（加合物）作为生物标志物来估计对反应性亲电化学品的暴露，其反映了对短寿命亲电体的暴露在蛋白质的停留时间内的整合（例如，几个星期到几个月）。在本提案中，我们将采用两阶段方法，直接与NIEHS 2012-2017战略计划保持一致。首先，我们将应用一种新的组学策略，称为内收组学，以绘制从出生前到21岁的早期生活障碍。利用这些实验的数据，以及从合作实验室收集的数据，我们将构建一个所有可检测的HSA-Cys 34的文库。 加合物最后，我们将开发和验证一种高通量多重检测方法，用于定量干血样中的靶向加合物组-使用简单且微创的足跟或手指针刺在滤纸上收集的血滴。鉴于关于生命早期环境暴露及其对儿童健康影响的人体体内数据极其缺乏，该提案为弥合科学知识方面的这一关键差距提供了一个独特的机会。该提案中开发的生物标志物方法将提供早期生命内收体的第一张地图，并将为未来研究中调查疾病和障碍的环境原因提供特定工具。

 DESCRIPTION (provided by applicant): Periods of fetal, infant, and early childhood development are remarkably venerable to environmental hazards, and exposures to toxic chemicals during these critical windows of susceptibility have been linked with disease, disabilities, and adverse health in childhood and across the entire life span. Consequently, the timing of exposure during early-life is a critical factor to consider when investigating environmental causes of disease. As a complement to the human genome, the concept of the exposome - representing the totality of human exposures occurring from conception onward - has become increasingly salient in the field of environmental health sciences for investigating disease etiologies. While it is currently not possible to measure all chemicals in blood samples using single experiments (analogous to gene-wide association studies for measuring genes), important classes of chemicals can be investigated during critical period of development. One important class of chemicals is electrophiles, which are highly reactive compounds that have been linked to a vast majority of cancers and chronic diseases. Electrophiles have both exogenous (e.g., environmental pollutants and diet) and endogenous (e.g., oxidative stress and inflammation) sources, and thus reflect a broad spectrum of important molecules ranging across the entire exposure-disease continuum. However, because electrophiles tend to have very short life spans in vivo, they normally cannot be measured directly in blood samples. This has motivated the use of protein addition products (adducts) as biomarkers for estimating exposures to reactive electrophilic chemicals, which reflect an integration of exposure to short-lived electrophiles over the residence time of the protein (e.g., weeks to months). In this proposal we will apply a two-stage approach that directly aligns with the NIEHS 2012-2017 Strategic Plan. First, we will apply a new omics strategy called adductomics to map the early-life exposome from before birth onward to age 21. Using data from these experiments, as well as data collected from collaborating laboratories, we will then crate a library of all detectable HSA-Cys34 adducts. Finally, we will develop and validate a high-throughput muiltiplexed assay for quantifying panels of targeted adducts in dried blood samples - drops of blood collected on filter paper using a simple and minimally-invasive heel or finger prick. Given the overwhelming lack of human in vivo data on early-life environmental exposures and their impacts on children's health, this proposal offers a unique opportunity to bridge this critical gap in scientific knowledge. The biomarker approaches developed in this proposal will provide the first maps of the early-life adductome, and will provide specific tools for investigating environmental causes of diseases and disorders in future studies.