Protein Adducts as Measures of Exposure Throughout Childhood Development

蛋白质加合物作为整个儿童发育过程中暴露量的衡量标准

• 批准号: 9332404
• 负责人: William E Funk
• 金额: $ 19.75万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9332404
• 关键词: 21 year old; Address; Age; Binding Sites; Biological Assay; Biological Markers; Biology; Birth; Blood; Blood Volume; Blood specimen; Carcinogens; Chemical Exposure; Chemicals; Child; Child health care; Childhood; Chronic Disease; Collaborations; Collection; Complement; Conceptions; Data; Detection; Development; Diet; Disease; Dose; Drops; Environment; Environmental Exposure; Environmental Hazards; Environmental Health; Environmental Pollutants; Equipment and supply inventories; Etiology; Exposure to; Fetus; Fingers; Foundations; Future; Genes; Goals; Growth and Development function; Health; Heel; Human; Human Genome; Individual; Infant; Inflammation; Knowledge; Laboratories; Letters; Libraries; Life; Link; Logistics; Longevity; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measures; Methods; Molecular Profiling; National Institute of Environmental Health Sciences; Newborn Infant; Oxidative Stress; Paper; Peptides; Plasma; Poison; Population Research; Predisposition; Proteins; Resolution; Risk Assessment; Risk Factors; Sample Size; Sampling; Serum Albumin; Source; Spottings; Strategic Planning; Time; Work; adduct; base; biomarker discovery; candidate marker; critical period; disability; early childhood; epidemiology study; experimental study; exposed human population; fetal; genome wide association study; in vivo; minimally invasive; nano; new technology; novel; postnatal; protein E; public health relevance; residence; tool

 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.

 描述（由申请人提供）：胎儿、婴儿和幼儿期的发育时期特别容易受到环境危害的影响，在这些关键的易感期接触有毒化学物质与儿童期和整个时期的疾病、残疾和不良健康有关在研究疾病的环境原因时，暴露组的概念代表了人类发生的总体暴露，因此在研究整个生命周期时，生命早期的暴露时间是一个需要考虑的关键因素。从受孕开始 - 在环境健康科学领域对于研究疾病病因已变得越来越重要，虽然目前不可能使用单个实验来测量血液样本中的所有化学物质（类似于测量基因的全基因关联研究），但很重要。在发育的关键时期可以研究一类重要的化学物质，它们是与绝大多数癌症和慢性疾病有关的高反应性化合物，具有外源性（例如环境污染物和慢性疾病）。饮食）和内源性（例如氧化应激和炎症）来源，从而反映了整个暴露-疾病连续体的广泛重要分子。然而，由于亲电子试剂在体内的寿命往往非常短，因此通常不能这促使人们使用蛋白质添加产物（加合物）作为生物标志物来估计活性亲电化学物质的暴露量，这反映了在停留时间内暴露于短寿命亲电试剂的综合情况。在此提案中，我们将采用与 NIEHS 2012-2017 战略计划直接一致的两阶段方法。从出生前到 21 岁的生命暴露组。利用这些实验的数据以及从合作实验室收集的数据，我们将创建一个包含所有可检测到的数据的库HSA-半胱氨酸34 最后，我们将开发并验证一种高通量多重检测，用于定量干燥血液样本中的目标加合物 - 使用简单且微创的脚后跟或手指刺破收集的血滴。该提案提供了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，为弥合科学知识方面的这一关键差距提供了独特的机会。该提案中开发的生物标记方法将提供早期生命的第一张地图。加合物组，并将在未来的研究中为调查疾病和失调的环境原因提供具体工具。