Developmental Core

项目摘要/摘要：发展核心 人类经常接触到环境中低水平的潜在危险化学品，饮食， 水、药品和职业暴露。其中许多化合物或它们的活性代谢物 可与大分子结合并产生毒性作用，导致神经毒性、内分泌紊乱、心血管疾病 以及其他疾病。其他化学物质可以诱导突变，导致癌症的发展。在过去的时间里 气相色谱/质谱联用(GC/MS)30年及最近的液-质联用 光谱分析(LC/MS)已被用来测量接触某些类别的化学品。这些 测量在很大程度上被限制在监测一种或几种化学物质的共同 毒物的类别。有一个迫切的需求尚未得到满足，需要开发分析方法来全面衡量 导致人类疾病的各种环境和饮食化学物质。随着……的出现 三重四极杆、离子陷阱和高分辨率精确质谱仪(HRAMS)，现在 可以在一次检测中筛查环境和饮食中的多种毒物，以捕获 毒物暴露的全部内容。串联质谱仪还可以测量多个生物标志物的影响 有毒物质，如氧化应激标志物和DNA加合物。此外，同样的技术可以测量一个 饮食中含有多种植物化学物质和营养素，可预防疾病。 我们建议开发全面的分析方法来测量广泛的环境 和饮食毒物，以及氧化应激的内源性标志物，以及营养物质和植物化学物质 对营养和生长都是必不可少的。我们将采用多阶段MSN和HRAMS扫描技术来 最大限度地增加化学物质和生物标志物的数量，这些化学物质和生物标志物可以使用不同的 生物切片剂。在目标1中，我们将开发方法来测量农药、包装材料中的化学物质、每种 稳定的多氟有毒物质，和选定的致癌物使用尿液和血浆，我们将使用头发作为 一种生物显微镜，用于筛选这些毒物的较长寿命的生物标记物。在目标2中，我们很好地开发了检测方法来测量- 通过测量多种酚类抗氧化剂在血浆和血浆中的摄取量和生物利用度，确定饮食中是否含有多种酚类抗氧化剂 尿液。在目标3中，我们将表征尿液、血浆中氧化应激的内源性生物标记物，并将实施- 采集头发和脚趾甲来测量长期接触这些生物标志物的情况。在目标4中，我们将检查唾液中的 烟草烟雾和电子烟中形成的活性挥发性醛，并测量它们在 口腔。福尔马林固定的石蜡包埋组织，一种未被开发的生物标本，用于测量DNA损伤，将 用于筛选烟草和肉类中的基因毒物的DNA加合物。方法的成功发展 在多种生物样品中检测这些化学物质和生物标志物将大大增加分析物的数量 HHEAR可以向寻求了解化学品对健康的影响和风险的合作者提供。

PROJECT SUMMARY/ABSTRACT: DEVELOPMENTAL CORE Humans are frequently exposed to low levels of potentially hazardous chemicals in the environment, diet, water, medicines, and through occupational exposures. Many of these compounds or their reactive metabolites can bind to macromolecules and exert toxic effects leading to neurotoxicity, endocrine disorders, cardiovascular and other diseases. Other chemicals can induce mutations leading to the development of cancer. Over the past 30 years gas chromatography/mass spectrometry (GC/MS) and more recently liquid chromatography/mass spectrometry (LC/MS) have been employed to measure exposures to certain classes of chemicals. These measurements have been largely restricted to monitoring a single or up to several chemicals within a common class of toxicants. There is a critical unmet need to develop analytical methods to comprehensively measure for a wide range of environmental and dietary chemicals that contribute to human diseases. With the emergence of triple quadrupole, ion trap, and high resolution accurate mass spectrometry (HRAMS) instruments, it is now possible to screen for multiple classes of toxicants in the environment and diet in a single assay to capture the totality of the toxicant exposome. Tandem MS instruments can also measure multiple biomarkers of effects of toxicants, such as oxidative stress markers and DNA adducts. Moreover, the same technologies can measure a wide panel of phytochemicals and nutrients in the diet that can protect against diseases. We propose to develop comprehensive analytical approaches to measure a wide range of environmental and dietary toxicants, as well as endogenous markers of oxidative stress, and nutrients and phytochemicals that are essential for nutrition and growth. We will employ multistage MSn and HRAMS scanning techniques to maximize the number of chemicals and biomarkers that can measured in a single assay using different biopsecimens. In Aim 1, we will develop methods to measure pesticides, chemicals in packaging materials, per- sistent polyfluorinated toxicants, and selected carcinogens using urine and plasma, and we will employ hair as a biospecimen to screen for longer-lived biomarkers of these toxicants. In Aim 2, we well develop assays to mea- sure for multiple phenolic antioxidants in the diet by measuring their uptake and bioavailability in plasma and urine. In Aim 3, we will characterize endogenous biomarkers of oxidative stress in urine, plasma, and we will em- ploy hair and toenails to measure long-term exposure to these biomarkers. In Aim 4, we will examine saliva for reactive volatile aldehydes formed in tobacco smoke and e-cigarettes and measure their DNA damage in the oral cavity. Formalin fixed paraffin embedded tissues, an untapped biospecimen to measure DNA damage, will be used to screen DNA adducts of genotoxicants in tobacco and meats. The successful development of methods to measure these chemicals and biomarkers in multiple biospecimens will greatly expand the number of analytes that the HHEAR can provide to collaborators who seek to understand health effects and risks of chemicals.