Developmental Core

项目总结/摘要：实验核心 人类经常暴露于环境、饮食、 水、药品和职业暴露。许多这些化合物或其反应性代谢物 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 和其它疾病。其他化学物质可以诱发突变，导致癌症的发展。过去 30年的气相色谱/质谱（GC/MS）和最近的液相色谱/质谱 已经使用了LC/MS（液相色谱/质谱）来测量对某些类别化学品的暴露。这些 测量已在很大程度上限于监测一个共同的单一或多达几个化学品 有毒物质的种类开发分析方法以全面衡量 导致人类疾病的各种环境和饮食化学品。的出现 三重四极杆，离子阱和高分辨率精确质谱（HRAMS）仪器，它现在是 可以在一次检测中筛选环境和饮食中的多种有毒物质， 有毒有害物质的总量。串联MS仪器还可以测量多个生物标志物的影响， 有毒物质，如氧化应激标记物和DNA加合物。此外，同样的技术可以测量 广泛的植物化学物质和营养素的饮食，可以防止疾病。 我们建议制定全面的分析方法，以衡量广泛的环境 以及氧化应激的内源性标志物，以及营养素和植物化学物质， 对营养和生长至关重要。我们将采用多级MSn和HRAMS扫描技术， 最大限度地增加化学品和生物标志物的数量，可以在一个单一的测定使用不同的 生物切片在目标1中，我们将开发方法来测量农药，包装材料中的化学品， 持续的多氟有毒物质和选定的致癌物质使用尿液和血浆，我们将采用头发作为 一个生物样本来筛选这些有毒物质的长期生物标志物。在目标2中，我们很好地开发了测定方法， 通过测量血浆中多种酚类抗氧化剂的吸收和生物利用度， 尿在目标3中，我们将表征尿液、血浆中氧化应激的内源性生物标志物，并且我们将 用头发和脚趾甲来测量这些生物标志物的长期暴露。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反应性挥发性醛，并测量它们在烟草烟雾和电子烟中的DNA损伤。 口腔福尔马林固定的石蜡包埋组织，一个未开发的生物标本，以衡量DNA损伤，将 用于烟草和肉类中遗传毒物的DNA加合物的筛选。方法的成功发展 在多个生物样本中测量这些化学物质和生物标志物将大大增加分析物的数量 HHEAR可以提供给寻求了解化学品对健康的影响和风险的合作者。

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.