Developmental Core

发展核心

• 批准号: 10414021
• 负责人: Robert J. Turesky
• 金额: $ 54.64万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10414021
• 关键词: Alcohols; Aldehydes; Analytical Biochemistry; Anti-Inflammatory Agents; Antioxidants; Binding; Biological; Biological Assay; Biological Availability; Biological Markers; Biological Monitoring; Blood; Cancer Center; Carcinogens; Cardiovascular system; Carpet; Centers for Disease Control and Prevention (U.S.); Chemical Exposure; Chemicals; Chronic; Clinical; Collaborations; DNA; DNA Adduction; DNA Adducts; DNA Damage; Designer Drugs; Detection; Development; Diet; Dietary Phytochemical; Disease; Eating; Electronic cigarette; Emergency Situation; Endocannabinoids; Endocrine Disruptors; Endocrine System Diseases; Endocrine disruption; Environment; Environmental Carcinogens; Epidemiology; Event; Exhibits; Exposure to; Fertility; Formalin; Fruit; Grain; Growth; Hair; Hazardous Chemicals; Health; Heart Diseases; Herbal Medicine; Herbicides; Hormones; Human; Immune; Immunologics; Impaired cognition; Induced Mutation; Inductively Coupled Plasma Mass Spectrometry; Industrialization; Inflammation; Insecticides; Intake; Ions; Kidney; Laboratories; Laboratory Animals; Link; Liver; Malignant Neoplasms; Mass Fragmentography; Mass Spectrum Analysis; Measurement; Measures; Meat; Medicine; Metals; Methodology; Methods; Minnesota; Monitor; Neurotoxins; Nutrient; Nutritional; Occupational Exposure; Oral cavity; Organophosphates; Oxidative Stress; Oxidative Stress Induction; Paraffin Embedding; Pesticides; Phytochemical; Plasma; Plastics; Poly-fluoroalkyl substances; Property; Psychosocial Assessment and Care; Psychosocial Stress; Public Health; Resolution; Resource Sharing; Risk; Risk Assessment; Rodent; Saliva; Scanning; Specimen; Stress; Structure of nail of toe; Techniques; Technology; Textiles; Time; Tissue Embedding; Tobacco; Tobacco smoke; Toxic Environmental Substances; Toxic effect; University of Minnesota Cancer Center; Urine; Vegetables; Volatilization; Water; Water Supply; analytical method; assay development; chemical group; chemical threat; cognitive function; dietary; dietary carcinogenesis; experience; genotoxicity; high throughput analysis; human disease; improved; instrument; liquid chromatography mass spectrometry; macromolecule; member; method development; neurotoxicity; novel; nutrition; opioid epidemic; opioid exposure; packaging material; phthalates; protective effect; pyrethroid; reproductive; response; toxicant; uptake

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.

项目摘要/摘要：发展核心 人类经常在环境中暴露于低水平的潜在危险化学物质，饮食， 水，药物和通过职业暴露。这些化合物或其反应性代谢产物中的许多 可以与大分子结合并发挥导致神经毒性，内分泌疾病，心血管的毒性作用 和其他疾病。其他化学物质可以诱导突变导致癌症的发展。过去 30年气体色谱/质谱法（GC/MS）和最近的液态色谱/质量 光谱法（LC/MS）已被用来测量某些化学品的暴露。这些 测量很大程度上仅限于监测一个共同的一种或多种化学物质 毒物类别。开发分析方法以全面衡量的分析方法有至关重要的需求 有助于人类疾病的各种环境和饮食化学物质。随着出现 三倍四极杆，离子陷阱和高分辨率精确质谱（HRAM）仪器，现在是 可以在环境中筛选多种类别的毒物，并在单个测定中进行饮食以捕获 毒剂的总体杂物。串联MS仪器还可以测量多种影响的生物标志物 有毒物质，例如氧化应激标记和DNA加合物。此外，相同的技术可以测量 饮食中可以预防疾病的植物化学物质和营养素的宽面板。 我们建议开发全面的分析方法，以衡量广泛的环境 和饮食中有毒物质，以及氧化应激的内源性标志物，以及养分和植物化学物质 对于营养和生长至关重要。我们将采用多阶段MSN和HRAMS扫描技术来 最大化可以在单个测定中使用不同的化学物质和生物标志物的数量 活生生素。在AIM 1中，我们将开发用于测量农药，包装材料中的化学物质的方法， 使用尿液和等离子体的纯种多氟毒物，并选择的致癌物，我们将使用头发作为 筛选这些有毒物质的生物标志物的生物测量。在AIM 2中，我们很好地开发了测定法 确保饮食中多种酚类抗氧化剂，通过测量血浆和血浆中的生物利用度 尿。在AIM 3中，我们将表征尿液，等离子体中氧化应激的内源性生物标志物，我们将em- ploy头发和趾甲，以测量这些生物标志物的长期接触。在AIM 4中，我们将检查唾液 在烟草和电子烟中形成的反应性挥发性醛，并测量其DNA损伤 口腔。福尔马林固定石蜡嵌入的组织，一种未开发的生物测量以测量DNA损伤，将 用于筛选烟草和肉类中遗传毒性剂的DNA加合物。成功发展方法 在多种生物测量中测量这些化学物质和生物标志物将大大扩大分析物的数量 HHEAR可以为寻求了解化学物质的健康影响和风险的合作者提供。