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.

项目概要/摘要：开发核心 人类经常接触环境、饮食、 水、药物以及职业接触。许多这些化合物或其活性代谢物 可以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 和其他疾病。其他化学物质可以诱导突变，导致癌症的发展。过去的事 30 年气相色谱/质谱 (GC/MS) 和最近的液相色谱/质谱 光谱法 (LC/MS) 已用于测量某些类别化学品的暴露情况。这些 测量在很大程度上仅限于监测公共区域内的单一或最多几种化学物质。 毒物类别。目前迫切需要开发分析方法来全面测量 多种导致人类疾病的环境和膳食化学物质。随着出现 三重四极杆、离子阱和高分辨率精确质谱 (HRAMS) 仪器，现在 可以通过一次检测来筛查环境和饮食中的多种有毒物质，以捕获 毒物暴露的总体。串联 MS 仪器还可以测量多种生物标志物的影响 有毒物质，例如氧化应激标记物和 DNA 加合物。此外，相同的技术可以测量 饮食中含有多种植物化学物质和营养素，可以预防疾病。 我们建议开发综合分析方法来测量广泛的环境 和膳食毒物，以及氧化应激的内源性标记物，以及营养物质和植物化学物质 对于营养和生长至关重要。我们将采用多级 MSn 和 HRAMS 扫描技术 最大限度地增加可使用不同方法在单次测定中测量的化学物质和生物标记物的数量 活组织检查。在目标 1 中，我们将开发测量包装材料中农药、化学物质的方法， 持久的多氟毒物，以及使用尿液和血浆选定的致癌物，我们将使用头发作为 用于筛选这些毒物的寿命较长的生物标志物的生物样本。在目标 2 中，我们很好地开发了测量方法 通过测量血浆和生物利用度来确定饮食中的多种酚类抗氧化剂 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 利用头发和脚趾甲来测量这些生物标志物的长期暴露情况。在目标 4 中，我们将检查唾液 烟草烟雾和电子烟中形成的活性挥发性醛并测量其 DNA 损伤 口腔。福尔马林固定石蜡包埋组织是一种尚未开发的用于测量 DNA 损伤的生物样本，将 用于筛选烟草和肉类中基因毒物的 DNA 加合物。方法开发成功 测量多个生物样本中的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影响和风险的合作者提供这些信息。