Biomarkers and mechanisms of metal and mixed metal exposures

金属和混合金属暴露的生物标志物和机制

基本信息

批准号：
10353202
负责人：
LAURIE G HUDSON
金额：
$ 35.08万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10353202
关键词：
Acute Address Adult Adverse effects Antioxidants Arsenic Atherosclerosis Autoimmunity Biological Biological Markers Biological Monitoring Blood Vessels Cell model Cells Chronic Chronic Disease Clinical Trials Collection Communities Community Health DNA Damage DNA Repair Gene DNA Repair Inhibition Data Decision Making Detection Development Diabetes Mellitus Disease Environment Environmental Exposure Environmental Health Environmental Protection Evaluation Experimental Models Exposure to Future Generations Goals Health Health Priorities Health Surveys Human Hypertension Immune Immune Targeting Immunologics Individual Inflammation Inflammatory Inflammatory Response Intervention Kidney Diseases Knowledge Link Lung Metal exposure Metals Micronutrients Mining Modification Native Americans New Mexico Nutrient Nutrition Surveys Outcome Oxidation-Reduction Oxidative Stress Oxidative Stress Induction Pattern Population Population Study Process Production Proteins Publishing Reactive Oxygen Species Research Risk Risk Assessment Risk Reduction Sampling Science Selenium Signal Recognition Particle Signal Transduction Site Superfund Testing Time Toxic effect Universities Uranium Vanadium Work Zinc Zinc Fingers base biological adaptation to stress cytokine cytotoxicity dietary experimental study exposure pathway exposure route immunoregulation immunotoxicity insight macromolecule member metal poisoning model design population based programs therapy development toxic metal tribal lands uptake wasting

项目摘要

Project #1 – BioProject on Community Exposures (BP Comm) - SUMMARY With partnering Native American communities, the UNM Metals Exposure and Toxicity Assessment on Tribal Lands in the Southwest (UNM METALS) team has obtained evidence for community level exposures and health risks associated with more than 1100 abandoned uranium mine (AUM) waste sites on their tribal lands. Biomonitoring results confirm that community members are exposed to uranium and other metals beyond national norms, leading to concerns about potential impact on health. Based on published and preliminary findings, we will test the hypothesis that exposure to the unique mixtures of environmental metals associated with AUMs promotes oxidative stress and inflammatory response, processes known to promote immune dysregulation and development of numerous chronic diseases. Furthermore, we hypothesize that dietary mitigation strategies can be elucidated based on mechanisms of toxicity of specific metals and metal mixtures. In Aim 1 we will work to delineate associations between metals detected by biomonitoring, and biomarkers of oxidative stress, inflammation and immune modulation. The findings from Aim 1 are expected to provide critical information on systemic consequences of environmental metal exposures. Although uranium has been the focus of community concern, findings from the UNM METALS Environmental Projects and human biomonitoring highlight that other toxic metals are prevalent in the environment and present at elevated levels in the population. Experimental studies in Aim 2 will focus on oxidative stress generated by community- relevant metals and metal mixtures as an underlying mechanism leading to alterations in inflammatory response and immune modulation. We will select experimental endpoints and exposure patterns observed in the community to optimize human relevance of Aim 2 studies. Detailed mechanistic analyses will be performed to establish the basis for metal interactions including potential beneficial metal-metal interactions of the antioxidant metal micronutrients (zinc/Zn and selenium/Se). Studies on Zn and Se interactions with toxic metals and metal mixtures may inform tractable strategies for mitigating the adverse effects of environmental metal exposures in human populations. This project is responsive to community concerns and the outcomes are expected to 1) provide insights into biological consequences of understudied toxic metals identified in environmental samples and elevated in biospecimens from the community, 2) expand mechanistic knowledge of the impact of specific metals and metal mixtures as well as the basis for metal:metal interactions in human immune cells, and 3) experimentally test the potential of mechanism-based interventions to confer protection from environmental metal exposures. BP Comm addresses SRP mandates 1, 2 and 4: Detection and Evaluation of Effects, Risk Assessment and Risk Reduction, respectively.

项目 #1 – 社区暴露生物项目 (BP Comm) - 摘要与美国原住民社区合作，新墨西哥州金属暴露和毒性评估西南部落土地 (UNM METALS) 团队已获得社区层面暴露的证据与部落内 1100 多个废弃铀矿 (AUM) 废物场相关的健康风险生物监测结果证实社区成员暴露于铀和其他金属。超出国家标准，导致人们担心对健康的潜在影响。根据初步调查结果，我们将检验以下假设：暴露于环境金属的独特混合物中与 AUM 相关的物质会促进氧化应激和炎症反应，这些过程已知会促进免疫失调和许多慢性疾病的发展。可以根据特定金属和金属的毒性机制阐明饮食缓解策略在目标 1 中，我们将努力描绘生物监测检测到的金属之间的关联，以及目标 1 的研究结果预计将有助于氧化应激、炎症和免疫调节的生物标志物。提供有关环境金属暴露的系统性后果的关键信息。一直是社区关注的焦点，UNM METALS 环境项目的调查结果和人类生物监测强调，其他有毒金属在环境中普遍存在，且浓度升高目标 2 中的实验研究将重点关注社区产生的氧化应激。相关金属和金属混合物作为导致炎症改变的潜在机制我们将选择观察到的实验终点和暴露模式。社区将进行详细的机制分析，以优化 Aim 2 研究的人类相关性。建立金属相互作用的基础，包括潜在有益的金属-金属相互作用抗氧化金属微量营养素（锌/锌和硒/硒）与有毒物质相互作用的研究。金属和金属混合物可以为减轻环境不利影响的易于处理的策略提供信息该项目响应社区关切和结果。预计将 1）提供对未充分研究的有毒金属的生物学后果的见解环境样本和社区生物样本的增加，2) 扩展机械知识特定金属和金属混合物的影响以及人体中金属与金属相互作用的基础免疫细胞，3) 通过实验测试基于机制的干预措施提供保护的潜力 BP Comm 解决了 SRP 要求 1、2 和 4：检测和分别是效果评估、风险评估和风险降低。