Biomarkers and mechanisms of metal and mixed metal exposures

项目1--社区暴露生物项目(BP Comm)--摘要 与美洲原住民社区合作，UNM金属暴露和毒性评估 西南部落土地(UNM Metals)小组已经获得了社区一级接触的证据 以及与其部落1100多个废弃铀矿(AUM)废弃场相关的健康风险 土地。生物监测结果证实，社区成员暴露于铀和其他金属 这超出了国家标准，导致人们担心对健康的潜在影响。基于已发布的和 初步发现，我们将检验这样一个假设，即暴露在环境金属的独特混合物中 与AUM相关的促进氧化应激和炎症反应的过程已知促进 免疫失调和多种慢性病的发展。此外，我们假设 可以根据特定金属和金属的毒性机制来阐明饮食缓解策略 混合物。在目标1中，我们将努力描述通过生物监测检测到的金属之间的联系，以及 氧化应激、炎症和免疫调节的生物标志物。来自AIM 1的发现预计将 提供有关环境金属暴露的系统性后果的关键信息。虽然铀 一直是社区关注的焦点，来自UNM金属环境项目和 人体生物监测强调，其他有毒金属普遍存在于环境中，并以较高的 人口中的水平。AIM 2的实验研究将集中在社区产生的氧化应激- 相关金属和金属混合物是导致炎症改变的潜在机制 反应和免疫调节。我们将选择观察到的实验端点和曝光图案 社区优化人类相关性的目标2研究。将进行详细的机械分析 建立金属相互作用的基础，包括潜在的有益的金属-金属相互作用 抗氧化金属微量营养素(锌/锌和硒/硒)。锌、硒与毒物相互作用的研究 金属和金属混合物可为减轻环境不利影响的可处理战略提供信息 人类人群中的金属暴露。这个项目回应了社区关注的问题和结果 预计将1)提供对未被研究的有毒金属的生物后果的见解 来自群落的环境样品和提升的生物群落，2)扩展机械知识 特定金属和金属混合物的影响以及金属：人体内金属相互作用的基础 免疫细胞，以及3)实验测试基于机制的干预提供保护的潜力 受环境金属暴露的影响。BP Comm解决了SRP任务1、2和4：检测和 效果评价、风险评估和降低风险。

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.