Inhalation of Contaminated Mine Waste Dusts as a Route for Systemic Metal Toxicity

吸入受污染的矿山废弃粉尘是导致全身金属中毒的途径

• 批准号: 9980907
• 负责人: Matthew J Campen
• 金额: $ 47.07万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980907
• 关键词: Address; Affect; Air; Air Pollution; Airborne Particulate Matter; Arsenic; Atmosphere; Automobile Driving; Biological; Biosensor; Blood Vessels; CD36 gene; Cardiovascular Diseases; Cardiovascular system; Chronic; Collaborations; Communities; Complex; Copper; Dust; Endothelial Cells; Endothelin-1; Endothelium; Environmental Pollution; Functional disorder; Hazard Identification; Health; Heavy Metals; In Vitro; Industry; Inflammatory; Inflammatory Response; Inhalation; Inhalation Exposure; Injury; Innate Immune Response; LDL Cholesterol Lipoproteins; Laboratories; Lead; Lectin; Link; Lung; Lung diseases; Mediating; Metabolic Diseases; Metal exposure; Metals; Mining; Modeling; Mus; Native-Born; Navajo; New Mexico; Nickel; Oils; Outcome; Particulate Matter; Pathway interactions; Population; Prevalence; Recording of previous events; Residual state; Risk Factors; Risk Management; Role; Route; Sampling; Secondary to; Serum; Shipping; Site; Soil; Solid; Southwestern United States; TLR4 gene; Tissue Donors; Toxic effect; Toxicology; Transition Elements; Uranium; Vanadium; Vascular Cell Adhesion Molecule-1; Vascular Diseases; Vascular Endothelium; Water; Work; cardiovascular disorder risk; circulating biomarkers; cohort; endothelial dysfunction; exposure route; immunoregulation; in vivo; intercellular cell adhesion molecule; member; metal poisoning; oxidized low density lipoprotein; public health relevance; receptor; remediation; repaired; response; stem; vascular inflammation; wasting

 DESCRIPTION (provided by applicant): Cardiovascular and metabolic diseases are on the rise nationally and a growing body of evidence highlights a role for environmental contaminants as adjunctive cardiovascular disease (CVD) factors. In New Mexico and the Navajo Nation, many abandoned and unremediated mining regions exist and continue to contaminate the land, water, and air. Inhalation of metal-rich particulate matter (PM) from mining waste may pose an unrecognized risk for cardiovascular and pulmonary disease in affected communities. A strong link exists between metals in airborne PM and adverse cardiovascular and pulmonary outcomes, especially chronic inflammatory vascular disease. However, much of the toxicology has focused on soluble forms of metal, which are more relevant to the burning of residual oil in the shipping industry. There are numerous sites in the Southwest US where mining waste has led to severe soil contamination of metals mixtures, leading to high levels of uranium (U), copper (Cu), vanadium (V), nickel (Ni), and arsenic (As), among others. We will assess direct and indirect atherogenic impacts of inhaled particulate matter obtained from communities with a history of mixed metals contamination. The working model relates to complex interactions in the lung that lead to secondary circulatory products that induce vascular endothelial inflammatory responses. Immunomodulatory receptors, such as CD36, TLR4, and the lechtin-like receptor for oxidized low-density lipoprotein (LOX-1) mediate vascular responses to other solid and gaseous components of air pollution. The impact of metals in driving vascular innate immune responses is poorly understood. We hypothesize that pulmonary exposures to metal-rich PM from mine waste-contaminated tribal regions will generate circulating factors such as oxidized LDL, which in turn activate inflammatory response and dysfunction in endothelial cells, dependent on immunomodulatory receptors. The following Aims will address this hypothesis in a mechanistic and translational manner. In the first Aim, we will compare the potency of inhaled dust samples from mining regions in terms of driving systemic vascular toxicity and serum inflammatory potential. In the second Aim, we will examine the role of oxLDL and immunomodulatory receptors in driving endothelial activation and dysfunction stemming from exposure to metal-rich PM. We will selectively antagonize the oxLDL/LOX-1 pathway in vivo and in vitro to assess outcomes of endothelial dysfunction and vascular inflammation. Lastly, in the third Aim we will model downwind exposures in a Navajo cohort to examine associations with circulating markers of endothelial injury and serum inflammatory potential. We will model windblown dust exposures and link to outcomes of inflammatory / endothelial injury markers (oxLDL, soluble ICAM and VCAM, endothelin-1) and serum bioactivity from a cohort of 252 members of the Navajo Nation. Characterization of health impacts of repairable PM from contaminated sites will provide important information related to hazard identification and biological plausibility to support prioritization of risk management and remediation strategies.

 描述（由适用提供）：心血管疾病和代谢疾病在全国范围内正在上升，越来越多的证据突出了作为辅助性心血管疾病（CVD）因素的环境污染物的作用。在新墨西哥州和纳瓦霍国，许多被遗弃和未造成的采矿地区存在，并继续污染土地，水和空气。在受影响的社区中，对富含金属的颗粒物（PM）吸入富含金属的颗粒物（PM）可能会对心血管和肺部疾病构成不可识别的风险。机载PM中的金属与心血管和肺部不良结局（尤其是慢性炎症性疾病）之间存在牢固的联系。但是，许多毒理学都集中在固体形式上，这些金属与运输行业中残留油的燃烧更相关。西南部有许多地点，采矿废物导致金属混合物的严重污染，导致高水平的铀（U），铜（CU），钒（V），镍（NI）和砷（AS）等。我们将评估从具有混合金属污染史的社区获得的合并特定物质的直接和间接动脉粥样硬化影响。该工作模型涉及肺部复杂的相互作用，导致造成血管内皮炎症反应的次级循环产物。用于氧化的低密度脂蛋白（LOX-1）培养基对空气污染的其他固体和气态成分的氧化的低密度脂蛋白（LOX-1）培养基反应的免疫调节受体，例如CD36，TLR4和Lechtin样受体。金属在驱动血管先天免疫调查的影响方面的影响很少。我们假设从矿物质废物污染的部落区域向金属丰富的PM暴露于金属富的PM将产生循环因子，例如氧化的LDL，这又激活了内皮细胞中炎症反应和功能障碍，取决于免疫调节受体。以下目的将以机械和翻译的方式解决这一假设。在第一个目标中，我们将在驱动系统性血管毒性和血清炎症潜力方面比较采矿区的遗传粉尘样品的效力。在第二个目标中，我们将研究OXLDL和免疫调节受体在驱动内皮激活和功能障碍的作用，导致暴露于金属富含金属的PM。我们将在体内和体外有选择地拮抗OXLDL/LOX-1途径，以评估内皮功能障碍和血管感染的结果。最后，在第三个目标中，我们将在纳瓦霍人队列中对顺风暴露进行建模，以检查与内皮损伤和血清炎症潜力的循环标记的关联。我们将建模Windblond粉尘暴露，并与炎症 /内皮损伤标记（OXLDL，Solid ICAM和VCAM，Endophelin-1）以及来自Navaajo Nation的252名成员组成的血清生物活性的结局。从受污染地点对可修复PM的健康影响的表征将提供与危害识别和生物学合理性有关的重要信息，以支持风险管理和补救策略的优先级。