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（由申请人提供）：心血管和代谢疾病在全国范围内呈上升趋势，越来越多的证据强调了环境污染物作为心血管疾病 (CVD) 辅助因素的作用。在新墨西哥州和纳瓦霍族保留地，许多废弃和未经治理的采矿场。吸入采矿废料中富含金属的颗粒物 (PM) 可能会对心血管和肺部疾病造成未被认识到的风险。空气中颗粒物中的金属与心血管和肺部不良后果（尤其是慢性炎症性血管疾病）之间存在密切联系。然而，大部分毒理学都集中在可溶性金属形式，这与残油的燃烧更相关。在美国西南部的许多地点，采矿废料导致金属混合物严重污染土壤，导致铀 (U)、铜 (Cu)、钒 (V)、镍 (Ni)、我们将评估从有混合金属污染历史的社区获得的吸入颗粒物的直接和间接致动脉粥样硬化影响。该工作模型与肺部复杂的相互作用有关，这些相互作用会导致二次循环产物的产生。血管内皮炎症反应，例如 CD36、TLR4 和氧化低密度脂蛋白的卵磷脂样受体。 (LOX-1) 介导血管对空气污染的其他固体和气体成分的反应 人们对金属对血管先天免疫反应的影响知之甚少。产生氧化 LDL 等循环因子，进而激活内皮细胞的炎症反应和功能障碍，以下目标将以机制和转化方式解决这一假设。第一个目标，我们将比较来自采矿区域的吸入粉尘样本在驱动全身血管毒性和血清炎症潜力方面的效力。第二个目标，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中的作用。我们将在体内和体外选择性地拮抗 oxLDL/LOX-1 通路，以评估内皮功能障碍和血管炎症的结果。我们将模拟纳瓦霍队列中的顺风暴露，以检查与内皮损伤循环标志物和血清炎症潜力的关联。我们将模拟风吹灰尘暴露，并将其与炎症/内皮损伤标志物（oxLDL、可溶性 ICAM 和 VCAM、内皮素-1）的结果联系起来。来自纳瓦霍族 252 名成员的血清生物活性表征来自污染场地的可修复颗粒物的健康影响，将为支持危害识别和生物学合理性提供重要信息。风险管理和补救策略的优先顺序。