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.