Metal-nutrient mixtures in epidemiologic and toxicologic studies of cardiovascular disease

心血管疾病流行病学和毒理学研究中的金属营养混合物

• 批准号: 10432074
• 负责人: Jaymie R Meliker
• 金额: $ 58.74万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-04 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10432074
• 关键词: Acute myocardial infarction; Adhesions; Apolipoprotein E; Arsenic; Arteries; Atherosclerosis; Behavioral; Biological Markers; Biometry; Cadmium; Calcium; Cardiovascular Diseases; Cell Adhesion; Chemicals; Cholesterol; Clinical Data; Cohort Studies; Collection; Complement; Cotinine; Creatinine; Data; Diabetes Mellitus; Elements; Endothelial Cells; Endothelium; Epidemiology; Event; Exposure to; Food; Frequencies; Funding; Generations; Health; Hypertension; In Vitro; Incidence; Joints; Knockout Mice; Lipids; Magnesium; Measures; Metals; Methods; Modeling; Morbidity - disease rate; National Institute of Environmental Health Sciences; Nutrient; Osmolalities; Participant; Pathway interactions; Physical activity; Play; Population; Prevention; Process; Prospective Studies; Prospective cohort; Questionnaires; Reactive Oxygen Species; Regression Analysis; Reporting; Research Design; Risk; Risk Factors; Role; Sample Size; Sampling; Science; Side; Smoking; Source; Spottings; Sum; Techniques; Tobacco smoking behavior; Toxicology; Translational Research; Urine; Woman; calcification; cardiovascular disorder risk; cardiovascular risk factor; cohort; design; diet and cancer; endothelial dysfunction; epidemiology study; follow-up; hazard; in vitro Assay; in vivo; innovation; macrophage; men; mortality; mouse model; never smoker; novel; population based; prospective; protective factors; public health relevance; random forest; recruit; urinary; virtual

Abstract This proposal is designed to extend and complement our R01-funded case-cohort study of cadmium (Cd) and acute myocardial infarction (AMI). Herein we will add arsenic (As), calcium (Ca), and magnesium (Mg) to our case-cohort study and include epidemiologic and toxicologic mixtures analyses. The four elements we have selected are compelling for their independent role in cardiovascular disease (CVD) and as a mixture. As increases plaque formation and adhesion to endothelium and Cd also induces endothelial dysfunction and atherosclerosis; yet it is not clear if the effects of As and Cd are synergistic or competing. To potentially counteract these processes, Mg is important for modulating endothelial function. While Ca’s role is equivocal, its role in calcification of the arteries is undeniable, making it important to consider as well. Our efficient case-cohort study design includes 810 cases of AMI and a comparison subcohort of 600 men and 600 women selected randomly from never smokers at risk of AMI at the start of follow-up, leveraging the prospective population-based Danish Diet Cancer and Health Cohort. We are already funded to measure Cd, creatinine, osmolality, and cotinine in baseline urine samples. We now propose to additionally analyze As species, Mg, and Ca in urine among ~2000 participants selected into this case-cohort study, along with pre-existing food frequency questionnaire data on Mg and Ca. In Aim 1 we will evaluate the association between each of As, Ca, and Mg, and incidence of AMI. This will be one of the largest prospective studies of these elements in relation to AMI. In Aim 2 we will apply mixtures methods (Bayesian kernel machine regression, weighted quantile sum regression, random forests) to evaluate the interactive and joint effects of Cd, As, Ca, and Mg in relation to AMI risk. In Aim 3 we will apply in vitro and in vivo approaches to study combined effects of exposure to these elements to investigate the toxicologic mechanisms and pathways of activity. Each Aim is independently compelling and will provide important scientific contributions but together the complementary approaches have the potential to provide evidence of consistency in findings across the distinct approaches. Triangulating data across in vitro, in vivo and epidemiologic analyses represents a translational bridge as depicted in the NIEHS translational research framework. The scope of this virtual consortium will enrich our understanding of the relationships between Cd, As, Mg, Ca, and CVD. Other innovative features of our study include leveraging an existing efficient case-cohort design, large sample size, a large number of incident AMI events, controlling for tobacco smoking, in vitro assays of pro-atherogenic mechanisms, and in vivo studies of atherosclerosis. Sources of exposure to these elements are well known, therefore the identification of mixtures of these elements as cardiovascular risk/protective factors can have major implications for the prevention and control of CVD.

抽象的 该提案旨在扩展和补充我们 R01 资助的镉 (Cd) 和 急性心肌梗塞（AMI）。在此，我们将砷 (As)、钙 (Ca) 和镁 (Mg) 添加到我们的 病例队列研究，包括流行病学和毒理学混合物分析。我们拥有的四个要素 选择的药物因其在心血管疾病（CVD）中的独立作用以及作为混合物的作用而引人注目。作为 增加斑块形成和对内皮的粘附，镉还会诱发内皮功能障碍 动脉粥样硬化;但目前尚不清楚 As 和 Cd 的影响是协同作用还是竞争作用。潜在地 镁可以抵消这些过程，对于调节内皮功能很重要。虽然 Ca 的角色是模棱两可的，但它 在动脉钙化中的作用是不可否认的，因此考虑这一点也很重要。我们高效的案例队列 研究设计包括 810 例 AMI 病例以及由 600 名男性和 600 名女性组成的比较小组 在随访开始时，利用基于人群的前瞻性数据，从有 AMI 风险的从不吸烟者中随机抽取 丹麦饮食癌症与健康队列。我们已经获得资金来测量镉、肌酐、渗透压和 基线尿液样本中的可替宁。我们现在建议另外分析尿液中的砷、镁和钙 入选本案例队列研究的约 2000 名参与者，以及先前存在的食物频率 Mg 和 Ca 的问卷数据。在目标 1 中，我们将评估 As、Ca 和 Mg 之间的关联， 和 AMI 的发生率。这将是对这些与 AMI 相关的因素进行的最大规模的前瞻性研究之一。在 目标 2 我们将应用混合方法（贝叶斯核机器回归、加权分位数和回归、 随机森林）来评估 Cd、As、Ca 和 Mg 与 AMI 风险相关的交互和联合效应。瞄准 3 我们将应用体外和体内方法来研究暴露于这些元素的综合影响 研究毒理学机制和活性途径。每个目标都是独立引人注目的并且将 提供了重要的科学贡献，但互补的方法一起有潜力 提供不同方法的研究结果一致性的证据。在体外、体内对数据进行三角测量 体内和流行病学分析代表了一个转化桥梁，如 NIEHS 转化中所述 研究框架。这个虚拟联盟的范围将丰富我们对这些关系的理解 介于 Cd、As、Mg、Ca 和 CVD 之间。我们研究的其他创新特征包括利用现有的高效 病例队列设计、大样本量、大量 AMI 事件、控制吸烟、 促动脉粥样硬化机制的体外测定和动脉粥样硬化的体内研究。接触来源 这些元素是众所周知的，因此将这些元素的混合物鉴定为心血管 风险/保护因素可能对 CVD 的预防和控制产生重大影响。