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

摘要 该提案旨在扩展和补充我们的R 01资助的镉（Cd）和 急性心肌梗死（AMI）。在本文中，我们将向我们的组合物中添加砷（As）、钙（Ca）和镁（Mg）。 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）中的独立作用和作为混合物而引人注目。作为 增加斑块形成和粘附到内皮，Cd也诱导内皮功能障碍， 动脉粥样硬化;但目前尚不清楚，如果As和Cd的影响是协同或竞争。以潜在地 尽管镁可以抵消这些过程，但镁对于调节内皮功能是重要的。虽然Ca的作用是模棱两可的， 在动脉钙化中的作用是不可否认的，因此也必须考虑。我们高效的病例队列 研究设计包括810例AMI和600例男性和600例女性的对照亚组 随机从随访开始时有AMI风险的从不吸烟者中，利用基于前瞻性人群的 丹麦饮食癌症和健康队列。我们已经获得资金来测量镉，肌酐，渗透压， 基线尿样中的可替宁。我们现在建议另外分析尿中的As种类、Mg和Ca 沿着预先存在的食物频率，在被选入该病例队列研究的约2000名参与者中， Mg和Ca的问卷调查数据。在目标1中，我们将评估As、Ca和Mg中的每一个之间的关联， 和AMI的发病率。这将是这些因素与AMI相关的最大的前瞻性研究之一。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），以评估镉，砷，钙，镁的相互作用和联合作用与AMI的风险。在Aim中 我们将应用体外和体内方法研究暴露于这些元素的综合效应， 研究毒理学机制和活动途径。每一个目标都是独立的， 提供了重要的科学贡献，但互补的方法有可能 提供不同方法的结果一致性的证据。在体外和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翻译桥梁，如NIEHS翻译 研究框架。这一虚拟联盟的范围将丰富我们对各种关系的理解， Cd、As、Mg、Ca和CVD之间的关系。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。暴露源 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的预防和控制有重大影响。

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.