Causal Molecular Mechanisms Linking Drinking Water Metal Exposures to Cardiometabolic Disease

项目4摘要 长期接触金属和类金属(下称金属)对人体心血管和 新陈代谢健康。生活在北部平原的美洲原住民消耗的井水中含有较高的 砷(As)和铀(U)是超级基金现场常见的污染物。这些人群中的金属暴露是 从流行病学上讲，这与心血管疾病和糖尿病的高发病率有关。然而，预防或 治疗与地下水金属暴露相关的疾病负担有限，因为对 金属单独暴露和联合暴露的分子机制。为了填补这一空白，哥伦比亚大学的项目4 大学北方平原超级基金研究计划(CUNP-SRP)将建立与人类相关的小鼠 慢性金属暴露和心脏代谢性疾病的模型，以全面评估这些机制。 我们将利用基因工程小鼠模型来研究发育脆弱性、组织和 细胞水平的影响，以及暴露-结果关系的特定分子介质。我们将暴露老鼠 环境相关浓度的砷和/或铀，以及含有天然 北部平原地区人们消费的高浓度As/U混合物(在项目1中收集)。然后我们将确定 这些暴露对心脏代谢的影响，将早期生命与终生暴露进行比较，并确定如何 饮食中的叶酸可以减轻毒性。目标1将界定以下方面的健康影响和发展脆弱性 转基因小鼠的早期或终生暴露于饮用水中的砷/铀。小白鼠 心脏代谢健康将通过一系列临床、组织学、行为学和 功能测试，重点是动脉粥样硬化、高血压、肥胖症和糖尿病 高脂血症模型。此外，这一目标将产生As和/或U暴露的动物组织的生物库，用于 未来的研究，为与其他SRP中心合作的研究项目创造了一个广阔的资源。目标 2将分析小鼠早期或终生接触AS/U饮酒后改变的多组学生物标志物 水。DNA甲基化、基因表达和代谢组将在小鼠的血液、肝脏和 AIM 1收集的胰腺样本揭示了金属暴露和心脏代谢的分子标志物 疾病。老鼠的分子签名将与项目3中的人类分子签名进行比较，以识别 保守的致病机制及血液生化标记物在代表靶器官中的作用 病理学在人类观察性研究中通常是不存在的。目标3将评估与人类相关的 补充叶酸降低砷毒性的可能性和机制。从实验室开始 小鼠通过甲基化迅速消除消耗的AS，我们将使用代谢类似于 人类。通过这三个目标，我们将建立一个有效的因果发现科学动物模型体系。 并测试治疗干预措施，以应对广泛和不成比例的疾病负担 影响北部平原部落人口的地下水金属暴露。

Project 4 Summary Chronic exposure to metals and metalloids (hereafter metals) is detrimental to human cardiovascular and metabolic health. Native Americans living in the Northern Plains consume well water with elevated levels of arsenic (As) and uranium (U), common Superfund site contaminants. Metal exposures in these populations are epidemiologically linked to high rates of cardiovascular disease and diabetes. However, strategies to prevent or treat the disease burdens related to groundwater metal exposures have been limited by poor understanding of the molecular mechanisms of individual and combined metal exposures. To fill this gap, Project 4 of the Columbia University Northern Plains Superfund Research Program (CUNP-SRP) will establish human-relevant mouse models of chronic metal exposures and cardiometabolic disease to comprehensively evaluate such mechanisms. We will leverage genetically engineered mouse models to investigate developmental vulnerability, tissue and cellular level effects, and specific molecular mediators of exposure–outcome relationships. We will expose mice to environmentally relevant concentrations of As and/or U in addition to well water samples containing a naturally elevated As/U mixture that people in the Northern Plains consume (collected in Project 1). We will then determine the cardiometabolic effects of these exposures, compare early-life to lifelong exposures, and determine how dietary folate mitigates As toxicity. Aim 1 will define health impacts and developmental vulnerability of early-life or lifelong exposure to As/U in drinking water in genetically engineered mice. Mouse cardiometabolic health will be evaluated longitudinally with a battery of clinical, histological, behavioral, and functional tests with a focus on atherosclerosis, hypertension, adiposity and diabetes, in the context of a hyperlipidemic model. Moreover, this aim will generate a biobank of As and/or U exposed animal tissues for future studies, creating an expansive resource for collaborative research projects with other SRP centers. Aim 2 will profile mouse multi-omics biomarkers altered by early-life or lifelong exposure to As/U in drinking water. DNA methylation, gene expression, and the metabolome will be profiled in mouse blood, liver, and pancreas samples collected in Aim 1 to reveal molecular markers of metal exposure and cardiometabolic disease. Molecular signatures in mice will be compared to Project 3 human molecular signatures to identify conserved pathogenic mechanisms as well as the utility of blood biospecimen markers to represent target organ pathologies not typically available in human observational research. Aim 3 will evaluate the human-relevant potential for and mechanisms of dietary folate supplementation to reduce As toxicity. Since laboratory mice rapidly eliminate consumed As via methylation, we will use mice that instead metabolize As similarly to humans. Through these three aims, we will establish a valid animal model system for causal discovery science and to test therapeutic interventions to tackle the extensive and disproportionate disease burden attributable to groundwater metal exposures affecting tribal populations in the Northern Plains.