Causal Molecular Mechanisms Linking Drinking Water Metal Exposures to Cardiometabolic Disease

饮用水金属暴露与心血管代谢疾病之间的因果分子机制

• 批准号: 10354272
• 负责人: Brandon L Pearson
• 金额: $ 29.14万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10354272
• 关键词: Adult Children; Affect; Alleles; Animal Model; Apolipoprotein E; Arsenic; Atherosclerosis; Behavioral; Biological Markers; Biological Models; Blood; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Chemicals; Chronic; Chronic Disease; Clinical; Collaborations; Communities; Consumption; DNA Methylation; Data; Development; Developmental Toxicant; Diabetes Mellitus; Dietary Factors; Dietary Intervention; Elements; Epidemiology; Epigenetic Process; Experimental Animal Model; Exposure to; Folic Acid; Future; Gene Expression; Genetically Engineered Mouse; Half-Life; Health; Heart; Histologic; Human; Hypertension; Immunologics; Individual; Inflammation; Intervention; Knowledge; Laboratory mice; Life; Link; Liver; Mediator of activation protein; Metabolic; Metabolism; Metal exposure; Metals; Methylation; Modeling; Modification; Molecular; Molecular Profiling; Monitor; Mus; Native Americans; Obesity; Observational Study; Organ; Outcome; Pancreas; Participant; Pathogenicity; Pathology; Pathway interactions; Persons; Physiological; Population; Relative Risks; Research; Research Project Grants; Resources; Risk; Role; Sampling; Science; Signal Recognition Particle; Site; South Dakota; Superfund; System; Testing; Therapeutic Intervention; Tissues; Toxic effect; Toxicology; Transgenic Mice; Universities; Uranium; Urine; Water; animal tissue; biobank; body system; burden of illness; cardiometabolism; cell type; cohort; community engagement; contaminated drinking water; data modeling; diabetes risk; dietary; disease phenotype; drinking water; early life exposure; efficacy evaluation; folic acid supplementation; gene function; ground water; humanized mouse; improved; insight; intergenerational; lifestyle factors; metabolome; metabolomics; molecular marker; mouse model; multiple omics; mutant; northern plains; novel; prevent; preventive intervention; programs; response; screening; superfund site; therapeutic evaluation; tool; transcriptomics; urinary; water sampling; waterborne; well water

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.

项目4总结 长期暴露于金属和类金属（以下简称金属）对人体心血管和 代谢健康生活在北方平原的美洲原住民饮用井水， 砷（As）和铀（U），这是超级基金场地的常见污染物。这些人群中的金属暴露是 在流行病学上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有关的疾病负担受到了限制， 单个和组合金属暴露的分子机制。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）将建立人类相关的小鼠 慢性金属暴露和心脏代谢疾病的模型，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，和特定的分子介导的预后关系。我们会让老鼠 环境相关浓度的As和/或U，以及含有天然 北方平原居民消费的高浓度As/U混合物（项目1收集）。然后我们将决定 这些暴露对心脏代谢的影响，比较生命早期与终身暴露，并确定如何 膳食叶酸减轻砷的毒性。目标1将界定以下方面的健康影响和发展脆弱性： 在基因工程小鼠的早期生活或终身暴露于饮用水中的As/U。鼠标 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，在一个 高血压模型此外，该目标将产生As和/或U暴露的动物组织的生物库， 未来的研究，与其他SRP中心的合作研究项目创造了一个广阔的资源。目的 2将描绘小鼠多组学生物标志物，这些生物标志物因早期或终身暴露于饮用的As/U而改变 水DNA甲基化、基因表达和代谢组将在小鼠血液、肝脏和 目标1中收集的胰腺样本，以揭示金属暴露和心脏代谢的分子标志物 疾病小鼠中的分子特征将与项目3中的人类分子特征进行比较， 保守的致病机制以及血液生物标本标记物代表靶器官的效用 人类观察研究中通常无法获得的病理学。目标3将评估与人类相关的 补充叶酸降低砷毒性的潜力和机制。自实验室 小鼠通过甲基化快速消除消耗的As，我们将使用代谢As类似于 人类通过这三个目标，我们将为因果发现科学建立一个有效的动物模型体系 并测试治疗干预措施，以解决广泛和不成比例的疾病负担归因于 影响北方平原部落人口的地下水金属暴露。