Superfund Chemicals, Nutrition, and Multi-Organ Cardiovascular Risk

超级基金化学品、营养和多器官心血管风险

• 批准号: 10596286
• 负责人: YEKATERINA ZAYTSEVA
• 金额: $ 19.98万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-07 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596286
• 关键词: Acceleration; Acute; Address; Animal Model; Antibiotics; Atherosclerosis; Binding; Biological; Biological Markers; Blood Vessels; Cardiometabolic Disease; Cardiovascular Diseases; Cause of Death; Ceramides; Chemicals; Chronic; Data; Data Set; Development; Diet; Dietary Fiber; Dietary Intervention; Dioxins; Disease; Down-Regulation; Endothelium; Environment; Environmental Engineering technology; Environmental Exposure; Environmental Science; Enzymes; Epigallocatechin Gallate; Event; Exposure to; Fiber; Functional disorder; Future; Gene Expression; Genes; Goals; Green tea; Hazardous Waste Sites; Health; Hepatic; Hepatocyte; Human; In Vitro; Inflammation; Inflammatory; Insulin Resistance; Inulin; Life Cycle Stages; Link; Lipids; Liver; Liver Dysfunction; Low Density Lipoprotein Receptor; Macrophage; Mediating; Metabolic; Metabolic dysfunction; Metabolism; Methionine; Modeling; Molecular; Mus; NF-kappa B; Nutrient; Organ; Outcome; Oxidation-Reduction; Pathology; Peripheral; Permeability; Persons; Plants; Plasma; Poison; Poly-fluoroalkyl substances; Polychlorinated Biphenyls; Population; Pre-Clinical Model; Process; Production; Public Health; Reporting; Research; Risk; Sampling; Signal Pathway; Signal Transduction; Sphingolipids; Stains; Superfund; Technology; Testing; Toxic effect; United States; Vascular Endothelial Cell; Volatile Fatty Acids; animal data; atherosclerosis risk; biobank; body system; cardiovascular disorder risk; cardiovascular risk factor; chemical stability; choline deficient diet; chronic inflammatory disease; disorder risk; experimental study; exposed human population; gut bacteria; gut microbiota; halogenation; in vivo; lipid metabolism; liver injury; metabolic profile; metabolomics; nutrition; oxidation; persistent organic pollutants; pollutant; polyphenol; prebiotics; prevent; programs; response; stable isotope; superfund chemical; systemic inflammatory response; toxicant; transcriptomics; trimethyloxamine; vascular inflammation

PROJECT SUMMARY The overall goal of Project 1 is to understand the signaling pathways and metabolic or biological changes by which bioactive nutrients modulate impacts of acute or chronic exposure to persistent organic pollutants such as polychlorinated biphenyls (PCBs) and long-chain per- and polyfluoroalkyl substances (PFAS). Such persistent pollutants express significant chemical stability in the environment, and toxic insults from POPs are known to correlate with a range of post-exposure human health impacts, including vascular inflammation. Atherosclerosis, a chronic inflammatory disease, remains the leading cause of death in the United States. Biological events associated with inflammation and atherosclerosis can be modified by circulating toxicants and bioactive nutrients and their metabolites, which dictate final redox changes and inflammatory outcomes, by altering NF-kB and Nrf2 signaling. For example, preliminary data demonstrate down-regulation of PCB 126- mediated toxicity and inflammation by plant-derived bioactive nutrients, e.g., polyphenols, and fiber (e.g., inulin). Importantly, it is known that the pathology of atherosclerosis is dependent on the health and cross-talk of multiple tertiary organ systems including the liver and gut, as exemplified by recent findings linking PCB exposure with increased plasma levels of trimethylamine N-oxide (TMAO), a diet-derived metabolite formed through cross-talk between gut microbiota and hepatic oxidation and associated with risk of atherosclerosis. Preliminary findings indicate that persistent organic pollutants, and especially PCBs, caused liver dysfunction and alterations of gut microbiota, and that prior liver injury exacerbated PCB-mediated systemic inflammation. Metabolomic profiling further suggested that increased formation of pro-atherogenic metabolites (e.g., ceramides) may drive multi-organ inflammation and increased cardiovascular risk. Based on these findings, three specific aims test the hypotheses that 1) administration of PCB 126 and/or PFAS to mice increases cardiometabolic disease risk by increasing ceramide production via modulation of hepatic gene expression and/or the gut microbiota; 2) administration of green tea catechins and/or soluble inulin fiber in vivo decreases ceramides and thereby stabilizes cellular redox status, modulating NF-kB and Nrf2 signaling and pro- atherosclerotic pathologies as determined by en face and lipid staining in atherogenic LDL receptor-deficient mice; and 3) exposure to PCBs and/or PFAS increases pro-atherogenic metabolites (e.g., ceramides) through increased de novo synthesis in preclinical models. Transcriptomic and metabolomic technologies will be used to explore the mechanistic interactions between pollutant exposure, nutritional intervention, and cardiovascular disease (CVD) risks. These data will be confirmed in biobanked samples of humans with CVD. Results will support the paradigm that healthful nutrition interventions offer a powerful strategy to reduce disease risks associated with environmental toxic insults and to prevent inflammatory diseases, such as atherosclerosis, that have been linked to exposure to Superfund pollutants.

项目概要 项目 1 的总体目标是通过以下方式了解信号传导途径和代谢或生物变化： 哪些生物活性营养素可调节急性或慢性接触持久性有机污染物（例如 如多氯联苯 (PCB) 和长链全氟烷基物质和多氟烷基物质 (PFAS)。这样的 持久性污染物在环境中表现出显着的化学稳定性，持久性有机污染物的毒性损害 已知与一系列暴露后人类健康影响有关，包括血管炎症。 动脉粥样硬化是一种慢性炎症性疾病，仍然是美国的主要原因。 循环毒物可以改变与炎症和动脉粥样硬化相关的生物事件 和生物活性营养素及其代谢物，决定最终的氧化还原变化和炎症结果，通过 改变 NF-kB 和 Nrf2 信号传导。例如，初步数据表明 PCB 126- 的下调 植物源性生物活性营养素（例如多酚和纤维）介导的毒性和炎症 菊粉）。重要的是，众所周知，动脉粥样硬化的病理取决于健康状况和相互影响 包括肝脏和肠道在内的多个第三器官系统的影响，最近与 PCB 相关的研究结果就是例证 暴露于血浆中三甲胺 N-氧化物 (TMAO) 水平升高的情况下，TMAO 是一种由饮食形成的代谢物 通过肠道微生物群和肝脏氧化之间的相互作用，并与动脉粥样硬化的风险相关。 初步研究结果表明，持久性有机污染物，尤其是多氯联苯，会导致肝功能障碍 肠道微生物群的改变，以及先前的肝损伤加剧了 PCB 介导的全身炎症。 代谢组学分析进一步表明促动脉粥样硬化代谢物的形成增加（例如， 神经酰胺）可能会导致多器官炎症并增加心血管风险。基于这些发现， 三个具体目标测试以下假设：1) 给小鼠施用 PCB 126 和/或 PFAS 会增加 通过调节肝脏基因表达来增加神经酰胺的产生，从而降低心脏代谢疾病的风险 和/或肠道微生物群； 2)体内绿茶儿茶素和/或可溶性菊粉纤维的施用减少 神经酰胺，从而稳定细胞氧化还原状态，调节 NF-kB 和 Nrf2 信号传导并促进 通过 enface 和脂质染色确定致动脉粥样硬化 LDL 受体缺陷的动脉粥样硬化病理 老鼠； 3) 接触 PCB 和/或 PFAS 会增加促动脉粥样硬化代谢物（例如神经酰胺） 增加临床前模型中的从头合成。将使用转录组学和代谢组学技术 探索污染物暴露、营养干预和心血管之间的机制相互作用 疾病（CVD）风险。这些数据将在患有 CVD 的人类生物库样本中得到证实。结果将 支持健康营养干预措施为降低疾病风险提供有力策略的范例 与环境毒性损伤相关并预防炎症性疾病，例如动脉粥样硬化， 与接触超级基金污染物有关。