Superfund Chemicals, Nutrition, and Multi-Organ Cardiovascular Risk

项目摘要 项目1的总体目标是了解信号通路和代谢或生物学变化， 哪些生物活性营养素调节急性或慢性暴露于持久性有机污染物的影响， 多氯联苯（PCBs）和长链全氟烷基和多氟烷基物质（PFAS）。等 持久性污染物在环境中表现出显著的化学稳定性， 已知与暴露后的一系列人类健康影响相关，包括血管炎症。 动脉粥样硬化，一种慢性炎症性疾病，仍然是美国的主要死亡原因。 与炎症和动脉粥样硬化相关的生物学事件可以通过循环毒物来改变 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， 改变NF-kB和Nrf2信号传导。例如，初步数据表明，PCB126- 介导的毒性和炎症，例如，多酚，和纤维（例如， 菊粉）。重要的是，已知动脉粥样硬化的病理学依赖于健康和串扰。 包括肝脏和肠道在内的多个三级器官系统，最近的研究结果表明， 暴露与增加血浆水平的三甲胺N-氧化物（TMAO），饮食衍生的代谢物形成 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有关。 初步调查结果表明，持久性有机污染物，特别是多氯联苯，造成肝功能障碍 和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（例如， 神经酰胺）可能会导致多器官炎症和心血管风险增加。根据这些发现， 三个具体的目的测试假设，1）给小鼠施用PCB 126和/或PFAS增加 通过调节肝脏基因表达增加神经酰胺产生，增加心脏代谢疾病风险 和/或肠道微生物群; 2）在体内施用绿色茶儿茶素和/或可溶性菊粉纤维减少了 神经酰胺，从而稳定细胞的氧化还原状态，调节NF-κ B和Nrf2信号传导和促细胞凋亡。 在致动脉粥样硬化LDL受体缺陷型中通过表面和脂质染色确定的动脉粥样硬化病理学 小鼠;和3）暴露于PCB和/或PFAS增加促动脉粥样硬化代谢物（例如，神经酰胺）， 在临床前模型中增加从头合成。将使用转录组学和代谢组学技术 探讨污染物暴露、营养干预和心血管疾病之间的机制相互作用， 疾病（CVD）风险。这些数据将在CVD患者的生物库样本中得到证实。结果将 支持健康营养干预措施提供降低疾病风险的有力策略的范式 与环境毒性损伤相关的炎症性疾病，如动脉粥样硬化， 与接触超级基金污染物有关

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.