Superfund Chemicals, Nutrition, and Multi-Organ Cardiovascular Risk

项目总结 项目1的总体目标是通过以下方式了解信号通路和代谢或生物变化 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 作为多氯联苯(PCBS)和长链全氟烷基物质(PFAS)。是这样的 持久性污染物表示环境中显著的化学稳定性，持久性有机污染物的有毒侮辱是 已知与暴露后对人类健康的一系列影响有关，包括血管炎症。 动脉粥样硬化是一种慢性炎症性疾病，在美国仍然是主要的死亡原因。 与炎症和动脉粥样硬化相关的生物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，它们决定了最终的氧化还原变化和炎症结果，通过 改变核因子-kB和Nrf2信号。例如，初步数据显示PCB126的下调- 由植物衍生的生物活性营养素，例如多酚和纤维(例如， 菊粉)。重要的是，我们知道动脉粥样硬化的病理依赖于健康和串扰。 包括肝脏和肠道在内的多个第三器官系统，最近发现将多氯联苯 暴露于血浆三甲胺N-氧化物(TMAO)水平升高，三甲胺N-氧化物是一种饮食衍生的代谢物 通过肠道微生物区系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。 肠道微生物区系的改变，以及先前的肝脏损伤加剧了多氯联苯介导的全身炎症。 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)可能导致多器官炎症，增加心血管风险。基于这些发现， 三个特定的目标测试假设：1)给小鼠注射多氯联苯126和/或全氟辛烷磺酸增加 通过调节肝脏基因表达增加神经酰胺产生的心脏代谢性疾病风险 和/或肠道微生物区系；2)体内绿茶儿茶素和/或可溶性菊糖纤维的服药减少 神经酰胺，从而稳定细胞的氧化还原状态，调节核因子-kB和Nrf2信号，并促进 致动脉粥样硬化性低密度脂蛋白受体缺陷的En Face和脂质染色确定的动脉粥样硬化病理 3)暴露于多氯联苯和/或全氟辛烷磺酸可通过以下途径增加致动脉粥样硬化的代谢物(如神经酰胺) 在临床前模型中增加从头合成。将使用转录组和代谢组技术 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。这些数据将在生物库中的心血管疾病患者样本中得到证实。结果将 支持健康营养干预提供了降低疾病风险的有力战略的范例 与环境有毒侮辱有关，并预防炎症性疾病，如动脉粥样硬化 与超级基金污染物的暴露有关。

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.