Understanding the influence of n-3 PUFA on pro-inflammatory aspects of mercury

描述(申请人提供)：环境重金属污染物汞(汞)是一种有效的神经毒素和免疫调节剂，在低暴露水平下被认为是导致认知障碍以及动物模型和人类群体中炎症和自身免疫性疾病的因素。然而，对也食用大量鱼类的低水平汞中毒人群的流行病学研究似乎表明，这些人群比同等水平的汞中毒人群更能抵抗汞的有害影响，这些人群不消费如此大量的鱼。由于鱼类含有特别高水平的n-3多不饱和脂肪酸(n-3 PUFA)，有人认为低水平汞中毒的有害影响可以通过饮食摄入n-3多不饱和脂肪酸来抵消。目前还没有关于n-3多不饱和脂肪酸如何与汞相互作用以防止低水平中毒的有害影响的机制了解。然而，我们先前已经证明，低水平汞中毒的一个后果是Fas(CD95)介导的信号转导和激活导致免疫系统中的细胞死亡(AICD)受到抑制。CD95信号和AICD在维持免疫系统动态平衡方面具有重要的生理意义，在动物和人类中，CD95信号的减弱与以淋巴结病和狼疮样炎性免疫病理为特征的自身免疫增殖性综合征有关。另一方面，一些研究人员报告说，n-3多不饱和脂肪酸具有抗炎特性，因为富含这些脂肪酸的饮食在改善几种自身免疫性疾病方面是有效的。值得注意的是，也有报道称n-3多不饱和脂肪酸的抗炎作用可能与其增强CD95信号和AICD的能力有关。这些发现导致了一种假设，即高饮食输入的n-3PUFA将通过恢复CD95正确地向激活的但汞中毒的淋巴细胞发出AICD信号的能力来防止低水平汞中毒的有害影响。这一提议旨在严格检验这一假设。将采用体外和体内模型，其中计划利用西方印迹技术，以及基于流式细胞仪的技术来绘制CD95信号网络。 公共卫生相关性：流行病学研究表明，高n-3多不饱和脂肪酸(n-3 PUFA)的饮食可以抵消与低水平汞(Hg)中毒相关的有害影响。我们之前的工作表明，低水平汞暴露有害的至少一个原因是免疫系统中的Fas(CD95)信号被破坏。本研究的目的是研究n-3多不饱和脂肪酸是否抵消汞中毒的有害影响，因为通过CD95途径的信号恢复。

DESCRIPTION (provided by applicant): The environmental heavy metal contaminant mercury (Hg) is a potent neurotoxin and immunomodulator that at low exposure levels has been implicated as a factor contributing to cognitive impairment as well as to inflammation and autoimmune disease in animal models and in human populations. However epidemiological studies of low level Hg intoxicated populations who also consume large amounts of fish, seem to show that these populations are more resistant to the detrimental effects of Hg than are equally Hg intoxicated populations who do not consume such large quantities of fish. Since fish have particularly high levels of n-3 polyunsaturated fatty acids (n-3 PUFA), it has been suggested that detrimental effects of low-level Hg intoxication may be counteracted by dietary ingestion of n-3 PUFA. Presently there is no mechanistic understanding of how n-3 PUFA might interact with Hg so as to prevent the harmful effects of low-level intoxication. However we have previously shown that one consequence of low-level Hg intoxication is that Fas (CD95) mediated signal transduction and activation induced cell death (AICD) in the immune system is depressed. CD95 signaling and AICD are physiologically important in maintaining immune system homeostasis, and attenuation of CD95 signaling is well known to be associated with an autoimmune proliferative syndrome characterized by lymphadenopathy and a lupus-like inflammatory immunopathology in animals and humans. On the other hand, several investigators have reported that n-3 PUFA have anti- inflammatory properties, as diets rich in these fatty acids are effective in ameliorating several autoimmune diseases. Significantly, it has also been reported that the anti-inflammatory properties of n-3 PUFA may be linked to their ability to enhance CD95 signaling and AICD. These findings lead to the hypothesis that high dietary inputs of n-3 PUFA will prevent harmful effects of low-level Hg intoxication by restoring the ability of CD95 to properly signal AICD in activated, but Hg intoxicated lymphocytes. This proposal is designed to rigorously test this hypothesis. Both in vitro and in vivo models will be employed, where the plan is to utilize western blotting techniques, as well as flow cytometric-based technology to map CD95 signaling networks. PUBLIC HEALTH RELEVANCE: Epidemiological studies suggest that diets high in n-3 polyunsaturated fatty acids (n-3 PUFA) can counteract detrimental effects associated with low-level mercury (Hg) intoxication. Our previous work has shown that at least one reason why low-level Hg exposure is harmful is because Fas (CD95) signaling in the immune system is disrupted. The purpose of this research is to investigate whether n-3 PUFA counteracts the harmful effects of Hg intoxication because signaling through the CD95 pathway is restored.