RCEES OpenIR  > 环境化学与生态毒理学国家重点实验室
硒对大鼠体内汞代谢及转化影响研究
张星
Subtype博士后
Thesis Advisor胡立刚
2019-12
Degree Grantor中国科学院生态环境研究中心
Place of Conferral北京
Degree Name理学
Degree Discipline环境科学
Keyword 汞颗粒 形态转化 分子机制
Abstract

        汞的毒性效应与其在生物体内的吸收、分布及形态转化等过程密切相关。硒具有减轻和抑制无机汞和甲基汞毒性的作用,然而所涉及的分子机制尚不清楚。目前推测的几种可能机制均与汞-硒之间的结合与转化密切相关,在海洋哺乳动物体内发现的硒化汞颗粒是其最直接的证据。作为一种惰性汞形态并且极有可能来自于甲基汞,硒化汞颗粒被认为是汞代谢和解毒的最终产物。尽管如此,目前尚未有甲基汞在体内转化为硒化汞颗粒的直接证据,对其生成机制及去向等过程更是知之甚少。受制于分析方法是重要原因之一,难以实现生物体内痕量硒化汞颗粒的有效检测。近年来蓬勃发展的纳米粒子定性/定量分析新技术,为环境和生物样品中痕量纳米粒子的检测提供了新的技术平台。
        本工作利用单颗粒(single particle, SP)-电感耦合等离子体质谱(Inductively Coupled Plasma Mass Spectrometry, ICP-MS)、高效液相色谱(High Performance Liquid Chromatography, HPLC)-ICP-MS 联用等技术手段研究硒化汞颗粒的生成 过程,在分子水平上探讨生物体内HgSe 颗粒的生成机制,探索硒对汞的体内代 谢及转化的影响机制。具体研究内容如下:
        1)在研究硒对汞体内代谢及转化影响时,硒暴露的形态、剂量、暴露方式等将显著影响实验结果。本章工作以大鼠作为模式生物,以亚硒酸钠作为硒源,研究了经灌胃后大鼠体内硒的吸收、代谢、分配、排出行为。结果表明,大鼠体内的硒呈现快速吸收持续排出的特征,最终留在体内的硒比例很低;肝脏、肾脏、血液、肌肉是硒的主要分布组织,分配比随时间变化;硒从尿液和粪便中持续排出,在后期以尿液排出为主;硒从肝脏不断由胆汁排出到肠道,存在肝肠循环过程。
        2)在本章工作中,利用大鼠实验研究了硒对无机汞和甲基汞体内代谢和形态转化的影响。首次证实了在大鼠体内存在硒促进甲基汞转化为含汞颗粒的过程,揭示了生物体内甲基汞去甲基化的一条新途径和新机制;发现了无机汞在体内转化为含汞颗粒的现象,并且当硒存在时血浆中生成的含汞颗粒物占据血浆总汞的比例高达70-80%,表明含汞颗粒可能是硒汞共暴露时生物体内的重要汞形态,对汞的体内代谢转化具有重要意义;硒对无机汞和甲基汞体内代谢和转化的影响存在差异,值得进一步深入研究。
        3) 为了探索硒化汞颗粒生成的分子机制,本章工作利用体外实验研究了汞与含硒生物分子结合与转化的化学过程,揭示了由无机汞(inorganic mercury, iHg)/甲基汞(methylmercury, MeHg)生成HgSe 颗粒的两种可能机制。结果表明,还原型的含硒生物分子(R-SeH 和HSe-)是该过程中的关键分子,而iHg 在该反应中的活性比MeHg 更强。
        本工作通过体内/体外实验研究了HgSe 颗粒体内生成过程及其对汞代谢的影响。首次证实了甲基汞与硒共暴露时在大鼠体内生成HgSe 颗粒的过程,发现硒对iHg/MeHg 向含Hg 颗粒转化具有显著促进作用,并且含Hg 颗粒态占总Hg比例高达8-80%,提示其在Hg 的体内代谢和解毒机制中十分重要。在未来的工作中,将系统深入地研究含Hg 颗粒在体内的生成动力学、体内运输、分布、排出行为及其机制,以期进一步揭示汞的体内代谢过程以及硒汞拮抗的分子机制。
 

Other Abstract

        Toxicity of mercury compounds is related with many in-vivo processes such as absorption, distribution and transformation. Selenium is widely known as an antagonist which can protect organisms from the toxicity of both inorganic mercury and methylmercury (MeHg) while the molecular mechanisms remain underlying.
        According to the high affinity between selenium and mercury, a few key Se-Hg compounds are thought to be very important in several possible mechanisms. Discovery of mercury selenide (HgSe) particles in livers and kidneys in marine mammals and sea birds was a powerful proof for Se-Hg interaction. As a kind of inert mercury species which was probably derived from MeHg, HgSe particles have been deemed to be the ultimate products for mercury metabolism and detoxification. However, there’s still no direct evidence for the in vivo transformation from MeHg to HgSe, let alone knowing the molecular mechanisms, which may due to the limitation of analytical techniques.
        Flourish of techniques for nanoparticles (NPs) quantification and quantitation in recent years provide a new powerful platform for the determination of trace NPs in environmental and biological samples.
In this work, SP-ICP-MS and HPLC-ICP-MS were used to study the formation process of HgSe particles. Formation mechanisms of HgSe particles both in vivo and in vitro were preliminarily explored at the molecular level, which was helpful for the understanding and explanation of selenium’s effect on the metabolism and transformation of mercury. The specific contents include the following parts:
        1) As we all known, the form, dose and exposure pathway of selenium will significantly affect the experimental results. The purpose of this experiment was to study the absorption, metabolism, distribution and excretion of selenite in rats after intragastric administration. The results showed that selenium was rapidly absorbed in rats and continuously excreted, and the final proportion of selenium remained in the body after 10 days was quite low. Liver, kidney, blood and muscle were the main distribution tissues of selenium, and the distribution ratio was time-dependent. Selenium was continuously excreted from urine and feces, mainly in urine in the later period. Selenium was continuously excreted from liver from bile, indicating the exist of enterohepatic circulation.
        2) In this chapter, the effects of selenium on metabolism and transformation of inorganic mercury and methylmercury were studied in vivo. For the first time, HgSe NPs were detected in the liver and kidney of rats after exposure of selenite and MeHg,which provides a new pathway for methylmercury demethylation and detoxification in vivo. It was also found that inorganic mercury transformed into Hg-containing NPs in rats after exposure of HgCl2. When selenium was present, Hg-containing NPs would surprisingly account for 70-80% of the total mercury in plasma, indicating that this new species may be quite important in the metabolism and transformation of mercury during selenium mercury co-exposure. The effects of selenium on the in vivo behavior of Hg2+ and MeHg is worth to be further investigated due to the observed similarity and differences between the two mercury species.
        3) In order to explore the molecular mechanism of the formation of HgSe NPs, the chemical reaction process between mercury and Se-containing biomolecules was studied in vitro. Two possible mechanisms of the formation of HgSe particles from Hg2+ / MeHg were revealed while Hg2+ showed a much stronger activity than MeHg. Besides,it was found that the formation of Se-containing biomolecules in reduced form (R-SeH and HSe-) was essential for HgSe NPs formation.
        In summary, formation process of HgSe particles was studied both in vivo and in vitro and the involved molecular mechanisms and its effect on mercury metabolism were explored. For the first time, the quite direct evidence of HgSe particles deriving from MeHg in vivo was obtained. Selenium was found to significantly enhance the transformation of iHg / MeHg to Hg-containing particles, the proportion of which was as high as 8-80% in total Hg, suggesting that it would be very important in the metabolism and detoxification mechanism of Hg. In the future work, the in vivo generation kinetics, transportation, distribution, excretion behavior of Hg-containing particles and the related mechanisms will be systematically investigated, in order to acquire a better understanding of Hg metabolism and Se-Hg antagonism.

Pages79
Language中文
Document Type学位论文
Identifierhttp://ir.rcees.ac.cn/handle/311016/42354
Collection环境化学与生态毒理学国家重点实验室
Recommended Citation
GB/T 7714
张星. 硒对大鼠体内汞代谢及转化影响研究[D]. 北京. 中国科学院生态环境研究中心,2019.
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