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题名: 持久性有机污染物2,3,7,8-TCDD和得克隆602的 免疫效应及机理研究
作者: 丰昱
学位类别: 博士
答辩日期: 2016-04
授予单位: 中国科学院研究生院
授予地点: 北京
导师: 赵斌
关键词: TCDD,得克隆602,免疫毒性,T细胞分化,B细胞分化 ; TCDD, Dec602, immunotoxiciy, T cell differentiation, B cell differentiation
其他题名: Mechanism study on immunotoxicity of persistent organic pollutants 2,3,7,8-TCDD and Dechlorane 602
学位专业: 环境科学
中文摘要:       免疫系统稳态的维持是生物体各项生命活动正常进行的基础之一,外源化合物的暴露可以导致免疫毒性效应,破坏免疫系统平衡。世界卫生组织发布的统计数据显示,环境污染物暴露导致的免疫毒性效应是多种疾病发生发展的重要诱因。环境污染物主要是人类生产生活过程中排放的各类化学物质,其中既有一直以来研究较多的传统污染物如持久性有机污染物,也有一些在环境中新检出的物质,如新型得克隆类阻燃剂。二恶英是首批被列入斯德哥尔摩公约受控名单的持久性有机污染物,一直以来也是环境污染物与人类健康效应研究中的一个重要研究对象。而得克隆602作为新型氯代阻燃剂被应用于生产生活中。研究表明其具有持久性有机污染物的特征,已在包括极地等全球多个地区的多种环境介质及动物体中检出,在日常饮食和人体也有检出,表明人类处于得克隆类物质暴露的风险中。然而目前还没有其毒理效应的研究。因此深入探索传统持久性有机污染物二恶英类物质的免疫毒理效应机制并初步评价新型污染物得克隆602的免疫健康效应有着重要意义。
    研究表明,二恶英长期和短期暴露均可导致哺乳动物体液免疫受到抑制,抗体分泌降低。这一过程可能其是抑制B淋巴细胞成熟分化而导致的,然而其中的分子机制,尤其是长期低剂量暴露条件下的机制还没有得到全面阐述。本研究中,我们使用低剂量长期暴露的条件研究其对小鼠免疫功能的影响,将传统的免疫毒理研究手段流式细胞术与新型高通量悬浮芯片检测技术及转录组学测序和生物信息学分析相结合,探索二恶英对长期暴露后小鼠脾脏分离的B淋巴的细胞毒性效应的分子机制。研究发现,与前人发现一致,抗体分泌受到明显抑制,细胞免疫也受到抑制。结合对B淋巴细胞转录组测序及后续生物信息学分析,我们发现B淋巴细胞的分化受到抑制,同时一系列与AhR和cAMP信号通路相关的基因表达发生了变化,表明cAMP信号通路参与了二恶英对B淋巴细胞毒性效应的调控,这种影响可能是通过与AhR信号通路相互作用形成的。此外,针对差异表达基因的进一步生物信息学分析还提示二恶英的长期暴露可能通过Ephrin信号通路导致B淋巴细胞发生非霍奇金淋巴瘤癌变,并提出了一系列长期暴露条件下,二恶英对B淋巴细胞毒性效应的新的靶基因。研究为全面理解二恶英针对B淋巴细胞的毒性效应和机制奠定了基础。
    在对新型污染物的免疫毒理研究中,我们应用动物体内实验及原代免疫细胞体外培养系统开展了得克隆602的免疫毒理效应研究,其中重点关注环境剂量急性暴露导致的对T淋巴细胞分化和B淋巴细胞功能的影响。在动物实验中,我们发现得克隆602暴露后,小鼠脾脏中Th1细胞和Th2细胞的转录因子的mRNA表达发生变化,同时脾脏中Th1细胞主要分泌的促炎性细胞因子减少,Th2细胞主要分泌的抗炎性细胞因子增加,结合血清中IgG1和IgG2a比例的变化,说明得克隆602可以使Th1/Th2平衡向着Th2方向发展,即抗炎效应增强。同时,血清中抗体的分泌量减少。这些结果说明得克隆602暴露可以导致机体免疫抑制效应的产生,削弱机体对微生物病原体等感染的抵抗力。我们在体外实验中初步验证了得克隆602抑制了Th0细胞向Th1细胞的分化,然而其分子机制还需要进一步探索,同时得克隆602的其他免疫学效应也应进行更加深入细致的研究。
    综上所述,本研究将传统免疫毒理的研究方法及新兴的生物技术相结合,一方面深入了对传统的免疫毒性污染物二恶英的B细胞免疫毒理机制的理解,并提出了非霍奇金淋巴瘤相关的新的毒理研究方向;另一方面也获得了新型污染物得克隆602存在免疫抑制效应的新数据。
英文摘要:       Homeostasis of the immune system is essential to maintain the well-functional status of human being. Chemical exposure can result in immunotoxicity, ranging from infection to autoimmune conditions. According to the statistical data released by World Health Organization (WHO), incidence of an increasing number of diseases is related to immunotoxicity caused by environmental pollutant exposure. Environmental pollutants are various kinds of chemicals discharged from human manufacture into the environment, among which not only traditional pollutants such as persistent organic pollutants (POPs) are characterized, there are also newly detected pollutants in the environment like Dechloranes. Dioxins are among the notorious dirty dozen and have been banned by Stockholm Convention. Generally, they are regarded as important subjects to demonstrate the relationship of environmental pollutants and biological health. Dechlorane 602 (Dec 602) which is used as a flame retardant shows some typical charcateristics of POPs, Dec 602 has been detected in various environmental media, even which collected from the polar area, and human breast milk as well as human serum. These suggest that human beings are bearing constant risk of Dec 602 exposure. To our knowledge, there is no report regarding the health effects of Dec 602, so it is of great importance to explore its toxic effects.
      Our results showed that exposure to dioxins lead to both humoral immune and cellular immune response supperssion. Dioxin exposure can significantly reduce antibody secretion, possibly by interfering B cell maturation into antibody secreting plasma cells. But the involving molecular mechanisms, especially in long-term dioxin exposure are not fully elucidated. In the current study, we used a long-term exposure murine model to study the effects of dioxins on mouse immune response. By traditional methods including flow cytometry and new high throughput Luminex analysis and transcriptome study, we studied immunotoxicity of isolated spleen B cells in the long-term exposure. We found that both humoral and cellular immune responses were suppressed, which is consistent with previous studies. The results of bioinformatics analysis showed that B cell differentiation was suppressed and a set of differentially expressed genes regulated by AhR and cAMP signaling pathways were identified, which indicates cAMP signaling pathway is involved in TCDD-induced differentiation suppression of B cell, and there might be crosstalk between cAMP signaling pathway and AhR signaling pathway. Besides, we found that TCDD could induce non-Hodgkin lymphoma by activating Ephrin signaling pathway. A set of novel target genes of TCDD induced B cell toxicity was also filed. This study establishes a foundamental research for better understanding toxicity and mechanisms of B cells in TCDD long-term exposure.
      In the immunotoxicity of emerging POPs, we used mouse model and primary lymphocytes cultivation to study the immune effects of Dec 602, especially its effects on T cell differentiation and B cell function after an acute exposure with environmental related doses. In animal experiment, pro-inflammation cytokines secreted by Th1 cells decreased while anti-inflammation cytokines secrected by Th2 cells increased. Transcriptional factors alterations at mRNA level and antibody secretion pattern change also suggested that Th1/Th2 balance shifted to Th2 response, which means that anti-inflammation responses are enhanced. These results, together with the fact that serum antibody decrease suggest that acute Dec 602 exposure results in immunosuppression. In vitro experiment verified that Dec 602 suppressed the differentiation of Th0 towards Th1 cell subset, however, the underlying molecular mechanism remains to be explored. Besides immunosuppression, other immune effects of Dec 602 are worth studying.
      In summary, the current study combines traditional methods and emerging biotechnologies to elucidate immunotoxicity of TCDD on B cells, we proposed a new study hypothesis regarding non-Hodgkin lymphoma. On the other hand, we get first hand data of immunosuppression effects of emerging POPs Dec 602, which provides guidance of its production and consumption.
内容类型: 学位论文
URI标识: http://ir.rcees.ac.cn/handle/311016/36790
Appears in Collections:环境化学与生态毒理学国家重点实验室_学位论文

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Recommended Citation:
丰昱. 持久性有机污染物2,3,7,8-TCDD和得克隆602的 免疫效应及机理研究[D]. 北京. 中国科学院研究生院. 2016.
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