發(fā)布時間：2022-12-06 19:14

　　毒理學(xué)的核心內(nèi)容是劑量效應(yīng)關(guān)系,以進(jìn)行風(fēng)險(xiǎn)評估與管理。劑量效應(yīng)關(guān)系通常采用閾值模型（主要應(yīng)用于非致癌物）和線性非閾值模型（主要應(yīng)用于致癌物）。近年來,一種新的劑量效應(yīng)關(guān)系模型即低劑量刺激、高劑量抑制的雙相劑量效應(yīng)（毒物興奮效應(yīng)）模型引起了廣泛關(guān)注。雙相劑量效應(yīng)模型推翻了傳統(tǒng)毒理學(xué)關(guān)于可通過毒物在高劑量下的效應(yīng)外推其在低劑量時的效應(yīng)的假設(shè),因而對當(dāng)前的風(fēng)險(xiǎn)評估工作是一種挑戰(zhàn)。近幾十年來,基于生物（如老鼠、細(xì)菌、微藻、細(xì)胞等）的生長、繁殖、壽命、生物發(fā)光等指標(biāo),建立的活體與離體生物實(shí)驗(yàn)?zāi)Ｐ捅粡V泛用于毒理學(xué)研究,使得毒性測試快速、廉價、可重復(fù)、穩(wěn)定、靈敏、可靠,因而已被應(yīng)用于實(shí)際的毒性測試和生態(tài)風(fēng)險(xiǎn)評價。肺是高度血管化的器官,暴露于大量通過呼吸和血液循環(huán)進(jìn)入的異生質(zhì)化合物如多氧聯(lián)苯（Polychlorinated biphenyls, PCBs）,因此,肺易受這些有毒化學(xué)品的侵害。本文以不同氯代數(shù)和不同結(jié)構(gòu)的四種PCBs同系物為受試化合物,包括2,2’,3,3’-tetrachlorobiphenyl （PCB40,非共平面4氯）,3,3’,4,4’-tetrachlorobiphenyl ... 

【文章頁數(shù)】：109 頁

【學(xué)位級別】：博士

【文章目錄】：
Acknowledgements
Abstract
摘要
Table of Contents
List of Tables
List of Figures
Chapter 1 Introduction
    1.1. Biphasic dose-response
    1.2. Biphasic dose response and its universality
    1.3. Significance of biphasic dose response in Environmental Science and risk assessmentpractices
    1.4. Polychlorinated bipheuyls sources and transmission routes
    1.5. PCBs exposure routes and health effects
    1.6. Human lungs fibroblast cell
    1.7. Progress in biphasic dose response using growth as end point
    1.8. Molecular and cellular mechanisms of biphasic responses
        1.8.1. Receptor-mediated and cell signaling-mediated biphasic mechanisms
        1.8.2. Antagonist-mediated enhancement of inhibitory responses
    1.9. PCB mediated biphasic dose response mechanisms using in-vivo model
    1.10. PCB mediated biphasic dose response mechanisms using in-vitro model
    1.11. Objectives of the study
    1.12. Research Idea
Chapter 2 Structure dependent four chlorinated PCBs cytotoxic effects to HELF cells andpotential molecular mechanisms
    2.1. Introduction
    2.2. Materials and methods
        2.2.1. Chemicals and reagents
        2.2.2. Cell culture
        2.2.3. Cell proliferation
        2.2.4. Cell cycle distribution and membrane integrity determination
        2.2.5. Western blot analysis
        2.2.6. Statistical analysis
    2.3. Results
        2.3.1. HELF cells proliferation induced by PCB40 and PCB77
        2.3.2. Response of membrane integrity
        2.3.3. HELF cell cycle and apoptosis
        2.3.4. Cyclin,kinases and capases protein expression
    2.4. Discussion
    2.5. Conclusion
Chapter 3 Biphasic dose response of non-coplanar and coplanar PCB with five chlorinationexposed to HELF cells and potential molecular mechanisms
    3.1. Introduction
    3.2. Materials and methods
        3.2.1. Chemicals and reagents
        3.2.2. Cell culture
        3.2.3. Cell proliferation test
        3.2.4. Measurement of oxidative stress
        3.2.5. Measurement of antioxidant enzymes
        3.2.6. Measuremnt of DNA damage
        3.2.7. Protein assay
        3.2.8. Western blot analysis
        3.2.9. Statistical analysis
    3.3. Results
        3.3.1. HELF cells proliferation induced by PCB101 and PCB118
        3.3.2. Oxidative stress induced by PCB101 and PCB118
        3.3.3. Antioxidant enzymes induced by PCB101 and PCB118
        3.3.4. DNA damage induced by PCB101 and PCB118
        3.3.5. Response of MAPK proteins exposed to PCB101 and PCB118
    3.4. Discussion
    3.5. Conclusion
Chapter 4 Conclusion and future perspectives
    4.1 Research a biphasic dose-response relationship by PCBs congeners
        4.1.1 Cellular process and oxidative stress
        4.1.2 Cell cycle related protein and MAPK pathway
    4.2 Application of the research
    4.3 Prospects
References
Curriculum Vitae



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