环境中苯系污染物与人类肿瘤相关DNA的相互作用研究

发布时间：2019-01-28 18:43

【摘要】：有机物种类繁多,应用广泛,因此常被用于人类生活资料中作为各种主、副材料,例如在衣食住行方面分别各有以下应用：衣物染料、食品添加剂、车辆燃料、日用品着色剂、增塑剂等等,而有机物被用作生活资料的同时也会在另一方面成为污染物,并引起相关影响人类生活的问题,例如：机动车尾气污染、食品安全问题、气候异常等等。可以说在生活环境中处处都会接触到各类有机物,对人类健康产生威胁。目前,各类环境中有机污染物与肿瘤相关疾病的关系被各领域广泛关注。癌症是基因引起的疾病,与人类相关的肿瘤相关DNA来源于原癌基因和抑癌基因。原癌基因参与促进细胞成长、进行有丝分裂,是致癌基因的前体,而抑癌基因则负责抑制细胞生长或是调控细胞分裂。当调控细胞生长的基因发生损坏或突变时,细胞失去控制,进行持续生长发展成为肿瘤。本文选取了三类有机污染物：多环芳烃衍生物类(简称PAHs,包括1-羟基芘、1-氨基芘、1-芘丁醇、1-芘丁胺)；多氯联苯类(简称PCBs,包括三氯联苯、四氯联苯、五氯联苯、六氯联苯)；内分泌干扰物(三氯生(TCS)、双酚A(BPA)),分别与两种肿瘤相关基因启动子区DNA(抑癌基因p53和原癌基因C-myc),运用多种谱学方法和聚丙烯酰胺凝胶电泳手段在分子水平上研究其相互作用机制,并探求不同结构(官能团种类、官能团长度、官能团位置及分子平面性)对不同序列DNA的作用影响。主要结论为：(1)PAHs的短链取代基可增加共轭π键的离域化程度,使其易与DNA碱基对之间发生偶极作用,而长链取代基可使分子极性增加,利于嵌插复合物的稳定性；-OH取代PAHs主要以沟槽和嵌插模式与DNA作用,-NH2取代PAHs主要以静电和嵌插模式与DNA作用；而对于同类取代基的PAHs与DNA的结合能力,短链取代强于长链取代；PAHs与p53DNA亲合力比C-myc DNA更强。(2)PCBs主要通过嵌插作用和静电作用与2种DNA结合,PCBs本身的类平面性提供了嵌插作用的可能性,且C1原子使PCBs具有正的静电势从而与DNA存在静电作用,双重作用使PCBs对DNA结构产生影响。(3)TCS部分嵌插入双螺旋DNA的沟区,且对p53相关DNA表现出更强的结合能力,且引起DNA双螺旋结构发生改变；双酚A与人类肿瘤相关DNA的作用为嵌插和静电作用,其结合能够影响双螺旋结构并使得双螺旋DNA含量减少。
[Abstract]:Organic compounds are widely used in many kinds of living materials, such as clothing, food, food and transportation. They are used as clothing dyes, food additives, vehicle fuels, daily necessities coloring agents. Plasticizers and so on, while organic matter is used as a means of living, it will also become a pollutant on the other hand, and cause related problems affecting human life, such as motor vehicle exhaust pollution, food safety problems, climate anomalies, etc. It can be said that in the living environment everywhere will be exposed to all kinds of organic matter, which is a threat to human health. At present, the relationship between various kinds of environmental organic pollutants and tumor-related diseases has been widely concerned. Cancer is a disease caused by genes. Human tumor-related DNA is derived from proto-oncogenes and tumor suppressor genes. Proto-oncogenes are involved in promoting cell growth and mitosis, and are precursors of oncogenes, while tumor suppressor genes are responsible for inhibiting cell growth or regulating cell division. When the gene that regulates cell growth is damaged or mutated, the cell loses control and continues to grow into a tumor. In this paper, three kinds of organic pollutants were selected: polycyclic aromatic derivatives (PAHs,) including 1-hydroxy pyrene, 1-aminopyrene, 1-pyrene butanol, 1-pyrene butylamine; Polychlorinated biphenyls (PCBs, for short including trichlorinated biphenyls, tetrachlorinated biphenyls, pentachlorinated biphenyls, hexachlorobenzenes); Endocrine disruptors (trichlorogenic (TCS), bisphenol A (BPA), and two kinds of tumor-associated gene promoter region DNA (suppressor gene p53 and proto-oncogene C-myc), respectively. Various spectroscopic methods and polyacrylamide gel electrophoresis were used to study the interaction mechanism at the molecular level, and to find out the different structures (functional groups, length of functional groups). The effect of functional group location and molecular planarity on the action of different sequences of DNA. The main conclusions are as follows: (1) the short chain substituents of PAHs can increase the degree of delocalization of conjugated 蟺 bonds and make it easy to interact with the DNA base pairs, while the long chain substituents can increase the molecular polarity and facilitate the stability of the intercalated complexes; -OH replaces PAHs mainly by groove and intercalation mode with DNA,-NH2 replaces PAHs by electrostatic and intercalation mode with DNA, and for PAHs and DNA of the same substituent, short chain is stronger than long chain. The affinity of PAHs to p53DNA is stronger than that of C-myc DNA. (2) PCBs binds to two kinds of DNA mainly through intercalation and electrostatic interaction. PCBs itself provides the possibility of intercalation. Moreover, C1 atom makes PCBs have positive electrostatic potential and has electrostatic interaction with DNA, and double action makes PCBs influence the structure of DNA. (3) TCS partially inserts the furrow region of double helix DNA, and shows stronger binding ability to p53 related DNA. The double helix structure of DNA was changed. The interaction between bisphenol A and human tumor-related DNA is intercalation and electrostatic interaction, which can affect the double helix structure and decrease the content of double helix DNA.
【学位授予单位】：南京师范大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R114

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