【摘要】：全球的污染物排放增加,帶來了巨大的健康和環(huán)境問題。重金屬如鎘(Cd)、鉛(Pb)、銅(Cu)、鉻(Cr),具有高毒性,是重要的環(huán)境污染物,通過工業(yè)廢水、城市和礦業(yè)資源等排放到環(huán)境中,到達(dá)水生環(huán)境,在水生生物體內(nèi)積累,經(jīng)由食物鏈對(duì)人類造成危害。斑馬魚是一種對(duì)環(huán)境污染物較為敏感的模式生物,已被廣泛應(yīng)用于胚胎發(fā)育毒理學(xué)、環(huán)境毒理學(xué)、病理毒理學(xué)、藥物毒理學(xué)等多個(gè)領(lǐng)域,并展現(xiàn)出其特有的優(yōu)勢(shì)。 本研究旨在全面評(píng)價(jià)重金屬(鎘,鉛,銅,鉻)對(duì)斑馬魚的毒性效應(yīng),了解重金屬毒性作用的特點(diǎn)、性質(zhì)、程度及毒性作用機(jī)制,明確重金屬(鎘,鉛,銅,鉻)對(duì)斑馬魚抗氧化防御系統(tǒng),細(xì)胞凋亡及免疫系統(tǒng)的毒性作用及其機(jī)制,為闡明重金屬毒性作用和重金屬污染的環(huán)境風(fēng)險(xiǎn)評(píng)估提供依據(jù)。主要研究?jī)?nèi)容包括：重金屬(鎘,鉛,銅,鉻)對(duì)斑馬魚抗氧化能力指數(shù)的影響、重金屬鎘(Cd)對(duì)斑馬魚成魚和胚胎的毒性作用及機(jī)制研究、重金屬鉛(Pb)對(duì)斑馬魚成魚和胚胎的毒性作用及機(jī)制研究、重金屬銅(Cu)對(duì)斑馬魚成魚的毒性作用研究、重金屬鉻(Cr)對(duì)斑馬魚成魚的毒性作用研究。主要研究結(jié)果如下： 1)本研究以抗氧化能力指數(shù)(Oxygen radical absorbance capacity, ORAC)檢測(cè)方法為基礎(chǔ),建立一種機(jī)體清除自由基能力的檢測(cè)方法,并應(yīng)用于生物抗氧化能力的的評(píng)價(jià)。研究選用國際標(biāo)準(zhǔn)試驗(yàn)用魚-斑馬魚作為試驗(yàn)生物,針對(duì)過氧自由基(ROO·)進(jìn)行檢測(cè),以偶氮化合物AAPH作為氧自由基來源,熒光素鈉(FL)為熒光指示劑,并以維生素E類似物Trolox為定量標(biāo)準(zhǔn),觀察自由基與熒光素鈉作用后熒光強(qiáng)度的衰退過程,檢測(cè)各種物質(zhì)加入反應(yīng)體系后延緩熒光素鈉熒光強(qiáng)度衰退的能力,以此評(píng)價(jià)反應(yīng)體系中抗氧化劑的抗氧化能力。本研究所建立的定量分析方法具有特異性強(qiáng)；精密度高,變異系數(shù)小于5%；準(zhǔn)確度在97%-108%之間；重現(xiàn)性佳(變異系數(shù)是2.92%)；定量檢出限和最低檢測(cè)限分別為3.03和1.00μmol Trolox/mg protein,可接受相關(guān)系數(shù)(R2)≥0.99。依據(jù)所建立的定量分析方法對(duì)斑馬魚ORAC生理正常值進(jìn)行檢測(cè),正常值范圍為0-50μmol Trolox/mg protein,并根據(jù)重金屬對(duì)斑馬魚ORAC的影響,對(duì)重金屬的污染程度和毒性效應(yīng)進(jìn)行了評(píng)級(jí)和分類,提高了試驗(yàn)數(shù)據(jù)互認(rèn)程度,推動(dòng)了抗氧化防御系統(tǒng)生物標(biāo)志物在環(huán)境污染監(jiān)測(cè)中的應(yīng)用。 2)重金屬鎘(Cd)對(duì)斑馬魚成魚和胚胎的毒性作用及機(jī)制研究結(jié)果表明：重金屬Cd對(duì)斑馬魚成魚和胚胎的96h-LCso分別為24.341mg/L和46.67mg/L,胚胎孵化抑制作用的96h-EC50為42.499mg/L。重金屬Cd引起斑馬魚成魚SOD活性升高,MDA含量增加,ROS水平明顯升高；抗氧化防御系統(tǒng)相關(guān)基因Mn-SOD,Cu/Zn-SOD, Nrf2,HO-1mRNA表達(dá)水平上調(diào)；細(xì)胞凋亡相關(guān)基因bc1-2mRNA表達(dá)水平下調(diào),而p53mRNA表達(dá)水平上調(diào)；免疫系統(tǒng)相關(guān)基因-α,IL-1β,INF-γ和IL-8mRNA表達(dá)水平均顯著性升高；MAPKs信號(hào)轉(zhuǎn)導(dǎo)通路相關(guān)基因p38a,p38b,ERK2,ERK3和核轉(zhuǎn)錄因子AP-1亞家族c-jun mRNA表達(dá)水平均上升。重金屬Cd引起斑馬魚胚胎心率減慢,體長(zhǎng)減��；ROS水平顯著升高；抗氧化防御系統(tǒng)相關(guān)基因Mn-SOD,Cu/Zn-SOD,CAT,Nrf2,HO-1mRNA表達(dá)水平上調(diào)；細(xì)胞凋亡相關(guān)基因bc1-2和p53mRNA表達(dá)水平均上調(diào)；免疫系統(tǒng)相關(guān)基因TNF-a,IL-1β,INF-y mRNA表達(dá)水平均顯著性升高；MAPKs信號(hào)轉(zhuǎn)導(dǎo)通路相關(guān)基因p38a,p38b,ERK2,ERK3,JNK1和核轉(zhuǎn)錄因子AP-1亞家族c-jun,c-fos以及NF-κB亞家族relA mRNA表達(dá)水平均升高。以上結(jié)果提示Cd對(duì)斑馬魚成魚和胚胎均具有明顯的毒性作用,能夠誘導(dǎo)氧化應(yīng)激,細(xì)胞凋亡及免疫毒性的發(fā)生,毒性作用機(jī)制與MAPKs信號(hào)轉(zhuǎn)導(dǎo)通路相關(guān)。 3)重金屬鉛(Pb)對(duì)斑馬魚成魚和胚胎的毒性作用及機(jī)制研究結(jié)果表明：重金屬Pb對(duì)斑馬魚成魚和胚胎的96h-LC50分別為0819mg/L口22.574mg/L,胚胎孵化抑制作用的96h-ECso為19.594mg/Lo重金屬Pb引起斑馬魚成魚SOD活性升高,MDA含量增加,ROS水平明顯升高；抗氧化防御系統(tǒng)相關(guān)基因Mn-SOD,Cu/Zn-SOD,Nrf2,HO-1mRNA表達(dá)水平上調(diào)；細(xì)胞凋亡相關(guān)基因bcl-2mRNA表達(dá)水平下調(diào),而p53mRNA表達(dá)水平上調(diào)；免疫系統(tǒng)相關(guān)基因TNF-a,IL-1β, INF-γ和IL-8mRNA表達(dá)水平均顯著性升高：MAPKs信號(hào)轉(zhuǎn)導(dǎo)通路相關(guān)基因p38a,p38b, ERK2,JNK1和核轉(zhuǎn)錄因子AP-1亞家族c-jun, c-fos以及NF-κB亞家族nfkb2mRNA表達(dá)水平均上升。重金屬Pb引起斑馬魚胚胎心率減慢,體長(zhǎng)減�。籖OS水平顯著升高；抗氧化防御系統(tǒng)相關(guān)基因Mn-SOD,Cu/Zn-SOD,CAT,Nrf2,HO-1mRNA表達(dá)水平上調(diào)；細(xì)胞凋亡相關(guān)基因bc1-2和p53mRNA表達(dá)水平均上調(diào)；免疫系統(tǒng)相關(guān)基因TNF-α,IL-1βINF-γ mRNA表達(dá)水平均顯著性升高；MAPKs信號(hào)轉(zhuǎn)導(dǎo)通路相關(guān)基因p38a,p38b,ERK2,ERK3,JNK1和核轉(zhuǎn)錄因子AP-1亞家族c-jun,c-fos以及NF-κB相關(guān)基因relA mRNA表達(dá)水平均上升。以上結(jié)果提示Pb對(duì)斑馬魚成魚和胚胎均具有明顯的毒性作用,能夠誘導(dǎo)氧化應(yīng)激,細(xì)胞凋亡及免疫毒性的發(fā)生,毒性作用機(jī)制與MAPKs信號(hào)轉(zhuǎn)導(dǎo)通路相關(guān)。 4)重金屬銅(Cu)對(duì)斑馬魚成魚的毒性作用研究結(jié)果表明：重金屬Cu對(duì)斑馬魚成魚的96h-LC5o0為0.462mg/L;引起SOD活性升高,MDA含量增加,ROS水平明顯升高；抗氧化防御系統(tǒng)相關(guān)基因Mn-SOD,Cu/Zn-SOD,Nrf2,mRNA表達(dá)水平上調(diào)；細(xì)胞凋亡相關(guān)基因p53mRNA表達(dá)水平上調(diào)；免疫系統(tǒng)相關(guān)基因TNF-a, IL-1β, INF-γ(?)IL-8mRNA表達(dá)水平均顯著性升高。以上結(jié)果提示Cu對(duì)斑馬魚成魚具有明顯的毒性作用,能夠誘導(dǎo)氧化應(yīng)激,細(xì)胞凋亡及免疫毒性的發(fā)生。 5)重金屬鉻(Cr)對(duì)斑馬魚成魚的毒性作用研究結(jié)果表明：重金屬Cr對(duì)斑馬魚成魚的96h-LC5o為113.808mg/L；引起SOD活性升高,MDA含量增加,ROS水平明顯升高；抗氧化防御系統(tǒng)相關(guān)基因Mn-SOD,Cu/Zn-SOD,Nrf2,mRNA表達(dá)水平上調(diào)；細(xì)胞凋亡相關(guān)基因p53mRNA表達(dá)水平上調(diào)；免疫系統(tǒng)相關(guān)基因TNF-a, IL-1β, INF-γ和IL-8mRNA表達(dá)水平均顯著性升高。以上結(jié)果提示Cr對(duì)斑馬魚成魚具有明顯的毒性作用,能夠誘導(dǎo)氧化應(yīng)激,細(xì)胞凋亡及免疫毒性的發(fā)生。 本研究對(duì)傳統(tǒng)的ORAC方法進(jìn)行了一定程度上的改良,并將此法應(yīng)用于環(huán)境污染監(jiān)測(cè)和毒理學(xué)研究,研究了重金屬(鎘,鉛,銅,鉻)對(duì)斑馬魚抗氧化防御系統(tǒng)的影響,并全面評(píng)價(jià)了重金屬(鎘,鉛,銅,鉻)對(duì)斑馬魚成魚和胚胎的毒性效應(yīng)及作用機(jī)制,發(fā)現(xiàn)氧化應(yīng)激,細(xì)胞凋亡和免疫毒性之間存在著緊密的聯(lián)系。
[Abstract]:Heavy metals, such as cadmium (Cd), lead (Pb), copper (Cu), and chromium (Cr), are highly toxic and are important environmental pollutants. They are discharged into the environment through industrial waste water, urban and mining resources, and accumulate in aquatic organisms and are caused by food chains. Zebrafish is a more sensitive model organism for environmental pollutants. It has been widely used in many fields, such as embryonic development toxicology, environmental toxicology, pathological toxicology, drug toxicology and so on, and has shown its unique advantages.
The purpose of this study is to evaluate the toxic effects of heavy metals (cadmium, lead, copper and chromium) on zebrafish, to understand the characteristics, properties, degree and mechanism of toxic effects of heavy metals, and to clarify the toxic effects and mechanisms of heavy metals (cadmium, lead, copper, chromium) on zebrafish antioxidant defense system, cell apoptosis and immune system, in order to clarify the toxicity of heavy metals. The effects of heavy metals (cadmium, lead, copper, chromium) on the antioxidant capacity index of zebrafish, the toxic effects and mechanisms of heavy metal cadmium (Cd) on zebrafish adult and embryos, the toxicity and mechanism of heavy metal lead (Pb) on the adult and embryo of zebrafish, are the main contents of the study. The toxic effects of heavy metal copper (Cu) on adult zebrafish were studied. The toxic effects of heavy metal chromium (Cr) on adult zebrafish were studied.
1) based on the Oxygen radical absorbance capacity (ORAC) detection method, a method for detecting the free radical scavenging capacity of the body was established and applied to the evaluation of biological antioxidant capacity. The study selected the international standard test fish zebra fish as experimental creature and the peroxy free radical (ROO). By using azo compound AAPH as the source of oxygen free radicals, fluorescein sodium (FL) as a fluorescent indicator, and using the vitamin E analogue Trolox as the quantitative standard, the fluorescence intensity decline process after the action of free radicals and fluorescein sodium was observed, and the ability to delay the fluorescence intensity decline of fluorescein sodium after various substances were added to the reaction system was evaluated. The anti oxidant ability of the antioxidant in the system of valence reaction. The quantitative analysis method established in this study is specific, high precision, the coefficient of variation is less than 5%; the accuracy is between 97%-108%; the reproducibility is good (the coefficient of variation is 2.92%); the quantitative detection limit and the minimum detection limit are 3.03 and 1 mu mol Trolox/mg protein, acceptable The correlation coefficient (R2) > 0.99. was measured on the normal value of zebrafish ORAC according to the quantitative analysis method established. The normal range was 0-50 Mu mol Trolox/mg protein. According to the influence of heavy metal on zebrafish ORAC, the pollution degree and toxic effect of heavy metals were rated and classified, and the degree of mutual recognition of the test data was improved. The application of biomarkers of antioxidant defense system in environmental pollution monitoring has been activated.
2) the toxic effect and mechanism of heavy metal cadmium (Cd) on the adult and embryo of zebrafish showed that the 96h-LCso of heavy metal Cd to zebrafish adult and embryo was 24.341mg/L and 46.67mg/L respectively. The 96h-EC50 of the inhibition of embryo hatching was 42.499mg/L. heavy metal Cd that caused the increase of SOD activity of the zebrafish fish, the MDA content increased and the ROS level was obvious. The expression level of Mn-SOD, Cu/Zn-SOD, Nrf2 and HO-1mRNA was up regulation, the expression level of bc1-2mRNA was down, and the expression level of p53mRNA was up regulated, and the expression level of the immune system related genes - alpha, IL-1 beta, INF- - y and IL-8mRNA were all significantly increased; the MAPKs signal transduction pathway related genes P3 The expression level of c-jun mRNA in 8a, p38b, ERK2, ERK3 and nuclear transcription factor AP-1 subfamily all increased. Heavy metal Cd caused the heart rate of zebrafish embryos to slow down, the body length decreased, and the ROS level increased significantly; the expression level of anti oxidant defense system related genes Mn-SOD, Cu/Zn-SOD, CAT, and expressions were up regulated; apoptosis related genes and expressions and expressions The levels of the immune system related genes TNF-a, IL-1 beta, and INF-y mRNA increased significantly, and the MAPKs signal transduction pathway related gene p38a, p38b, ERK2, ERK3, JNK1 and nuclear factor AP-1 subfamily c-Jun, as well as the nuclear factor kappa family were both elevated. Both have obvious toxic effects, which can induce oxidative stress, apoptosis and immune toxicity. The mechanism of toxicity is related to MAPKs signal transduction pathway.
3) the toxic effect and mechanism of heavy metal lead (Pb) on zebrafish adult and embryo showed that the 96h-LC50 of heavy metal Pb to zebrafish adult and embryo was 0819mg/L 22.574mg/L respectively. The 96h-ECso of inhibition of embryo hatching was 19.594mg/Lo heavy metal Pb causing the increase of SOD activity of zebrafish adult fish, MDA content increased, ROS level was obvious. The expression level of Mn-SOD, Cu/Zn-SOD, Nrf2, HO-1mRNA was up regulated, the expression level of bcl-2mRNA was down, and the expression level of p53mRNA was up regulated, and the expression levels of TNF-a, IL-1 beta, INF- gamma and IL-8mRNA in the immune system related genes were significantly increased: MAPKs signal transduction pathway related genes. P38a, p38b, ERK2, JNK1 and nuclear transcription factor AP-1 subfamily c-Jun, c-fos and NF- kappa B subfamily nfkb2mRNA expression level increased. Heavy metal Pb caused zebrafish embryo heart rate slowing, body length decreased; ROS level increased significantly; antioxidant defense system related genes up regulation; cell apoptosis The expression levels of related genes bc1-2 and p53mRNA were all up-regulated, the expression level of TNF- alpha and IL-1 beta INF- gamma mRNA in the immune system related genes increased significantly, and the expression level of MAPKs signal transduction pathway related genes p38a, p38b, ERK2, ERK3, JNK1 and nuclear transcription factor related genes increased. The results suggest that Pb has obvious toxic effects on the adult and embryo of zebrafish, and can induce oxidative stress, cell apoptosis and the occurrence of immuno toxicity, and the mechanism of toxicity is related to the MAPKs signal transduction pathway.
4) the toxicity of heavy metal copper (Cu) to zebrafish adult fish showed that the 96h-LC5o0 of heavy metal Cu to zebrafish was 0.462mg/L, the activity of SOD increased, the content of MDA increased, the level of ROS increased obviously; the levels of Mn-SOD, Cu/Zn-SOD, Nrf2, mRNA expression of the antioxidant defense system related genes were up regulated; apoptosis related genes p53mRNA The expression level of the immune system related genes TNF-a, IL-1 beta, INF- gamma (?) IL-8mRNA increased significantly. The above results suggest that Cu has obvious toxic effects on zebrafish adult fish, and can induce oxidative stress, cell apoptosis and immuno toxicity.
5) the toxic effect of heavy metal chromium (Cr) on zebrafish adult fish showed that the 96h-LC5o of heavy metal Cr to zebrafish was 113.808mg/L, the activity of SOD increased, the content of MDA increased, the level of ROS increased obviously; the expression level of the genes related to antioxidant defense system Mn-SOD, Cu/Zn-SOD, Nrf2, mRNA increased; apoptosis related genes p53m The expression level of RNA was up and the expression level of immune system related genes TNF-a, IL-1 beta, INF- gamma and IL-8mRNA increased significantly. The above results suggest that Cr has obvious toxic effect on zebrafish adult fish, and can induce oxidative stress, cell apoptosis and immuno toxicity.
In this study, the traditional ORAC method was improved to a certain extent. This method was applied to environmental pollution monitoring and toxicology research, and the effects of heavy metals (cadmium, lead, copper and chromium) on the antioxidant defense system of zebrafish were studied. The toxic effects of heavy metals (cadmium, lead, copper, chromium) on the adult and embryo of zebrafish were evaluated. It is found that there is a close relationship between oxidative stress, apoptosis and immune toxicity.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R994

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