本文選題：砷 + 角化��； 參考：《新疆醫(yī)科大學(xué)》2015年博士論文

【摘要】：目的:本研究通過體內(nèi)、體外實(shí)驗(yàn)對(duì)家兔及人角質(zhì)形成細(xì)胞染砷,了解砷在皮膚角質(zhì)形成細(xì)胞和皮膚組織中的代謝規(guī)律及內(nèi)暴露劑量,觀察砷對(duì)皮膚角質(zhì)形成細(xì)胞和皮膚組織的影響,探討Nrf2-ARE信號(hào)通路在砷誘導(dǎo)皮膚角化紊亂中的作用及砷氧化損傷的皮膚毒性機(jī)制;通過對(duì)砷誘導(dǎo)皮膚角化紊亂差異蛋白的研究,在蛋白質(zhì)分子水平探討砷致皮膚角化紊亂的機(jī)制并尋找敏感標(biāo)記物。為砷性皮膚損傷的防治提供新的思路及科學(xué)依據(jù)。方法:1)采用MTT還原法檢測(cè)HacaT細(xì)胞生長情況,確定亞砷酸鈉的LC50及染毒濃度,染毒濃度分別為24h LC50的1/50、1/20、1/10,即1.30μmol/L、3.25μmol/L、和6.50μmol/L;觀察時(shí)間為24h、48h、72h;2)流式細(xì)胞儀檢測(cè)HacaT細(xì)胞的凋亡情況;3)將30只健康成年清潔級(jí)雄性家兔隨機(jī)分為5組,每組6只,分別為對(duì)照組(去離子水)及亞砷酸鈉染毒組。采用自由飲水方式連續(xù)染毒12周。染毒劑量分別為LD50的1/100、1/50、1/20、1/10,即L:0.13mg/千克體重(kg.w)、M:0.26mg/(kg.w)、MH:0.65mg/(kg.w)和H:1.30mg/(kg.w);4)染毒12周結(jié)束后,家兔背部同一部位皮膚取樣,電鏡下觀察皮膚細(xì)胞及組織的形態(tài)學(xué)改變;5)采集家兔處死前24h尿樣,并取家兔肝臟組織,采用高效液相色譜-氫化物發(fā)生原子熒光光譜(HPLC-HGAFS)法檢測(cè)家兔尿、肝臟、皮膚的iAsⅢ、iAsⅤ、一甲基胂酸(Monomethylarsonic acid,MMA)和二甲基胂酸(Dimethylarsinic acid,DMA)含量;6)通過實(shí)時(shí)熒光定量PCR(Real-time polymerase chain reaction,RT-PCR)檢測(cè)染砷HacaT細(xì)胞和家兔皮膚Nrf2 mRNA的表達(dá)水平;7)通過相應(yīng)試劑盒方法檢測(cè)染砷家兔皮膚CAT、8-OHdG、MPO、GSH-Px、GST、SOD和MDA及HO-1含量或活力,總蛋白采用BCA法檢測(cè);8)用雙向凝膠電泳(two-dimensional gel electrophoresis,2-DE)篩選砷誘導(dǎo)角化紊亂家兔皮膚的差異蛋白點(diǎn),膠內(nèi)酶切后,利用基質(zhì)輔助激光解析電離飛行時(shí)間質(zhì)譜(Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry,MALDI-TOF-MS)結(jié)合NCBI(nr)非冗余數(shù)據(jù)庫檢索對(duì)差異蛋白進(jìn)行鑒定;9)用RT-PCR檢測(cè)HacaT細(xì)胞CK1、CK10和家兔皮膚CK1、CK10、CK2及蛋白質(zhì)二硫鍵異構(gòu)酶(protein disulfide isomerase,pdi)mrna的表達(dá)水平。結(jié)果:1)1.30μmol/l亞砷酸鈉染毒48h能顯著促進(jìn)hacat細(xì)胞增殖;3.25μmol/l亞砷酸鈉染毒96h、6.25μmol/l亞砷酸鈉染毒72h顯著抑制hacat細(xì)胞增殖(p均0.05);2)1.30μmol/l亞砷酸鈉能抑制hacat細(xì)胞凋亡,24h時(shí)凋亡率最低;3.25μmol/l、6.25μmol/l亞砷酸鈉染毒48h、72h可使hacat細(xì)胞凋亡率逐漸升高(p均0.05);3)電鏡下可見,和對(duì)照組相比各染毒組家兔皮膚細(xì)胞形態(tài)和表皮尤其是皮膚角質(zhì)層結(jié)構(gòu)發(fā)生了改變。0.13mg/(kg.w)砷染毒12周即可出現(xiàn)角化紊亂,隨砷染毒劑量的升高,家兔皮膚細(xì)胞形態(tài)改變及角化紊亂程度加重;4)染毒12周后家兔尿中總砷、iasⅢ及dma含量水平隨砷染毒劑量的升高呈逐漸升高的趨勢(shì),與對(duì)照組比較,h砷染毒劑量組總砷、iasⅢ及dma含量水平升高(p均0.05)。iasⅤ含量水平無明顯變化趨勢(shì)。mma含量水平隨砷染毒劑量升高呈現(xiàn)逐漸升高的趨勢(shì),與對(duì)照組比較,mh及h砷染毒劑量組其含量水平升高(p0.05)。與對(duì)照組比較,各砷染毒劑量組pmi值均升高(p0.05)。與對(duì)照組比較,除l砷染毒劑量組外,其余砷染毒劑量組smi值均升高(p0.05);各染毒組家兔皮膚總砷及dma含量高于對(duì)照組,且隨染毒劑量升高而升高(p0.05);各形態(tài)砷中,dma含量最高。iasⅢ含量除mh組外,各染毒組高于對(duì)照組;iasⅤ含量各組均高于對(duì)照組,mma含量l組和h低于對(duì)照組,mh組高于對(duì)照組(p均0.05)。兔肝臟中總砷含量水平隨砷染毒劑量的升高呈逐漸升高的趨勢(shì),與對(duì)照組比較,m、mh、h砷染毒劑量組總砷含量水平升高(p0.05)。肝臟中iasⅢ含量在各組間沒有統(tǒng)計(jì)學(xué)差異;肝臟中iasⅤ含量m組與其他組相比升高(p0.05)。肝臟中mma含量在各組間沒有統(tǒng)計(jì)學(xué)差異;肝臟中dma含量在各組中不同,與對(duì)照組相比,mh和h染砷劑量組其含量升高(p0.05)。家兔皮膚和尿中砷以dma形態(tài)為主,肝臟中各種形態(tài)砷分布未發(fā)現(xiàn)規(guī)律;隨著砷染毒劑量升高,皮膚dma所占比例有升高的趨勢(shì)。皮膚和尿的總砷和dma含量與肝臟總砷和dma含量呈正相關(guān);5)亞砷酸鈉染毒能使hacat細(xì)胞nrf2mrna表達(dá)發(fā)生改變,1.30μmol/l亞砷酸鈉染毒使mrna表達(dá)上調(diào),隨著染毒時(shí)間延長、染毒濃度增加使mrna表達(dá)逐漸下調(diào)(p0.05)。砷染毒48h后hacat細(xì)胞nrf2mrna表達(dá)水平與細(xì)胞活性呈正相關(guān)關(guān)系;l、m組家兔皮膚nrf2mrna的表達(dá)上調(diào);mh、h組皮膚nrf2mrna的表達(dá)下調(diào),其中l(wèi)、h組與對(duì)照組相比差異有統(tǒng)計(jì)學(xué)意義(p0.05)。6)染砷家兔皮膚8-ohdg在h組,mda在mh和h組比對(duì)照升高(p0.05);cat和ho-1在m、mh和h組,gsh-px在h組比對(duì)照降低(p0.05);gst在h組比對(duì)照升高(p0.05);sod和mpo在各組無明顯差異。染砷家兔皮膚nrf2mrna表達(dá)與ho-1、gsh-px水平呈正相關(guān)關(guān)系,與mda、8-ohdg水平呈負(fù)相關(guān)關(guān)系;7)2-de電泳蛋白斑點(diǎn)清晰可見,各組蛋白斑點(diǎn)數(shù)在100-200之間,其中對(duì)照組蛋白斑點(diǎn)數(shù)為119,而其余4組蛋白斑點(diǎn)均為129個(gè)并全部匹配。對(duì)照組和其余各組的蛋白斑點(diǎn)匹配率為92.24%。與對(duì)照相比差異表達(dá)的蛋白點(diǎn)有45個(gè),鑒定出20種差異蛋白。其中細(xì)胞角蛋白Ⅱ型蛋白、GST-P和PDI可能與砷的皮膚毒性有關(guān);8)細(xì)胞角蛋白Ⅱ型蛋白在各砷染毒組家兔皮膚表達(dá),而在對(duì)照組中無表達(dá);HacaT染砷后CK1、CK10 mRNA表達(dá)發(fā)生改變,1.30μmol/L亞砷酸鈉染毒能使mRNA表達(dá)上調(diào),隨著染毒時(shí)間延長、染毒濃度增加mRNA表達(dá)逐漸下調(diào)(P0.05);染砷家兔皮膚CK1、CK2、CK10 mRNA在L組表達(dá)上調(diào),H組表達(dá)下降至正常或下調(diào)(P0.05)。染砷家兔皮膚PDI蛋白表達(dá)量隨染砷劑量升高而先下調(diào)后上調(diào);PDI mRNA在MH和H組,隨染砷劑量升高表達(dá)量上升(P0.05)。結(jié)論:亞砷酸鈉可在動(dòng)物角質(zhì)形成細(xì)胞和皮膚組織中發(fā)生生物轉(zhuǎn)化并形成一系列代謝產(chǎn)物,隨染毒劑量增加,皮膚砷負(fù)荷增加,可致皮膚氧化損傷,并引起角質(zhì)形成細(xì)胞和皮膚組織Nrf2表達(dá)變化,并隨染毒時(shí)間和濃度變化呈雙向性;砷通過調(diào)控Nrf2水平繼而影響皮膚角質(zhì)形成細(xì)胞的增殖和凋亡及皮膚組織Nrf2-ARE信號(hào)通道下游酶的改變,皮膚氧化-抗氧化平衡被破壞,出現(xiàn)角化紊亂等形態(tài)學(xué)改變。砷代謝及Nrf2-ARE信號(hào)通路在砷致皮膚角化紊亂中發(fā)揮重要作用。差異蛋白研究發(fā)現(xiàn)PDI和CK1、CK2、CK10在砷誘導(dǎo)的皮膚角化紊亂中發(fā)揮作用;而細(xì)胞角蛋白異常是反應(yīng)砷誘導(dǎo)皮膚角化紊亂較敏感的指標(biāo)。
[Abstract]:Objective: To investigate the effects of arsenic on keratinocytes and skin tissues in skin keratinocytes and skin tissues, the effects of arsenic on keratinocytes and skin tissue of skin were observed and the role of Nrf2-ARE signaling pathway in the derangement of skin induced by arsenic was investigated. And the skin toxicity mechanism of arsenic oxidative damage; through the study of arsenic induced skin keratosis differential protein, the mechanism of arsenic induced dermatosis and sensitive markers were explored at the protein molecular level. New ideas and scientific basis for the prevention and control of arsenic skin injury were provided. Method: 1) the MTT reduction method was used to detect HacaT cell growth. For a long time, the LC50 and the concentration of sodium arsenite were determined and the concentration of the poisoned concentration was 24h LC50 1/50,1/20,1/10, 1.30 mu mol/L, 3.25 mu mol/L, and 6.50 mu mol/L, and the observation time was 24h, 48h, 72h; 2) flow cytometry to detect the apoptosis of HacaT cells; 3) 30 healthy adult clean grade male rabbits were randomly divided into 5 groups, 6 in each group, respectively The control group (deionized water) and sodium arsenite dyed group were treated with free drinking water for 12 weeks. The dose of 1/100,1/50,1/20,1/10, L:0.13mg/ kg body weight (kg.w), M:0.26mg/ (kg.w), MH:0.65mg/ (kg.w) and H:1.30mg/ (kg.w); 4) were taken at the end of the same part of the rabbit's back, and the skin was observed under the electron microscope, and the skin was observed under electron microscope. The morphologic changes of skin and tissue; 5) collect the 24h urine before death in rabbits and take the rabbit liver tissue, and use high performance liquid chromatography - hydride generation atomic fluorescence spectrometry (HPLC-HGAFS) to detect the urine, liver, iAs III, iAs V, Monomethylarsonic acid, MMA, and two methyl arsine (Dimethylarsinic acid, DM). A) content; 6) the expression level of arsenic HacaT cells and rabbit Nrf2 mRNA was detected by real-time fluorescent quantitative PCR (Real-time polymerase chain reaction, RT-PCR); 7) the arsenic rabbit skin was detected by the corresponding kit method. Two-dimensional gel electrophoresis (2-DE) was used to screen the differential protein points of the deranged rabbit skin with arsenic induced diagonalization. After the gel enzyme was cut, the matrix assisted laser analytical ionization time of flight mass spectrometry (Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry) was combined with non redundant data. 9) the expression level of HacaT cells CK1, CK10 and rabbit skin CK1, CK10, CK2 and protein two sulfur bond isomerase (protein disulfide isomerase, PDI) mRNA were detected by RT-PCR. Results: 1) 1.30 micron sodium arsenite could significantly promote cell proliferation; 3.25 Mu sodium arsenite was exposed to 6.25 mu. /l sodium arsenite exposure significantly inhibited the proliferation of HaCaT cells (P 0.05); 2) 1.30 mu mol/l sodium arsenite could inhibit apoptosis of HaCaT cells and the lowest apoptosis rate in 24h; 3.25 mu mol/l, 6.25 micron sodium arsenite infected 48h, 72h could increase the apoptosis rate of HaCaT cells (0.05); 3) under electron microscope, compared with the control group, the skin of each infected group was thin skin. The cell morphology and epidermis, especially the skin cuticle structure changed.0.13mg/ (kg.w) arsenic exposure for 12 weeks, can appear keratinization disorder. With the increase of arsenic exposure dose, the skin cell morphology change and the degree of keratinization disorder increased; 4) the total arsenic in urine in the rabbit after 12 weeks of exposure, the level of IAS III and DMA increased gradually with the increase of arsenic exposure dose. The rising trend, compared with the control group, the total arsenic, IAS III and DMA levels in the H arsenic exposure group increased (P 0.05), the level of.Ias V was not obviously changed, and the level of.Mma content increased gradually with the increase of arsenic exposure dose. Compared with the control group, the content level of MH and H arsenic poisoning group increased (P0.05). Compared with the control group, the content level of the arsenic Dyeing Group was higher than the control group. The PMI value of each arsenic exposure group increased (P0.05). Compared with the control group, the SMI value of the remaining arsenic exposure dose group increased (P0.05) except for the L arsenic exposure dose group, and the total arsenic and DMA content in the skin of the infected rabbits was higher than that in the control group, and increased with the increase of the dose (P0.05), and the highest.Ias III content of DMA content in each form of arsenic, except for MH group, was all dyed. The content of IAS V in each group was higher than that in the control group. The content of MMA content in group L and h was lower than that of the control group, and the MH group was higher than the control group (P 0.05). The level of total arsenic in the liver of the rabbit increased gradually with the increase of arsenic exposure dose. Compared with the control group, the level of total arsenic in the group of M, MH and H arsenic poisoning was increased (P0.05). The IAS III contained in the liver. There was no statistical difference between the groups. The content of IAS V in the liver was higher than that in the other groups (P0.05). There was no statistical difference in the content of MMA in the liver. The content of DMA in the liver was different in each group. Compared with the control group, the content of MH and h increased (P0.05). The arsenic in the skin and urine of the rabbit was mainly in the form of DMA, and in the liver, the liver was mainly in the liver and in the liver. The distribution of arsenic in various forms was not found. With the increase of arsenic exposure dose, the proportion of DMA in the skin increased. The total arsenic and DMA content in the skin and urine were positively correlated with the total arsenic and DMA content in the liver. 5) sodium arsenite can make the expression of nrf2mrna in HaCaT cells change, and the expression of mRNA is up to up with 1.30 mol/l sodium arsenite, with the increase of mRNA expression. The expression of mRNA expression gradually decreased (P0.05). The expression level of nrf2mrna in HaCaT cells was positively correlated with the activity of nrf2mrna after arsenic exposure to 48h; L, the expression of nrf2mrna in the skin of the rabbit group was up regulated, and the expression of nrf2mrna in the H group was down down, and the L, there was a significant difference between the H group and the control group. Rabbit skin 8-OHdG in group H, MDA in group MH and H (P0.05), cat and HO-1 in M, MH and H group, GSH-Px in the group compared with the control, and there is no significant difference in each group. 7) 2-DE electrophoresis protein spots were clearly visible, the number of spots in each group was 100-200, of which the number of spots in the control group was 119, and the other 4 groups of protein spots were all 129 and all matched. The matching rate of the protein spots in the control group and the rest of the other groups was 45, and 20 kinds of differential eggs were identified. Cytokeratin type II protein, GST-P and PDI may be related to the skin toxicity of arsenic; 8) cytokeratin type II protein is expressed in the skin of the rabbits exposed to arsenic, but no expression in the control group; the expression of CK1, CK10 mRNA in HacaT after arsenic contamination is changed, and the expression of mRNA in 1.30 Mu sodium arsenate can increase the expression of mRNA and as the time of exposure prolongs. The expression of mRNA, CK1, CK2, CK10 mRNA in the L group was up regulated and the expression of H group decreased to normal or down (P0.05). The expression of PDI protein in the skin of arsenic infected rabbits was down regulated with the increase of arsenic dose, and PDI mRNA was in the group and increased with the increase of arsenic dose. Sodium arsenite can produce biotransformation and form a series of metabolites in the keratinocytes and skin tissues of animals. As the dose increases, the arsenic load of skin increases, the skin oxidative damage can be induced, and the expression of Nrf2 in keratinocytes and skin tissues is changed, and the change of arsenic in the skin is bidirectional with the change of time and concentration, and arsenic is regulated by N The RF2 level affects the proliferation and apoptosis of skin keratinocytes and the changes in the downstream enzymes of the skin tissue Nrf2-ARE signaling pathway, the oxidative balance of the skin is destroyed and the morphological changes of keratinization disorder occur. Arsenic metabolism and Nrf2-ARE signaling pathway play an important role in arsenic induced derangement in the skin. Differential protein studies found PD I and CK1, CK2 and CK10 play a role in arsenic induced keratinization disorder, and cytokeratin abnormalities are sensitive indicators for arsenic induced keratinization disorders.
【學(xué)位授予單位】：新疆醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R135.1

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