發(fā)布時(shí)間：2018-03-24 06:13

  本文選題：硫丹　切入點(diǎn)：HUVEC-C細(xì)胞　出處：《大連海事大學(xué)》2017年碩士論文

【摘要】：硫丹是一種應(yīng)用廣泛的有機(jī)氯農(nóng)藥,在2011年被斯德哥爾摩公約列為持久性有機(jī)污染物,在環(huán)境介質(zhì)中廣泛存在,具有高毒性、持久性、生物富集性、可長距離傳輸?shù)奶攸c(diǎn),因此,其對(duì)人類健康的遠(yuǎn)期危害不能被忽視。前期研究發(fā)現(xiàn)硫丹具有血管內(nèi)皮細(xì)胞毒性,能夠引起血管內(nèi)皮細(xì)胞周期阻滯、凋亡和炎癥反應(yīng),導(dǎo)致血管內(nèi)皮細(xì)胞功能失調(diào),考慮可能與人類疾病關(guān)系密切。為了揭示硫丹暴露引起血管內(nèi)皮細(xì)胞功能失調(diào)的分子機(jī)制及與人類疾病的關(guān)系,本課題探討了硫丹對(duì)血管內(nèi)皮細(xì)胞基因表達(dá)譜的影響并進(jìn)行了人類疾病預(yù)測(cè)分析。本研究采用DNA microarray分析了硫丹暴露(20,40,60μM)對(duì)HUVEC-C細(xì)胞的基因表達(dá)譜的影響,利用GO分析和KEGG Pathway探討了硫丹暴露引起的HUVEC-C細(xì)胞表型變化與基因表達(dá)變化間的關(guān)聯(lián),進(jìn)一步聯(lián)合NextBio和Metacore數(shù)據(jù)庫預(yù)測(cè)了與硫丹暴露最相關(guān)的人類疾病、心血管疾病和癌癥;篩選了促進(jìn)前列腺癌發(fā)展的關(guān)鍵基因,最后驗(yàn)證了硫丹促進(jìn)前列腺癌發(fā)展的作用及其關(guān)鍵基因的功能。結(jié)果表明,硫丹能夠引起差異表達(dá)的基因數(shù)量增加,具有劑量依賴性關(guān)系。硫丹引起多種生物學(xué)過程和信號(hào)通路發(fā)生變化與硫丹引起血管內(nèi)皮細(xì)胞損傷的表型變化一致。低劑量硫丹(20μM)暴露引起下調(diào)的基因主要涉及細(xì)胞骨架調(diào)節(jié),較高劑量(40μM和60μM)硫丹暴露引起下調(diào)的基因涉及細(xì)胞周期和凋亡而上調(diào)的基因涉及炎癥反應(yīng)和癌的轉(zhuǎn)錄失調(diào)信號(hào)通路。硫丹暴露與人類的消化系統(tǒng)疾病、代謝疾病、心血管疾病和癌癥相關(guān)。其中最相關(guān)的癌癥是肝癌、前列腺癌和白血病。硫丹促進(jìn)前列腺癌發(fā)展的關(guān)鍵基因是PTP4A3,可能通過提高PTP4A3的mRNA表達(dá)水平而促進(jìn)前列腺癌的遷移能力。這項(xiàng)研究將為揭示硫丹暴露引起人類疾病的分子機(jī)制提供新的依據(jù)。
[Abstract]:Endosulfan, a widely used organochlorine pesticide, was listed as a persistent organic pollutant by the Stockholm Convention in 2011. It is widely present in environmental media and has the characteristics of high toxicity, persistence, bioconcentration and long distance transport. Therefore, its long-term harm to human health can not be ignored. Previous studies have found that endosulfan has vascular endothelial cell toxicity, can cause vascular endothelial cell cycle arrest, apoptosis and inflammation, leading to vascular endothelial cell dysfunction, In order to reveal the molecular mechanism of vascular endothelial cell dysfunction caused by endosulfan exposure and its relationship with human disease, In this study, the effect of endosulfan on gene expression profile of vascular endothelial cells (VECs) and the prediction of human disease were studied. DNA microarray was used to analyze the effect of endosulfan exposure on the gene expression profile of HUVEC-C cells. Go analysis and KEGG Pathway were used to explore the relationship between phenotypic changes and gene expression changes in HUVEC-C cells induced by endosulfan exposure. Furthermore, combined with NextBio and Metacore databases, the most relevant human diseases, cardiovascular diseases and cancer were predicted. The key genes for the development of prostate cancer were screened, and the role of endosulfan in promoting the development of prostate cancer and the function of the key genes were verified. The results showed that endosulfan could cause an increase in the number of differentially expressed genes, The changes in many biological processes and signal pathways induced by endosulfan are consistent with the phenotypic changes in vascular endothelial cell injury induced by endosulfan. The down-regulated genes induced by exposure to low-dose endosulfan 20 渭 M mainly involve cytoskeletal regulation. Exposure to endosulfan at a higher dose of 40 渭 M and 60 渭 M involves down-regulated genes related to cell cycle and apoptosis, while up-regulated genes involve inflammatory responses and transcriptional dysfunctional signaling pathways of cancer. Endosulfan exposure is associated with diseases of the human digestive system, metabolic diseases, Cardiovascular disease is associated with cancer. The most relevant cancer is liver cancer. Prostate cancer and leukemia. The key gene that endosulfan promotes the development of prostate cancer is PTP4A3, which may promote the migration of prostate cancer by increasing the level of mRNA expression of PTP4A3. This study will be used to reveal that endosulfan exposure causes human disease. To provide a new basis for the molecular mechanism.
【學(xué)位授予單位】：大連海事大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R114

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