本文選題：Xrcc1 + 精子發(fā)生　； 參考：《南京醫(yī)科大學(xué)》2017年博士論文

【摘要】：不孕不育一直是生殖健康研究領(lǐng)域一個(gè)亟待解決的重大科學(xué)問(wèn)題。據(jù)世界衛(wèi)生組織預(yù)測(cè),在21世紀(jì),不孕不育將成為僅次于腫瘤和心腦血管病的第三大疾病。研究表明,半個(gè)多世紀(jì)以來(lái),人類(lèi)精液質(zhì)量顯著下降,精子生成障礙已成為男性不育最常見(jiàn)的病因,也是我國(guó)成年男性生殖健康面臨的最主要威脅。精子生成障礙可能與遺傳因子改變,環(huán)境化學(xué)污染物暴露等密切相關(guān)。精子發(fā)生是一個(gè)連續(xù)的細(xì)胞分裂分化過(guò)程,包括精原細(xì)胞分裂增殖、精母細(xì)胞減數(shù)分裂和精子細(xì)胞變態(tài)三個(gè)主要階段,最終形成成熟的精子。在這個(gè)復(fù)雜的過(guò)程中,生物體與生俱來(lái)的DNA損傷修復(fù)機(jī)制能夠及時(shí)修復(fù)來(lái)源于外界環(huán)境或生物體自身產(chǎn)生的損傷。本實(shí)驗(yàn)室前期通過(guò)原發(fā)性無(wú)精子癥病例對(duì)照研究發(fā)現(xiàn),DNA損傷修復(fù)基因X射線修復(fù)交叉互補(bǔ)蛋白1(X-Ray Repair Cross Complementing 1,XRCC1)單核苷酸多態(tài)性是原發(fā)性無(wú)精子癥的遺傳易感因素,但無(wú)法解釋精子生成障礙的分子機(jī)制。本研究首先構(gòu)建了 Xrcc1基因敲除小鼠模型研究其在精子發(fā)生中的作用;由于人類(lèi)遺傳物質(zhì)相對(duì)穩(wěn)定,短時(shí)間內(nèi)的人類(lèi)的遺傳變異是有限的,因此精子生成障礙也有可能受到環(huán)境因素的影響,環(huán)境因素種類(lèi)眾多,進(jìn)而我們選擇在生殖系統(tǒng)中缺乏安全性評(píng)價(jià)的納米材料作為研究對(duì)象,來(lái)評(píng)價(jià)納米材料對(duì)雄性生殖的影響。我們的研究假設(shè)是:1.DNA損傷修復(fù)基因Xrcc1在小鼠精子發(fā)生中有著至關(guān)重要的作用;2.代表性納米材料可能對(duì)生殖細(xì)胞DNA造成損傷,進(jìn)而影響精子發(fā)生過(guò)程。為驗(yàn)證上述假設(shè):1.基于Xrcc1全敲除小鼠胚胎致死的報(bào)道,我們采用Cre-Loxp條件性基因敲除策略構(gòu)建原始生殖細(xì)胞特異的Xrcc1基因敲除小鼠模型,綜合評(píng)價(jià)該模型中小鼠精子發(fā)生過(guò)程及其狀態(tài);2.通過(guò)小鼠精原干細(xì)胞體外培養(yǎng),探討Xrcc1在其正常生理功能的作用;3.通過(guò)納米材料的體外生殖細(xì)胞系的評(píng)價(jià),探討環(huán)境因素在精子生成障礙中的作用。第一部分DNA損傷修復(fù)基因Xrcc1在雄性小鼠生殖功能中的作用及機(jī)制研究目的XRCC1能夠作為DNA損傷修復(fù)過(guò)程中的招募蛋白,與DNA損傷修復(fù)過(guò)程中的修復(fù)蛋白相互作用,發(fā)揮DNA損傷修復(fù)能力。以往研究表明DNA損傷修復(fù)過(guò)程在生殖細(xì)胞中的意義重大。然而,Xrcc1在維持精子發(fā)生以及生殖系統(tǒng)中的確切功能尚不清楚。方法我們通過(guò)Cre-Loxp原理構(gòu)建原始生殖細(xì)胞條件性基因敲除Xrcc1的小鼠模型,結(jié)合生殖功能評(píng)價(jià)實(shí)驗(yàn)、病理學(xué)檢測(cè)、以及分子機(jī)制研究,綜合闡明Xrcc1在小鼠精子發(fā)生過(guò)程中的作用。結(jié)果通過(guò)交配生育實(shí)驗(yàn)發(fā)現(xiàn)Xrcc1完全敲除的小鼠出現(xiàn)不育的表型。與對(duì)照組相比,Xrcc1敲除組小鼠的精子數(shù)目和精子活力均顯著降低。睪丸組織病理結(jié)果提示Xrcc1敲除組曲細(xì)精管有明顯的病理改變。Xrcc1敲除組小鼠精原細(xì)胞發(fā)現(xiàn)凋亡的發(fā)生、睪丸組織氧化應(yīng)激的增加和線粒體功能紊亂。此外,Xrcc1敲除組小鼠的精原細(xì)胞干性因子受到損傷。結(jié)論缺失Xrcc1后,小鼠的精原細(xì)胞干性發(fā)生紊亂,小鼠睪丸的線粒體功能受損以及出現(xiàn)凋亡現(xiàn)象。Xrcc1參與小鼠精子發(fā)生的正常生理過(guò)程。第二部分DNA損傷修復(fù)基因Xrcc1在小鼠精原干細(xì)胞中的作用及機(jī)制研究目的為進(jìn)一步明確小鼠原始生殖細(xì)胞中Xrcc1的缺失,線粒體功能異常、及細(xì)胞內(nèi)氧化應(yīng)激狀態(tài)的關(guān)系,采用體外精原干細(xì)胞(Spermatogonia Stem Cells,SSCs)模型來(lái)驗(yàn)證這一假設(shè)。方法通過(guò)建立SSCs模型,同時(shí)構(gòu)建Xrcc1干擾RNA包裝的腺病毒,通過(guò)腺病毒敲減SSCs中的Xrcc1,同時(shí)處理抗氧劑N-乙酰半胱氨酸(N-acety1-L-cysteine,NAC)來(lái)評(píng)價(jià)SSCs中的氧化應(yīng)激狀態(tài)及線粒體功能指標(biāo)。結(jié)果Xrcc1缺乏可以引起SSCs的自我更新和自我分化因子減少,氧化應(yīng)激相關(guān)指標(biāo)增加,造成線粒體基因組上編碼呼吸鏈復(fù)合物的轉(zhuǎn)錄本減少、細(xì)胞ATP水平降低,并且降低精子發(fā)生相關(guān)基因的表達(dá)。NAC的補(bǔ)充可以緩解因Xrcc1的減少而引起的氧化應(yīng)激和線粒體基因組上編碼呼吸鏈復(fù)合物的轉(zhuǎn)錄本減少和細(xì)胞ATP水平的降低,但對(duì)自我更新和自我分化因子和精子發(fā)生相關(guān)基因表達(dá)沒(méi)有作用。結(jié)論在SSCs中,Xrcc1的減少可以通過(guò)氧化應(yīng)激來(lái)影響細(xì)胞線粒體功能,以及通過(guò)其他途徑來(lái)影響SSCs的干性維持和精子發(fā)生。第三部分代表性納米材料暴露對(duì)小鼠精母細(xì)胞DNA的影響第一節(jié)多壁碳納米管對(duì)小鼠精母細(xì)胞的影響目的多壁碳納米管在許多領(lǐng)域廣泛使用,已有研究報(bào)道其高劑量可以造成雄性小鼠生殖系統(tǒng)可逆性損傷。然而,低劑量多壁碳納米管的生殖效應(yīng)數(shù)據(jù)有限。方法運(yùn)用鼠源性精母細(xì)胞系模型(GC-2spd)評(píng)價(jià)多壁碳納米管的生殖毒性效應(yīng)。采用細(xì)胞活力實(shí)驗(yàn)選擇不影響細(xì)胞活力的劑量,透射電子顯微鏡觀察多壁碳納米管在細(xì)胞中的蓄積情況,PCR方法檢測(cè)多壁碳納米管對(duì)生殖細(xì)胞DNA的影響。結(jié)果發(fā)現(xiàn)0.5μg/mL的多壁碳納米管在精母細(xì)胞系中不引起細(xì)胞活力降低。在這個(gè)劑量下,細(xì)胞周期和細(xì)胞活性氧(Reactive Oxygen Species,ROS)水平均沒(méi)有影響。但是,與對(duì)照相比,該劑量下多壁碳納米管能夠蓄積在線粒體,引起精母細(xì)胞線粒體DNA的損傷,線粒體氧耗率和細(xì)胞ATP水平也有不同程度下降。結(jié)論0.5μg/mL多壁碳納米管可以特異性的導(dǎo)致生殖細(xì)胞線粒體DNA損傷具潛在生殖毒性。第二節(jié)納米氧化鋅對(duì)小鼠支持細(xì)胞和精母細(xì)胞DNA的影響目的納米氧化鋅作為近年來(lái)在生活領(lǐng)域應(yīng)用廣泛的納米材料,雖然大多數(shù)研究者聚焦于納米氧化鋅的人體健康效應(yīng),然而涉及雄性生殖系統(tǒng)的數(shù)據(jù)非常有限。方法以鼠源性支持細(xì)胞(TM-4)和精母細(xì)胞(GC-2spd)作為體外模型,研究亞致死劑量納米氧化鋅的生殖效應(yīng)及其分子機(jī)制。運(yùn)用分子生物學(xué)方法闡明納米氧化鋅對(duì)支持細(xì)胞功能和精母細(xì)胞DNA的影響。結(jié)果兩個(gè)細(xì)胞模型中8μg/mL納米氧化鋅是亞致死劑量,ROS均增加。支持細(xì)胞的納米氧化鋅處理組,谷胱甘肽水平下降,丙二醛水平上升,支持細(xì)胞中血睪屏障相關(guān)蛋白(ZO-1,occludin,claudin-5和connexin-43)均下調(diào);納米氧化鋅處理后出現(xiàn)細(xì)胞膜通透性增加和腫瘤壞死因子α分泌增多。精母細(xì)胞中出現(xiàn)細(xì)胞S期阻滯和DNA損傷,抗氧化劑NAC處理可部分挽救這一表型。結(jié)論納米氧化鋅暴露可引起細(xì)胞ROS產(chǎn)生、生殖細(xì)胞DNA損傷,以及下調(diào)支持細(xì)胞的血睪屏障相關(guān)蛋白,進(jìn)而使得血睪屏障完整性被破壞。這些影響可以被抗氧化劑部分逆轉(zhuǎn),提示納米氧化鋅通過(guò)氧化應(yīng)激途徑發(fā)揮上述毒效應(yīng)。
[Abstract]:Infertility has always been a major scientific problem to be solved in the field of reproductive health. According to the WHO, infertility will become the third largest disease after cancer and cardiovascular disease in twenty-first Century. Research shows that semen quality has decreased significantly in more than half a century and the disorder of spermatogenesis has become a male. The most common cause of infertility is the most important threat to the reproductive health of adult males in China. The disturbance of spermatogenesis may be closely related to changes in genetic factors and exposure to environmental chemical pollutants. Spermatogenesis is a continuous cell division and differentiation process, including spermatogonial cell division, meiosis and sperm fines. In this complex process, the inherent DNA damage repair mechanism can repair the damage caused by the external environment or the organism itself in this complex process. In the early stage of the laboratory, the DNA damage repair gene X shot was found by the primary azoospermia case control study. Single nucleotide polymorphisms of line repair cross complementary protein 1 (X-Ray Repair Cross Complementing 1, XRCC1) are genetic predisposing factors of primary azoospermia, but it is unable to explain the molecular mechanism of spermatogenesis disorder. This study first constructed a Xrcc1 gene knockout mouse model to study its role in spermatogenesis; due to human genetic material. The quality is relatively stable, and the genetic variation of human in a short time is limited, so the disturbance of spermatogenesis may also be affected by environmental factors and there are many environmental factors. Then we choose nanomaterials that lack safety assessment in the reproductive system as the research object to evaluate the effect of nano materials on male reproduction. The study assumes that the 1.DNA damage repair gene Xrcc1 plays a vital role in spermatogenesis in mice; 2. representative nanomaterials may cause damage to the germ cell DNA and then affect the process of spermatogenesis. To verify the hypothesis: 1. we use the Cre-Loxp conditional gene based on the death of the Xrcc1 full knockout mouse embryo. The knockout strategy was used to construct the Xrcc1 gene knockout mouse model of primordial germ cells, and to evaluate the spermatogenesis and the state of spermatogenesis in this model. 2. through the culture of mouse spermatogonial stem cells in vitro, the role of Xrcc1 in its normal physiological function was explored. 3. the environmental factors were discussed by the evaluation of the in vitro germ cell line of nanomaterials. The role of DNA damage repair gene Xrcc1 in the reproductive function of male mice and its mechanism research purpose XRCC1 can be used as a recruitment protein in the process of DNA damage repair, interacting with the repair proteins in the process of DNA damage repair, and exerting the ability to repair DNA damage. The previous study showed that the DNA injury was repaired. Complex processes are of great significance in germ cells. However, the exact function of Xrcc1 in maintaining spermatogenesis and reproductive system is still unclear. Methods we constructed a mouse model of primitive germ cell knockout Xrcc1 by Cre-Loxp principle, combined with the evaluation of reproductive function, pathological examination, and molecular mechanism research. The effect of Xrcc1 in the process of spermatogenesis in mice was elucidated. Results the male sterile phenotype of Xrcc1 completely knockout mice was found through the mating fertility experiment. Compared with the control group, the sperm number and sperm vitality of the Xrcc1 knockout mice were significantly lower. The pathological results of the testicular histology suggest that the Xrcc1 knockout group of seminiferous tubules has obvious pathology. The spermatogonial cells in the.Xrcc1 knockout mice found the occurrence of apoptosis, the increase of oxidative stress in the testicular tissue and the dysfunction of mitochondria. In addition, the spermatogonial factor of the spermatogonial cells in the Xrcc1 knockout mice was damaged. After the deletion of Xrcc1, the spermatogonial stem of the mice was disordered, the mitochondrial function of the mice was damaged and the loss of the spermatogonial function of the mice was damaged. The death phenomenon.Xrcc1 participates in the normal physiological process of spermatogenesis in mice. Second the role and mechanism of DNA damage repair gene Xrcc1 in mouse spermatogonial stem cells in order to further clarify the deletion of Xrcc1 in the primitive germ cells of mice, the abnormal function of mitochondria, and the relationship between the oxidative stress in cells and the use of spermatogonial stem in vitro. The Spermatogonia Stem Cells (SSCs) model is used to verify this hypothesis. By establishing a SSCs model, the adenovirus interfering with RNA packaging is constructed, the Xrcc1 in SSCs is knocked down by adenovirus and the antioxidant N- acetylcysteine (N-acety1-L-cysteine, NAC) is also treated to evaluate the oxidative stress state and mitochondrial function in the SSCs. Results Xrcc1 deficiency could cause the self-renewal of SSCs and the decrease of self differentiation factor and the increase of the related indexes of oxidative stress, which resulted in the decrease of the transcriptional book of the respiratory chain complex in the mitochondrial genome, the decrease of the cell ATP level and the reduction of the expression of.NAC related to the spermatogenesis related genes, which could relieve the decrease of Xrcc1. Oxidative stress and the decrease of transcriptional transcript of the respiratory chain complex encoded by the mitochondrial genome and the decrease of cell ATP levels, but no effect on self renewal and the expression of self differentiation and spermatogenesis related genes. Conclusion in SSCs, the decrease of Xrcc1 can affect cell mitochondrial function through oxidative stress and through it His approach affects the dry maintenance of SSCs and spermatogenesis. Third the effects of the representation of nanomaterials on mouse spermatocyte DNA: the first section of the effect of multi wall carbon nanotubes on mouse spermatocytes; multi wall carbon nanotubes are widely used in many fields. However, the reproductive effect of low dose multi wall carbon nanotubes was limited. The reproductive toxicity of multi wall carbon nanotubes was evaluated by the mouse derived spermatogonial model (GC-2spd). The cell viability experiment was used to select the dose which did not affect the cell viability, and the multi wall carbon nanotubes were observed in the cells by transmission electron microscope. The effect of multi wall carbon nanotubes on the reproductive cell DNA was detected by the PCR method. The results showed that the 0.5 u g/mL multi walled carbon nanotubes did not decrease the cell viability in the spermatocyte line. At this dose, the cell cycle and the level of Reactive Oxygen Species, ROS were not affected. The lower multi wall carbon nanotubes can accumulate in the mitochondria, cause the damage of the mitochondrial DNA of spermatocyte, the oxygen consumption rate of mitochondria and the ATP level of the cell also decrease in varying degrees. Conclusion 0.5 mu g/mL multi wall carbon nanotubes can specifically lead to the potential reproductive toxicity of the mitochondrial DNA damage in the germ cells. The second section of nano Zinc Oxide supports the mice. The effect of cellular and spermatocyte DNA on nano Zinc Oxide as a widely used nano material in the field of life in recent years. Although most researchers focus on the human health effects of nanoscale Zinc Oxide, the data involved in the male reproductive system are very limited. Methods using mouse derived support cells (TM-4) and spermatocyte (GC-2spd) are used as a method. In vitro model, the reproductive effect and molecular mechanism of sublethal dose of nano Zinc Oxide were studied. The effect of nanoscale Zinc Oxide on the function of support cell and DNA of spermatocyte was elucidated by molecular biological methods. Results in two cell models, 8 g/mL nanoscale Zinc Oxide was sublethal dose and ROS increased. The nano Zinc Oxide treatment of support cells In the group, the level of glutathione decreased, the level of malondialdehyde increased, and the blood testis barrier related proteins (ZO-1, occludin, claudin-5 and connexin-43) in the supporting cells were all downregulated. The membrane permeability and tumor necrosis factor alpha secretion increased after the nano Zinc Oxide treatment. The S phase block and DNA damage in the spermatocyte and the antioxidant NAC were found in the spermatocyte. Conclusion the nano Zinc Oxide exposure can cause ROS production, DNA damage of germ cells, and down regulation of blood testis barrier related proteins in the supporting cells, which can cause the integrity of the blood testis barrier to be destroyed. These effects can be reversed by the antioxidant part, suggesting that nanoscale Zinc Oxide plays a role in the oxidative stress pathway. The toxic effects mentioned above.

【學(xué)位授予單位】：南京醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R114

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7 周紅;鄭江;王良喜;丁國(guó)富;魯永玲;潘文東;羅平;肖光夏;;CpG DNA誘導(dǎo)全身炎癥反應(yīng)綜合征的作用及其機(jī)制研究[A];全國(guó)燒傷創(chuàng)面處理、感染專(zhuān)題研討會(huì)論文匯編[C];2004年

8 ;EFFECTS OF Ku70-DEFICIENT ON ARSENITE-INDUCED DNA DOUBLE STRAND BREAKS, CHROMOSOMAL ALTERATIONS AND CELL CYCLE ARREST[A];海峽兩岸第三屆毒理學(xué)研討會(huì)論文摘要[C];2005年

9 李經(jīng)建;冀中華;蔡生民;;小溝結(jié)合方式中的DNA媒介電荷轉(zhuǎn)移[A];第十三次全國(guó)電化學(xué)會(huì)議論文摘要集（下集）[C];2005年

10 ;The interaction between Levofloxacine Hydrochloride and DNA mediated by Cu~(2+)[A];湖北省化學(xué)化工學(xué)會(huì)2006年年會(huì)暨循環(huán)經(jīng)濟(jì)專(zhuān)家論壇論文集[C];2006年

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