本文關鍵詞：PAHs致男（雄）性生殖損害中端粒和線粒體損傷效應和機制研究　出處：《第三軍醫(yī)大學》2017年博士論文　論文類型：學位論文

  更多相關文章： 多環(huán)芳烴 苯并[a]芘 端粒 線粒體 生精細胞凋亡 雄性生殖毒性

【摘要】：研究背景多環(huán)芳烴(Polycyclic aromatic hydrocarbons,PAHs)是一類重要的環(huán)境污染物,能通過呼吸、飲食、飲水和皮膚等多種途徑進入人體。PAHs分布廣泛,多種PAHs化學物并具有致癌性和致突變性,被國際癌癥研究中心(IARC)劃分為很可能的人類致癌物。此外,研究發(fā)現PAHs及其活性中間產物也能影響雄性生殖功能,最終導致不育。動物實驗和人群流行病學研究均報道PAHs暴露水平升高與精液質量下降和精子DNA損傷相關,增加男性不育的風險。然而,PAHs對男性生殖能力的潛在影響仍然存在不確定性,尤其是在普通人群低劑量接觸暴露中,PAHs暴露與雄性生殖損傷之間的弱效應,可能僅用常規(guī)的精液質量難以衡量,而需要尋找環(huán)境PAHs低暴露條件下致雄性生殖損傷的更敏感的生物標志物。此外,PAHs誘發(fā)雄性生殖毒性的分子事件及其潛在的機制仍不清楚。因此,對遺傳損傷的分子機制進行溯源,發(fā)現PAHs造成生殖細胞損害的分子靶點,將為探索反映PAHs雄性生殖損害的生物標志物提供重要的依據。端粒和線粒體DNA在維持基因組完整性和細胞正常生理功能中起重要作用。既往的研究表明,PAHs能誘導細胞端粒DNA和線粒體損傷,提示端粒和線粒體結構和功能的異�？赡苁荘AHs造成雄性生殖損害的重要靶點。本研究中,以本課題組開展的大學生生殖健康隊列研究(MARHCS)為基礎,分析PAHs環(huán)境暴露與精子端粒DNA和線粒體DNA損傷的關聯。進一步選擇PAHs的典型代表物B[a]P及其代謝產物BPDE開展體外和體內實驗,探討其對雄性生殖細胞端粒和線粒體結構和功能的損傷效應及其在雄性生殖損害中的作用及機制。研究內容1.重慶市大學生人群PAHs暴露與精子遺傳損傷和精液質量的關聯研究以本課題組在2013-2015年開展的MARHCS隊列研究為基礎,采用2014年第一次隨訪的人群(n=666)生物樣本(尿液和精液)進行PAHs內暴露水平和精子多項損傷指標的評價。采用GC-MS檢測尿液中PAHs代謝產物水平,熒光定量PCR檢測精子端粒長度和精子mtDNAcn,JC-1檢測精子線粒體膜電位,Long-PCR檢測mt DNA完整性,Annexin V-FITC檢測精子凋亡以及常規(guī)精液質量指標。在此基礎上,分析了PAHs尿代謝產物與上述精子損傷相關指標的關聯。通過人群研究探討PAHs環(huán)境暴露致男性生殖損傷的生物標志物。2.BPDE和B[a]P誘導生精細胞衰老和凋亡過程中端粒損傷機制研究建立了BPDE染毒的小鼠精母細胞株GC-2模型。采用臺盼藍染色法檢測細胞存活率,Annexin V/PI結合流式細胞儀分析檢測細胞凋亡,SA-β-Gal染色的方法檢測細胞衰老,用于評價BPDE對GC-2細胞的毒性效應;進一步采用熒光定量PCR和末端限制片段長度分析(TRF)的方法檢測細胞端粒長度,FISH結合γ-H2AX免疫熒光方法檢測端粒DNA斷裂,TRAP-PCR-ELISA檢測端粒酶活性以及Western blot檢測端粒酶逆轉錄酶(TERT)的蛋白表達水平,用于評價BPDE對GC-2細胞的端粒損傷效應。另外,采用Western blot檢測DNA損傷反應通路相關蛋白的表達,觀察BPDE對GC-2細胞內DNA損傷反應的激活情況。在此基礎上,采用sh RNA-TERT和p LV-EGFP-TERT載體構建了TERT干擾和再表達的GC-2轉染細胞模型,研究TERT基因在BPDE誘導的細胞衰老和凋亡中的作用。在細胞實驗結果基礎上,我們建立了B[a]P(0、5、10和20 mg/kg)灌胃染毒SD大鼠7天動物模型,進一步驗證體外GC-2細胞實驗的結果。3.BPDE誘導生精細胞凋亡過程中線粒體損傷機制研究建立了BPDE染毒的GC-2細胞模型。采用NAO染色方法檢測線粒體質量、RT-PCR檢測mtDNAcn的改變、JC-1檢測線粒體膜電位的變化、Western blot檢測線粒體呼吸鏈關鍵蛋白COX IV、轉錄共激活因子PGC-1α以及線粒體凋亡通路相關蛋白,如Cyt C、caspase-9、caspase-3的表達水平,以評價BPDE對生精細胞的線粒體功能、線粒體生物合成和線粒體途徑凋亡的影響。在此基礎上,采用PGC-1α激活劑ZLN005預處理GC-2細胞后,檢測BPDE對上述線粒體損傷相關指標的影響,以明確PGC-1α在BPDE誘導的生精細胞線粒體損傷和細胞凋亡中的作用。此外,利用上述構建的TERT干擾和再表達轉染細胞,進一步研究BPDE誘導的生精細胞線粒體損傷效應,探討端粒調控與線粒體損傷之間的聯系,以明確TERT在BPDE誘導的生精細胞線粒體損傷中的作用。研究結果1.人群PAHs暴露與精子端粒長度和精子線粒體拷貝數的相關性本研究共檢測了8種PAHs尿代謝產物,包括1-OHNap、2-OHNap、1-OHPhe、2-OHPhe、3-OHPhe、4-OHPhe、2-OHFlu和1-OHPyr。研究結果顯示,尿中1-OHPyr和1-OHNap與精子端粒長度呈負相關,1-OHPyr(β=-0.385;95%可信區(qū)間[CI]:-0.749~-0.021;1-OHNap(-0.079;95%CI:-0.146~-0.011)。尿中2-OHPhe、3-OHPhe、∑Phe metabolites和2-OHFlu水平與精子mtDNAcn呈負相關,2-OHPhe(-9.427;95%CI:-17.586~-0.459);3-OHPhe(-11.488;95%CI:-19.462~-2.725);∑Phe metabolites(-9.635;95%CI:-17.965~-0.688);2-OHFlu(-11.692;95%CI:-19.647~-2.949)。尿中PAHs代謝物與精子線粒體膜電位和mt DNA完整性之間沒有統(tǒng)計學上顯著關聯。此外,未觀察到這8種PAHs尿代謝產物與精子凋亡和常規(guī)精液質量指標(包括精液量、精液密度、精子總數和精子前向運動百分率)之間的相關性。上述結果提示,低水平PAHs暴露可能造成精子端粒和線粒體損傷,并且精子端粒長度和精子mtDNAcn改變可能作為低劑量PAHs環(huán)境暴露致男性生殖損傷的敏感指標。2.BPDE和B[a]P誘導生精細胞衰老和凋亡過程中端粒損傷機制研究BPDE對GC-2細胞具有顯著的毒性效應,能引起生精細胞增殖抑制、衰老和凋亡。進一步研究發(fā)現,BPDE處理能誘導GC-2細胞端粒損傷,包括端粒長度縮短,端粒DNA斷裂,以及DNA損傷反應通路(ATM/Chk1/p53/p21)的激活。端粒酶是調節(jié)雄性生殖細胞端粒長度的重要因素,研究結果顯示BPDE處理可引起細胞端粒酶活性以及端粒酶活性限速因子TERT的蛋白表達水平的降低,提示端粒結構和功能異常是BPDE誘導雄性生殖細胞損傷的靶點。此外,采用建立的TERT轉染細胞模型發(fā)現,干擾TERT的表達,可加重BPDE誘導的端粒損傷、細胞衰老、細胞凋亡以及DNA損傷反應通路的激活,恢復TERT的表達則部分對抗了BPDE的損傷效應。這些結果提示TERT參與介導了BPDE誘導的端粒DNA損傷相關的生精細胞衰老和凋亡。此外,體內動物實驗結果顯示B[a]P染毒可引起大鼠生精細胞端�？s短,TERT蛋白表達水平降低以及DNA損傷反應的激活,并誘發(fā)睪丸毒性,包括生精細胞凋亡和衰老,睪丸組織結構改變等,這些結果進一步驗證了細胞實驗結果。3.BPDE誘導生精細胞凋亡過程中線粒體損傷機制研究BPDE處理引起GC-2細胞線粒體質量降低,mtDNAcn下降,線粒體膜電位降低,線粒體生物合成和氧化磷酸化相關蛋白COX IV和PGC-1α的表達水平降低,線粒體凋亡途徑相關蛋白Cyt C、caspase-9和caspase-3的表達升高,表明BPDE可導致線粒體功能損傷和生物合成障礙。GC-2細胞預處理PGC-1α激活劑ZLN005后降低了BPDE誘導的線粒體損傷和細胞凋亡,提示PGC-1α參與調控BPDE誘導的線粒體損傷相關的生精細胞凋亡。此外,進一步分析BPDE誘導的端粒與線粒體損傷的聯系,采用TERT轉染細胞模型研究顯示:TERT抑制可加重BPDE誘導的線粒體損傷,包括線粒體質量、mtDNAcn、線粒體膜電位以及線粒體凋亡途徑相關蛋白的表達.;相反,恢復TERT表達則部分對抗了BPDE對線粒體損傷效應,提示TERT通過調控PGC-1α的表達,參與調控BPDE誘導的線粒體損傷。研究結論流行病學研究顯示,重慶市大學生人群中PAHs內暴露水平與精子端粒長度縮短和精子mtDNAcn降低存在顯著的關聯,提示精子端粒DNA和線粒體DNA可能是PAHs化學物造成男性生殖損傷的敏感靶點。小鼠精母細胞GC-2和大鼠染毒實驗進一步證實,PAHs的典型代表物B[a]P及其活性代謝產物BPDE可誘導生精細胞的端粒和線粒體結構及功能異常,最終導致細胞的衰老和凋亡等生殖毒性。這一過程中,BPDE可抑制TERT表達,通過端粒損傷及DNA損傷反應途徑造成生殖毒性;另一方面BPDE可抑制PGC-1α表達,通過線粒體損傷和凋亡途徑造成生殖毒性。其中TERT基因在這兩條途徑中起關鍵調控作用。
[Abstract]:The research background of polycyclic aromatic hydrocarbons (Polycyclic aromatic, hydrocarbons, PAHs) is a kind of important environmental pollutants, through breathing, eating, drinking and skin and other ways to enter the body of.PAHs PAHs are widely distributed, a variety of chemical substances and has carcinogenicity and mutagenicity, by International Cancer Research Center (IARC) classified as probable human carcinogen. In addition, the study found that PAHs and its active intermediates can also affect male reproductive function, resulting in infertility. Epidemiological survey and animal experiments have reported that elevated PAHs exposure level associated with the decline in semen quality and sperm DNA damage, increase the risk of male infertility. However, the potential effect of PAHs on male reproductive ability still exists the uncertainty, especially in the general population exposure to low dose exposure, PAHs exposure and weak effect between male reproductive damage, may only use the conventional semen quality It is difficult to measure, and the need to find PAHs low environmental exposure induced more sensitive biomarkers of injury to male reproductive conditions. In addition, the molecular events of male reproductive toxicity induced by PAHs and its potential mechanism is still not clear. Therefore, the molecular mechanism of genetic damage to the source, the molecular target of germ cell damage caused by PAHs that will provide an important basis for exploring the biomarkers reflecting PAHs male reproductive damage. Telomere and mitochondrial DNA plays an important role in maintaining genomic integrity and normal cell physiological function. Previous studies indicated that PAHs cells and mitochondrial damage induced by telomere DNA, suggesting that telomere and mitochondrial structure and function abnormalities may be important target PAHs caused male reproductive damage. In this study, the research on College Students' reproductive health research group carried out the queue (MARHCS) based on analysis of environmental exposure and PAHs Related damage to sperm telomere DNA and mitochondrial DNA in vitro and in vivo. To carry out the typical B[a]P further choice of PAHs and its metabolite BPDE, investigate the male germ cells of telomere and mitochondrial structure and function in male reproductive damage effects and damage of the function and mechanism. The MARHCS cohort study associated with the sperm genetic damage and semen quality by our research group carried out in 2013-2015 exposure of PAHs 1. content of college students in Chongqing city population based, by 2014 the first follow-up group (n=666) in biological samples (urine and semen) to evaluate the PAHs exposure level and sperm number index. The metabolites of PAHs to detect the level of GC-MS in urine fluorescence quantitative PCR detection of sperm, sperm telomere length and mtDNAcn, JC-1 detection of sperm mitochondrial membrane potential, Long-PCR detection of MT DNA integrity, Annexin V-FIT C detection of sperm apoptosis and normal semen quality indicators. On this basis, analyzed the related indexes related to PAHs urinary metabolites and the sperm damage. Through the crowd of PAHs exposure induced male reproductive damage biomarkers of.2.BPDE and B[a]P induced spermatogenic cell aging and apoptosis in the process of telomere damage mechanism of mice spermatocyte cell line GC-2 induced by BPDE model. Using trypan blue staining assay cell viability, Annexin combined with V/PI cell apoptosis was detected by flow cytometry analysis, -Gal staining method of SA- beta cell senescence, for evaluation of BPDE on GC-2 cell toxicity; further analysis using fluorescence quantitative PCR and terminal restriction fragment the length (TRF) method for detection of telomere length of FISH cells, combined with gamma -H2AX immunofluorescence method for detecting telomere DNA fracture, TRAP-PCR-ELISA detection of telomerase activity and Wester N blot detection of telomerase reverse transcriptase (TERT) protein expression levels, for evaluation of the effect of BPDE on telomere damage of GC-2 cells. In addition, the expression of Western blot detected the DNA damage response pathway, activation of BPDE was observed in GC-2 cells in response to injury of DNA. On this basis, the model of TERT GC-2 transfected cells then the interference and expression by SH RNA-TERT and P LV-EGFP-TERT vector. The effect of TERT gene on BPDE induced cell senescence and apoptosis of the cells. Based on the experimental results, we established B[a]P (0,5,10 mg/ and 20 kg) by gavage for 7 days in SD rats animal model, further validation of GC-2 cells in vitro experiment results.3.BPDE induced apoptosis of spermatogenic cells in the process of mitochondrial damage mechanism of establishment of GC-2 cell model by BPDE. NAO was used to detect the quality of mitochondrial staining method for detection of mtDNAcn modified RT-PCR Change, change of mitochondrial membrane potential detection of JC-1, Western and blot to detect the mitochondrial respiratory chain key protein COX IV transcriptional coactivator PGC-1 alpha and mitochondrial apoptosis pathway related proteins such as Cyt, C, caspase-9, the expression level of Caspase-3, BPDE to evaluate the mitochondrial function of spermatogenic cells, affect mitochondrial biogenesis and mitochondrial pathway of apoptosis. On this basis, using PGC-1 alpha activators ZLN005 pretreated GC-2 cells, influence index correlation detection BPDE on the mitochondrial damage, in order to clear the PGC-1 alpha in BPDE induced spermatogenic cell mitochondrial damage and apoptosis. In addition, the constructed by TERT interference and expression in transfected cells, further research the effect of mitochondrial damage of spermatogenic cells induced by BPDE, between telomere regulation and mitochondrial damage linked to clear TERT in BPDE induced spermatogenic cell mitochondria The role of injury. Results: 1. people exposed to PAHs and sperm telomere length and sperm mitochondrial copy number between this study detected 8 PAHs urinary metabolites, including 1-OHNap, 2-OHNap, 1-OHPhe, 2-OHPhe, 3-OHPhe, 4-OHPhe, 2-OHFlu and 1-OHPyr. the results of study showed that urinary 1-OHPyr and 1-OHNap and sperm telomere length negative correlation, 1-OHPyr (beta =-0.385; 95% CI: [CI] -0.749~-0.021; 1-OHNap (-0.079; 95%CI:-0.146~-0.011). Urinary 2-OHPhe, 3-OHPhe, Phe, metabolites and 2-OHFlu and sigma level of sperm mtDNAcn was negatively correlated with 2-OHPhe (-9.427; 95%CI:-17.586~-0.459); 3-OHPhe (-11.488; 95%CI:-19.462~-2.725); Sigma Phe metabolites (-9.635; 95%CI:-17.965~-0.688); 2-OHFlu (-11.692; 95%CI:-19.647~-2.949). No statistically significant correlation between urinary PAHs metabolites and sperm mitochondrial membrane potential and MT DNA integrity. In addition, not Observed the 8 PAHs urinary metabolites and sperm apoptosis and sperm quality index (including semen volume, sperm density, sperm count and sperm motility). The correlation between these results suggest that low levels of PAHs exposure may cause sperm damage and mitochondrial telomere, telomere length and sperm and sperm mtDNAcn as may change low dose PAHs exposure induced male reproductive damage sensitive index.2.BPDE and B[a]P induce senescence and apoptosis of spermatogenic cells in the process of telomere damage mechanism of BPDE toxicity effect on GC-2 cells, can cause spermatogenic cell proliferation, senescence and apoptosis. Further studies showed that BPDE treatment can telomere GC-2 induced cell injury, including the length of the telomere, telomere DNA damage and DNA damage response pathway (ATM/Chk1/p53/p21). The activation of telomerase is regulated in male reproductive cell An important factor in the length, the results showed that BPDE treatment could induce lower expression of telomerase activity and telomerase activity rate limiting factor TERT protein, suggesting that telomere structure and function abnormalities are targets of male germ cells injury induced by BPDE. In addition, the TERT transfected cell model showed that expression of TERT interference, can aggravate the telomere BPDE damage induced cell senescence, apoptosis and activation of the DNA damage response pathway, the expression of TERT is part of the recovery against the damage effect of BPDE. These results suggest that TERT is involved in telomere DNA mediated BPDE induced injury of spermatogenic cell senescence and apoptosis related. In addition, in vivo animal experiments showed that B[a]P exposure induced rat spermatogenic cell telomere shortening, and reduce the expression level of activation of the DNA damage response protein TERT, and induced testicular toxicity, including apoptosis of spermatogenic cells And aging, testicular tissue structure changes, these results further verify the experimental results of cell apoptosis of spermatogenic cells in the process of mitochondrial damage mechanism of BPDE induced mitochondrial GC-2 cells induced by.3.BPDE quality decreased, mtDNAcn decreased the mitochondrial membrane potential was decreased and the expression level of mitochondrial biogenesis and oxidative phosphorylation related protein COX, IV and PGC-1 decreased alpha the mitochondrial apoptosis pathway related protein, Cyt C, increased expression of caspase-9 and Caspase-3, found that BPDE can cause.GC-2 damage and mitochondrial function disorder biosynthesis in cells pretreated with PGC-1 alpha activators ZLN005 reduced mitochondrial damage and apoptosis induced by BPDE, suggesting that PGC-1 is involved in the regulation of alpha BPDE induced mitochondrial injury related to apoptosis of spermatogenic cells. In addition, the further analysis of BPDE induced mitochondrial damage and telomere links using TERT transfected cell model Show: TERT can increase the inhibition of BPDE induced mitochondrial injury, including mitochondrial mass, mtDNAcn, mitochondrial membrane potential and mitochondrial apoptosis pathway related protein expression.; instead, restoration of TERT expression is part of against the damage effect of BPDE on mitochondria, suggesting that TERT regulate the expression of PGC-1 alpha, involved in the regulation of BPDE induced mitochondrial injury epidemiology. The research results show that, Chongqing City College Students PAHs exposure levels and sperm telomere shortening and sperm mtDNAcn decreased significant association, suggesting that sperm telomere DNA and mitochondrial DNA may be a sensitive target for male reproductive damage caused by PAHs. GC-2 chemical exposure experiments of spermatocytes in mice and rats confirmed that PAHs is the typical representative of B[a]P and its active metabolite BPDE can induce spermatogenic cell telomere and mitochondrial structure and function abnormalities, leading to fine The reproductive toxicity of cell senescence and apoptosis. In this process, BPDE can inhibit the expression of TERT by telomere damage and DNA damage response pathway caused by reproductive toxicity; on the other hand, BPDE can inhibit PGC-1 expression, mitochondrial damage and apoptosis caused by way of reproductive toxicity. The TERT gene plays a key role in the two in the way.

【學位授予單位】：第三軍醫(yī)大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R114

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