【摘要】：全氟辛烷磺�；衔�(perfluorooctane sulfonate, PFOS)是一種代表性的全氟化合物(perfluorinated compounds, PFCs),由于其出色的穩(wěn)定性及疏水疏油等特性而長久以來被廣泛地應用于各種民用及工業(yè)產(chǎn)品中。PFOS分布于多種環(huán)境介質中,已造成全球性污染。研究表明,PFOS具有包括生殖毒性在內(nèi)的多系統(tǒng)毒性,如影響雄性動物體內(nèi)的性激素水平、減弱其生育能力等。流行病學研究還表明男性精液質量下降可能與PFOS暴露有關。雖然國內(nèi)外的此類研究已經(jīng)初步對PFOS的生殖毒性做了肯定性結論,但是PFOS的具體生殖毒作用有哪些尤其是PFOS的生殖毒作用靶點及其涉及的雄性生殖損傷機制均尚未闡明。此外,近年來國外相繼有文獻證實雌激素受體(ERs)與精子發(fā)生的調控過程密切相關,而我們的前期預實驗結果表明PFOS可以影響小鼠睪丸組織內(nèi)ERs的表達,那么PFOS所引起的雄性生殖損傷是否也是ERs參與調控的結果呢?鑒于此,我們開展了本研究。本研究通過分別建立體內(nèi)和體外染毒模型,從睪丸功能和結構以及精子發(fā)生等方面觀察PFOS對雄性小鼠生殖系統(tǒng)的影響,探討ERs在PFOS影響精子發(fā)生中的作用并初步闡明其分子機制,為深入研究PFOS的毒作用尤其生殖毒性機制提供基礎,同時也為PFOS環(huán)境污染的控制和政府決策提供理論依據(jù)。第一部分PFOS對雄性小鼠生殖系統(tǒng)的影響目的以雄性成年小鼠為染毒模型,從整體動物水平研究PFOS暴露對小鼠的生殖毒作用。方法36只雄性C57小鼠隨機分為3組,分別為對照組(0.1%DMSO油溶液灌胃)、低劑量PFOS染毒組(0.5mg/kg/d PFOS灌胃)和高劑量PFOS染毒組(10mg/kg/d PFOS灌胃),染毒35d后稱重并處死小鼠。采用計算機輔助精子分析(CASA)系統(tǒng)對附睪尾部精子進行計數(shù)分析；放射免疫法檢測血清性激素水平；HE染色法觀察睪丸組織的結構形態(tài)；原位末端標記術(TUNEL)觀察睪丸中細胞凋亡情況；免疫組化及蛋白質印跡法檢測ERα、ERβ、細胞增殖及凋亡相關蛋白的定位和表達。結果10mg/kg/d PFOS染毒可以使小鼠體重、睪丸重量、睪丸臟器系數(shù)、血清睪酮水平及精子數(shù)均顯著下降,而雌二醇水平變化不明顯；形態(tài)學觀察結果顯示生精小管出現(xiàn)病理性改變,表現(xiàn)為生精細胞層次減少及排列紊亂、生精上皮出現(xiàn)空泡化改變；TUNEL結果表明PFOS可以顯著誘導生精細胞凋亡；PFOS還可使Bax、cleaved caspase-3、cleaved caspase-9和ERβ表達水平上升而PCNA和ERα水平下降。在0.5mg/kg/d PFOS染毒組,除ERβ表達水平上升外,其余蛋白表達水平與對照組無明顯差異。結論一定劑量的PFOS暴露可使雄性小鼠產(chǎn)生生殖毒性作用,小鼠精子數(shù)的下降可能與睪丸組織中生精細胞凋亡的增加以及ERα、ERβ和細胞增殖與凋亡相關蛋白表達水平的改變有關。第二部分雌激素受體在PFOS影響精子發(fā)生中的作用及機制目的以生殖細胞株GC-2 spd(小鼠精母細胞系)為染毒模型,從細胞水平探討ERs在PFOS誘導生精細胞凋亡中的作用及機制。方法分別以0μM、50μm、100μM和PFOS染毒GC-2細胞24h或48h,采用細胞毒性試驗(MTT法)和流式細胞術觀察PFOS對GC-2細胞增殖、凋亡及細胞周期的影響；蛋白質印跡法檢測PFOS染毒對GC-2細胞中ERα、ERβ p-ERKl/2及下游細胞增殖及凋亡相關蛋白表達水平的影響,以探討PFOS誘導細胞凋亡的機制；通過ERa和ERβ激動劑或拮抗劑的加入,探討并驗證ERa和ERβ在PFOS誘導GC-2細胞凋亡中的作用；報告基因法觀察PFOS對ERa和ERβ轉錄活性的影響,確認PFOS是否通過ERs基因組模式發(fā)揮毒效應；最后采用RT-PCR法檢測PFOS對參與調控ERs表達的相關miRNA的影響,分析PFOS如何干擾ERs的表達。結果100μM、150μM的PFOS可以顯著抑制GC-2細胞增殖、使其發(fā)生G0/G1期阻滯并誘導其凋亡的發(fā)生。與對照組相比,100μM、150μM的PFOS還可引起ERβ、Bax、cleaved caspase-3和cleaved caspase-9的蛋白表達水平上調而ERα、 pERK1/2、 Bcl-2、PCNA和cyclin D1表達下調。ERβ激動劑的加入可加劇PFOS對GC-2細胞增殖、凋亡以及pERK1/2、細胞增殖和凋亡相關蛋白表達的影響,而ERa激動劑的加入則可部分逆轉PFOS所致的以上改變。報告基因實驗結果顯示PFOS染毒對ERa和ERβ轉錄活性無明顯影響。此外,100μM、150μM的PFOS還可以使GC-2細胞中miR-145和miR-206表達水平上調而miR-92下調。結論PFOS可以顯著抑制GC-2細胞增殖并誘導其凋亡,這些效應的產(chǎn)生可能是通過PFOS干擾ERs表達從而啟動ERs的非基因組模式,即抑制ERK1/2的磷酸化、繼而干擾其下游包括Bax、Bcl、caspase-9和caspase-3在內(nèi)的線粒體凋亡通路及細胞周期相關蛋白cyclin D1的表達而引起的。此外,PFOS染毒還顯著影響GC-2細胞中miR-145、miR-206和miR-92的表達水平,這可能是我們所觀察到的ERs表達發(fā)生變化的重要原因。第三部分PFOS對雌激素受體β基因敲除小鼠精子發(fā)生的影響目的以雌激素受體β基因敲除(ERβKO)雄性小鼠為染毒模型,從動物水平進一步驗證雌激素受體在PFOS影響小鼠精子發(fā)生中的作用。方法11只ERPKO雄性小鼠,按照隨機分組的原則分為2組,分別為：對照組(5只,0.1%DMSO油溶液灌胃)和PFOS染毒組(6只,8mg/kg/d PFOS灌胃)。12只野生型(WT)雄性小鼠,按照隨機分組的原則分為2組,每組6只,分別為：對照組(0.1%DMSO油溶液灌胃)和PFOS染毒組(8mg/kg/d PFOS灌胃)。染毒35d后稱重并處死小鼠。通過計算機輔助精子分析(CASA)系統(tǒng)對附睪尾部精子進行計數(shù)及分析；放射免疫法檢測血清性激素水平；HE染色法觀察睪丸組織的結構形態(tài)；原位末端標記術(TUNEL)觀察睪丸中細胞凋亡情況；免疫組化及蛋白質印跡法檢測細胞增殖及凋亡相關蛋白的定位和表達分析。結果無PFOS處理的WT小鼠和ERβKO小鼠在精子數(shù)、睪丸組織結構、生精細胞凋亡指數(shù)、血清睪酮水平及雌二醇水平方面均無顯著差異。8mg/kg/d PFOS染毒可以使這兩種小鼠的精子數(shù)、血清睪酮水平、PCNA蛋白表達水平顯著下降而生精細胞凋亡指數(shù)及Bax和cleaved caspase-3的表達水平上升,但對小鼠的體重、睪丸重量和血清雌二醇水平無明顯影響。進一步比較PFOS處理組的WT小鼠和ERβKO小鼠,發(fā)現(xiàn)WT小鼠的生精細胞凋亡指數(shù)顯著高于ERβKO小鼠,其余指標在PFOS處理的這兩種小鼠間無明顯差異。結論：ERβ表達缺失對雄性小鼠的精子數(shù)、睪丸組織結構、血清睪酮水平及雌二醇水平均無明顯影響；與野生型小鼠相比,PFOS誘導的ERβKO小鼠生精細胞凋亡指數(shù)顯著下降,提示ERβ表達缺失對于PFOS誘導生精細胞凋亡可以起到一定的保護作用。
[Abstract]:The perfluorooctane sulfonyl compound (perfluorooctane sulfonate, PFOS) is a representative perfluorocompound (perfluorinated compounds, PFCs). Due to its excellent stability and hydrophobic oil and oil properties, the perfluoroalkyl sulfonyl compound has long been widely used in various civil and industrial products with.PFOS in a variety of environmental mediums. Spherical pollution. Studies have shown that PFOS has multiple systemic toxicity including reproductive toxicity, such as the effects of sex hormone levels in the male animals and their fertility. The epidemiological study also suggests that the quality of male semen may be associated with PFOS exposure. Although this study at home and abroad has preliminarily done the reproductive toxicity of PFOS Affirmative conclusions, but the specific reproductive toxicity of PFOS, especially the target of the reproductive toxicity of PFOS and the mechanism of male reproductive injury, has not been clarified. In addition, in recent years, there have been some literatures that have confirmed that the estrogen receptor (ERs) is closely related to the regulation of the regulation of spermatogenesis, and our pretest results show that PFO S can affect the expression of ERs in the testicular tissue of mice, then whether the male reproductive damage caused by PFOS is also the result of the regulation of ERs participation? In view of this, we carried out this study. This study was conducted by establishing both in vivo and in vitro poisoned models to observe the reproduction of PFOS on male mice from the aspects of testis function, structure and spermatogenesis. The effect of ERs on the effect of PFOS on spermatogenesis was discussed and its molecular mechanism was preliminarily clarified, which provided a basis for the in-depth study of the toxic effect of PFOS, especially on the mechanism of reproductive toxicity, and also provided a theoretical basis for the control of environmental pollution in PFOS and government decision-making. The first part of the effect of PFOS to the reproductive system of male mice was aimed at males. 36 male C57 mice were randomly divided into 3 groups: the control group (0.1%DMSO oil solution gavage), the low dose PFOS group (0.5mg/kg/d PFOS gavage) and the high dose PFOS venom group (10mg/kg/d PFOS gavage), and the weight of the toxic 35d after 35d, and the weight of the mice after 35d. A computer assisted sperm analysis (CASA) system was used to count the spermatozoa in the epididymis; the level of serum sex hormone was detected by radioimmunoassay; the structure of the testicular tissue was observed by HE staining; in situ end labeling (TUNEL) was used to observe the cell apoptosis in the testis, and the immunohistochemical and Western blot methods were used to detect ER alpha, ER Results 10mg/kg/d PFOS can reduce the weight of mice, the weight of the testis, the coefficient of testicular organ, the level of serum testosterone and the number of sperm, but the level of estradiol is not obvious. Morphological observation shows the pathological changes in the seminiferous tubules, which are spermatogenic cells. TUNEL results showed that PFOS could induce apoptosis of spermatogenic cells, and PFOS also increased the level of Bax, cleaved Caspase-3, cleaved caspase-9 and ER beta, while PCNA and ER alpha levels decreased. The expression level was not significantly different from that of the control group. Conclusion a certain dose of PFOS exposure could produce reproductive toxicity in male mice. The decrease of sperm count in mice may be related to the increase of spermatogenic cell apoptosis in the testis tissue and the changes of ER alpha, ER beta and cell proliferation and apoptosis related protein expression. The second part of estrogen receptor is in P The effect and mechanism of FOS on spermatogenesis and the mechanism aim to use the germ cell line GC-2 SPD (mouse spermatocyte line) as a poisoned model to explore the role and mechanism of ERs in the apoptosis of spermatogenic cells induced by PFOS from the cell level. The methods were 0 u M, 50 mu m, 100 mu M and PFOS GC-2 cells 24h or 48h, and the cytotoxicity test and flow cytometry were used. The effects of PFOS on the proliferation, apoptosis and cell cycle of GC-2 cells were observed, and the effect of PFOS on the expression of ER alpha, ER beta p-ERKl/2 and downstream cell proliferation and apoptosis related protein in GC-2 cells was detected by Western blot, in order to explore the mechanism of PFOS induced apoptosis, and the addition of ERa and ER beta agonists or antagonists was discussed. The effect of ERa and ER beta on the apoptosis of GC-2 cells induced by PFOS was verified. The effect of PFOS on the transcriptional activity of ERa and ER beta was observed and the toxic effect of PFOS was confirmed through the ERs genome pattern. Finally, RT-PCR method was used to detect the effect of PFOS on the related regulation of ERs expression. PFOS can inhibit the proliferation of GC-2 cells and induce G0/G1 phase block and induce apoptosis of GC-2 cells. Compared with the control group, 100 u M, 150 mu PFOS can also cause ER beta, Bax, cleaved caspase-3 and protein expression up regulation. The addition of the agent could aggravate the effect of PFOS on the proliferation, apoptosis and the expression of pERK1/2, cell proliferation and apoptosis related proteins, while the addition of ERa agonists could partly reverse the above changes caused by PFOS. The results of the reported gene experiment showed that PFOS had no obvious effect on the transcriptional activity of ERa and ER beta. In addition, 100 u M, the PFOS of 150 mu M was also possible. The expression level of miR-145 and miR-206 in GC-2 cells is up regulated and miR-92 is down regulated. Conclusion PFOS can significantly inhibit the proliferation and induce apoptosis of GC-2 cells. These effects may be induced by PFOS interfering ERs expression to initiate the non genomic pattern of ERs, that is, to inhibit the phosphorylation of ERK1/2, and then interfere with the downstream of Bax, Bcl, etc. The apoptosis pathway of mitochondria and the expression of cell cycle related protein cyclin D1, including the expression of spase-3 and the expression of miR-145, miR-206 and miR-92 in GC-2 cells, may be an important reason for the changes in the expression of ERs in the GC-2 cells. The third part PFOS knocks on the estrogen receptor beta gene. The effect of spermatogenesis in mice was based on the estrogen receptor beta gene knockout (ER beta KO) male mice as a poisoned model. The role of estrogen receptor in the spermatogenesis of mice was further verified from the animal level. Methods 11 male ERPKO mice were divided into 2 groups according to the principle of random grouping: the control group (5, 0.1%DMSO oil soluble). The male mice of.12 only wild type (WT) were divided into 2 groups according to the principle of random grouping, and 6 rats in each group were divided into 2 groups according to the principle of randomization. The control group (0.1%DMSO oil solution gavage) and PFOS poisoning group (8mg/kg/d PFOS gavage) were weighed and executed after 35d. The system of computer assisted sperm analysis (CASA) system was used. The sperm of epididymis tail was counted and analyzed; the level of serum sex hormone was detected by radioimmunoassay; the structure of the testicular tissue was observed by HE staining; in situ end labeling (TUNEL) was used to observe the cell apoptosis in the testis, and the localization and expression analysis of cell proliferation and apoptosis related proteins were detected by immunohistochemistry and Western blot. There were no significant differences in sperm count, testicular tissue structure, spermatogenic cell apoptosis index, serum testosterone level and estradiol level in the WT mice without PFOS treatment and ER beta KO mice. The number of sperm, the level of serum testosterone, the level of PCNA protein and the apoptotic index of spermatogenic cells were significantly decreased in the two mice. The expression level of Bax and cleaved caspase-3 increased, but had no significant influence on the weight of the mice, the weight of the testis and the level of serum estradiol. Further comparison of the WT mice and ER beta KO mice in the PFOS treatment group showed that the apoptosis index of spermatogenic cells in WT mice was significantly higher than that of the ER beta KO mice, and the other indexes were not significantly worse among the two mice treated PFOS. Conclusion: the loss of ER beta expression has no significant effect on sperm count, testicular tissue structure, serum testosterone level and estradiol level in male mice. Compared with wild type mice, the apoptosis index of spermatogenic cells induced by PFOS in ER beta KO mice decreased significantly, suggesting that the deletion of ER beta expression may play a certain role in the apoptosis of spermatogenic cells induced by PFOS. Protective effect.
【學位授予單位】：南京醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R114

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10 呂永龍;王佩;謝雙蔚;王鐵宇;;新興產(chǎn)業(yè)發(fā)展與新型污染物的排放和污染控制——以全氟辛烷磺酸(PFOS)類新型污染物為例[A];第十五屆中國科協(xié)年會第24分會場：貴州發(fā)展戰(zhàn)略性新興產(chǎn)業(yè)中的生態(tài)環(huán)境保護研討會論文集[C];2013年

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10 李笑;我國一般人群血清中PFOS和PFOA分布特征及基準值[D];大連理工大學;2011年

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