本文主要研究内容
作者曾群（2019）在《亚砷酸钠对小鼠雄性生殖和糖稳态的影响及葡萄皮提取物的缓解作用》一文中研究指出：砷(As)是一种自然界中广泛分布的环境污染物,可通过饮水、呼吸道等途径进入人体,造成机体各组织器官损伤,引起癌症和多种疾病发生。近年来,砷对雄性生殖健康的潜在危害日益引起人们的重视。动物短期砷暴露实验已经证实,砷可通过抑制睾酮合成,降低精子质量、诱导睾丸氧化应激,干扰正常的精子发生。但是至今为止,长期砷暴露的毒性作用及其相关机制仍然不是很清楚,且缺乏有效的防治措施。目前一致认为氧化应激与砷诱导的组织器官损伤密切相关,提示通过抗氧化、减轻氧化应激能缓解砷引起的损伤。因此,探寻安全有效的抗氧化物质己成为研究的热点。葡萄果皮中含有大量的花色苷,具有很强的抗氧化能力。然而,葡萄果皮提取物(GSE)能否减轻砷诱导的雄性器官氧化损伤及其它损伤,保护正常精子发生,目前尚未见报道。流行病学调查发现,慢性饮水型砷暴露可增大患糖尿病的风险。氧化应激与糖尿病的发生关系密切。许多证据也已表明砷摄入能扰乱机体的葡萄糖稳态。肝脏是糖代谢的重要器官。迄今为止,长期砷暴露对糖稳态的影响、肝脏氧化应激程度、肝脏损伤、炎症反应及其肝脏胰岛素敏感性和肝脏葡萄糖转运影响的研究尚少。基于小鼠对砷蓄积的靶器官与人类砷中毒的靶器官具有一致性,本课题以小鼠为实验材料,探讨了亚砷酸钠(NaAs02)长期暴露引起的雄性生殖毒性及作用机制,分析了 GSE对砷致雄性生殖毒性的缓解作用,研究了砷暴露对小鼠葡萄糖稳态的影响。主要实验结果如下:1.通过对雄性C57BL/6小鼠饮水砷染毒连续6个月,染毒剂量为5和50 ppm砷,探讨长期NaAsO2暴露对精子发生、睾酮合成、雄激素结合蛋白(ABP)和Ddx3y表达的影响及其作用机制。结果表明,砷暴露组精子计数和精子运动降低,精子畸形率升高。两个砷处理组小鼠均出现生精上皮生精细胞和精子数减少及Johnsen评分降低,提示小鼠精子发生障碍。与此同时,砷降低血清睾酮,伴随促黄体生成素受体(LHR),类固醇合成急速调节蛋白(StAR)和17β-径基类固醇脱氢酶(17β-HSD)mRNA下调。砷也以剂量依赖方式下调ABP和Ddx3ymRNA。与基因转录水平变化一致,砷处理组小鼠睾丸StAR,17β-HSD和Ddx3y蛋白表达降低。这些结果表明,长期砷暴露可能通过下调睾酮生物合成途径中多个基因表达降低睾酮、抑制ABP基因表达干扰雄激素稳态、下调Ddx3y表达,导致小鼠精子发生障碍。2.为阐明NaAs02诱导雄性生殖毒性的可能机制,在前期研究的基础上,进一步评估了长期砷暴露对小鼠睾丸氧化应激、细胞周期阻滞和细胞凋亡的影响。结果表明,睾丸总超氧化物歧化酶(T-SOD)活性和谷胱甘肽(GSH)含量降低,活性氧(ROS)和丙二醛(MDA)含量增加,提示砷诱导睾丸产生氧化应激。Pearson相关性分析显示抗氧化剂(GSH和T-SOD)与ROS呈负相关,且GSH与ROS间的相关系数(r=-0.822)高于T-SOD和ROS间的相关系数(r=-0.718)。此外,砷引起睾丸G2/M期细胞阻滞,伴有p53和p2lmRNA表达增加、细胞周期蛋白依赖性激酶2(cdc2)和细胞周期蛋白B1(cyclin B1)mRNA和蛋白水平降低、p-cdc2(Tyr1 5)表达增多。砷暴露上调Bax mRNA和蛋白表达及Bax/Bc1-2比值,激活Caspase-3,诱导睾丸细胞凋亡.。综上所述,长期砷暴露引起的睾丸毒性可能与睾丸的氧化损伤、G2/M细胞阻滞和睾丸细胞凋亡有关,这些改变增加了精子发生障碍和男性不育的风险。3.前期研究证实砷诱导雄性生殖毒性的主要机制是氧化应激,提示通过抗氧化、减轻氧化应激可缓解砷引起的雄性生殖损伤。本实验通过雄性昆明种小鼠饮水(含10 ppm砷)染毒,同时给予GSE干预,连续60 d,评价GSE对砷致雄性生殖毒性的影响。结果表明:砷暴露使生精小管中各级生精细胞和精子减少、附睾精子降低和精子畸形率增加,这些影响可被GSE与砷联合作用缓解。此外,砷处理使睾丸H2O2和MDA含量升高,T-SOD活性和GSH含量降低,表明睾丸产生了氧化损伤,GSE干预可减轻睾丸的氧化损伤。与此同时,砷暴露增加BaxmRNA表达及Bax/Bcl-2比值,GSE干预后抑制Bax mRNA及降低Bax/B cl-2比值。砷摄入下调睾酮合成关键基因LHR和17β-HSD mRNA,GSE干预则增加LHR和17β-HSD mRNA表达;砷处理增加肿瘤坏死因子α(TNF-α)和白细胞介素6(IL-6)mRNA表达,推测睾丸产生炎症反应,GSE干预可减轻砷致睾丸的炎症反应。以上结果提示,GSE可能通过减轻砷致睾丸氧化损伤和炎症反应、增加睾酮合成关键基因(LHR,17β-HSD)mRNA和降低促凋亡基因Bax mRNA及Bax/B cl-2比值缓解砷诱导的雄性生殖毒性,对砷致小鼠精子发生障碍起到一定保护作用。4.通过饮水NaAsO2暴露,研究砷对小鼠葡萄糖稳态的影响及相关作用机制。结果发现,C57BL/6小鼠经饮水暴露5、50 ppm砷6个月,每月空腹血糖和1-4个月内葡萄糖耐量与对照组无明显变化。在5个月、6个月后导致葡萄糖耐量受损且具有剂量和时间依赖性。与此同时,砷诱导肝脏产生氧化应激反应,该反应与同期糖耐量受损呈正相关。此外,砷暴露5个月、6个月后,血清丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)活性在50 ppm砷组显著升高;HE染色观察到砷暴露组小鼠肝脏结构损伤,炎性细胞浸润。同时,砷组肝脏促炎因子肿瘤坏死因子TNF-αmRNA上调,胰岛素受体底物(IRS2)和葡萄糖转运蛋白(GLUT2)mRNA下调。研究结果表明,长期砷暴露可能通过诱导肝脏氧化应激、肝脏损伤、炎症反应、胰岛素受体后信号转导障碍和肝脏葡萄糖转运异常引起糖稳态受损。综上所述:长期砷暴露,可致小鼠睾丸结构损伤,使附睾精子减少、精子畸形率增加,精子发生障碍,产生雄性生殖毒性。砷暴露抑制睾酮合成、引起睾丸氧化损伤、诱导G2/M期细胞阻滞和细胞凋亡。GSE干预后,可通过减轻睾丸氧化损伤、炎症反应、调节睾酮合成关键基因和凋亡相关基因缓解砷引起的雄性生殖损伤,该研究将为砷致雄性生殖毒性的防治提供实验证据。另外,砷暴露还可引起小鼠葡萄糖耐量受损、干扰葡萄糖稳态。糖稳态受损可能与肝脏氧化应激、肝脏损伤、炎症反应、胰岛素受体后信号转导障碍和肝脏葡萄糖转运异常有关。
Abstract
shen (As)shi yi chong zi ran jie zhong an fan fen bu de huan jing wu ran wu ,ke tong guo yin shui 、hu xi dao deng tu jing jin ru ren ti ,zao cheng ji ti ge zu zhi qi guan sun shang ,yin qi ai zheng he duo chong ji bing fa sheng 。jin nian lai ,shen dui xiong xing sheng shi jian kang de qian zai wei hai ri yi yin qi ren men de chong shi 。dong wu duan ji shen bao lou shi yan yi jing zheng shi ,shen ke tong guo yi zhi gao tong ge cheng ,jiang di jing zi zhi liang 、you dao gao wan yang hua ying ji ,gan rao zheng chang de jing zi fa sheng 。dan shi zhi jin wei zhi ,chang ji shen bao lou de du xing zuo yong ji ji xiang guan ji zhi reng ran bu shi hen qing chu ,ju que fa you xiao de fang zhi cuo shi 。mu qian yi zhi ren wei yang hua ying ji yu shen you dao de zu zhi qi guan sun shang mi qie xiang guan ,di shi tong guo kang yang hua 、jian qing yang hua ying ji neng huan jie shen yin qi de sun shang 。yin ci ,tan xun an quan you xiao de kang yang hua wu zhi ji cheng wei yan jiu de re dian 。pu tao guo pi zhong han you da liang de hua se gan ,ju you hen jiang de kang yang hua neng li 。ran er ,pu tao guo pi di qu wu (GSE)neng fou jian qing shen you dao de xiong xing qi guan yang hua sun shang ji ji ta sun shang ,bao hu zheng chang jing zi fa sheng ,mu qian shang wei jian bao dao 。liu hang bing xue diao cha fa xian ,man xing yin shui xing shen bao lou ke zeng da huan tang niao bing de feng xian 。yang hua ying ji yu tang niao bing de fa sheng guan ji mi qie 。hu duo zheng ju ye yi biao ming shen she ru neng rao luan ji ti de pu tao tang wen tai 。gan zang shi tang dai xie de chong yao qi guan 。qi jin wei zhi ,chang ji shen bao lou dui tang wen tai de ying xiang 、gan zang yang hua ying ji cheng du 、gan zang sun shang 、yan zheng fan ying ji ji gan zang yi dao su min gan xing he gan zang pu tao tang zhuai yun ying xiang de yan jiu shang shao 。ji yu xiao shu dui shen xu ji de ba qi guan yu ren lei shen zhong du de ba qi guan ju you yi zhi xing ,ben ke ti yi xiao shu wei shi yan cai liao ,tan tao le ya shen suan na (NaAs02)chang ji bao lou yin qi de xiong xing sheng shi du xing ji zuo yong ji zhi ,fen xi le GSEdui shen zhi xiong xing sheng shi du xing de huan jie zuo yong ,yan jiu le shen bao lou dui xiao shu pu tao tang wen tai de ying xiang 。zhu yao shi yan jie guo ru xia :1.tong guo dui xiong xing C57BL/6xiao shu yin shui shen ran du lian xu 6ge yue ,ran du ji liang wei 5he 50 ppmshen ,tan tao chang ji NaAsO2bao lou dui jing zi fa sheng 、gao tong ge cheng 、xiong ji su jie ge dan bai (ABP)he Ddx3ybiao da de ying xiang ji ji zuo yong ji zhi 。jie guo biao ming ,shen bao lou zu jing zi ji shu he jing zi yun dong jiang di ,jing zi ji xing lv sheng gao 。liang ge shen chu li zu xiao shu jun chu xian sheng jing shang pi sheng jing xi bao he jing zi shu jian shao ji Johnsenping fen jiang di ,di shi xiao shu jing zi fa sheng zhang ai 。yu ci tong shi ,shen jiang di xie qing gao tong ,ban sui cu huang ti sheng cheng su shou ti (LHR),lei gu chun ge cheng ji su diao jie dan bai (StAR)he 17β-jing ji lei gu chun tuo qing mei (17β-HSD)mRNAxia diao 。shen ye yi ji liang yi lai fang shi xia diao ABPhe Ddx3ymRNA。yu ji yin zhuai lu shui ping bian hua yi zhi ,shen chu li zu xiao shu gao wan StAR,17β-HSDhe Ddx3ydan bai biao da jiang di 。zhe xie jie guo biao ming ,chang ji shen bao lou ke neng tong guo xia diao gao tong sheng wu ge cheng tu jing zhong duo ge ji yin biao da jiang di gao tong 、yi zhi ABPji yin biao da gan rao xiong ji su wen tai 、xia diao Ddx3ybiao da ,dao zhi xiao shu jing zi fa sheng zhang ai 。2.wei chan ming NaAs02you dao xiong xing sheng shi du xing de ke neng ji zhi ,zai qian ji yan jiu de ji chu shang ,jin yi bu ping gu le chang ji shen bao lou dui xiao shu gao wan yang hua ying ji 、xi bao zhou ji zu zhi he xi bao diao wang de ying xiang 。jie guo biao ming ,gao wan zong chao yang hua wu qi hua mei (T-SOD)huo xing he gu guang gan tai (GSH)han liang jiang di ,huo xing yang (ROS)he bing er quan (MDA)han liang zeng jia ,di shi shen you dao gao wan chan sheng yang hua ying ji 。Pearsonxiang guan xing fen xi xian shi kang yang hua ji (GSHhe T-SOD)yu ROScheng fu xiang guan ,ju GSHyu ROSjian de xiang guan ji shu (r=-0.822)gao yu T-SODhe ROSjian de xiang guan ji shu (r=-0.718)。ci wai ,shen yin qi gao wan G2/Mji xi bao zu zhi ,ban you p53he p2lmRNAbiao da zeng jia 、xi bao zhou ji dan bai yi lai xing ji mei 2(cdc2)he xi bao zhou ji dan bai B1(cyclin B1)mRNAhe dan bai shui ping jiang di 、p-cdc2(Tyr1 5)biao da zeng duo 。shen bao lou shang diao Bax mRNAhe dan bai biao da ji Bax/Bc1-2bi zhi ,ji huo Caspase-3,you dao gao wan xi bao diao wang .。zeng shang suo shu ,chang ji shen bao lou yin qi de gao wan du xing ke neng yu gao wan de yang hua sun shang 、G2/Mxi bao zu zhi he gao wan xi bao diao wang you guan ,zhe xie gai bian zeng jia le jing zi fa sheng zhang ai he nan xing bu yo de feng xian 。3.qian ji yan jiu zheng shi shen you dao xiong xing sheng shi du xing de zhu yao ji zhi shi yang hua ying ji ,di shi tong guo kang yang hua 、jian qing yang hua ying ji ke huan jie shen yin qi de xiong xing sheng shi sun shang 。ben shi yan tong guo xiong xing kun ming chong xiao shu yin shui (han 10 ppmshen )ran du ,tong shi gei yu GSEgan yu ,lian xu 60 d,ping jia GSEdui shen zhi xiong xing sheng shi du xing de ying xiang 。jie guo biao ming :shen bao lou shi sheng jing xiao guan zhong ge ji sheng jing xi bao he jing zi jian shao 、fu gao jing zi jiang di he jing zi ji xing lv zeng jia ,zhe xie ying xiang ke bei GSEyu shen lian ge zuo yong huan jie 。ci wai ,shen chu li shi gao wan H2O2he MDAhan liang sheng gao ,T-SODhuo xing he GSHhan liang jiang di ,biao ming gao wan chan sheng le yang hua sun shang ,GSEgan yu ke jian qing gao wan de yang hua sun shang 。yu ci tong shi ,shen bao lou zeng jia BaxmRNAbiao da ji Bax/Bcl-2bi zhi ,GSEgan yu hou yi zhi Bax mRNAji jiang di Bax/B cl-2bi zhi 。shen she ru xia diao gao tong ge cheng guan jian ji yin LHRhe 17β-HSD mRNA,GSEgan yu ze zeng jia LHRhe 17β-HSD mRNAbiao da ;shen chu li zeng jia zhong liu huai si yin zi α(TNF-α)he bai xi bao jie su 6(IL-6)mRNAbiao da ,tui ce gao wan chan sheng yan zheng fan ying ,GSEgan yu ke jian qing shen zhi gao wan de yan zheng fan ying 。yi shang jie guo di shi ,GSEke neng tong guo jian qing shen zhi gao wan yang hua sun shang he yan zheng fan ying 、zeng jia gao tong ge cheng guan jian ji yin (LHR,17β-HSD)mRNAhe jiang di cu diao wang ji yin Bax mRNAji Bax/B cl-2bi zhi huan jie shen you dao de xiong xing sheng shi du xing ,dui shen zhi xiao shu jing zi fa sheng zhang ai qi dao yi ding bao hu zuo yong 。4.tong guo yin shui NaAsO2bao lou ,yan jiu shen dui xiao shu pu tao tang wen tai de ying xiang ji xiang guan zuo yong ji zhi 。jie guo fa xian ,C57BL/6xiao shu jing yin shui bao lou 5、50 ppmshen 6ge yue ,mei yue kong fu xie tang he 1-4ge yue nei pu tao tang nai liang yu dui zhao zu mo ming xian bian hua 。zai 5ge yue 、6ge yue hou dao zhi pu tao tang nai liang shou sun ju ju you ji liang he shi jian yi lai xing 。yu ci tong shi ,shen you dao gan zang chan sheng yang hua ying ji fan ying ,gai fan ying yu tong ji tang nai liang shou sun cheng zheng xiang guan 。ci wai ,shen bao lou 5ge yue 、6ge yue hou ,xie qing bing an suan zhuai an mei (ALT)he tian dong an suan zhuai an mei (AST)huo xing zai 50 ppmshen zu xian zhe sheng gao ;HEran se guan cha dao shen bao lou zu xiao shu gan zang jie gou sun shang ,yan xing xi bao jin run 。tong shi ,shen zu gan zang cu yan yin zi zhong liu huai si yin zi TNF-αmRNAshang diao ,yi dao su shou ti de wu (IRS2)he pu tao tang zhuai yun dan bai (GLUT2)mRNAxia diao 。yan jiu jie guo biao ming ,chang ji shen bao lou ke neng tong guo you dao gan zang yang hua ying ji 、gan zang sun shang 、yan zheng fan ying 、yi dao su shou ti hou xin hao zhuai dao zhang ai he gan zang pu tao tang zhuai yun yi chang yin qi tang wen tai shou sun 。zeng shang suo shu :chang ji shen bao lou ,ke zhi xiao shu gao wan jie gou sun shang ,shi fu gao jing zi jian shao 、jing zi ji xing lv zeng jia ,jing zi fa sheng zhang ai ,chan sheng xiong xing sheng shi du xing 。shen bao lou yi zhi gao tong ge cheng 、yin qi gao wan yang hua sun shang 、you dao G2/Mji xi bao zu zhi he xi bao diao wang 。GSEgan yu hou ,ke tong guo jian qing gao wan yang hua sun shang 、yan zheng fan ying 、diao jie gao tong ge cheng guan jian ji yin he diao wang xiang guan ji yin huan jie shen yin qi de xiong xing sheng shi sun shang ,gai yan jiu jiang wei shen zhi xiong xing sheng shi du xing de fang zhi di gong shi yan zheng ju 。ling wai ,shen bao lou hai ke yin qi xiao shu pu tao tang nai liang shou sun 、gan rao pu tao tang wen tai 。tang wen tai shou sun ke neng yu gan zang yang hua ying ji 、gan zang sun shang 、yan zheng fan ying 、yi dao su shou ti hou xin hao zhuai dao zhang ai he gan zang pu tao tang zhuai yun yi chang you guan 。
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标签：氧化应激论文; 细胞凋亡论文; 雄性生殖毒性论文; 葡萄糖稳态论文; 山西大学2019-11-12论文;