我国是世界上最大的蛋鸡饲养国，商品蛋鸡虽然产蛋性能在高峰期已经达到最大，但是其使用年限短，全期产蛋率并不高，仍然具有巨大的繁殖和生产潜力。而如何提高商品蛋鸡产蛋率，延长生产周期，从而缓解环境压力，这些都是生产上亟待解决的问题。正常情况下，家禽的卵巢中仅有1‰的卵泡能最终发育成熟并排卵，大多数卵泡发生闭锁。与哺乳动物不同，蛋鸡的卵泡闭锁一般主要发生在初级卵泡和前等级(小白、大白和小黄)卵泡阶段，其发生一般是通过凋亡、自噬和其他未知途径死亡，其中以凋亡为主[1-2]。研究发现卵泡内一定量的活性氧自由基(reactive oxygen species，ROS)对卵泡发育和排卵具有重要的生理作用，然而ROS的过度堆积会引起氧化应激，诱导卵泡闭锁，造成繁殖性能衰退[3-4]。对于产蛋鸡而言，随着集约化程度的提高，产蛋或其他应激因素(热应激、霉菌毒素、重金属等)可引起氧化应激，进而导致卵泡闭锁，这可能是降低蛋鸡全期产蛋率和生产潜力的根本原因，而氧化应激是多种应激因素损害繁殖性能的共同机制。因此，探讨氧化应激导致卵泡闭锁的机制对挖掘家禽生产性能有重要理论和实践意义。本文针对氧化应激对卵泡闭锁的影响及机制进行综述，旨在为家禽卵泡闭锁机制的研究提供理论依据，也为繁殖学的理论研究和人类卵巢疾病研究提供科学的参考。
1 家禽卵泡的命运家禽在孵化时拥有约480万个原始卵泡，但终生仅排卵500~1 000个，不足1‰，还具有巨大的生产潜力。与哺乳动物类似，家禽的原始卵泡主要存在3种命运(图 1)[5]：第一，维持静默状态，构成原始卵泡库(primordial follicle reserve，PFR)；第二，在外部因子(各类繁殖激素、生长因子、细胞因子等)的刺激下原始卵泡被激活，发育成初级卵泡、前等级卵泡[直径1~8 mm：包括小白卵泡(SWF，直径＜1 mm)、大白卵泡(LWF，直径2~5 mm)、小黄卵泡(SYF，直径5~8 mm)、大黄卵泡(LYF，直径9~12 mm)]和等级卵泡(按体积大小分别为F1~F7)，并发育成熟和最终排卵，若遇应激和疾病等因素导致发育受阻，则会发生卵泡闭锁；第三，静默状态的原始卵泡经历细胞凋亡、自噬或其他未知途径死亡，形成卵泡闭锁[2]。卵泡闭锁是指卵泡及其中的卵母细胞在发育过程中停止生长并逐渐退化的现象。成熟卵泡主要由卵黄、卵母细胞、颗粒细胞层和膜细胞层(图 1)等组成。由于家禽和哺乳动物一样，在出生后缺乏生殖干细胞[5]，因而其在胚胎发育时期所建立的原始卵泡库是出生后生殖细胞的唯一来源，而卵泡闭锁的数量直接影响家禽产蛋率的高低。
2 氧化应激可以导致卵泡闭锁
氧化应激(oxidative stress)是指机体在内外环境各种有害刺激下，体内产生的ROS和活性氮自由基(reactive nitrogen species，RNS)过多，超过机体自由基清除能力，从而引起细胞和组织器官损伤的现象。研究发现氧自由基的过度堆积会引起氧化应激，造成繁殖性能衰退[3-4]。ROS是细胞通路的重要调控分子，能调控细胞周期和细胞凋亡[6]。已有研究表明，卵泡内一定量的ROS对其发育和排卵具有重要的生理作用[7]，然而ROS过度升高将会导致氧化应激，诱导卵泡闭锁[3, 8-9]。在哺乳动物上的研究发现，氧化应激会降低卵巢各阶段卵泡数量，损伤卵巢功能[10-14]。有研究发现添加抗氧化剂(如茶多酚提取物)可以缓解由金属钼和镉诱导氧化应激时卵泡数量的下降[15-16]，在哺乳动物上的研究也发现已知的强抗氧化剂(原花青素、没食子酸、维生素E、白藜芦醇)可以缓解颗粒细胞的凋亡[17-19]，进一步说明了氧化应激与卵泡闭锁关系密切。
3 氧化应激导致卵泡闭锁的机制卵泡主要由卵母细胞、颗粒细胞层和膜细胞层组成，是卵巢的基本功能单位。目前的研究表明，氧化应激可以导致颗粒细胞和卵母细胞的凋亡，并均可导致卵泡闭锁[2, 20]，其中关于颗粒细胞介导的卵泡闭锁的研究较多，也更为深入。
3.1 颗粒细胞介导的卵泡闭锁机制颗粒细胞通过间隙连接与卵母细胞相连，可以与卵母细胞进行物质交换，对卵母细胞静默、激活和死亡等命运起决定作用。前人研究证实，颗粒细胞的凋亡是引起卵泡闭锁的根本原因，当颗粒细胞凋亡数量达到10%时，标志着卵泡进入闭锁状态[5]。目前的研究发现氧化应激可以引起颗粒细胞凋亡[21-25]。
颗粒细胞凋亡是一个各种信号传导系统参与的复杂生理生化反应过程，包括线粒体途径、死亡受体途径和内质网途径[26-27]。第1条途径由线粒体介导，细胞色素c(cytochrome c，Cyt-c)从线粒体释放是细胞凋亡的关键步骤。释放的Cyt-c与细胞凋亡诱导因子(apoptosis-inducing factor, AIF)结合，并与半胱天冬蛋白酶(cysteine aspartate-specific protease，Caspase)9结合形成凋亡小体[Cyt-c/d ATP/凋亡酶激活因子-1(apoptotic protease activating factor-1, Apaf-1)]，进而招募、激活下游凋亡执行者Caspase 3和8。而被激活的Caspase裂解细胞内重要的参与细胞功能调控和修复DNA的蛋白，如细胞骨架调节有关蛋白和DNA修复酶聚腺苷二磷酸核糖聚合酶(poly ADP-ribose polymerase，PARP)，最终引起细胞凋亡[28]。第2条途径为死亡受体途径，主要参与因子为Fas/FasL、肿瘤坏死因子(tumor necrosis factor，TNF)及肿瘤坏死因子相关凋亡诱导配体(TNF-related apoptosis-inducing ligand，TRAIL)，最终线粒体途径和死亡受体途径都可以通过Caspase 8和10的激活，再进一步激活Caspase 3来诱导细胞凋亡。而第3条途径为内质网途径，主要机制是内质网应激(蛋白质错误折叠或未折叠、内质网胁迫)导致Caspase 7和12的激活，并进一步激活Caspase 9，促进细胞凋亡的发生[29-30]。此外，B细胞淋巴瘤-2(B-cell lymphoma-2，Bcl-2)家族中的促凋亡蛋白[如Bcl-2相关X蛋白(Bcl2-associated X protein，Bax)、Bcl-2同源拮抗剂(Bcl-2 homologous antagonist/killer，Bak)、Bcl-2样蛋白11(Bcl-2 protein like 11，Bim)等]和抗凋亡蛋白[Bcl-2、B细胞淋巴瘤-xL(B-cell lymphoma-2 xL，Bcl-xL)和髓样细胞白血病-1(myeloid cell leukemia-1, Mcl-1)]是参与调控细胞凋亡的关键蛋白。在小鼠模型上的研究表明，氧化应激可以提高小鼠卵巢ROS和丙二醛(malondialdehyde，MDA)浓度，引起卵泡闭锁，降低小鼠卵巢中各阶段卵泡数量[31-33]。另外，叉头转录因子1家族成员叉头框蛋白O1(forkhead box protein O1，FoxO1)是促使卵泡闭锁和颗粒细胞凋亡的关键因子[34]，可以通过调控促凋亡基因TRAIL、FasL和p53上调凋亡调控因子(p53 up-regulated modulator of apoptosis，PUMA)的表达，促进细胞凋亡[35-36]。研究表明，氧化应激可以引起颗粒细胞内FoxO1的高表达，从而调控其下游基因，引起颗粒细胞凋亡。而磷脂酰肌醇-3-激酶(phosphatidylinositol3-kinase, PI3-K)受FoxO1的调控，Wang等[37]研究证明卵泡刺激素(follicle-stimulating hormone，FSH)可以通过下调蛋白激酶A(protein kinase A，PKA)-PI3K-蛋白激酶B(protein kinase B，AKT)-FoxO1轴缓解颗粒细胞凋亡。刘泽群[38]研究表明，氧化应激[过氧化氢(H2O2)处理]可以导致卵巢颗粒细胞凋亡，此过程是通过c-Jun氨基末端激酶(c-Jun N-terminal kinase，JNK)/FoxO1/PUMA信号通路来实现的。另外，也有研究表明，在顺铂治疗卵巢癌过程中JNK也可激活PUMA导致卵巢癌细胞发生凋亡[39]。其他研究也发现PUMA可以通过下调下游抗凋亡蛋白(Mcl-1和Bcl-xL)基因的表达，从而促进由顺钯诱导的卵巢癌细胞的凋亡[40-41]。此外，Wnt/β-连环蛋白(β-catenin)信号通路也被证明是调节卵泡生长、发育和成熟的一个关键途径，可以调节颗粒细胞的增殖和凋亡，该通路受损时，会导致抗穆勒氏管激素(anti-Mullerian hormone，AMH)表达下降，导致卵母细胞提前成熟，原始卵泡库耗竭，从而引起哺乳动物卵巢早衰[42]。Wang等[43]研究发现，家禽闭锁卵泡中参与Wnt4的信号通路的基因弱于其他优势卵泡，进而表明Wnt4信号通路参与了家禽卵泡闭锁。
此外，近年来的研究发现自噬也参与了卵泡闭锁的过程。自噬是真核细胞中高度保守的自我更新过程，其特征是将细胞质物质吞噬到双膜囊泡(自噬体)中，随后在溶酶体中降解[44]。通常，自噬机制对于清除功能障碍的蛋白质和细胞器是必不可少的[45]，但过度自噬也会导致细胞死亡[44]。研究表明，具有正常ROS产生量的哺乳动物细胞通常表现出基础自噬活性，而过度自噬可诱导遭受氧化损伤的细胞自我毁灭[46]；进一步研究证明，在卵泡闭锁期间，卵泡颗粒细胞中自噬信号升高[47-48]。Shen等[25, 49]和Lou等[50]研究表明，氧化应激可以通过激活FoxO1依赖的PI3K-AKT-FoxO1轴和目的沉默信息调节因子1(silent information regulator 1, SIRT1)-FoxO1-自噬相关蛋白7(autophagy related protein 7，ATG7)轴以及抑制哺乳动物雷帕霉素靶蛋白复合物1(mammalian or mechanistic target of rapamycin complex 1, mTORC1)和促进p53信号通路导致鼠颗粒细胞自噬，进而引起卵泡闭锁。氧化应激还可以通过JNK的激活促进自噬关键蛋白Beclin1的表达，进而诱导颗粒细胞自噬[51]，而SIRT1已经被证明在卵巢中大量存在，且与卵巢的抗氧化和衰老密切相关；并且，研究进一步发现褪黑素可以通过抑制JNK/Bcl2/Beclin1信号传导，也可以通过抑制SIRT1信号通路，来抑制颗粒细胞因氧化损伤而导致的自噬[25, 32, 51]。Kang等[52]通过3-硝基丙酸构建鹅颗粒细胞氧化应激模型，研究发现，抑制Bcl-2会促进Caspase 3基因的表达，从而引起鹅颗粒细胞自噬和凋亡。Li等[14]研究发现，热应激引起的氧化应激可以通过死亡受体通路(FasL-Fas和TNF-α)引起细胞凋亡，进而降低蛋鸡的产蛋率。
3.2 卵母细胞凋亡介导的卵泡闭锁机制家禽卵母细胞是卵泡内最大的细胞，被颗粒细胞和膜细胞包裹，卵母细胞的凋亡也是导致卵泡闭锁的主要原因[53]。人和模型动物上的大量研究表明，ROS的大量产生或抗氧化系统的失衡会导致卵母细胞凋亡，是减少卵泡储备的重要原因[54-56]。有研究表明，由氟化物引起的氧化应激可以导致卵母细胞发生凋亡，损伤卵巢功能。Luan等[57]和Nguyen等[58]研究发现，cyclophosphamide或cisplatin(常用的癌症化疗药物)会通过线粒体凋亡途径(Cyt-c-Bax/Bcl2-Caspase)引起卵母细胞凋亡，减少原始卵泡的数量。Nguyen等[58]和Myers等[59]进一步研究发现，促凋亡蛋白PUMA及其上游关键信号Tap63(p63)是参与癌症治疗药物(cyclophosphamide、cisplatin、doxorubicin)，可导致线粒体途径的卵母细胞凋亡，并最终降低原始卵泡储备的关键信号通路[57, 60]。
另外，人及模型动物上的研究表明，卵母细胞的自噬也参与了哺乳动物青春期卵泡大量闭锁[61]。卵母细胞可以经历多种形式的程序性死亡途径[62-63]：1)自噬的诱导促进了凋亡的发生；2)自噬和凋亡共同发生，促进细胞程序性死亡。Xu等[64]通过研究发现，沉默信息调节因子2(silent information regulator 2，SIRT2)失活是卵母细胞衰老的关键机制，而SIRT2的抑制作用有助于成熟后卵母细胞的自噬依赖性细胞凋亡；已有研究也发现SIRT1信号通路参与了氧化应激诱导卵泡闭锁的过程，激活SIRT1信号通路有助于卵泡的存活[63, 65-66]。因此，在出生后卵母细胞死亡介导卵泡闭锁的机制在不同的时期中可能有不同的途径，但家禽上氧化应激对卵母细胞凋亡机制的研究相对缺乏，有待进一步研究。
4 抗氧化剂对卵泡闭锁的影响抗氧化剂是清除过量ROS的清除剂，有助于维持机体的氧化/抗氧化剂平衡，包括酶类抗氧化系统和非酶类抗氧化系统[51]，后者主要由天然和合成的抗氧化剂构成，包含维生素C、维生素E、植物多酚(茶多酚、白藜芦醇、槲皮素等)等[34, 51]。近年来，大量模式动物上的研究表明，在癌症治疗以及卵泡体外培养过程中，使用抗氧化剂可以提高卵泡的存活和卵巢的功能[16, 37]。
茶多酚是茶叶里面的主要多酚类活性物质，已被证明具有强抗氧化和抗凋亡活性[67]。研究表明注射或者口服茶多酚均可以降低卵母细胞的凋亡和卵泡闭锁，并增加原始卵泡库的数量，从而延缓小鼠卵巢的衰老[16, 68]。体外试验进一步揭示茶多酚中的表没食子儿茶素-3-没食子酸酯(epigallocatechin-3-gallate，EGCG)可以通过PI3K-AKT信号通路降低腔前卵泡闭锁[69]。本实验室的前期研究也表明，饲粮中添加茶多酚可以缓解过渡金属钼和钒引起的氧化应激，提高蛋鸡产蛋率和鸡蛋抗氧化性能[15, 70-71]。
白藜芦醇是研究最多的天然多酚类化合物之一，存在于70多种植物和红酒中，具有抗氧化、抗炎、抗肿瘤和延缓衰老等作用[72]。最近大量研究表明白藜芦醇可以缓解氧化应激，降低卵泡闭锁，增加原始卵泡数量，进而延缓卵巢寿命[16, 73-75]。Jiang等[75]在小鼠卵巢早衰模型中的研究发现白藜芦醇可以缓解卵巢早衰导致的卵巢氧化损伤和卵巢炎症，并且发现其作用机制与hedgehog(Hh)通路相关。另外，由于白藜芦醇是SIRT1的激活剂，其缓解氧化应激，降低卵泡闭锁的机制可能与其激活SIRT1及其下游通路(FoxO1)有关[17, 76]。
槲皮素是一种广泛存在于水果、蔬菜和树叶中的天然自由基清除剂，动物(鼠、猪和禽)模型上的研究表明槲皮素可以增加卵巢中抗氧化酶的活性，缓解由重金属(镉)造成的卵巢功能降低，降低由氧化应激(H2O2、重金属镉、T-2毒素诱导)引发的颗粒细胞凋亡，从而提高卵巢功能[16, 77-80]。
此外，其他植物提取物如姜黄素(curcumin)[81-84]、原花青素[85]、辣椒素[82]等也可以缓解氧化应激导致的颗粒细胞的凋亡和卵泡闭锁，缓解卵巢氧化损伤，但抗氧化剂对卵泡闭锁的作用目前研究的还不深入，机制有待进一步揭示。
5 小结卵泡闭锁是影响家禽产蛋性能和繁殖性能的重要因素，近年来的研究表明氧化应激是诱导卵泡闭锁的重要因素之一，而凋亡和自噬均是卵母细胞和颗粒细胞死亡的重要机制。已有的研究表明，氧化应激可以通过线粒体途径、内质网应激途径以及死亡受体途径引起颗粒细胞和卵母细胞的凋亡，也可以通过FoxO1依赖的自噬通路引起颗粒细胞和卵母细胞的死亡；同时，抗氧化物质如茶多酚、白藜芦醇、槲皮素等还可以缓解氧化应激，降低卵泡闭锁。因此，深入研究并揭示卵泡闭锁的关键机制，可为通过营养手段调控卵泡的闭锁，提高家禽的繁殖性能提供理论基础。
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