2. 锦州医科大学, 锦州 121001
2. Jinzhou Medical University, Jinzhou 121001, China
镰刀菌毒素是由镰刀菌合成的高毒性、低分子质量的次级代谢产物, 包括玉米赤霉烯酮(zearalenone, ZEA)和脱氧雪腐镰刀菌烯醇(deoxynivalenol, DON)。镰刀菌产生的毒素广泛存在于霉变的玉米、小麦、大麦、燕麦、高粱等谷物中[1]。ZEA(又称F-2毒素)是一种雌激素类似物, ZEA及其衍生物给人类和动物健康造成巨大威胁, 表现在影响生长发育, 破坏生殖系统[2]、肝脏系统[2]、免疫系统[3], 造成氧化损伤[4], 并引发肿瘤[5]。除此之外, 还具有遗传毒性[6]和细胞毒性[7]。DON(又称呕吐毒素或脱氧瓜萎镰刀菌烯醇)是肠毒素, 对哺乳动物具有较强的毒性, 能够引起人和动物食欲下降, 生长迟缓, 肝脏、脾脏受损[8], 还会改变神经内分泌信号和肠道完整性[9], 此外还具有遗传毒性[10]。
世界上每年约有25%的谷物会遭受到不同程度的霉菌毒素污染。随着全球异常气候的频发和谷物贸易的激增, 增加了饲料原料同时受多种霉菌毒素污染的风险。目前, 对于单一霉菌毒素对动物健康、动物生产影响的报道较多, 我国《饲料卫生标准》霉菌毒素的限量标准也是以1种毒素剂量为准。但是, 实际上饲料原料和全价配合饲料中往往是多种霉菌毒素同时存在, 特别是多数饲料原料会同时受到ZEA和DON的污染[11], 并且ZEA和DON间存在协同、相加、增效、拮抗等不同效应。近几年的报道表明, ZEA和DON具有联合毒性, 如生殖毒性[12]、遗传毒性[13]、细胞毒性[4]和免疫毒性[14]。由于ZEA和DON的高发生率和高毒性已严重威胁动物的生产性能和人类健康, 影响了畜牧业生产, 因此迫切需要得到控制和解决。因此, 本文介绍了ZEA和DON对动物的毒害作用, 并阐述了2种毒素的联合作用毒性, 对畜牧业生产中存在的霉菌毒素污染问题提出建议和展望。
1 生殖毒性ZEA浓度过高会导致雌激素超负荷, 雌性动物表现为外阴水肿、假发情、不育、流产和胎儿吸收等; 雄性动物表现为包皮水肿、睾丸萎缩及精液质量降低[15-16]; 可引起雌性大鼠卵巢和子宫组织病理学改变, 血清卵泡刺激素(FSH)含量升高和17β-雌二醇(E2)含量降低[2]; 雄性小鼠精子浓度和活动率下降, 畸形率增高[16]。此外, ZEA因与类固醇激素具有同源性, 能干扰激素代谢。ZEA和α-玉米赤霉烯醇(α-ZOL)可抑制人绒毛膜促性腺激素诱导的睾酮分泌, 并与3β-羟基类固醇脱氢酶(3β-HSD)、P450胆固醇侧链裂解酶(P450scc)和类固醇激素合成急性调节蛋白(StAR)的转录下降有关[17]。DON的生殖毒性与ZEA相似, 雌性动物表现为生殖器官形态和功能异常, 卵巢颗粒细胞和卵母细胞增殖和活力受到抑制, 成熟率降低, 减数分裂Ⅱ期卵母细胞比例降低, 孕酮和雌激素合成受到干扰, 进而引起胚胎毒性[12]。雄性SD大鼠暴露于DON后, 其睾丸和附睾尾部精子数量减少, 精子尾部畸形; FSH和促黄体生成素含量剂量依赖性增加, 血清睾酮含量剂量依赖性下降; 生殖细胞退化、细胞核形态异常增加[18]。
ZEA或其代谢物α-Zol和DON联合作用影响卵泡颗粒细胞(GC)的增殖和类固醇生成[19]。ZEA+DON可导致青年母猪卵母细胞成熟率下降, 其卵母细胞减数分裂过程中染色质形态异常, 影响卵子的发育能力[20]; 妊娠75 d的母猪妊娠期动物流产或胚胎畸形[21]。Ranzenigo等[22]的研究也发现, ZEA+DON对胰岛素样生长因子-Ⅰ(IGF-Ⅰ)诱导的E2的产生有两相作用, 即低剂量能增加E2产量而高剂量能抑制E2产量, 同时发现ZEA+DON对GC的增殖和类固醇生成存在剂量依赖性的影响。
2 肠道毒性胃肠道通常是ZEA和DON毒性发挥的第1靶向组织。ZEA可破坏肠道屏障功能, 在细胞水平上抑制功能性蛋白质、小肽的合成和紧密连接蛋白质的表达, 同时影响肠腔内营养物质的消化、吸收、代谢和转运[23]。ZEA可降低猪盲肠和结肠中杯状细胞的数量, 增加大肠中淋巴细胞和浆细胞的数量, 诱导黏膜上皮细胞超微结构的变化[24]。DON可通过抑制十二指肠黏蛋白2(MUC2)基因表达和修饰黏蛋白单糖组成改变鸡肠道黏液层[25]。亚慢性的暴露于DON会导致动物"短暂性生态失调", 影响结肠内微生物的多样性, 产气荚膜梭菌的数量减少, 而肠杆菌的数量没有变化[26]。也有学者未观察到暴露于DON的大鼠肠道微生物的组成和多样性的改变[27]。
ZEA+DON联合作用会损伤猪肠道屏障功能的完整性, 导致组织学变化, 对病原体的防御机能下降[14, 24]。Wan等[28]研究报道, 猪小肠上皮细胞(IPEC-J2细胞)单独或联合暴露于ZEA和DON时, 其细胞上清液抵抗大肠杆菌的活性显著降低。ZEA+DON联合作用有加性效应, 也有非加性效应[29-30]。例如, 也有研究未观察到ZEA+DON对猪空肠绒毛高度和隐窝中杯状细胞百分比的叠加效应[31]。
3 免疫毒性ZEA和DON通过小肠屏障后, 第2靶向目标便是免疫系统。ZEA可抑制小鼠T淋巴细胞中活化信号的形成和传递, 干扰活化T细胞核因子(NFAT)和核因子-κB(NF-κB)的信号通路, 并且在活化后减少细胞因子的分泌[3]。Chen等[32]研究表明, ZEA能诱导断奶后母猪脾脏白细胞介素-2(IL-2)含量线性下降, 白细胞介素-1β(IL-1β)和白细胞介素-6(IL-6)的mRNA表达线性上调, 而干扰素-γ(IFN-γ)的mRNA表达线性下调。DON是鸡坏死性肠炎的诱发因素[33], 可增加Ⅱ型猪圆环病毒(PCV-2)的复制[34]; 降低猪蓝耳病病毒(PRRSV)的体液免疫的应答能力, 导致肺损伤和死亡率增加[35]; 损害肉鸡对病毒疫苗的体液免疫应答, 导致传染性支气管炎病毒或新城疫病毒疫苗等失效[36]。
ZEA+DON联合作用于5周龄仔猪, 28 d后仔猪肝脏和淋巴器官发生组织学改变, 淋巴结和脾脏的淋巴细胞凋亡显著增加[14]。Girgis等[37]报道, ZEA+DON联合作用影响鸡艾美球虫诱导的免疫应答, 降低抗艾美球虫剂的效果, 延迟由艾美球虫诱导肠道损伤的恢复。免疫细胞是低剂量的ZEA和DON的主要靶向目标[31]。火鸡采食含ZEA+DON的饲粮后第3周淋巴细胞总数降低, 第6周时CD4+淋巴细胞百分比增加[37]。小鼠连续4次注射ZEA+DON后, 免疫球蛋白M(IgM)含量显著降低, 白细胞介素-1(IL-1)和白细胞介素-4(IL-4)含量显著升高, 且表现出亚加性效应[38]。
4 遗传毒性ZEA可使DNA断裂, 影响微核形成和DNA加合物的形成, 从而导致DNA及其结构受损, 干扰细胞分裂, 最终阻碍DNA复制, 抑制细胞增殖[39]。Muthulakshmi等[6]研究发现, ZEA可引起斑马鱼的受精胚DNA损伤, 其损伤程度与ZEA剂量和时间有关。Yu等[10]研究发现, DON能促进妊娠小鼠胎盘中的活性氧(ROS)累积, ROS上调了核因子E2相关因子2/血红素加氧酶-1(Nrf2/HO-1)通路, 导致了氧化应激, 而氧化应激可能是DON诱导的胚胎毒性的关键分子机制。DON可诱导氧化性DNA损伤, 并由于非整倍体效应而增加着丝粒阳性微核的形成[40], 与特定微生物群在啮齿动物空肠上皮细胞DNA损伤中具有协同作用[27]。
ZEA+DON联合作用抑制了65%的DNA合成, 并存在加性效应; 诱导DNA断裂, DNA甲基化[13], 通过表观遗传修饰作用降低了小鼠卵母细胞的发育能力[41]。Malekinejad等[42]研究发现, DON可引起约34%的猪卵母细胞形成纺锤体畸型, 未发现不同比例的ZEA+DON对抑制卵母细胞成熟存在协同作用。
5 细胞毒性Othmen等[43]研究表明, 在卵母细胞的减数分裂过程中, α-ZOL和β-玉米赤霉烯醇(β-ZOL)对卵母细胞具有毒性作用, α-ZOL通过抑制细胞活力, 蛋白质、DNA合成, 以及诱导氧化损伤和应激蛋白质过表达而引起细胞毒性。ZEA可使线粒体膜电位(MMP)下降, 细胞周期停滞在G0/G1阶段, 这表明线粒体介导了细胞凋亡的增强[7]。DON能诱导IPEC-J2细胞的细胞毒性, 细胞内ROS累积和线粒体依赖性细胞凋亡[44]。Wang等[45]首次报道了Janus激酶/信号转导子和转录激活子(JAK/STAT)激活介导了应答DON的巨噬细胞的炎症反应和细胞凋亡, MMP降低, B细胞B淋巴细胞瘤-2/Bcl-2相关X蛋白(Bcl-2/Bax)比例降低。
ZEA+DON联合作用诱导Caco-2细胞凋亡, 降低细胞活力[13]。且ZEA+DON联合染毒效应大于单独染毒效应, 呈亚加性效应[46]。Smith等[47]研究报道了HepaRG人肝细胞暴露ZEA+DON 1 h后, ZEA+DON组合比单独的ZEA或DON可导致蛋白质组学发生更大变化, 而在24 h后观察到相反的变化。Wentzel等[4]研究表明, ZEA+DON对体外培养的HepG2和Caco-2细胞具有高度的细胞毒性。
6 神经毒性ZEA可抑制斑马鱼乙酰胆碱酯酶(AChE)活性, 而AChE能降解乙酰胆碱, 保证神经信号在生物体内的正常传递, 促进神经元的发育和神经再生[6]。DON可通过改变仔猪海马神经细胞神经递质的分泌及脂质过氧化影响钙稳态, 产生神经毒性[48]; DON还可降低血脑屏障的完整性[49]。低于100 nmol/L的DON能增加LPS引起的神经胶质细胞的炎症; 而高于300 nmol/L的DON则抑制了神经胶质细胞的炎症[50]。ZEA和DON单独和联合作用均会诱导神经症状, 产生脑毒性[51], 其联合作用可导致小鼠脑损伤[52]。
7 致癌性及其他毒性ZEA及代谢物可促进激素依赖性肿瘤的发展, α-ZOL在罹患乳腺癌的风险中具有潜在作用[5]。DON通过诱导小鼠皮肤水肿增生、鸟氨酸脱羧酶(ODC)活性和丝裂原活化蛋白激酶(MAPK)活化而引发皮肤肿瘤[53]。国际癌症研究机构(IARC)已认定DON为3类致癌物[54]。ZEA还诱导大鼠肝组织损伤[2], 妊娠大鼠肾脏机能紊乱, 肾脏Toll样受体4(TLR4)和炎性细胞因子mRNA和蛋白质表达增加, 并与ZEA呈剂量依赖关系[55]。DON可导致雄性小鼠肝淋巴细胞聚集和谷丙转氨酶(ALT)活性升高, 产生轻度炎症[56]; 肾脏的细胞凋亡率以及血清肌酐和尿素氮含量升高[57]。ZEA+DON联合作用可导致肝细胞空泡化, 肝脏发生组织学改变[14]; 诱导小鼠肾脏的细胞调亡, 造成功能紊乱和氧化应激, 并与ZEA和DON的剂量、时间存在依赖关系[57], ZEA+DON表现出亚加成性肾毒性作用[57]。此外, ZEA和DON还具有血液毒性和骨髓毒性, Ficheux等[58]体外研究表明, ZEA+DON联合作用会导致造血细胞减少, 引起粒性白血球缺乏症或/和血小板数量减少, 严重会导致再生障碍性贫血, ZEA+DON联合作用对骨髓的毒性呈现加和效应。
8 小结饲料的生产和储存过程中容易被霉菌和镰刀菌污染, 产生霉菌毒素。动物采食含有ZEA和DON的饲料会出现病理变化和临床症状, 表现为消化道、生殖器官、免疫系统、组织细胞及致癌等病变。霉菌毒素中毒降低了动物的生产性能, 造成经济损失, 或还会间接危害消费者的健康。因此, 有效控制和消除饲料中的霉菌毒素, 是养殖业健康发展的保障之一。根据霉菌毒素不同的作用机理, 目前应用的去除ZEA和DON的方法主要有物理脱毒法、化学脱毒法和生物脱毒法。生物脱毒法是将特定的微生物或其产生的酶加入霉变的饲料中, 在动物的消化道降解霉菌毒素, 破坏毒素结构, 生成低毒或无毒的降解产物。生物脱毒法能够避免应用物理脱毒法和化学脱毒法如强酸、强碱、高温或吸附对饲料的营养物质破坏和使饲料营养价值降低。生物脱毒法对饲料和环境没有污染, 具有很好的降解效果。将来的发展方向是利用微生物基因工程技术构建生物酶的高效表达工程菌, 分离获得纯酶。霉菌毒素降解酶法与物理脱毒法和化学脱毒法相比具有特异性强、脱毒彻底、对环境无污染等特点, 在畜牧生产中具有广阔的应用前景, 是减轻饲料行业霉菌毒素危害的重要技术手段。
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