Chinese Journal of Animal Nutrition >

2024 , Vol. 36 >Issue 5: 3306 - 3316

DOI: https://doi.org/10.12418/CJAN2024.283

RESEARCH PAPER

Protective Effects of Lycopene on Ileum Injury of Mice Exposed to Zearalenone, Deoxynivalenol and Aflatoxin B1

  • GAN Qiuyun , 1 ,
  • LIANG Tianzeng 1 ,
  • WEN Lijian 1 ,
  • ZUO Cuige 1 ,
  • LIU Yulan 1 ,
  • LIU Jinsong 2 ,
  • YANG Caimei 2 ,
  • LIN Jia , 1, *
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  • 1 Hubei Key Laboratory of Animal Nutrition and Feed Science, College of Animal Science and Nutrition Engineering, Wuhan Polytechnic University, Wuhan 430023, China
  • 2 Zhejiang Huijia Biotechnology Co., Ltd., Anji 313307, China
* lecturer, E-mail:

Received date: 2023-10-07

  Online published: 2024-05-15

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Abstract

The aim of this study was to investigate the protective effects of lycopene (LYC) on ileum injury of mice exposed to zearalenone (ZEN), deoxynivalenol (DON) and aflatoxin B1 (AFB1) and its mechanism. A total of 80 specific pathogen free (SPF) male ICR mice of 6-week-old with body weight of (31.01±0.29) g were randomly divided into 4 groups (20 mice per group), which were control group, LYC group, mycotoxin group and LYC+mycotoxin group, respectively. After 10 days of adaptive feeding, the mice were given continuous intragastric administration of 10 mg/kg LYC or its equivalent solvent for 14 days, followed by intraperitoneal injection of 10 mg/kg ZEN+1 mg/kg DON+0.5 mg/kg AFB1 or its equivalent solvent. At the end of the treatment, the mice were fasted for 24 h, then weighed and killed, and the ileum samples were collected immediately for testing. The results showed as follows: 1) compared with the control group, the crypt depth of ileum of mice in mycotoxin group was extremely significantly increased (P<0.01), and the villus height to crypt depth ratio of ileum was significantly decreased (P<0.05); compared with mycotoxin group, the villus height of ileum in LYC+mycotoxin group had a tendency to increase (P>0.05), and the crypt depth of ileum had a tendency to decrease (P>0.05). 2) Compared with the control group, the distribution of claudin-1, zonula occludens-1 (ZO-1) and occludin in ileum of mice in mycotoxin group was decreased; compared with mycotoxin group, the distribution of claudin-1, ZO-1 and occludin in ileum in LYC+mycotoxin group was increased. 3) Compared with the control group, the tight junctions in ileal epithelial cells of mice in mycotoxin group were blurred, the mitochondrial membrane was dissolved, the cristae were broken, and the mitochondria were swollen and vacuolated seriously; compared with mycotoxin group, the tight junctions in ileal epithelial cells in LYC+mycotoxin group were intact and clear, and the mitochondria showed slight swelling and vacuolation. 4) Compared with the control group, the protein expression levels of receptor interaction protein 3 (RIP3) and mixed series protein kinase domain-like protein (MLKL) in ileum of mice in mycotoxin group were significantly or extremely significantly increased (P<0.05 or P<0.01); compared with mycotoxin group, the RIP3 protein expression level in ileum in LYC+mycotoxin group was significantly decreased (P<0.05). 5) Compared with the control group, the mRNA expression levels of receptor interacting protein 1 (RIP1), RIP3 and MLKL in ileum in mycotoxin group were extremely significantly increased (P<0.01); compared with mycotoxin group, the mRNA expression levels of RIP1 and RIP3 in ileum in LYC+mycotoxin group were extremely significantly decreased (P<0.01). In conclusion, LYC can maintain the integrity of intestinal mucosal barrier and mitochondrial structure, and inhibit the programmed necrosis signaling pathway in ileum, so as to alleviate the ileum injury of mice caused by ZEN, DON and AFB1 combined exposure.

Key words： lycopene; mycotoxin; mice; ileum injury; mitochondrial damage; programmed necrosis

Cite this article

GAN Qiuyun , LIANG Tianzeng , WEN Lijian , ZUO Cuige , LIU Yulan , LIU Jinsong , YANG Caimei , LIN Jia . Protective Effects of Lycopene on Ileum Injury of Mice Exposed to Zearalenone, Deoxynivalenol and Aflatoxin B1[J]. Chinese Journal of Animal Nutrition, 2024 , 36(5) : 3306 -3316 . DOI: 10.12418/CJAN2024.283

霉菌毒素污染是危害动物饲料安全的重要因素之一,主要包括玉米赤霉烯酮(ZEN)、呕吐毒素(DON)以及黄曲霉毒素B1(AFB1)[1]。据调查,全国饲料及原料受1种以上霉菌毒素污染的占85%以上,且检出率最高的是ZEN、DON和AFB1,其最高限量分别为1.5 mg/kg、5 mg/kg和50 μg/kg,被认为是污染饲料以及引起动物中毒的主要霉菌毒素[2⇓-4]。ZEN、DON和AFB1不仅检出率高,且出现不同程度的超标现象,其中DON超标率可至17.6%,而ZEN和AFB1在玉米副产物中的超标率分别为17.27%和10.11%,均在一定程度上超过了我国《饲料卫生标准》(GB 13078—2017)中的安全标准。
研究表明,AFB1是霉菌毒素中毒性最强的一种,其会影响动物回肠组织正常的结构形态,可诱导氧化应激和细胞凋亡,从而引起回肠组织损伤和炎症反应等[5⇓-7]。DON的摄入可诱导动物小肠内微生物菌群失调,间接引起线粒体损伤和凋亡,破坏肠道屏障功能[8⇓⇓⇓-12]。ZEN容易被肠上皮细胞直接吸收,其毒性暴露可降低抗氧化酶的活性来诱导动物机体氧化应激[13⇓-15],从而破坏小肠中原有的保护屏障,造成小肠组织功能紊乱[16-17]。王晓敏等[18]研究表明,ZEN、DON以及AFB1联合共染对仔猪肠上皮细胞IPEC-J2毒性比单一霉菌毒素的更强。因此,霉菌毒素可单独引起小肠损伤,但霉菌毒素的联合作用则可能会增加动物小肠组织损伤的严重性。不过,目前关于2种以上霉菌毒素联合共染引起的回肠组织损伤的研究报道还很有限。
番茄红素(lycopene,LYC)是一种具有高抗氧化潜能的类胡萝卜素[19]。研究表明,LYC可通过保护脂类、蛋白质和DNA免受氧化损伤而产生有益作用[20-21]。Lin等[22]研究表明,LYC可通过提高小鼠的抗氧化能力来抵御小肠上皮屏障的破坏,从而缓解ZEN、DON及AFB1这3种霉菌毒素联合共染诱导的氧化损伤。但目前关于LYC对霉菌毒素联合作用导致的小鼠回肠损伤的保护作用及机制尚不清楚。
因此,本研究通过3种霉菌毒素(ZEN、DON及AFB1)的联合暴露建立肠道损伤模型,来探究ZEN、DON及AFB1联合暴露引起的小鼠回肠损伤,同时通过添加LYC,来探究LYC对ZEN、DON及AFB1联合暴露引起的小鼠回肠损伤的缓解作用及机制,为开发营养添加剂以及预防霉菌毒素共污染提供新的思路和方法。

1 材料与方法

1.1 试验材料

1.1.1 试验动物

本试验使用的80只6周龄无特异病原体(SPF)级ICR雄性小鼠[体重为(31.01±0.29) g],购自华中科技大学同济医学院。

1.1.2 主要试剂

ZEN纯度>98.65%(MCE公司),DON纯度≥98%(Sigma-Aldrich公司),AFB1纯度>99.94%(MCE公司),LYC纯度≥95%。

1.2 试验设计

将80只小鼠随机分为4个组(每组20只),各组处理情况见表1。本试验主要参考Lin等[22]、Zhu等[23]、Ji等[24]和黄洋等[25]的研究报道确定3种霉菌毒素的染毒剂量,LYC的剂量主要参考Rajput等[26]、Pan等[27]以及Li等[28]的研究。将小鼠适应性饲养10 d后,连续灌胃10 mg/kg LYC或等量其溶剂14 d,随后腹腔注射10 mg/kg ZEN+1 mg/kg DON+0.5 mg/kg AFB1或等量溶剂。在处理结束时,小鼠禁食24 h后称重并处死,立即收集回肠样本,以便于进一步检测分析。小鼠基础饲粮组成及营养水平见表2。
表1 动物分组及处理

Table 1 Animal grouping and treatment

项目
Items		 玉米赤霉烯酮
ZEN		 呕吐毒素
DON		 黄曲霉毒素B1
AFB1		 番茄红素
LYC
对照组CON group
LYC组LYC group 10 mg/kg
霉菌毒素组Co-M group 10 mg/kg 1 mg/kg 0.5 mg/kg
LYC+霉菌毒素组LYC+Co-M group 10 mg/kg 1 mg/kg 0.5 mg/kg 10 mg/kg
表2 小鼠基础饲粮组成及营养水平(风干基础)

Table 2 Composition and nutrient levels of the basal diet for mice (air-dry basis)

项目Items 含量Content
原料Ingredients/(g/kg)
玉米淀粉Corn starch 465.692
麦芽糖糊精Maltodextrin 125.000
蔗糖Sucrose 100.000
纤维素Cellulose 50.000
大豆油Soybean oil 70.000
τ-丁基氢醌τ-butylhydroquinone 0.008
矿物质复合物Mineral complex 35.000
维生素复合物Vitamin complex 10.000
胆碱酒石酸氢盐Choline bitartrate 2.500
酪蛋白Casein 140.000
L-胱氨酸L-cystine 1.800
合计Total 1 000.000
营养水平Nutrient levels/%
粗蛋白质Crude protein 14.2
碳水化合物Carbohydrate 70.1
粗脂肪Crude fat 7.0

营养水平为实测值。

Nutrients levels were measured values.

1.3 饲养管理

所有小鼠均维持在标准实验室条件下,光照12 h/黑暗12 h循环,相对湿度(50±10)%,自由采食和饮水。所有程序均经武汉轻工大学动物科学与营养工程学院动物护理与使用委员会批准(WPU202001010)。

1.4 检测指标及方法

1.4.1 回肠形态结构分析

将小鼠解剖取其回肠组织并立即置于冰上,取一小块用10%多聚甲醛固定,石蜡包埋;将石蜡包埋的组织切成5 μm厚的切片,置于涂膜载玻片上,进行苏木精-伊红(HE)染色;然后在光学显微镜(BX53,Olympus,日本)下观察并拍照。回肠绒毛高度和隐窝深度的检测方法参照Lin等[22]和陈逢[29],统计每个样本至少30个定向良好的绒毛和隐窝。

1.4.2 回肠紧密连接蛋白分布测定

采用免疫荧光法检测回肠紧密连接蛋白的分布,测定方法参照Lin等[22],通过荧光成像系统(BX53,Olympus公司,日本)采集可视化形态学图像。

1.4.3 回肠组织超微结构分析

回肠组织超微电镜样本的制备方法参照Lin等[22],取小于1 mm3的回肠组织,采用4%的戊二醛固定样品,再用1%的锇酸固定。样品经过梯度酒精(30%、50%、70%、80%、85%、90%、95%和100%)进行15~20 min的2次脱水后,于渗透剂(丙酮∶环氧树脂=2∶1)中渗透包埋8~12 h。超薄切片采用醋酸铀酰和柠檬酸铅反染。肠道组织超微结构采用透射电子显微镜(FEI,美国)观察。

1.4.4 回肠程序性坏死信号通路相关分子蛋白表达量测定

采用Western Blot方法测定回肠程序性坏死信号通路相关分子受体相互作用蛋白1(receptor interaction protein 1,RIP1)、受体相互作用蛋白3(receptor interaction protein 3,RIP3)和混合系列蛋白激酶结构域样蛋白(mixed series protein kinase domain-like proteins,MLKL)的蛋白表达量。提取蛋白质的步骤按照凯基全蛋白提取(KGP2100)试剂盒提取,蛋白表达量测定的具体方法参照陈逢[29]。目的蛋白表达量分别以目的蛋白的条带强度和对应内参β-肌动蛋白(β-actin)的条带强度比值表示。

1.4.5 回肠程序性坏死信号通路相关分子mRNA表达量测定

采用实时定量PCR方法测定回肠程序性坏死信号通路相关分子RIP1、RIP3和MLKL的mRNA表达量。小鼠回肠RNA采用Trizol试剂(Invitrogen公司,美国),根据制造商的说明提取。采用逆转录试剂盒(Cowin biosciences,中国)将RNA定量并转录为cDNA,mRNA表达量测定的具体方法参照黄洋等[25]。引物序列见表3。实时定量PCR数据分析采用2-ΔΔCt计算方法,将每个目的基因的mRNA表达量归一化为β-肌动蛋白和磷酸甘油醛脱氢酶(GAPDH)的平均表达量,以此来计算各目的基因的mRNA表达量[22]。
表3 引物序列

Table 3 Primer sequences

基因
Genes		 引物序列
Primer sequences (5'—3')		 登录号
Accession number		 产物大小
Product size/bp
受体相互作用蛋白1
RIP1		 F:CTGACTGATGAACACCTGAACC
R:TCTGGCTGGCACGAATCAA		 XM_030247206.2 268
受体相互作用蛋白3
RIP3		 F:GGCTCTCGTCTTCAACAA
R:ACTGTGCTTGGTCATACTT		 XM_001164108.1 110
混合系列蛋白激酶结构域样蛋白
MLKL		 F:GCTGTTGCTGCTGCTTCA
R:CCACGGAGGTCCAAGATGT		 XM_006531443.5 256
β-肌动蛋白
β-actin		 F:CAGCCTTCCTTCTTGGGTAT
R:TGGCATAGAGGTCTTTACGG		 NM_007393.5 185
磷酸甘油醛脱氢酶
GAPDH		 F:ATGGTGAAGGTCGGTGTGAA
R:TGGAAGATGGTGATGGGCTT		 NM_001289726.1 254

1.5 数据统计分析

试验数据采用SPSS 19.0统计软件进行单因素方差分析(one-way ANOVA)及Tukey检验,采用GraphPad Prism 7.0软件进行图表绘制;试验结果以“平均值±标准误”来表示,P<0.01表示差异极显著,P<0.05表示差异显著。

2 结果与分析

2.1 LYC对霉菌毒素联合暴露小鼠回肠形态结构的影响

如图1所示,与对照组相比,霉菌毒素组小鼠回肠隐窝深度极显著提高(P<0.01),回肠绒毛高度/隐窝深度值显著降低(P<0.05);与霉菌毒素组相比,LYC +霉菌毒素组回肠绒毛高度有提高趋势(P>0.05),回肠隐窝深度有降低趋势(P>0.05)。
图1 LYC对霉菌毒素联合暴露小鼠回肠形态结构的影响

CON:对照组;LYC:LYC组;Co-M:霉菌毒素组;LYC+Co-M:LYC+霉菌毒素组。与对照组相比,***表示差异极显著(P<0.001),**表示差异极显著(P<0.01),*表示差异显著(P<0.05)。下图同。

Fig.1 Effects of LYC on morphology and structure of ileum of mice exposed to combined mycotoxin

CON:control group;LYC:LYC group;Co-M:mycotoxin group;LYC+Co-M:LYC+mycotoxin group.Compared with the control group, *** indicated extremely significant difference (P<0.001), ** indicated extremely significant difference (P<0.01), and * indicated significant difference (P<0.05). The same as below.

2.2 LYC对霉菌毒素联合暴露小鼠回肠紧密连接蛋白分布的影响

为了验证ZEN+DON+AFB1联合暴露对小鼠回肠紧密连接完整性的损伤作用,本试验采用免疫荧光试验评估了紧密连接蛋白封闭蛋白-1(claudin-1)、闭锁小带蛋白-1(ZO-1)和闭合蛋白(occludin)的分布。如图2所示,与对照组相比,霉菌毒素组小鼠回肠claudin-1、ZO-1和occludin的分布减少,而LYC组紧密连接蛋白分布没有明显差异;与霉菌毒素组相比,LYC+霉菌毒素组回肠claudin-1、ZO-1和occludin的分布增加。
图2 LYC对霉菌毒素联合暴露小鼠回肠紧密连接蛋白分布的影响

DAPI:4’,6-二脒基-2-苯基吲哚 4’,6-diamidino-2-phenylindole;Merge:和并;ZO-1:闭锁小带蛋白-1 zonula occludens-1;Occludin:闭合蛋白;Claudin-1:封闭蛋白-1。标尺为50 μm The scale is 50 μm。

Fig.2 Effects of LYC on distribution of tight junction protein in ileum of mice exposed to combined mycotoxin

2.3 LYC对霉菌毒素联合暴露小鼠回肠组织超微结构的影响

如图3所示,对照组和LYC组小鼠回肠组织细胞间的紧密连接以及线粒体超微结构完整,线粒体分布密集,双层膜清晰可见,线粒体嵴排列正常。与对照组相比,霉菌毒素组回肠上皮细胞紧密连接模糊化(红色箭头),线粒体膜溶解,嵴断裂,且线粒体出现严重的肿胀、空泡化(蓝色箭头);与霉菌毒素组相比,LYC+霉菌毒素组回肠上皮细胞紧密连接完整清晰,线粒体出现轻微的肿胀、空泡化。
图3 LYC对霉菌毒素联合暴露小鼠回肠组织超微结构的影响

红色箭头为紧密连接,蓝色箭头为线粒体。

Fig.3 Effects of LYC on ultrastructure of ileal tissues of mice exposed to combined mycotoxin

Red arrow indicated tight junction, and blue arrows indicated mitochondria.

2.4 LYC对霉菌毒素联合暴露小鼠回肠程序性坏死信号通路相关分子蛋白表达量的影响

如图4所示,与对照组相比,霉菌毒素组小鼠回肠RIP3和MLKL蛋白表达量显著或极显著提高(P<0.05或P<0.01),霉菌毒素组和LYC+霉菌毒素组回肠RIP1蛋白表达量均无显著差异(P>0.05);与霉菌毒素组相比,LYC+霉菌毒素组回肠RIP3蛋白表达量显著降低(P<0.05)。
图4 LYC对霉菌毒素联合暴露小鼠回肠程序性坏死信号通路相关分子蛋白表达量的影响

与霉菌毒素组相比,^^^表示差异极显著(P<0.001),^表示差异显著(P<0.05)。图5同。

Fig.4 Effects of LYC on protein expression levels of molecules associated with programmed necrosis signaling pathway in ileum of mice exposed to combined mycotoxin

Compared with Co-M group, ^^^ indicated extremely significant difference (P<0.001), and ^ indicated significant difference (P<0.05). The same as Fig.5.

2.5 LYC对霉菌毒素联合暴露小鼠回肠程序性坏死信号通路相关分子mRNA表达量的影响

如图5所示,与对照组相比,霉菌毒素组小鼠回肠RIP1、RIP3和MLKL的mRNA表达量极显著提高(P<0.01);与霉菌毒素组相比,LYC+霉菌毒素组回肠RIP1和RIP3的mRNA表达量极显著降低(P<0.01)。
图5 LYC对霉菌毒素联合暴露小鼠回肠程序性坏死信号通路相关分子mRNA表达量的影响

Fig.5 Effects of LYC on mRNA expression levels of molecules associated with programmed necrosis signaling pathway in ileum of mice exposed to combined mycotoxin

3 讨论

霉菌毒素作为重要的食品和饲料污染物,而小肠是动物机体消化吸收营养物质的主要场所。研究表明,霉菌毒素通过与肠黏膜接触,进而破坏动物的肠屏障功能,影响小肠对营养物质的吸收和代谢[30-31]。目前对单一霉菌毒素致动物肠道毒性作用的研究较多,但是关于霉菌毒素的联合污染效应及有效缓解霉菌毒素破坏营养添加剂的研究甚少。饲料中主要以ZEN、DON和AFB1这3种霉菌毒素联合污染为主。而LYC作为食物中来源的类胡萝卜素之一,具有抗氧化、抗炎等作用,能够有效缓解肠道损伤[32]。因此,本文主要探究ZEN、DON和AFB1 3种霉菌毒素联合处理对小鼠回肠的损伤作用以及LYC的营养防控作用机制。
回肠形态和功能的完整性可反映肠道健康状态,其中肠道绒毛高度、隐窝深度及绒毛高度/隐窝深度值是反映回肠形态和结构完整性的指标[33]。肠上皮细胞间的紧密连接可形成机械屏障,对维持回肠结构和功能的完整性也起到了重要作用,其中claudin-1、ZO-1和occludin是形成肠黏膜屏障功能的关键紧密连接蛋白[34]。田莎[35]研究表明,饲喂添加有AFB1的饲粮会引起肉鸡的回肠绒毛高度和绒毛高度/隐窝深度值降低,造成肠道结构和功能损伤,最终阻碍肠道的消化吸收。杨俊[36]研究发现,DON可引起仔猪肠道组织形态异常,仔猪小肠隐窝深度显著提高,绒毛高度及绒毛高度/隐窝深度值降低,紧密连接蛋白claudin-1、ZO-1和occludin的mRNA和蛋白表达量显著降低,且线粒体出现双层膜结构、嵴模糊的现象。本试验研究表明,ZEN、DON和AFB1联合暴露引起小鼠回肠隐窝深度提高,回肠绒毛高度和绒毛高度/隐窝深度值降低,回肠claudin-1、ZO-1和occludin分布减少,紧密连接模糊、水肿,线粒体出现肿胀及空泡化损伤。因此,ZEN、DON和AFB1联合暴露会造成小鼠回肠损伤,破坏回肠形态和功能的完整性,从而干扰肠道营养物质的消化吸收功能。然而,Liu等[37]给18头健康“杜长大”育肥猪饲喂200 mg/kg LYC,研究结果发现其空肠绒毛高度/隐窝深度值提高,紧密连接蛋白claudin-1表达提高。有研究报道,饲粮中添加LYC可缓解ZEN、DON和AFB1联合暴露引起的空肠损伤,提高小鼠空肠绒毛高度,降低隐窝深度以及绒毛高度/隐窝深度值,对空肠具有保护作用[22]。与前人的研究相一致的是,本研究在小鼠回肠中也发现了类似的结果,LYC可提高回肠绒毛高度、绒毛高度/隐窝深度值以及紧密连接蛋白claudin-1、ZO-1和occludin的分布,维持线粒体正常的形态结构,缓解ZEN、DON和AFB1联合暴露引起的回肠组织损伤。
程序性坏死是早期发现的一种新的细胞死亡形式,其不依赖于半胱氨酸天冬氨酸蛋白酶(Caspase)途径[38],RIP1、RIP3和MLKL是程序性坏死信号通路的关键调控因子[39]。有研究表明,AFB1可引起小鼠肝细胞程序性坏死信号通路相关分子蛋白RIP1、RIP3和MLKL表达量的提高[40];DON可引起肠上皮细胞RIP3和MLKL蛋白表达量显著提高,造成肠道细胞损伤并破坏肠道屏障功能[41];ZEN可通过上调受体相互作用蛋白激酶1(receptor interacting protein kinase 1,RIPK1)、受体相互作用蛋白激酶3(receptor interacting protein kinase 3,RIPK3)和磷酸化MLKL蛋白表达量,引起细胞坏死[42]。在本研究中,ZEN、DON和AFB1联合暴露能促使小鼠回肠RIP3和MLKL蛋白表达量以及RIP1、RIP3和MLKL mRNA表达量升高,造成小鼠回肠上皮细胞程序性坏死。然而,在张海洋[43]的研究中发现,LYC可抑制大鼠海马组织细胞RIP1、RIP3和MLKL蛋白表达量。本研究结果表明,LYC可降低霉菌毒素联合暴露小鼠回肠RIP3蛋白表达量以及RIP1和RIP3的mRNA表达量,缓解霉菌毒素联合暴露造成的肠道损伤,因此LYC对霉菌毒素共污染引起的小鼠回肠程序性坏死具有一定的预防作用。

4 结论

综上所述,ZEN、DON和AFB1联合暴露可诱发小鼠回肠上皮细胞线粒体损伤及程序性坏死,破坏回肠屏障功能进而造成小鼠回肠损伤,而LYC可有效缓解回肠上皮细胞线粒体损伤,通过回肠的程序性坏死信号通路,抑制ZEN、DON和AFB1联合暴露引起的小鼠回肠损伤,从而发挥对小鼠回肠的保护作用。

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