饲料中常见霉菌毒素对小鼠的联合毒性作用及机制的研究
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摘要
本试验在细胞水平和动物整体水平研究了黄曲霉毒素B1(AFB1)、玉米赤霉烯酮(ZEA)、呕吐毒素(DON)和伏马菌素B1(FB1)四种霉菌毒素对猪肾细胞、大鼠肝细胞和小鼠的联合毒性。
(1)对猪肾细胞(PK15)的联合毒性
将AFB1、ZEA、DON和FB1以不同浓度与PK15孵育12,24和48h后,采用MTT法和LDH释放法评价霉菌毒素的细胞毒性。结果表明：AFB1、ZEA、DON与PK15孵育48h后,EC50(50%效应浓度)分别为38.8、121.8和3.6μM,EC30(30%效应浓度)分别为26.9、86.6和1.8μm。且AFB1和ZEA均呈现时间效应和剂量效应关系,随着剂量增加和时间延长,霉菌毒素的细胞毒性增强。FB1浓度高达250μM且孵育48h后,PK15细胞活力仍大于70%。与霉菌毒素孵育24h后,AFB1、ZEA和DON能显著提高细胞LDH的释放,而FB1显著降低细胞LDH的释放。AFB1和DON均能显著提高细胞内活性氧和细胞凋亡率(P<0.05),而ZEA (10,20,40μM)对细胞内活性氧和细胞凋亡没有影响。四种霉菌毒素的细胞毒性大小顺序为DON> AFB1>ZEA>FB1。
以每种霉菌毒素EC30作为中心点(其中FB1浓度为15μM),设计二元和三元混合,依据剂量和效应进行逐步回归得到拟合方程,根据拟合方程中各系数的含义表明：AFB1和ZEA(暴露48h)、AFB1和DON(暴露12h)、及ZEA和DON(暴露12和48h)对PK15的毒性表现为协同效应；AFB1和FB1联合作用仅表现AFB1的细胞毒性。AFB1、ZEA和DON三者联合作用12或24h后,AFB1与ZEA表现为拮抗效应。
ZEA能缓解低浓度AFB1(1μM)诱导的细胞膜损伤和氧化损伤,但10μM ZEA与高浓度AFB1(5,10μM)能协同加剧细胞膜损伤和氧化损伤。10μMZEA主要能缓解由AFB1(1μM)诱导的细胞早期凋亡,可能是通过调控bcl-2和caspas-3及P53基因或蛋白的表达。
(2)对大鼠肝细胞(BRL)的联合毒性
将AFB1、ZEA、DON和FB1以不同浓度与BRL孵育12,24和48h后,采用MTT法和LDH释放法评价霉菌毒素的细胞毒性。结果表明：AFB1、ZEA、DON与BRL孵育48h后,ECso分别为37.9、100.3和13.3μM,EC30分别为29.2、91.6和3.27μM,160μM FB1基本不影响细胞活力。与霉菌毒素孵育24h后,AFB1、ZEA和DON能显著提高细胞LDH释放率,而FB1不影响细胞LDH的释放。AFB1和DON均能显著提高细胞内活性氧和细胞凋亡率(P<0.05),但ZEA (10,20,40μM对细胞内活性氧和细胞凋亡率没有影响。四种霉菌毒素对BRL的细胞毒性大小顺序为DON> AFB1>ZEA>FB1。
以每种霉菌毒素EC30为中心点(其中FB1的浓度为15μM),设计二元和三元混合,根据剂量和效应进行逐步回归得到拟合方程,根据拟合方程中各系数的含义表明：AFB1和ZEA(暴露48h),及AFB1和DON(暴露12,24,48h)对BRL的毒性表现为协同效应；AFB1和FB1联合作用仅表现AFB1的毒性。AFB1、ZEA和DON三者联合作用12、24和48h,AFB1与DON表现为协同效应。
AFB1与DON联合在细胞膜损伤和氧化损伤上表现为加型或协同效应。1μM AFB1与2μM DON联合能协同促进细胞凋亡,可能是通过降低bcl-2、促进bax和caspase-3及P53基因或蛋白的表达而促进细胞凋亡进程。
(3)对Balb/C小鼠的联合毒性
104只体重一致的4周龄雌性Balb/C小鼠适应一周后,随机分为13组,每组8只。具体分组如下：蒸馏水组、DMSO组、乙醇组、AFB1(2.5mg/kg.bw)、ZEA (5mg/kg.bw)、DON (5mg/kg.bw)、FB1(8mg/kg.bw)单一处理组及AFB1+ZEA、 AFB1+DON、AFB1+FB1、ZEA+DON、ZEA+FB1和DON+FB1联合处理组。联合组剂量采用单一剂量叠加,连续灌胃14d。
霉菌毒素对Balb/C小鼠体增重不存在联合作用。FB1能显著提高脾脏重,含有FB1的联合组能减弱由FB1导致的脾脏增重。AFB1和DON能协同提高血清ALT活性和肝脏MDA含量,协同降低肝脏SOD活性,加剧小鼠肝脏细胞损伤和氧化损伤；AFB1与DON还能协同提高caspase-3和P53的表达来促进肝脏细胞凋亡。ZEA和DON不仅能协同提高血清中雌二醇含量,还能协同提高caspase-3基因的表达促进细胞凋亡。与单一处理相比,两两联合使小鼠肝脏HSP70蛋白表达进一步增加,表明联合作用使小鼠应激加剧。两两联合(AFB1、ZEA和DON)影响小鼠脾脏促炎症因子IL-1β、IL-6和TNF-α在]mRNA水平的表达,进而可能影响机体的免疫功能。
通过上述试验结果可得出以下结论：(1)四种霉菌毒素对猪肾细胞和大鼠肝细胞的毒性趋势一致,大小依次为：DON>AFB1>ZEA>FB1。(2)霉菌毒素对细胞或机体的联合效应十分复杂,对不同的靶细胞或靶器官的效应不一致；AFB1与ZEA的联合作用方式与霉菌毒素的剂量呈依赖关系,ZEA能缓解低剂量AFB1造成的肾细胞毒性,但ZEA与高剂量AFB1呈现协同效应。(3)ZEA和DON两两联合导致小鼠脾脏促炎症因子的表达发生变化,可能影响脾脏的免疫功能。(4)AFB1和DON对大鼠肝细胞或小鼠肝脏损伤都体现为协同效应。
The aim of this study was to investigate the combined effects of aflatoxin B1(AFB1), zearalenone (ZEA), deoxynivalenol (DON) and fumonisin B1(FB1) on the porcine kidney cell, rat liver cell and Balb/C mice.
(1) The combined effects of the four predominant mycotoxins on procine kidney cell (PK15)
PK15were incubated with different concentrations of AFB1, ZEA, DON and FB1for12,24and48h, using MTT assay and LDH release assay to evaluate the cytotoxicity of the four mycotoxins. Exposure with mycotoxin for48h, the EC50of AFB1, ZEA and DON was38.8,121.8and3.6μM, and the EC30was26.9,86.6and1.8μM, which were calculated from dose-effect curves. The respones of AFB1, ZEA and DON were in a concentration-and time depended manner, the cytotoxicity was elevated with addition of dose and exposure time. Incubated with250μM FB1, cell viability was above70%, the EC50could not be obtained. With regard to ROS production and cell apoptosis, AFB1and DON significantly induced them in a concentration-dependent manner, but ZEA (10,20,40μM) had no effect on cell apoptosis and ROS production. The cytotoxicity of the four mycotoxins in increasing order:FB1 EC30of individual mycotoxins as the central point (FB1concentration was set to15μM), binary and ternary mixed was designed. Fitting equation was confirmed by stepwise regression based on the dose and effect, which showed synergetic effect after co-exposure of AFB1+ZEA, or AFB1+DON, or ZEA+DON; Co-exposure of AFB1and FB1, the equation just showed the cytotoxicity of AFB1. However, AFB1and ZEA showed antagonism in the ternary mixture.
ZEA could alleviate low concentrations of AFB1(1μM)-induced membrane damage and oxidative damage, but ZEA with the high concentration of AFB1synergistically exacerbate membrane damage and oxidative damage. ZEA weakened AFB1-induced apoptosis, mainly in the early apoptotic; related to slow down the process of apoptosis by bcl-2, caspase-3gene and p53protein expression.
(2) The combined effects of the four common mycotoxins on BRL
BRL were incubated with different concentrations of AFB1, ZEA, DON and FB1for12,24and48h, using MTT assay and LDH release assay to evaluate the cytotoxicity of the four mycotoxins. Exposure with mycotoxin for48h, the EC50of AFB1, ZEA and DON was37.9,100.3and36.5μM, and the EC30was29.2,91.6and3.27μM, which were calculated from dose-effect curves. The respones of AFB1, ZEA and DON were in a concentration-and time depended manner. Incubated with FB1, cell viability was not affected. With regard to ROS production and cell apoptosis, AFB1and DON significantly induced them (P<0.05), but ZEA (10,20,40μM) had no effect on cell apoptosis and ROS production. The cytotoxicity of the four mycotoxins in increasing order:FB1 EC30of individual mycotoxins as the central point (FB1concentration was set to15μM), binary and ternary mixed was designed. Fitting equation was confirmed by stepwise regression based on the dose and effect, which showed synergetic effect after co-exposure of AFB1+ZEA, or AFB1+DON; AFB1and DON showed synergism in the ternary mixture. Co-exposure of AFB1and FB1; the equation just showed cytotoxicity of AFB1.
AFB1and DON displayed additive or synergistic effects on the cell membrane damage and oxidative stress. Combination of1μM AFB1and2μM DON synergistically reduced bcl-2gene expression levels, and promote box, caspase-3, and p53expression and accelerate the process of apoptosis.
(3) The combined effects of the four common mycotoxins on Balb/C mice
One hundred and four4-week-old female Balb/C mice adapted for one week, then were randomly divided into13groups (n=8). Trials were grouped as follows:distilled water group, DMSO group, ethanol group, AFB1(2.5mg/kg.bw), ZEA (5mg/kg.bw), DON (5mg/kg.bw), FB1(8mg/kg.bw), AFB1+ZEA, AFB1+DON, AFB1+FB1, ZEA+DON, ZEA+FB1, and DON+FB1. The dose of combined groups superimposed on the single dose. The mice were administered orally by gavage once daily for14d.
There was no difference on the body weight of mice in all groups (P<0.05). FB1significantly increased weight of spleen; the combined group containing FB1could weaken the spleen weight gain caused by FB1. AFB1and DON synergistically increased serum ALT activity and MD A content in the liver, collaborative reduced SOD activity and strengthened liver cell damage and oxidative damage; AFB1and DON could promote apoptosis of liver by synergistic improving P53and caspase-3expression. ZEA and DON not only synergistically increased serum estradiol levels, but also synergistically improved caspase-3gene expression promotes apoptosis. Compared to individual treatment, the combined treatments further enhanced the expression of HSP70in the liver, indicating that the joint could exacerbate the stress in mice. Pro-inflammatory cytokines IL-1β, IL-6and TNF-α mRNA expression of spleen in AZ, AD or ZD mainly significantly affected (P<0.05), which may affected immune function.
In a word,(1) the cytotoxicity of mycotoxins on PK15and BRL was consistent, in increasing order FB1
(1)对猪肾细胞(PK15)的联合毒性
将AFB1、ZEA、DON和FB1以不同浓度与PK15孵育12,24和48h后,采用MTT法和LDH释放法评价霉菌毒素的细胞毒性。结果表明：AFB1、ZEA、DON与PK15孵育48h后,EC50(50%效应浓度)分别为38.8、121.8和3.6μM,EC30(30%效应浓度)分别为26.9、86.6和1.8μm。且AFB1和ZEA均呈现时间效应和剂量效应关系,随着剂量增加和时间延长,霉菌毒素的细胞毒性增强。FB1浓度高达250μM且孵育48h后,PK15细胞活力仍大于70%。与霉菌毒素孵育24h后,AFB1、ZEA和DON能显著提高细胞LDH的释放,而FB1显著降低细胞LDH的释放。AFB1和DON均能显著提高细胞内活性氧和细胞凋亡率(P<0.05),而ZEA (10,20,40μM)对细胞内活性氧和细胞凋亡没有影响。四种霉菌毒素的细胞毒性大小顺序为DON> AFB1>ZEA>FB1。
以每种霉菌毒素EC30作为中心点(其中FB1浓度为15μM),设计二元和三元混合,依据剂量和效应进行逐步回归得到拟合方程,根据拟合方程中各系数的含义表明：AFB1和ZEA(暴露48h)、AFB1和DON(暴露12h)、及ZEA和DON(暴露12和48h)对PK15的毒性表现为协同效应；AFB1和FB1联合作用仅表现AFB1的细胞毒性。AFB1、ZEA和DON三者联合作用12或24h后,AFB1与ZEA表现为拮抗效应。
ZEA能缓解低浓度AFB1(1μM)诱导的细胞膜损伤和氧化损伤,但10μM ZEA与高浓度AFB1(5,10μM)能协同加剧细胞膜损伤和氧化损伤。10μMZEA主要能缓解由AFB1(1μM)诱导的细胞早期凋亡,可能是通过调控bcl-2和caspas-3及P53基因或蛋白的表达。
(2)对大鼠肝细胞(BRL)的联合毒性
将AFB1、ZEA、DON和FB1以不同浓度与BRL孵育12,24和48h后,采用MTT法和LDH释放法评价霉菌毒素的细胞毒性。结果表明：AFB1、ZEA、DON与BRL孵育48h后,ECso分别为37.9、100.3和13.3μM,EC30分别为29.2、91.6和3.27μM,160μM FB1基本不影响细胞活力。与霉菌毒素孵育24h后,AFB1、ZEA和DON能显著提高细胞LDH释放率,而FB1不影响细胞LDH的释放。AFB1和DON均能显著提高细胞内活性氧和细胞凋亡率(P<0.05),但ZEA (10,20,40μM对细胞内活性氧和细胞凋亡率没有影响。四种霉菌毒素对BRL的细胞毒性大小顺序为DON> AFB1>ZEA>FB1。
以每种霉菌毒素EC30为中心点(其中FB1的浓度为15μM),设计二元和三元混合,根据剂量和效应进行逐步回归得到拟合方程,根据拟合方程中各系数的含义表明：AFB1和ZEA(暴露48h),及AFB1和DON(暴露12,24,48h)对BRL的毒性表现为协同效应；AFB1和FB1联合作用仅表现AFB1的毒性。AFB1、ZEA和DON三者联合作用12、24和48h,AFB1与DON表现为协同效应。
AFB1与DON联合在细胞膜损伤和氧化损伤上表现为加型或协同效应。1μM AFB1与2μM DON联合能协同促进细胞凋亡,可能是通过降低bcl-2、促进bax和caspase-3及P53基因或蛋白的表达而促进细胞凋亡进程。
(3)对Balb/C小鼠的联合毒性
104只体重一致的4周龄雌性Balb/C小鼠适应一周后,随机分为13组,每组8只。具体分组如下：蒸馏水组、DMSO组、乙醇组、AFB1(2.5mg/kg.bw)、ZEA (5mg/kg.bw)、DON (5mg/kg.bw)、FB1(8mg/kg.bw)单一处理组及AFB1+ZEA、 AFB1+DON、AFB1+FB1、ZEA+DON、ZEA+FB1和DON+FB1联合处理组。联合组剂量采用单一剂量叠加,连续灌胃14d。
霉菌毒素对Balb/C小鼠体增重不存在联合作用。FB1能显著提高脾脏重,含有FB1的联合组能减弱由FB1导致的脾脏增重。AFB1和DON能协同提高血清ALT活性和肝脏MDA含量,协同降低肝脏SOD活性,加剧小鼠肝脏细胞损伤和氧化损伤；AFB1与DON还能协同提高caspase-3和P53的表达来促进肝脏细胞凋亡。ZEA和DON不仅能协同提高血清中雌二醇含量,还能协同提高caspase-3基因的表达促进细胞凋亡。与单一处理相比,两两联合使小鼠肝脏HSP70蛋白表达进一步增加,表明联合作用使小鼠应激加剧。两两联合(AFB1、ZEA和DON)影响小鼠脾脏促炎症因子IL-1β、IL-6和TNF-α在]mRNA水平的表达,进而可能影响机体的免疫功能。
通过上述试验结果可得出以下结论：(1)四种霉菌毒素对猪肾细胞和大鼠肝细胞的毒性趋势一致,大小依次为：DON>AFB1>ZEA>FB1。(2)霉菌毒素对细胞或机体的联合效应十分复杂,对不同的靶细胞或靶器官的效应不一致；AFB1与ZEA的联合作用方式与霉菌毒素的剂量呈依赖关系,ZEA能缓解低剂量AFB1造成的肾细胞毒性,但ZEA与高剂量AFB1呈现协同效应。(3)ZEA和DON两两联合导致小鼠脾脏促炎症因子的表达发生变化,可能影响脾脏的免疫功能。(4)AFB1和DON对大鼠肝细胞或小鼠肝脏损伤都体现为协同效应。
The aim of this study was to investigate the combined effects of aflatoxin B1(AFB1), zearalenone (ZEA), deoxynivalenol (DON) and fumonisin B1(FB1) on the porcine kidney cell, rat liver cell and Balb/C mice.
(1) The combined effects of the four predominant mycotoxins on procine kidney cell (PK15)
PK15were incubated with different concentrations of AFB1, ZEA, DON and FB1for12,24and48h, using MTT assay and LDH release assay to evaluate the cytotoxicity of the four mycotoxins. Exposure with mycotoxin for48h, the EC50of AFB1, ZEA and DON was38.8,121.8and3.6μM, and the EC30was26.9,86.6and1.8μM, which were calculated from dose-effect curves. The respones of AFB1, ZEA and DON were in a concentration-and time depended manner, the cytotoxicity was elevated with addition of dose and exposure time. Incubated with250μM FB1, cell viability was above70%, the EC50could not be obtained. With regard to ROS production and cell apoptosis, AFB1and DON significantly induced them in a concentration-dependent manner, but ZEA (10,20,40μM) had no effect on cell apoptosis and ROS production. The cytotoxicity of the four mycotoxins in increasing order:FB1
ZEA could alleviate low concentrations of AFB1(1μM)-induced membrane damage and oxidative damage, but ZEA with the high concentration of AFB1synergistically exacerbate membrane damage and oxidative damage. ZEA weakened AFB1-induced apoptosis, mainly in the early apoptotic; related to slow down the process of apoptosis by bcl-2, caspase-3gene and p53protein expression.
(2) The combined effects of the four common mycotoxins on BRL
BRL were incubated with different concentrations of AFB1, ZEA, DON and FB1for12,24and48h, using MTT assay and LDH release assay to evaluate the cytotoxicity of the four mycotoxins. Exposure with mycotoxin for48h, the EC50of AFB1, ZEA and DON was37.9,100.3and36.5μM, and the EC30was29.2,91.6and3.27μM, which were calculated from dose-effect curves. The respones of AFB1, ZEA and DON were in a concentration-and time depended manner. Incubated with FB1, cell viability was not affected. With regard to ROS production and cell apoptosis, AFB1and DON significantly induced them (P<0.05), but ZEA (10,20,40μM) had no effect on cell apoptosis and ROS production. The cytotoxicity of the four mycotoxins in increasing order:FB1
AFB1and DON displayed additive or synergistic effects on the cell membrane damage and oxidative stress. Combination of1μM AFB1and2μM DON synergistically reduced bcl-2gene expression levels, and promote box, caspase-3, and p53expression and accelerate the process of apoptosis.
(3) The combined effects of the four common mycotoxins on Balb/C mice
One hundred and four4-week-old female Balb/C mice adapted for one week, then were randomly divided into13groups (n=8). Trials were grouped as follows:distilled water group, DMSO group, ethanol group, AFB1(2.5mg/kg.bw), ZEA (5mg/kg.bw), DON (5mg/kg.bw), FB1(8mg/kg.bw), AFB1+ZEA, AFB1+DON, AFB1+FB1, ZEA+DON, ZEA+FB1, and DON+FB1. The dose of combined groups superimposed on the single dose. The mice were administered orally by gavage once daily for14d.
There was no difference on the body weight of mice in all groups (P<0.05). FB1significantly increased weight of spleen; the combined group containing FB1could weaken the spleen weight gain caused by FB1. AFB1and DON synergistically increased serum ALT activity and MD A content in the liver, collaborative reduced SOD activity and strengthened liver cell damage and oxidative damage; AFB1and DON could promote apoptosis of liver by synergistic improving P53and caspase-3expression. ZEA and DON not only synergistically increased serum estradiol levels, but also synergistically improved caspase-3gene expression promotes apoptosis. Compared to individual treatment, the combined treatments further enhanced the expression of HSP70in the liver, indicating that the joint could exacerbate the stress in mice. Pro-inflammatory cytokines IL-1β, IL-6and TNF-α mRNA expression of spleen in AZ, AD or ZD mainly significantly affected (P<0.05), which may affected immune function.
In a word,(1) the cytotoxicity of mycotoxins on PK15and BRL was consistent, in increasing order FB1
引文
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