镍对雄性大鼠的生殖毒性及原花青素的保护作用研究
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摘要
本研究以健康性成熟Wistar雄性大鼠为研究对象,通过建立动物模型来探讨镍对雄性大鼠的生殖毒性和葡萄籽原花青素(GSPE)的保护作用及可能的机制。本研究选择雄性大鼠48只,随机分为6组,每组8只,即：Control组(NS),硫酸镍(Ni) 1.25 mg/kg、2.50mg/kg、5.00 mg/kg组,2.50 mg/kg Ni加GSPE (50 mg/kg和100mg/kg)组。每日称重,腹腔注射Ni染毒并灌胃给NS或GSPE,连续30 d。染毒结束次日,乙醚麻醉并颈椎脱臼处死大鼠,分别采集附睾及睾丸样本,进行检测,包括精子运动参数；睾丸细胞凋亡及细胞周期；谷胱甘肽过氧化物酶(GSH-Px)、过氧化氢酶(CAT)、诱导性一氧化氮合酶(iNOS)及总一氧化氮合酶(TNOS)活性和丙二醛(MDA)、过氧化氢(H2O2)及一氧化氮(NO)的含量；睾丸细胞Bax、Caspase-3和c-kit蛋白表达水平。结果如下：
1.整个实验期间,各组动物体重均衡,且未发现动物死亡现象。同期,各实验组动物体重和睾丸脏器系数与Control组比较均无显著性差异(p>0.05)。
2.与Control组比较,2.50mg Ni组曲线速度(VCL)和平均移动角度(MAD)显著升高,直线性(LIN)、前向性(STR)及精子密度(ρ)显著降低；5.00 mgNi组VCL显著升高,直线速度(VSL)、平均路径速度(VAP)、LIN、STR及ρ显著降低(p<0.05)。与2.50mg Ni组比较,50 mg GSPE组VCL和MAD显著降低,STR和ρ显著升高；100mg GSPE组VCL和MAD显著降低,STR、LIN、摆动性(WOB)和ρ显著升高(p<0.05)。
3.与Control组比较,2.50和5.00mg Ni组大鼠睾丸细胞凋亡率均显著升高(p<0.05),G0/G1期细胞相对增多,S期细胞显著降低(p<0.05)。与2.50 mgNi组比较,50和100 mg GSPE组大鼠睾丸细胞凋亡率均显著降低,G0/G1期细胞相对减少,S期细胞显著增多(p<0.05)。
4.与Control组比较,1.25mg Ni组大鼠睾丸组织CAT酶活力显著降低,H2O2含量显著升高(p<0.05)；2.50和5.00mg Ni组大鼠睾丸组织CAT和GSH-Px活力显著降低(p<0.01),MDA和H2O2含量显著升高(p<0.05)。与2.50 mg Ni组比较,50 mg GSPE组大鼠睾丸组织CAT酶活力略有升高及MDA含量略有降低,GSH-Px酶活力显著升高及H2O2含量显著降低(p<0.05)；100 mg GSPE组大鼠睾丸组织GSH-Px和CAT酶活力略有升高,MDA和H2O2含量显著降低(p<0.05)。
5.与Control组比较,各Ni组大鼠睾丸组织iNOS酶活力和NO含量均显著升高；5.00 mg Ni组大鼠睾丸组织TNOS酶活力显著升高(p<0.01)。与1.25和2.50mg Ni组比较,5.00mg Ni组大鼠睾丸组织iNOS酶活力和NO含量均显著升高(p<0.01)。与2.50mg Ni组比较,50 mg GSPE组大鼠睾丸组织iNOS酶活力和NO含量均显著降低(p<0.05)；100 mg GSPE组大鼠睾丸组织iNOS酶活力和NO含量均显著降低(p<0.01)。
6.与Control组比较,2.50和5.00mg Ni组大鼠睾丸细胞Bax蛋白表达量均显著升高(p<0.01)。与Control组比较,各Ni实验组大鼠睾丸细胞Caspase-3前体蛋白表达量均显著升高,且均出现Caspase-3切割片段,并呈剂量效应关系。与2.50 mg Ni组比较,50和100 mg GSPE组大鼠睾丸细胞Bax、Caspase-3前体及其切割片段蛋白表达量均显著降低(p<0.05)。
7.与Control组比较,2.50和5.00mg Ni组大鼠睾丸细胞c-kit蛋白表达量均显著升高(p<0.01)。与2.50mg Ni组比较,50和100mg GSPE组大鼠睾丸细胞c-kit蛋白表达量均显著降低(p<0.01)。
本研究结果显示,过量Ni暴露可引起雄性大鼠精子运动参数改变,导致生殖损伤。究其原因,可能与Ni增强大鼠睾丸组织氧化应激效应、致使Bax、c-kit蛋白表达上调,进而上调并激活睾丸细胞Caspase-3蛋白,导致睾丸生殖细胞周期紊乱及生殖细胞凋亡有关。然而,GSPE对Ni致生殖毒性具有拮抗作用,这可能是由于GSPE可以直接清除H2O2,降低NO和MDA水平,下调Bax和c-kit蛋白表达,进而下调及降低Caspase-3蛋白活性、抑制氧化应激和细胞凋亡,最终拮抗Ni的生殖毒性。
The major objectives of the present study were to determine whether nickel sulfate (Ni)-induced reproductive damage occurs via apoptosis and oxidative stress and to examine the expression of Bax, Caspase-3 and c-kit and their effects on Ni exposure. This study also explored the protective effects of grape seed Procyanidin extract (GSPE) against Ni toxicity in the testes. Wistar rats were treated with normal saline, Ni alone (1.25,2.50, and 5.00 mg/kg/day), and Ni (2.50 mg/kg/day) plus GSPE (50 and 100 mg/kg/day). Thus, sperm motility, testicular apoptosis, oxidative stress, and the expression of related proteins were investigated to explore their possible mechanisms. The results were showed as follow:
1. During the 30 day treatment period, body weight and relative testes weight did not show significant changes among the control and experimental groups. No deaths occurred in any of the groups.
2. Significant increases in curvilinear velocity (VCL) and decreases in linearity (LIN), straightness (STR), and density of spermatozoa (p) in the 2.50 and 5.00 mg Ni groups were observed compared with the control group (p<0.05). The results also showed significant increases in mean angular deviation (MAD) in the 2.50 mg Ni group and decreases in average path velocity (VAP) and straight line velocity (VSL) in the 5.00 mg Ni group compared with the control group (p<0.05). No significant differences in amplitude of lateral head displacement (ALH), beat cross frequency (BCF), and wobble (WOB) were found between the control group and Ni groups. All GSPE groups displayed significant decreases in VCL and MAD and increases in STR and p compared with the 2.50 mg Ni group (p<0.05). Moreover, LIN and WOB significantly increased in the 100 mg GSPE group (p<0.05).
3. A significant decrease in the percentage of S-phase cells was observed in the 2.50 and 5.00 mg Ni groups compared with the control group. The percentage of GO/G1-and G2/M-phase cells showed relative increases. The rate of testicular cell apoptosis in all Ni groups was higher than the control group, but only the 2.50 and 5.00 mg Ni groups demonstrated significant increases compared with the control group. The addition of GSPE resulted in an increase in the percentage of S-phase cells and a decrease in the rate of apoptosis, indicating that GSPE may maintain a normal testicular cell cycle and decrease the incidence of apoptosis.
4. Ni treatment significantly decreased glutathione peroxidase (GSH-Px) and catalase (CAT) activity and increased malondialdehyde (MDA) and hydrogen peroxide (H2O2) content in the testes of rats, especially in the 2.50 and 5.00 mg Ni groups (p<0.05). A significant increase in the activity of GSH-Px was observed in the 50 mg GSPE group compared with the 2.50 mg Ni group (p< 0.05). A significant decrease in MDA content was observed in the 100 mg GSPE group compared with the 2.50 mg Ni group (p<0.05). Significant decreases in H2O2 content were observed in all GSPE groups compared with the 2.50 mg Ni group (p<0.05).
5. The analysis of enzyme activity in testicular tissue isolated from control and experimental animals revealed a significant increase in nitric oxide (NO) content and inducible nitric oxide synthase (iNOS) activity in all three Ni groups (p<0.05). However, the levels in the 5.00 mg Ni group were much higher than in the other two Ni groups (p<0.05).Significant increases in total nitric oxide synthase (TNOS) activity were found in the 5.00 mg Ni group compared with the control group and the other two Ni groups (p<0.05). A significant decrease in iNOS activity and a decrease in NO content were observed in the two GSPE groups compared with the 2.50 mg Ni group (p<0.05).
6. Western blot analysis showed that the expression of Bax and Pro-caspase-3 protein increased in the 2.50 and 5.00 mg Ni groups compared with controls (p<0.05). At the same time, Pro-caspase-3 protein increased significantly and cleaved-caspase-3 protein expression occured from 1.25 to 5.00 mg Ni groups. Furthermore, the expression of cleaved-caspase-3 protein increased in a dose-dependent manner in all three Ni groups. GSPE significantly reduced Bax and Pro-and cleaved-caspase-3 expression in the testes of rats exposed to 2.50 mg Ni (p<0.05).
7. Western blot analysis showed that the expression of c-kit increased in the 2.50 and 5.00 mg Ni groups compared with controls (p<0.05). GSPE significantly reduced c-kit expression in the testes of rats exposed to Ni (p<0.05).
Collectively, These results demonstrate the following:(1) Ni exhibits reproductive toxicity in rats by decreasing sperm at concentrations of 2.50 and 5.00 mg; (2) intratesticular oxidative stress, c-kit overexpression and apoptosis play pivotal roles in reproductive damage induced by Ni; and (3) GSPE enhances sperm motility by downregulating c-kit expression and offsetting the apoptosis and oxidative stress induced by Ni by directly decreasing MDA and NO, scavenging H2O2, and downregulating Bax, Pro-and cleaved-Caspase-3 protein expression.
1.整个实验期间,各组动物体重均衡,且未发现动物死亡现象。同期,各实验组动物体重和睾丸脏器系数与Control组比较均无显著性差异(p>0.05)。
2.与Control组比较,2.50mg Ni组曲线速度(VCL)和平均移动角度(MAD)显著升高,直线性(LIN)、前向性(STR)及精子密度(ρ)显著降低；5.00 mgNi组VCL显著升高,直线速度(VSL)、平均路径速度(VAP)、LIN、STR及ρ显著降低(p<0.05)。与2.50mg Ni组比较,50 mg GSPE组VCL和MAD显著降低,STR和ρ显著升高；100mg GSPE组VCL和MAD显著降低,STR、LIN、摆动性(WOB)和ρ显著升高(p<0.05)。
3.与Control组比较,2.50和5.00mg Ni组大鼠睾丸细胞凋亡率均显著升高(p<0.05),G0/G1期细胞相对增多,S期细胞显著降低(p<0.05)。与2.50 mgNi组比较,50和100 mg GSPE组大鼠睾丸细胞凋亡率均显著降低,G0/G1期细胞相对减少,S期细胞显著增多(p<0.05)。
4.与Control组比较,1.25mg Ni组大鼠睾丸组织CAT酶活力显著降低,H2O2含量显著升高(p<0.05)；2.50和5.00mg Ni组大鼠睾丸组织CAT和GSH-Px活力显著降低(p<0.01),MDA和H2O2含量显著升高(p<0.05)。与2.50 mg Ni组比较,50 mg GSPE组大鼠睾丸组织CAT酶活力略有升高及MDA含量略有降低,GSH-Px酶活力显著升高及H2O2含量显著降低(p<0.05)；100 mg GSPE组大鼠睾丸组织GSH-Px和CAT酶活力略有升高,MDA和H2O2含量显著降低(p<0.05)。
5.与Control组比较,各Ni组大鼠睾丸组织iNOS酶活力和NO含量均显著升高；5.00 mg Ni组大鼠睾丸组织TNOS酶活力显著升高(p<0.01)。与1.25和2.50mg Ni组比较,5.00mg Ni组大鼠睾丸组织iNOS酶活力和NO含量均显著升高(p<0.01)。与2.50mg Ni组比较,50 mg GSPE组大鼠睾丸组织iNOS酶活力和NO含量均显著降低(p<0.05)；100 mg GSPE组大鼠睾丸组织iNOS酶活力和NO含量均显著降低(p<0.01)。
6.与Control组比较,2.50和5.00mg Ni组大鼠睾丸细胞Bax蛋白表达量均显著升高(p<0.01)。与Control组比较,各Ni实验组大鼠睾丸细胞Caspase-3前体蛋白表达量均显著升高,且均出现Caspase-3切割片段,并呈剂量效应关系。与2.50 mg Ni组比较,50和100 mg GSPE组大鼠睾丸细胞Bax、Caspase-3前体及其切割片段蛋白表达量均显著降低(p<0.05)。
7.与Control组比较,2.50和5.00mg Ni组大鼠睾丸细胞c-kit蛋白表达量均显著升高(p<0.01)。与2.50mg Ni组比较,50和100mg GSPE组大鼠睾丸细胞c-kit蛋白表达量均显著降低(p<0.01)。
本研究结果显示,过量Ni暴露可引起雄性大鼠精子运动参数改变,导致生殖损伤。究其原因,可能与Ni增强大鼠睾丸组织氧化应激效应、致使Bax、c-kit蛋白表达上调,进而上调并激活睾丸细胞Caspase-3蛋白,导致睾丸生殖细胞周期紊乱及生殖细胞凋亡有关。然而,GSPE对Ni致生殖毒性具有拮抗作用,这可能是由于GSPE可以直接清除H2O2,降低NO和MDA水平,下调Bax和c-kit蛋白表达,进而下调及降低Caspase-3蛋白活性、抑制氧化应激和细胞凋亡,最终拮抗Ni的生殖毒性。
The major objectives of the present study were to determine whether nickel sulfate (Ni)-induced reproductive damage occurs via apoptosis and oxidative stress and to examine the expression of Bax, Caspase-3 and c-kit and their effects on Ni exposure. This study also explored the protective effects of grape seed Procyanidin extract (GSPE) against Ni toxicity in the testes. Wistar rats were treated with normal saline, Ni alone (1.25,2.50, and 5.00 mg/kg/day), and Ni (2.50 mg/kg/day) plus GSPE (50 and 100 mg/kg/day). Thus, sperm motility, testicular apoptosis, oxidative stress, and the expression of related proteins were investigated to explore their possible mechanisms. The results were showed as follow:
1. During the 30 day treatment period, body weight and relative testes weight did not show significant changes among the control and experimental groups. No deaths occurred in any of the groups.
2. Significant increases in curvilinear velocity (VCL) and decreases in linearity (LIN), straightness (STR), and density of spermatozoa (p) in the 2.50 and 5.00 mg Ni groups were observed compared with the control group (p<0.05). The results also showed significant increases in mean angular deviation (MAD) in the 2.50 mg Ni group and decreases in average path velocity (VAP) and straight line velocity (VSL) in the 5.00 mg Ni group compared with the control group (p<0.05). No significant differences in amplitude of lateral head displacement (ALH), beat cross frequency (BCF), and wobble (WOB) were found between the control group and Ni groups. All GSPE groups displayed significant decreases in VCL and MAD and increases in STR and p compared with the 2.50 mg Ni group (p<0.05). Moreover, LIN and WOB significantly increased in the 100 mg GSPE group (p<0.05).
3. A significant decrease in the percentage of S-phase cells was observed in the 2.50 and 5.00 mg Ni groups compared with the control group. The percentage of GO/G1-and G2/M-phase cells showed relative increases. The rate of testicular cell apoptosis in all Ni groups was higher than the control group, but only the 2.50 and 5.00 mg Ni groups demonstrated significant increases compared with the control group. The addition of GSPE resulted in an increase in the percentage of S-phase cells and a decrease in the rate of apoptosis, indicating that GSPE may maintain a normal testicular cell cycle and decrease the incidence of apoptosis.
4. Ni treatment significantly decreased glutathione peroxidase (GSH-Px) and catalase (CAT) activity and increased malondialdehyde (MDA) and hydrogen peroxide (H2O2) content in the testes of rats, especially in the 2.50 and 5.00 mg Ni groups (p<0.05). A significant increase in the activity of GSH-Px was observed in the 50 mg GSPE group compared with the 2.50 mg Ni group (p< 0.05). A significant decrease in MDA content was observed in the 100 mg GSPE group compared with the 2.50 mg Ni group (p<0.05). Significant decreases in H2O2 content were observed in all GSPE groups compared with the 2.50 mg Ni group (p<0.05).
5. The analysis of enzyme activity in testicular tissue isolated from control and experimental animals revealed a significant increase in nitric oxide (NO) content and inducible nitric oxide synthase (iNOS) activity in all three Ni groups (p<0.05). However, the levels in the 5.00 mg Ni group were much higher than in the other two Ni groups (p<0.05).Significant increases in total nitric oxide synthase (TNOS) activity were found in the 5.00 mg Ni group compared with the control group and the other two Ni groups (p<0.05). A significant decrease in iNOS activity and a decrease in NO content were observed in the two GSPE groups compared with the 2.50 mg Ni group (p<0.05).
6. Western blot analysis showed that the expression of Bax and Pro-caspase-3 protein increased in the 2.50 and 5.00 mg Ni groups compared with controls (p<0.05). At the same time, Pro-caspase-3 protein increased significantly and cleaved-caspase-3 protein expression occured from 1.25 to 5.00 mg Ni groups. Furthermore, the expression of cleaved-caspase-3 protein increased in a dose-dependent manner in all three Ni groups. GSPE significantly reduced Bax and Pro-and cleaved-caspase-3 expression in the testes of rats exposed to 2.50 mg Ni (p<0.05).
7. Western blot analysis showed that the expression of c-kit increased in the 2.50 and 5.00 mg Ni groups compared with controls (p<0.05). GSPE significantly reduced c-kit expression in the testes of rats exposed to Ni (p<0.05).
Collectively, These results demonstrate the following:(1) Ni exhibits reproductive toxicity in rats by decreasing sperm at concentrations of 2.50 and 5.00 mg; (2) intratesticular oxidative stress, c-kit overexpression and apoptosis play pivotal roles in reproductive damage induced by Ni; and (3) GSPE enhances sperm motility by downregulating c-kit expression and offsetting the apoptosis and oxidative stress induced by Ni by directly decreasing MDA and NO, scavenging H2O2, and downregulating Bax, Pro-and cleaved-Caspase-3 protein expression.
引文
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