邻苯二甲酸二丁酯和苯并[a]芘对雄性大鼠的联合生殖毒性研究
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摘要
随着工业的发展,大量有机污染物的排放,使得环境中有机物的污染日益严重,尤其是持久性有机污染物(persistent organic pollutants, POPs)的污染问题已经引起广泛的关注。由于持久性有机污染物种类繁多,并在生物群落中累积,而且其对于动物及人类健康的影响往往具有协同作用,人类长期处于低剂量暴露状态。因此,研究POPs长期低剂量联合作用对人类健康的影响显得十分重要。经过本课题组前期对重庆主城区及三峡库区水中有机物的检测发现,邻苯二甲酸酯类和多环芳烃类是污染最为广泛的两类有机污染物,其中邻苯二甲酸酯类的邻苯二甲酸二丁酯(dibutyl phthalate,DBP)污染最为严重,而苯并[a]芘(benzo(a)pyrene, B[a]P)则是多环芳烃类化合物中毒性最强的。以往的研究表明DBP具有显著的雄性生殖毒性,可导致雄性啮齿类动物睾丸萎缩、重量减轻、睾丸标志酶活性下降、精母细胞和精子细胞丧失、曲细精管变性萎缩、生殖道畸形等生殖损害。对B[a]P研究主要集中在它的致癌性及其机制,生殖毒性研究相对较少,也有研究结果表明B[a]P具有雄性生殖毒性,可以导致睾丸重量减轻,精子数量和精子活力下降,睾酮浓度下降。但以往的研究多是采用单一化合物高剂量染毒,其结果并不能很好地反映低剂量联合暴露下的损伤作用。
为进一步搞清重庆市主城区及三峡库区水中两类主要有机污染物联合毒性及其作用机制,本研究选用DBP和B[a]P作为有机污染物的代表,单独和联合作用于雄性大鼠,从整体水平观察其生殖毒性作用,并利用分子生物学技术探讨其可能的毒性作用机制。
主要研究结果如下:
1、本实验显示DBP和B[a]P对大鼠的体重及一般情况无明显影响,重要脏器未见明显的病变,睾丸及附睾脏器系数无明显改变,肝脏器系数有增加趋势,提示肝脏对化合物的毒性作用较为敏感。
2、组织病理观察显示DBP在本实验剂量下对大鼠睾丸组织形态学改变不明显,而B[a]P可以引起睾丸曲细精管萎缩,生精细胞层数减少,生精上皮空泡变性等病理改变。电镜观察显示两类化合物均可以引起睾丸细胞线粒体肿胀,内质网扩张等损害。两者联合使用后的作用与B[a]P单独使用的作用类似,但联合使用后的毒性未见明显增加。
3、精子评价结果:DBP和B[a]P在染毒早期刺激精子数量增加,二者联合使用后呈现出与DBP单独使用一样的趋势。在染毒后期,刺激效应消失,低剂量联合染毒组精子数量明显下降。B[a]P组在染毒3个月后精子畸形率明显增加,而DBP组改变不明显,高剂量联合染毒组在染毒的第一、三个月畸形率均增高。
4、DBP和B[a]P在一定浓度和染毒时间内均可以刺激睾酮的分泌,B[a]P的刺激作用强于DBP,二者联合后的兴奋效应弱于B[a]P单独作用。
5、DBP和B[a]P均可以影响支持细胞ABP和Tf的mRNA表达,而且都表现为先抑制后增强的趋势,但对Tf的增强作用要晚于ABP。二者联合使用后的变化趋势与单独染毒组类似。
6、DBP和B[a]P对睾丸组织抗氧化系统的影响不明显,B[a]P可以抑制SOD酶的活力,但对CAT酶的活力表现为增强作用,二者联合使用后对SOD及GSH-PX的活力有一定的影响,对CAT酶仍表现为增强作用。各染毒组的MDA含量无明显增加,提示机体处于代偿状态,未产生明显的氧化损伤。
7、DBP和B[a]P低剂量组均可以抑制细胞的增殖,而两个高剂量组都呈现出一过性的刺激细胞增殖的现象,但随着染毒时间延长,这种刺激作用消失。二者联合使用后仍然明显抑制了细胞增殖,但与单独染毒组比较差异不明显。
8、DBP没有明显诱导生精细胞凋亡,B[a]P两个剂量组均明显诱导了细胞凋亡,提示B[a]P具有比DBP更强的生殖毒性,两者联合使用后仍然可以诱导细胞凋亡,显示出类似B[a]P单独使用的作用,但联合使用后毒性未见增强。
9、各染毒组ERK的总蛋白表达变化相差不显著,DBP低剂量组可以明显抑制磷酸化ERK1/2的表达,而B[a]P则是高剂量组抑制了磷酸化ERK1/2的表达,联合染毒后仍然抑制磷酸化蛋白的表达,但两个剂量组出现抑制效应的时间不一致。
10、DBP和B[a]P低剂量组均可诱导磷酸化的JNK和总JNK的表达,而高剂量组只增加了JNK的磷酸化水平,对总JNK表达无影响。二者联合使用后不影响JNK总蛋白的表达,只在染毒3个月时明显增加了磷酸化JNK的表达,联合染毒组与单独染毒组差异不显著。
结论:
DBP和B[a]P在本实验剂量下均对雄性生殖系统有一定的损伤作用,但这种损伤作用并不都表现为抑制效应,在某些指标上反而显现出兴奋效应,如睾酮的合成,支持细胞ABP和Tf的表达。由于生精过程是一个复杂的非单向调节过程,因此不论是对细胞功能的刺激或抑制都有可能会对生精过程产生影响。本研究结果还显示B[a]P的毒性效应大于DBP,这种效应可以从组织病理学改变、精子畸形率、生精细胞凋亡等观察指标上反映出来。二者联合使用后的损伤作用呈现出以B[a]P作用为主的趋势,没有出现明显的毒性增强的表现,显示出两者联合使用后产生了一定的拮抗效应。
Along with the development of human society and expanding process scale of industry and agriculture, more and more pollutants were discharged into environment and increased the contamination of organic pollutants, especial persistant organic pollutants (POPs). The POPs are chemical substances that persist in the environment, bioaccumulate through the food web, and pose a risk of causing adverse effects to human health. Because the POPs are mixtured in the environment and affect the human health in a combination pattern, it is very important to study the combination toxicity of the POPs. Our previous studies show that phthalates and polycyclic aromatic hydrocarbon (PAHs) are the most popular pollutants in surface water. Both of them have been showed to possess repeoductive toxicity, which can lead to the atrophy of testis, loss of spermatocyte and decreasing of T concentration. But most of previous studies are carried on by using single compounds at high dosage and the results can’t reflect the adverse effect exposure to mixture pollutants at low dosage. In the present study we chose DBP and B[a]P as the model chemicals of organic pollutants in surface water, and test the single or combined reproductive toxicity of them on male rats and the mechanism also be investigated by using molecular biological techniques.
The main results of this study are as follows:
1. In this study, the growth and general appearance of the animals treated with DBP and B[a]P were normal throughout the experiment. No obvious lesion were observed in major organs, including testis and epididymis. The coefficient of liver were increased slightly. The observation indicated that liver were sensitive for toxic effect.
2. The changes of histomorphology in the groups treated with DBP were insignificant, but the atrophy seminiferous tubules and vacuoles degeneration of seminiferous epithelium were observed in the groups treated with B[a]P at both dosages. The testicular ultrastructure observed by electronic microscope showed that both of DBP and B[a]P caused mitochondrion dropsy and endoplasmic reticulum expanding in testicular cells. The adverse effect of combined groups were similar with B[a]P groups. The toxicity in combined groups were not stronger than that of DBP or B[a]P groups alone.
3. The result of sperm evaluation showed that the sperm amounts were increased in the early period of the experiment in the two groups treated with DBP and B[a]P. The tendency in combined treatment groups were similar with DBP groups. But in the late period of experiments, the stimulation effect were disappeared and the sperm amounts were decreased significantly in combined treatment groups of low dosage. Comparaed with control grouop, the percentages of abnormal sperm were increased in B[a]P groups at the 3rd month and in combined treatment group of high dosage at the 1st and 3rd months, respectively.
4. Both of DBP and B[a]P can stimulate the secretion of Testosterone and this effect in B[a]P groups were stronger than that of DBP groups. The stimulation effect in combined treatment groups were weaker than that of B[a]P group.
5. The expression of androgen-binding protein(ABP)and transferring(Tf) were affected by DBP and B[a]P. The ABP mRNA level were inhibited at the 1st month, then increased from the 2nd month to 3rd month in each treatment group. The Tf mRNA level were inhibited at the 1st and 2nd month while increased at the 3rd month in each treatment group. The similar tendency were observed in combined treatment groups.
6. The effect of DBP and B[a]P on the antioxidant system in testis were insignificant. The activity of SOD in B[a]P groups were decreased while the activity of CAT in these groups were increased. There were no significant difference in the activity of SOD、CAT and GSH-PX between DBP groups and control group. In combined treatment groups, the activity of SOD and GSH-PX were partly inhibited but the activity of CAT were stimulated. The amount of MDA were not increased significantly between treatment groups and control. This result suggested that the antioxidant systems in testis were in a compensation state and no obviously oxidative damages were showed.
7. Cell proliferation were inhibited respectively in low dosage groups of DBP and B[a]P. In high dosage groups of DBP and B[a]P, a transitory increasing of cell proliferation were observed, but these phenomenon disappeared along with prolongation of the treatment time. Compared with control group, cell proliferation were also significantly decreased in combined treatment groups, but the differences were not significantly between the combined treatment groups and DBP or B[a]P groups alone.
8. There were no significant differences for the spermatogenic cell apoptosis between control and DBP groups. In B[a]P groups, the spermatogenic cell apoptosis were significantly elevated, which is reflected that the reproductive toxicity of B[a]P is more severe than DBP. Spermatogenic cell apoptosis were also increased in combined treatment groups and showed the similar effect of B[a]P.
9. The expression of ERK1/2, phospho-ERK1/2, JNK and phospho-JNK in testis were determined by Western blot. The results showed that the total ERK1/2 protein levels were not affected in all treatment groups at three time points. Phospho-ERK1/2 (p-ERK1/2) levels were markedly decreased after exposure to 50mg/kg.bw DBP and 5mg/kg.bw B[a]P. This inhibited effect were also occurred in combined treatment group of low dosage at the 2nd month and high dosage at the 3rd month, repectively. The data suggested that both DBP and B[a]P induced expression of ERK1/2 phosphorylated protein, but the time point of the inhibited effect is different in the groups of two dosages.
10. The expression of both total JNK and phospho-JNK were induced in low dosage of DBP and B[a]P group. Only phosphorylation levels of JNK were enhanced in high dosage of DBP and B[a]P group. In combined treatment groups, no significant changes in total JNK levels occurred but phosphor-JNK levels were markedly elevated at the 3rd month. There were no significant differences between combined treatment groups and DBP or B[a]P groups. These results indicated that DBP and B[a]P can induce both total and phosphorylated JNK levels.
Conclusion:
Both DBP and B[a]P can cause certain adverse effect on the male reproductive system at the dosages of our experiment and the adverse effect were not appeared only as inhibited effect. Biphasis effect were observed in some results, such as Testerone content, expression of ABP and Tf mRNA. The biphasis effect showed exciting effect at early stage of the treatment and then inhibited along with the increasing of dosage. Because the regulation of spermatogenesis is a complex and non-unidirectional process, any factors which can excite or inhibit the cell functions may affect the spermatogenesis. The results of this study showed that the toxicity of B[a]P is more severe than that of DBP. The toxicity can be reflected from the histopathology observation, ratio of abnormal sperms and spermatogenic cell apoptosis. In present study, most damage effect treated by combination of DBP and B[a]P were similar to that of B[a]P and enhanced effect of the toxicity were not observed. This result suggest that some antagonistic effects were generated after combined DBP with B[a]P. Considering that the combined effect is complicated, the mechanism of this effect should be probed in the further research.
为进一步搞清重庆市主城区及三峡库区水中两类主要有机污染物联合毒性及其作用机制,本研究选用DBP和B[a]P作为有机污染物的代表,单独和联合作用于雄性大鼠,从整体水平观察其生殖毒性作用,并利用分子生物学技术探讨其可能的毒性作用机制。
主要研究结果如下:
1、本实验显示DBP和B[a]P对大鼠的体重及一般情况无明显影响,重要脏器未见明显的病变,睾丸及附睾脏器系数无明显改变,肝脏器系数有增加趋势,提示肝脏对化合物的毒性作用较为敏感。
2、组织病理观察显示DBP在本实验剂量下对大鼠睾丸组织形态学改变不明显,而B[a]P可以引起睾丸曲细精管萎缩,生精细胞层数减少,生精上皮空泡变性等病理改变。电镜观察显示两类化合物均可以引起睾丸细胞线粒体肿胀,内质网扩张等损害。两者联合使用后的作用与B[a]P单独使用的作用类似,但联合使用后的毒性未见明显增加。
3、精子评价结果:DBP和B[a]P在染毒早期刺激精子数量增加,二者联合使用后呈现出与DBP单独使用一样的趋势。在染毒后期,刺激效应消失,低剂量联合染毒组精子数量明显下降。B[a]P组在染毒3个月后精子畸形率明显增加,而DBP组改变不明显,高剂量联合染毒组在染毒的第一、三个月畸形率均增高。
4、DBP和B[a]P在一定浓度和染毒时间内均可以刺激睾酮的分泌,B[a]P的刺激作用强于DBP,二者联合后的兴奋效应弱于B[a]P单独作用。
5、DBP和B[a]P均可以影响支持细胞ABP和Tf的mRNA表达,而且都表现为先抑制后增强的趋势,但对Tf的增强作用要晚于ABP。二者联合使用后的变化趋势与单独染毒组类似。
6、DBP和B[a]P对睾丸组织抗氧化系统的影响不明显,B[a]P可以抑制SOD酶的活力,但对CAT酶的活力表现为增强作用,二者联合使用后对SOD及GSH-PX的活力有一定的影响,对CAT酶仍表现为增强作用。各染毒组的MDA含量无明显增加,提示机体处于代偿状态,未产生明显的氧化损伤。
7、DBP和B[a]P低剂量组均可以抑制细胞的增殖,而两个高剂量组都呈现出一过性的刺激细胞增殖的现象,但随着染毒时间延长,这种刺激作用消失。二者联合使用后仍然明显抑制了细胞增殖,但与单独染毒组比较差异不明显。
8、DBP没有明显诱导生精细胞凋亡,B[a]P两个剂量组均明显诱导了细胞凋亡,提示B[a]P具有比DBP更强的生殖毒性,两者联合使用后仍然可以诱导细胞凋亡,显示出类似B[a]P单独使用的作用,但联合使用后毒性未见增强。
9、各染毒组ERK的总蛋白表达变化相差不显著,DBP低剂量组可以明显抑制磷酸化ERK1/2的表达,而B[a]P则是高剂量组抑制了磷酸化ERK1/2的表达,联合染毒后仍然抑制磷酸化蛋白的表达,但两个剂量组出现抑制效应的时间不一致。
10、DBP和B[a]P低剂量组均可诱导磷酸化的JNK和总JNK的表达,而高剂量组只增加了JNK的磷酸化水平,对总JNK表达无影响。二者联合使用后不影响JNK总蛋白的表达,只在染毒3个月时明显增加了磷酸化JNK的表达,联合染毒组与单独染毒组差异不显著。
结论:
DBP和B[a]P在本实验剂量下均对雄性生殖系统有一定的损伤作用,但这种损伤作用并不都表现为抑制效应,在某些指标上反而显现出兴奋效应,如睾酮的合成,支持细胞ABP和Tf的表达。由于生精过程是一个复杂的非单向调节过程,因此不论是对细胞功能的刺激或抑制都有可能会对生精过程产生影响。本研究结果还显示B[a]P的毒性效应大于DBP,这种效应可以从组织病理学改变、精子畸形率、生精细胞凋亡等观察指标上反映出来。二者联合使用后的损伤作用呈现出以B[a]P作用为主的趋势,没有出现明显的毒性增强的表现,显示出两者联合使用后产生了一定的拮抗效应。
Along with the development of human society and expanding process scale of industry and agriculture, more and more pollutants were discharged into environment and increased the contamination of organic pollutants, especial persistant organic pollutants (POPs). The POPs are chemical substances that persist in the environment, bioaccumulate through the food web, and pose a risk of causing adverse effects to human health. Because the POPs are mixtured in the environment and affect the human health in a combination pattern, it is very important to study the combination toxicity of the POPs. Our previous studies show that phthalates and polycyclic aromatic hydrocarbon (PAHs) are the most popular pollutants in surface water. Both of them have been showed to possess repeoductive toxicity, which can lead to the atrophy of testis, loss of spermatocyte and decreasing of T concentration. But most of previous studies are carried on by using single compounds at high dosage and the results can’t reflect the adverse effect exposure to mixture pollutants at low dosage. In the present study we chose DBP and B[a]P as the model chemicals of organic pollutants in surface water, and test the single or combined reproductive toxicity of them on male rats and the mechanism also be investigated by using molecular biological techniques.
The main results of this study are as follows:
1. In this study, the growth and general appearance of the animals treated with DBP and B[a]P were normal throughout the experiment. No obvious lesion were observed in major organs, including testis and epididymis. The coefficient of liver were increased slightly. The observation indicated that liver were sensitive for toxic effect.
2. The changes of histomorphology in the groups treated with DBP were insignificant, but the atrophy seminiferous tubules and vacuoles degeneration of seminiferous epithelium were observed in the groups treated with B[a]P at both dosages. The testicular ultrastructure observed by electronic microscope showed that both of DBP and B[a]P caused mitochondrion dropsy and endoplasmic reticulum expanding in testicular cells. The adverse effect of combined groups were similar with B[a]P groups. The toxicity in combined groups were not stronger than that of DBP or B[a]P groups alone.
3. The result of sperm evaluation showed that the sperm amounts were increased in the early period of the experiment in the two groups treated with DBP and B[a]P. The tendency in combined treatment groups were similar with DBP groups. But in the late period of experiments, the stimulation effect were disappeared and the sperm amounts were decreased significantly in combined treatment groups of low dosage. Comparaed with control grouop, the percentages of abnormal sperm were increased in B[a]P groups at the 3rd month and in combined treatment group of high dosage at the 1st and 3rd months, respectively.
4. Both of DBP and B[a]P can stimulate the secretion of Testosterone and this effect in B[a]P groups were stronger than that of DBP groups. The stimulation effect in combined treatment groups were weaker than that of B[a]P group.
5. The expression of androgen-binding protein(ABP)and transferring(Tf) were affected by DBP and B[a]P. The ABP mRNA level were inhibited at the 1st month, then increased from the 2nd month to 3rd month in each treatment group. The Tf mRNA level were inhibited at the 1st and 2nd month while increased at the 3rd month in each treatment group. The similar tendency were observed in combined treatment groups.
6. The effect of DBP and B[a]P on the antioxidant system in testis were insignificant. The activity of SOD in B[a]P groups were decreased while the activity of CAT in these groups were increased. There were no significant difference in the activity of SOD、CAT and GSH-PX between DBP groups and control group. In combined treatment groups, the activity of SOD and GSH-PX were partly inhibited but the activity of CAT were stimulated. The amount of MDA were not increased significantly between treatment groups and control. This result suggested that the antioxidant systems in testis were in a compensation state and no obviously oxidative damages were showed.
7. Cell proliferation were inhibited respectively in low dosage groups of DBP and B[a]P. In high dosage groups of DBP and B[a]P, a transitory increasing of cell proliferation were observed, but these phenomenon disappeared along with prolongation of the treatment time. Compared with control group, cell proliferation were also significantly decreased in combined treatment groups, but the differences were not significantly between the combined treatment groups and DBP or B[a]P groups alone.
8. There were no significant differences for the spermatogenic cell apoptosis between control and DBP groups. In B[a]P groups, the spermatogenic cell apoptosis were significantly elevated, which is reflected that the reproductive toxicity of B[a]P is more severe than DBP. Spermatogenic cell apoptosis were also increased in combined treatment groups and showed the similar effect of B[a]P.
9. The expression of ERK1/2, phospho-ERK1/2, JNK and phospho-JNK in testis were determined by Western blot. The results showed that the total ERK1/2 protein levels were not affected in all treatment groups at three time points. Phospho-ERK1/2 (p-ERK1/2) levels were markedly decreased after exposure to 50mg/kg.bw DBP and 5mg/kg.bw B[a]P. This inhibited effect were also occurred in combined treatment group of low dosage at the 2nd month and high dosage at the 3rd month, repectively. The data suggested that both DBP and B[a]P induced expression of ERK1/2 phosphorylated protein, but the time point of the inhibited effect is different in the groups of two dosages.
10. The expression of both total JNK and phospho-JNK were induced in low dosage of DBP and B[a]P group. Only phosphorylation levels of JNK were enhanced in high dosage of DBP and B[a]P group. In combined treatment groups, no significant changes in total JNK levels occurred but phosphor-JNK levels were markedly elevated at the 3rd month. There were no significant differences between combined treatment groups and DBP or B[a]P groups. These results indicated that DBP and B[a]P can induce both total and phosphorylated JNK levels.
Conclusion:
Both DBP and B[a]P can cause certain adverse effect on the male reproductive system at the dosages of our experiment and the adverse effect were not appeared only as inhibited effect. Biphasis effect were observed in some results, such as Testerone content, expression of ABP and Tf mRNA. The biphasis effect showed exciting effect at early stage of the treatment and then inhibited along with the increasing of dosage. Because the regulation of spermatogenesis is a complex and non-unidirectional process, any factors which can excite or inhibit the cell functions may affect the spermatogenesis. The results of this study showed that the toxicity of B[a]P is more severe than that of DBP. The toxicity can be reflected from the histopathology observation, ratio of abnormal sperms and spermatogenic cell apoptosis. In present study, most damage effect treated by combination of DBP and B[a]P were similar to that of B[a]P and enhanced effect of the toxicity were not observed. This result suggest that some antagonistic effects were generated after combined DBP with B[a]P. Considering that the combined effect is complicated, the mechanism of this effect should be probed in the further research.
引文
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