噻二唑类杀菌剂对大鼠甲状腺干扰作用研究
摘要
甲状腺素对于机体具有不可或缺的重要意义。在众多的甲状腺素干扰物中，农药所占比例最大。噻二唑类农药由于其广谱、高效、低残留、持效期长等优点在我国主要作为杀菌剂得到广泛应用，暴露人群较大。本研究选取了噻枯唑以及与其化学结构相似的噻森铜、噻菌铜农药，利用20d雌鼠青春期实验对SD大鼠进行灌胃染毒，观察了三种药物对大鼠血清甲状腺素水平、甲状腺重量、甲状腺滤泡上皮细胞增殖以及甲状腺激素代谢关键酶等的影响，探讨噻二唑类农药对甲状腺功能的干扰作用及其机制，为这些化合物的风险管理与评价提供科学依据。主要研究结果如下：
1、设定噻枯唑各组的给药剂量分别为10、20、40mg／kg／d，噻森铜各组的给药剂量分别为5、10、15mg／kg／d，噻菌铜各组的给药剂量分别为4、10、20和30mg／kg／d。通过灌胃染毒SD大鼠后，发现三种噻二唑类杀菌剂均能使大鼠甲状腺重量增加。
2、利用ELISA大鼠激素测定试剂盒对大鼠血清T_3、T_4、TSH进行测定。测定结果显示：噻枯唑各剂量组均能使大鼠血清T_3、T_4水平显著降低，TSH水平显著增加；噻森铜染毒后5、10mg／kg／d剂量组能显著降低血清T_3水平；噻菌铜试验中的20和30mg／kg／d剂量组能显著降低大鼠血清T_3、T_4水平，同时显著增加血清TSH水平。
3、在脏器重量和激素测定的基础上，利用组织形态学手段对三种药物可能的甲状腺干扰作用做进一步验证。实验结果表明：噻枯唑各剂量组均能对大鼠甲状腺功能产生明显影响，具体表现为甲状腺滤泡上皮细胞出现增殖和肥大。而噻森铜各染毒组没有出现明显的组织病理学改变。对于噻菌铜，实验发现4mg／kg／day的染毒剂量对大鼠甲状腺功能不产生任何可见影响，但随着染毒剂量的升高，噻菌铜具有明显促进甲状腺滤泡上皮细胞增生、降低滤泡中胶体面积和直径的作用。
4、鉴于增殖细胞核抗原的敏感性优于组织病理学，本研究又利用免疫组化技术研究噻森铜染毒后大鼠体内甲状腺细胞增殖表达情况，以期进一步对其是否具有甲状腺功能干扰作用进行验证。结果表明，噻森铜在所设定的最高剂量15mg／kg／d下能够引起甲状腺滤泡细胞轻微的增生，虽然这种结果与空白组相比并没有统计上的差异性，但是可能具有生物学意义。
5、最后通过测定大鼠体内甲状腺素代谢酶活性对三种药物可能的甲状腺干扰作用机制进行探讨。结果表明，噻枯唑染毒的10、20mg／kg／d剂量组能显著抑制GST酶活性，10mg／kg／d剂量组能显著诱导UDPGT活性；噻森铜染毒的10、15mg／kg／d剂量组能显著抑制GST酶活性，5、10mg／kg／d剂量组能显著抑制UDPGT的活性；噻菌铜染毒的30mg／kg／d剂量组能显著抑制GST酶活性，但同时能显著诱导UDPGT活性。
6、噻森铜的甲状腺干扰作用机制可能不同于噻枯唑和噻菌铜，其具体的作用机制还有待进一步研究。
It is widely accepted that thyroid hormones play predominantly a nuclear roleand function in the growth and differentiation of many organs. Pesticide in THs hadthe greatest proportion. Due to thiadiazole compound's excellent bioactivities andvarious chemical structures, as well as the high activity and low toxicity, it isbecoming a new research hotspot for more and more scientists. In the present study,we used the pubertal female rat assay to detect the effect of bismerthiazol, saisentongand thiodiazole-copper on thyroid function in the intact juvenile female rat. We haveexamined the effect of these pesticides on several thyroid endpoints: serum hormoneconcentrations, thyroid gland weights, hyperplasia of thyroid follicular cells, as wellas hepatic microsome enzyme activities of thyroid metabolism. The disturbance effectand possible action mechanism were studied, which will provide scientific basis forrisk management of these compounds. The main results and conclusions are asfollows:
1、Pubertal female rats were exposed to three thiadiazole compounds(bismerthiazol, saisentong and thiodiazole-copper) at different dosages of 10, 20,40mg/kg, 5, 10, 15mg/kg and 4, 10, 20, 30mg/kg, respectively, by oral gavage andthe control group was administered with vehicle alone. After treatments, the rats weresacrificed. The results indicated that three thiadiazole compounds administration wereincreased thyroid gland weights.
2、The serum triiodothyronine(T_3), thyroxine(T_4) and thyroid stimulatinghormone(TSH) concentrations were determined by ELISA kits. The results indicatedthat a statistically significant decrease in serum T_3 and T_4 was observed in allbismerthiazol groups, meanwhile, the TSH was increased significantly in allbismerthiazol treated groups. In saisentong groups, the surm T_3 was found decreasedsignificantly at dosage of 5 and 10mg/kg. Thiodiazole-copper administration weredecreased serum T_3, T_4 and increased surm TSH at the dosage of 20 and 30mg/kg.
3、In order to validate whether these pesticide have effect on the thyroid, thehistopathological examination was conducted based on the measurement of organweights and hormone. The results indicated all the group of bismerthiazol could haveeffect on the thyroid function significantly. The primary microscopic change of thethyroid follicular was diffuse hypertrophy and hyperplasia. There was no notablechange in the all saisentong treated groups. In all treated groups of thiodiazole-copper,the primary microscopic change of the thyroid gland was colloid depletion that wasoften associated with increased numbers of follicles in which lumens were decreasedin diameter and were devoid of colloid, though the dose of 4mg/kg/day inthiodiazole-copper did not be observed having effect on the thyroid function.
4、The immunohistochemical of proliferating cell nuclear antigen on thyroidgland was studied in saisentong treatment groups to confirm whether saisentong haveeffect on the thyroid follicular cells. The result indicates that the dosage of 15mg/kg/dcould produce hyperplasia of thyroid follicular cells slightly, though this result is notstatistically significant for control groups, this finding may be biologicallymeaningful.
5、Since UDPGT is an important hepatic enzyme that metabolizes T_4, helpingcharacterize possible biochemical mechanisms for thyroid hormone, the hepaticenzyme activity was tested at last. The results indicated the GST was restrained atdoses of 10, 20mg/kg/d and the UDPGT was induced at 10mg/kg/d in bismerthiazolgroups. In saisentong treated groups, the GST was restrained at doses of 10, 15mg/kg/d and the UDPGT was induced at dosage of 5, 10mg/kg/d. Thiodiazole-copperadministration were restrained GST and induced UDPGT at the same dosage of30mg/kg/d.
6、The action mechanism of saisentong in disturbing thyroid may be different tobismerthiazol and thiodiazole-copper, which needs to be studied further.
1、设定噻枯唑各组的给药剂量分别为10、20、40mg／kg／d，噻森铜各组的给药剂量分别为5、10、15mg／kg／d，噻菌铜各组的给药剂量分别为4、10、20和30mg／kg／d。通过灌胃染毒SD大鼠后，发现三种噻二唑类杀菌剂均能使大鼠甲状腺重量增加。
2、利用ELISA大鼠激素测定试剂盒对大鼠血清T_3、T_4、TSH进行测定。测定结果显示：噻枯唑各剂量组均能使大鼠血清T_3、T_4水平显著降低，TSH水平显著增加；噻森铜染毒后5、10mg／kg／d剂量组能显著降低血清T_3水平；噻菌铜试验中的20和30mg／kg／d剂量组能显著降低大鼠血清T_3、T_4水平，同时显著增加血清TSH水平。
3、在脏器重量和激素测定的基础上，利用组织形态学手段对三种药物可能的甲状腺干扰作用做进一步验证。实验结果表明：噻枯唑各剂量组均能对大鼠甲状腺功能产生明显影响，具体表现为甲状腺滤泡上皮细胞出现增殖和肥大。而噻森铜各染毒组没有出现明显的组织病理学改变。对于噻菌铜，实验发现4mg／kg／day的染毒剂量对大鼠甲状腺功能不产生任何可见影响，但随着染毒剂量的升高，噻菌铜具有明显促进甲状腺滤泡上皮细胞增生、降低滤泡中胶体面积和直径的作用。
4、鉴于增殖细胞核抗原的敏感性优于组织病理学，本研究又利用免疫组化技术研究噻森铜染毒后大鼠体内甲状腺细胞增殖表达情况，以期进一步对其是否具有甲状腺功能干扰作用进行验证。结果表明，噻森铜在所设定的最高剂量15mg／kg／d下能够引起甲状腺滤泡细胞轻微的增生，虽然这种结果与空白组相比并没有统计上的差异性，但是可能具有生物学意义。
5、最后通过测定大鼠体内甲状腺素代谢酶活性对三种药物可能的甲状腺干扰作用机制进行探讨。结果表明，噻枯唑染毒的10、20mg／kg／d剂量组能显著抑制GST酶活性，10mg／kg／d剂量组能显著诱导UDPGT活性；噻森铜染毒的10、15mg／kg／d剂量组能显著抑制GST酶活性，5、10mg／kg／d剂量组能显著抑制UDPGT的活性；噻菌铜染毒的30mg／kg／d剂量组能显著抑制GST酶活性，但同时能显著诱导UDPGT活性。
6、噻森铜的甲状腺干扰作用机制可能不同于噻枯唑和噻菌铜，其具体的作用机制还有待进一步研究。
It is widely accepted that thyroid hormones play predominantly a nuclear roleand function in the growth and differentiation of many organs. Pesticide in THs hadthe greatest proportion. Due to thiadiazole compound's excellent bioactivities andvarious chemical structures, as well as the high activity and low toxicity, it isbecoming a new research hotspot for more and more scientists. In the present study,we used the pubertal female rat assay to detect the effect of bismerthiazol, saisentongand thiodiazole-copper on thyroid function in the intact juvenile female rat. We haveexamined the effect of these pesticides on several thyroid endpoints: serum hormoneconcentrations, thyroid gland weights, hyperplasia of thyroid follicular cells, as wellas hepatic microsome enzyme activities of thyroid metabolism. The disturbance effectand possible action mechanism were studied, which will provide scientific basis forrisk management of these compounds. The main results and conclusions are asfollows:
1、Pubertal female rats were exposed to three thiadiazole compounds(bismerthiazol, saisentong and thiodiazole-copper) at different dosages of 10, 20,40mg/kg, 5, 10, 15mg/kg and 4, 10, 20, 30mg/kg, respectively, by oral gavage andthe control group was administered with vehicle alone. After treatments, the rats weresacrificed. The results indicated that three thiadiazole compounds administration wereincreased thyroid gland weights.
2、The serum triiodothyronine(T_3), thyroxine(T_4) and thyroid stimulatinghormone(TSH) concentrations were determined by ELISA kits. The results indicatedthat a statistically significant decrease in serum T_3 and T_4 was observed in allbismerthiazol groups, meanwhile, the TSH was increased significantly in allbismerthiazol treated groups. In saisentong groups, the surm T_3 was found decreasedsignificantly at dosage of 5 and 10mg/kg. Thiodiazole-copper administration weredecreased serum T_3, T_4 and increased surm TSH at the dosage of 20 and 30mg/kg.
3、In order to validate whether these pesticide have effect on the thyroid, thehistopathological examination was conducted based on the measurement of organweights and hormone. The results indicated all the group of bismerthiazol could haveeffect on the thyroid function significantly. The primary microscopic change of thethyroid follicular was diffuse hypertrophy and hyperplasia. There was no notablechange in the all saisentong treated groups. In all treated groups of thiodiazole-copper,the primary microscopic change of the thyroid gland was colloid depletion that wasoften associated with increased numbers of follicles in which lumens were decreasedin diameter and were devoid of colloid, though the dose of 4mg/kg/day inthiodiazole-copper did not be observed having effect on the thyroid function.
4、The immunohistochemical of proliferating cell nuclear antigen on thyroidgland was studied in saisentong treatment groups to confirm whether saisentong haveeffect on the thyroid follicular cells. The result indicates that the dosage of 15mg/kg/dcould produce hyperplasia of thyroid follicular cells slightly, though this result is notstatistically significant for control groups, this finding may be biologicallymeaningful.
5、Since UDPGT is an important hepatic enzyme that metabolizes T_4, helpingcharacterize possible biochemical mechanisms for thyroid hormone, the hepaticenzyme activity was tested at last. The results indicated the GST was restrained atdoses of 10, 20mg/kg/d and the UDPGT was induced at 10mg/kg/d in bismerthiazolgroups. In saisentong treated groups, the GST was restrained at doses of 10, 15mg/kg/d and the UDPGT was induced at dosage of 5, 10mg/kg/d. Thiodiazole-copperadministration were restrained GST and induced UDPGT at the same dosage of30mg/kg/d.
6、The action mechanism of saisentong in disturbing thyroid may be different tobismerthiazol and thiodiazole-copper, which needs to be studied further.
引文
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