氟吗啉内分泌干扰作用的研究
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摘要
内分泌干扰物质是能够改变内分泌系统的结构或功能,引起生物体及其后代,生物体的种群及亚种群水平产生不良反应的外来化合物或混合物,目前关于内分泌干扰物质的研究正日益受到广泛的关注。农药是内分泌干扰物质的主要来源,氟吗啉作为我国第一个拥有自主知识产权的农用杀菌剂,关于它的内分泌干扰作用还知之甚少,所以我们采用体内、体外的实验方法,对其内分泌干扰作用及其可能的机制进行研究。
首先,本课题组选用了大鼠28天反复经口毒性实验对氟吗啉内分泌干扰作用进行全面初步探讨。结果表明,氟吗啉对雄性大鼠的体重有一定影响,其中100mg／kg剂量组的毒性在27天左右表现出来,而300mg／kg剂量组的毒性在染毒开始就出现,此后逐渐恢复；而对于雌性大鼠来说,氟吗啉300mg／kg剂量组的毒性在染毒开始就出现,直到14天后才逐渐恢复,总的来说,氟吗啉对雌性和雄性大鼠都有毒性作用,对雌鼠持续时间更长而对雄鼠的毒性更大一些。氟吗啉对大鼠的肝脏具有损伤作用,可引起肝脏脂肪变性,病变主要出现在肝小叶周边区,肝脏的脂肪变性又引起了球蛋白、血糖和胆固醇的变化。从血液生化学结果看出,氟吗啉能引起雄性大鼠贫血,主要是小细胞低色素性贫血,氟吗啉引起的雌性大鼠贫血没有雄性大鼠损伤严重,贫血可能是由于氟吗啉对大鼠的造血功能损伤引起的,同时贫血又引起了血钾的变化。在本实验条件下,氟吗啉可能没有类雄激素和抗雄激素作用,以及类雌激素和抗雌激素作用。从甲状腺相关结果得出,氟吗啉可能引起甲状腺干扰作用,作用较弱。氟吗啉的NOAEL为<30mg/kg/day。
随后,本课题组选用了子宫增重实验和MCF-7细胞增殖实验检测氟吗啉雌激素干扰作用。在子宫增重实验中,雌激素的子宫干湿重的绝对和相对重量都显著增加,说明雌激素模型制备成功,此试验方法适用于类雌激素效应的检测；三苯氧胺组的子宫干湿重的绝对和相对重量都显著降低,说明此试验方法适用于抗雌激素效应的检测。本实验条件下,氟吗啉各组的子宫干湿重的绝对和相对重量都无差别,说明氟吗啉可能没有类雌激素或抗雌激素效应。在MCF-7细胞增殖实验中,雌二醇对MCF-7细胞增殖的结果显示,其作为阳性药结果可信。氟吗啉对MCF-7细胞增殖的结果表明,在本实验条件下,氟吗啉不具有雌激素受体活性,这与此前的子宫增重实验和大鼠28天反复经口毒性实验的结论一致。此外,在10-5～10-9mol／L剂量下,氟吗啉未表现出细胞毒性。综上所述,认为氟吗啉不具有雌激素样活性。
接着,本课题组采用Hershberger实验检测其雄激素干扰作用,实验中丙酸睾酮组的结果说明丙酸睾酮模型制备成功,说明此试验方法适用于类雄激素效应的检测；同样的,氟他胺组实验结果可以说明,此试验方法适用于抗雄激素效应的检测。本实验条件下,证明氟吗啉可能没有类雄激素或抗雄激素效应。与大鼠28天反复经口给药毒性实验所得结论相似。
最后,本课题组采用20天雌性大鼠青春期毒性实验和20天雄性大鼠青春期毒性实验检测氟吗啉甲状腺素干扰作用,结果可以看出,氟吗啉有甲状腺干扰作用,引起动物的甲状腺功能减退。
综上所述,氟吗啉可能没有类雄激素和抗雄激素效应及类雌激素和抗雌激素效应,而有弱甲状腺干扰作用。
Endocrine disruptors are the exogenous substances that not only change the structure and function of endocrine system but also cause adverse effects at the levels of organism, its progeny, and the subpopulation of organism. It is extensively concerned about the current researches on endocrine disruptors increasingly. The major resources of endocrine disruptors are pesticides, among which flumorph is the first agricultural fungicide which has independent intellectual property rights in China, and it's known little about its function on interference function of endocrine system, thus we fully explore the possible mechanisms in vivo and in vitro.
Firstly, in the repeated 28-day oral toxicity study based on the OECD draft protocols we fully investigate the interference effects on endocrine system. The results show that the flumorph has some effects on the growth of male rats that the toxicity showed up in the dose of 100mg/kg in about 27 days, while it showed up soon after taking poison in the dose of 300mg/kg, and the body gradually recovered. For female rats, the toxicity showed up in the dose of 300mg/kg soon after taking poison, and the body gradually recovered until 14 days. In general, flumorph has toxic effects on not only the female rats but also the males, the lasting time is longer for the female rats and the toxic effect is larger for the male ones.
Flumorph has damage to the liver of rats which causes the liver steatosis, lobular lesions occurred mainly in the surrounding area, and liver steatosis has caused the change of globulin, blood sugar and cholesterol. The results of blood-biochemistry show that flumorph can cause anemia of male rats, mainly small cell hypo-pigment anemia; anemia caused by flumorph in female rats is less serious than that in male rats, which may be due to the reason that flumorph damage the hematopoietic function of rats, and anemia has caused the change of serum potassium simultaneously. The research results shows that flumorph probably don't have the functions of paraandrogen and anti-androgen, as well as paraestrogen and anti-estrogen under this experimental condition. Flumorph may cause a light interference function of thyroid from the results obtained from thyroid hormone. The NOAEL of flumorph was<30mg/kg/day.
Secondly, our group chooses the Uterotrophic assay and the MCF-7 cell-proliferation assay to detect the para-interference function of its estrogen. In the Uterotrophic assay, the absolute and the relative weights of the uterine dry weight and wet weight increases significantly in the estrogen-group, which says the estrogen model is made successfully; While the absolute and the relative weights of the uterine dry weight and wet weight decreases significantly in the tamoxifen-group, indicating that the method in this test is suitable for the detection of paraestrogen or anti-estrogen. Flumorph probably doesn't have the effects of para-estrogenic or anti-estrogenic estrogenic under this experimental condition. In the MCF-7 cell-proliferation assay, the result of the estradiol acting on the MCF-7 cells-proliferation shows that it is credible for estradiol acts as a negative drug. And it shows that under this experimental condition, flumorph doesn't have the activity of estrogen receptors, which is the same as the previous studies about the results of the uterine weight-gain test and the improved the repeated 28-day oral toxicity study. In addition, estradiol did not show cytotoxicity in the dose of 10-5 -10-9mol/L. In summary, flumorph doesn't have estrogenic activity.
Thirdly, our group used Hershberger assay to detect the interfere function of androgen, with the results of the experiment group vice gonadal testosterone propionate indicating that the testosterone propionate model was made successfully; Uniformly, the result of flutamide illustrates that this test method is suitable for the detection of para-androgenic effect and anti-androgenic effect. Under this experimental condition, it is proved that flumorph probably doesn't have para-androgenic or anti-androgenic effect, and it is the same as the result of the repeated 28-day oral toxicity study.
Finally, our group used 20-day pubertal female assay and 20-day pubertal male assay to detect the interference function of thyrine, and to study its possible mechanisms. From the results of 20-day pubertal female assay we can see that flumorph has interfere function to the thyroid, causing hypothyroidism in animals, and is more toxical to adolescent rats. From the results of 20-day pubertal male assay we can see flumorph has interfere function to the thyroid, causing adolescent male rats hypothyroidism.
In conclusion, flumorph probably doesn't have the effects of para-androgen and anti-androgen e as well as the effects of para-estrogen and anti-estrogen, while it has a weak interference function to thyroid.
首先,本课题组选用了大鼠28天反复经口毒性实验对氟吗啉内分泌干扰作用进行全面初步探讨。结果表明,氟吗啉对雄性大鼠的体重有一定影响,其中100mg／kg剂量组的毒性在27天左右表现出来,而300mg／kg剂量组的毒性在染毒开始就出现,此后逐渐恢复；而对于雌性大鼠来说,氟吗啉300mg／kg剂量组的毒性在染毒开始就出现,直到14天后才逐渐恢复,总的来说,氟吗啉对雌性和雄性大鼠都有毒性作用,对雌鼠持续时间更长而对雄鼠的毒性更大一些。氟吗啉对大鼠的肝脏具有损伤作用,可引起肝脏脂肪变性,病变主要出现在肝小叶周边区,肝脏的脂肪变性又引起了球蛋白、血糖和胆固醇的变化。从血液生化学结果看出,氟吗啉能引起雄性大鼠贫血,主要是小细胞低色素性贫血,氟吗啉引起的雌性大鼠贫血没有雄性大鼠损伤严重,贫血可能是由于氟吗啉对大鼠的造血功能损伤引起的,同时贫血又引起了血钾的变化。在本实验条件下,氟吗啉可能没有类雄激素和抗雄激素作用,以及类雌激素和抗雌激素作用。从甲状腺相关结果得出,氟吗啉可能引起甲状腺干扰作用,作用较弱。氟吗啉的NOAEL为<30mg/kg/day。
随后,本课题组选用了子宫增重实验和MCF-7细胞增殖实验检测氟吗啉雌激素干扰作用。在子宫增重实验中,雌激素的子宫干湿重的绝对和相对重量都显著增加,说明雌激素模型制备成功,此试验方法适用于类雌激素效应的检测；三苯氧胺组的子宫干湿重的绝对和相对重量都显著降低,说明此试验方法适用于抗雌激素效应的检测。本实验条件下,氟吗啉各组的子宫干湿重的绝对和相对重量都无差别,说明氟吗啉可能没有类雌激素或抗雌激素效应。在MCF-7细胞增殖实验中,雌二醇对MCF-7细胞增殖的结果显示,其作为阳性药结果可信。氟吗啉对MCF-7细胞增殖的结果表明,在本实验条件下,氟吗啉不具有雌激素受体活性,这与此前的子宫增重实验和大鼠28天反复经口毒性实验的结论一致。此外,在10-5～10-9mol／L剂量下,氟吗啉未表现出细胞毒性。综上所述,认为氟吗啉不具有雌激素样活性。
接着,本课题组采用Hershberger实验检测其雄激素干扰作用,实验中丙酸睾酮组的结果说明丙酸睾酮模型制备成功,说明此试验方法适用于类雄激素效应的检测；同样的,氟他胺组实验结果可以说明,此试验方法适用于抗雄激素效应的检测。本实验条件下,证明氟吗啉可能没有类雄激素或抗雄激素效应。与大鼠28天反复经口给药毒性实验所得结论相似。
最后,本课题组采用20天雌性大鼠青春期毒性实验和20天雄性大鼠青春期毒性实验检测氟吗啉甲状腺素干扰作用,结果可以看出,氟吗啉有甲状腺干扰作用,引起动物的甲状腺功能减退。
综上所述,氟吗啉可能没有类雄激素和抗雄激素效应及类雌激素和抗雌激素效应,而有弱甲状腺干扰作用。
Endocrine disruptors are the exogenous substances that not only change the structure and function of endocrine system but also cause adverse effects at the levels of organism, its progeny, and the subpopulation of organism. It is extensively concerned about the current researches on endocrine disruptors increasingly. The major resources of endocrine disruptors are pesticides, among which flumorph is the first agricultural fungicide which has independent intellectual property rights in China, and it's known little about its function on interference function of endocrine system, thus we fully explore the possible mechanisms in vivo and in vitro.
Firstly, in the repeated 28-day oral toxicity study based on the OECD draft protocols we fully investigate the interference effects on endocrine system. The results show that the flumorph has some effects on the growth of male rats that the toxicity showed up in the dose of 100mg/kg in about 27 days, while it showed up soon after taking poison in the dose of 300mg/kg, and the body gradually recovered. For female rats, the toxicity showed up in the dose of 300mg/kg soon after taking poison, and the body gradually recovered until 14 days. In general, flumorph has toxic effects on not only the female rats but also the males, the lasting time is longer for the female rats and the toxic effect is larger for the male ones.
Flumorph has damage to the liver of rats which causes the liver steatosis, lobular lesions occurred mainly in the surrounding area, and liver steatosis has caused the change of globulin, blood sugar and cholesterol. The results of blood-biochemistry show that flumorph can cause anemia of male rats, mainly small cell hypo-pigment anemia; anemia caused by flumorph in female rats is less serious than that in male rats, which may be due to the reason that flumorph damage the hematopoietic function of rats, and anemia has caused the change of serum potassium simultaneously. The research results shows that flumorph probably don't have the functions of paraandrogen and anti-androgen, as well as paraestrogen and anti-estrogen under this experimental condition. Flumorph may cause a light interference function of thyroid from the results obtained from thyroid hormone. The NOAEL of flumorph was<30mg/kg/day.
Secondly, our group chooses the Uterotrophic assay and the MCF-7 cell-proliferation assay to detect the para-interference function of its estrogen. In the Uterotrophic assay, the absolute and the relative weights of the uterine dry weight and wet weight increases significantly in the estrogen-group, which says the estrogen model is made successfully; While the absolute and the relative weights of the uterine dry weight and wet weight decreases significantly in the tamoxifen-group, indicating that the method in this test is suitable for the detection of paraestrogen or anti-estrogen. Flumorph probably doesn't have the effects of para-estrogenic or anti-estrogenic estrogenic under this experimental condition. In the MCF-7 cell-proliferation assay, the result of the estradiol acting on the MCF-7 cells-proliferation shows that it is credible for estradiol acts as a negative drug. And it shows that under this experimental condition, flumorph doesn't have the activity of estrogen receptors, which is the same as the previous studies about the results of the uterine weight-gain test and the improved the repeated 28-day oral toxicity study. In addition, estradiol did not show cytotoxicity in the dose of 10-5 -10-9mol/L. In summary, flumorph doesn't have estrogenic activity.
Thirdly, our group used Hershberger assay to detect the interfere function of androgen, with the results of the experiment group vice gonadal testosterone propionate indicating that the testosterone propionate model was made successfully; Uniformly, the result of flutamide illustrates that this test method is suitable for the detection of para-androgenic effect and anti-androgenic effect. Under this experimental condition, it is proved that flumorph probably doesn't have para-androgenic or anti-androgenic effect, and it is the same as the result of the repeated 28-day oral toxicity study.
Finally, our group used 20-day pubertal female assay and 20-day pubertal male assay to detect the interference function of thyrine, and to study its possible mechanisms. From the results of 20-day pubertal female assay we can see that flumorph has interfere function to the thyroid, causing hypothyroidism in animals, and is more toxical to adolescent rats. From the results of 20-day pubertal male assay we can see flumorph has interfere function to the thyroid, causing adolescent male rats hypothyroidism.
In conclusion, flumorph probably doesn't have the effects of para-androgen and anti-androgen e as well as the effects of para-estrogen and anti-estrogen, while it has a weak interference function to thyroid.
引文
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