氯氰菊酯和甲基对硫磷混配对大鼠激素和免疫功能交互作用分析
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摘要
目的：探讨混配农药(氯氰菊酯和甲基对硫磷)对大鼠生殖激素、甲状腺激素与免疫功能的影响是否存在交互作用，为识别、评价和控制农药的潜在危害及危险度评定提供科学依据。
方法：本实验按三因素(甲基对硫磷、氯氰菊酯和性别)两水平(农药使用、不使用与雌和雄)析因设计，将80只Wistar大鼠随机分入8个组。甲基对硫磷、氯氰菊酯均采用1／30LD_(50)(甲基对硫磷为0.23mg／kg，氯氰菊酯为8mg／kg)，对照组采用菜籽色拉油。隔日对大鼠灌胃1次，共30天，记录每天的体重。灌胃结束后称重并处死大鼠，称量脏器湿重，计算脏器相对重量。测定促黄体生成激素(LH)、促卵泡成熟激素(FSH)、雌二醇(E_2)、睾酮(T)；三碘甲状腺原氨酸(T_3)、四碘甲状腺原氨酸(T_4)、促甲状腺激素(TSH)；免疫球蛋白G(IgG)、免疫球蛋白A(IgA)及淋巴细胞转化率、中性粒细胞吞噬率及吞噬指数。利用广义估计方程(GEE)和混合线性模型分析农药对大鼠体重的影响情况。
结果：本实验发现：(1)在免疫功能方面，甲基对硫磷和氯氰菊酯混配对淋巴细胞转化率和血清IgA浓度为拮抗作用。单独使用甲基对硫磷和氯氰菊酯均能降低淋巴细胞转化率和IgG。(2)对甲状腺激素影响中，单独使用甲基对硫磷能使体内T_4升高，T_3有降低的趋势。(3)对雌性动物中，甲基对硫磷和氯氰菊酯混配的交互作用对E_2为协同作用。在使用甲基对硫磷情况下，氯氰菊酯能使体内E_2的浓度升高1.44倍；在使用氯氰菊酯的情况下，甲基对硫
磷也能使体内E:的浓度增加1.21倍。而单独使用甲基对硫磷能升高血清中FSH的浓度。在
雄性动物中，氛佩菊酷能升高血清中EZ的浓度。(4)甲基对硫磷和抓佩菊酷混配对大鼠的卵
巢和肾脏相对重量交互作用为拮抗作用。单独使用氛氛菊酩能引起附辜的相对重量减少。对
其它指标甲基对硫磷和氛氛菊酷混配均表现为相加作用。(5)典型相关分析，发现甲状腺激素
与生殖激素之间相关系数为0.533，免疫指标与甲状腺激素之间相关系数为0.589，免疫指标
与生殖激素之间相关系数为0.841。(6)性别、单独使用氛氮菊酷和甲基对硫磷和氛佩菊酷混
配影响大鼠的体重增长，对体重的影响大小顺序为性别>氯氰菊酷>甲基对硫磷。
结论:本实验发现，生殖激素中的雌二醉是个比较敏感的指标，特别在雌鼠中，甲基对
硫磷和氛氛菊酷均使其较大幅度的升高，表现为协同作用。提示这两种农药可能有类雌激素
样作用，且雌性对其较为敏感。甲基对硫磷能使乃有降低的趋势和升高几的含量。甲基对
硫磷和氯氛菊酷的混配对大鼠的免疫系统产生了抑制效应，对淋巴细胞转化率及IgA为拮抗
作用。生殖激素、甲状腺激素和免疫指标之间存在相对的独立性和稳定性，它们之间的联系
主要是对机体产生直接效应的生物学指标上相关程度较大(如几、FSH和T3)。性别、单
独使用氛氛菊酷和甲基对硫磷和抓氛菊酷混配影响大鼠的体重增长。
Objective: To identify the interaction of reproductive hormone, thyroid hormone and immunological function in rats after exposure to combined pesticides of cypermethrin and methylparathion. It is purpose to provide science evidence to identify, evaluate and control the sub-risk and risk assessment of pesticides.
Method: In this study, 80 2-month-old Wistar rats are divided randomly into 8 groups according to the factorial design (3 factors and 2 levels). Each group is force-fed the l/30LD50 of cypermethrion equivalent dose of methyl-parathion (cypermethrion is 0.23mg/kg and methyl-parathion is 8mg/kg) once two days for 30 days. The control group is force-fed vegetable seed oil. Pesticides are dissolved in vegetable seed oil. The rats are killed after the one month treatment and the viscera relative weights are measured. The serum genital hormone that are Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), Estradiol (E2) and Testosterone (T) , the serum thyroid hormone including Triiodothyronine (T3) , Tetraiodothyronine (T4) and Thyroid stimulating hormone (TSH), IgG and IgA level are measured by using Radioimmunoassay(RIA). Lymphocyte translation rates and ambivert grainy cell phagocytosis rates, phagocytosis index and compositive index are measured by the mid-stream blood. The change of rats' weight is a
nalyzed via generalized estimating equations (GEE) and mixed linear model and the order is sex > cypermethrin > methylparathion.
Results: Our results show:
(a) Regarding immunological function, we find the interaction of combined pesticides is
antagonistic effect in Lymphocyte translation rates and IgA. Using of cypermethrin and methylparathion separately can decrease Lymphocyte translation rates and the serum level of IgG.
(b) Regarding thyroid hormone, the level of T3 can decrease and that of T4 can show the trend of increasing on exposure to methylparathion.
(c) Regarding the reproductive hormone, the effect of E2 in female rats is synergism effect. The pesticides of cypermethrin can increase the level of E2 reaching 1.44 times on the condition of using methylparathion, while the pesticides of methylparathion can increase the level of E2 amount to 1.21 times on condition of cypermethrin. The level of FSH can go up on exposure to methylparathion. The level of serum E2 in male can increase on exposure to pesticides of cypermethrin.
(d)The interaction of combined pesticides is antagonistic effect in the relative weight of kidney ovary and the pesticide of cypermethrin can reduce the relative weight of epididymis. The interaction of combined pesticides is additive-effect in other signs. (e)The correlation coefficient of thyroid hormone and reproductive hormone is 0.53363. The correlation coefficient of thyroid hormone and immunological function is 0.589456. The correlation coefficient of reproductive hormone and immunological function is 0.841428. (f) It is sex, using pesticides of cypermethrin alone and combined pesticides that have effect
on the development weight of rats.
Conclusion: From data in the experimentation, we can infer that E2 is a sensitive sign in the reproductive hormone, especially in female rats. The combined pesticides make it increase and the interaction is synergistic effect. The serum FSH level on the exposure to methyl parathion can be affected. All results indicate that these two pesticides perhaps belong to EDCs and have estrogen-like effect. The female rats are sensitive to combined pesticides. In the thyroid hormone, the level of T3 can decrease and that of T4 can show the trend of increasing on exposure to methylparathion. We find that the immunological function of rats is suspended by combined pesticides. Especially the effect Of lymphocyte translation rates and IgG level in serum are synergism. It is indicates that these three systems have partial independency and stabilization. The relationship between them only is represented in active bio-substance(such as E FSH and TS). Our results suggest that the weight of rats can be affected by exposure to
combined pesti
方法：本实验按三因素(甲基对硫磷、氯氰菊酯和性别)两水平(农药使用、不使用与雌和雄)析因设计，将80只Wistar大鼠随机分入8个组。甲基对硫磷、氯氰菊酯均采用1／30LD_(50)(甲基对硫磷为0.23mg／kg，氯氰菊酯为8mg／kg)，对照组采用菜籽色拉油。隔日对大鼠灌胃1次，共30天，记录每天的体重。灌胃结束后称重并处死大鼠，称量脏器湿重，计算脏器相对重量。测定促黄体生成激素(LH)、促卵泡成熟激素(FSH)、雌二醇(E_2)、睾酮(T)；三碘甲状腺原氨酸(T_3)、四碘甲状腺原氨酸(T_4)、促甲状腺激素(TSH)；免疫球蛋白G(IgG)、免疫球蛋白A(IgA)及淋巴细胞转化率、中性粒细胞吞噬率及吞噬指数。利用广义估计方程(GEE)和混合线性模型分析农药对大鼠体重的影响情况。
结果：本实验发现：(1)在免疫功能方面，甲基对硫磷和氯氰菊酯混配对淋巴细胞转化率和血清IgA浓度为拮抗作用。单独使用甲基对硫磷和氯氰菊酯均能降低淋巴细胞转化率和IgG。(2)对甲状腺激素影响中，单独使用甲基对硫磷能使体内T_4升高，T_3有降低的趋势。(3)对雌性动物中，甲基对硫磷和氯氰菊酯混配的交互作用对E_2为协同作用。在使用甲基对硫磷情况下，氯氰菊酯能使体内E_2的浓度升高1.44倍；在使用氯氰菊酯的情况下，甲基对硫
磷也能使体内E:的浓度增加1.21倍。而单独使用甲基对硫磷能升高血清中FSH的浓度。在
雄性动物中，氛佩菊酷能升高血清中EZ的浓度。(4)甲基对硫磷和抓佩菊酷混配对大鼠的卵
巢和肾脏相对重量交互作用为拮抗作用。单独使用氛氛菊酩能引起附辜的相对重量减少。对
其它指标甲基对硫磷和氛氛菊酷混配均表现为相加作用。(5)典型相关分析，发现甲状腺激素
与生殖激素之间相关系数为0.533，免疫指标与甲状腺激素之间相关系数为0.589，免疫指标
与生殖激素之间相关系数为0.841。(6)性别、单独使用氛氮菊酷和甲基对硫磷和氛佩菊酷混
配影响大鼠的体重增长，对体重的影响大小顺序为性别>氯氰菊酷>甲基对硫磷。
结论:本实验发现，生殖激素中的雌二醉是个比较敏感的指标，特别在雌鼠中，甲基对
硫磷和氛氛菊酷均使其较大幅度的升高，表现为协同作用。提示这两种农药可能有类雌激素
样作用，且雌性对其较为敏感。甲基对硫磷能使乃有降低的趋势和升高几的含量。甲基对
硫磷和氯氛菊酷的混配对大鼠的免疫系统产生了抑制效应，对淋巴细胞转化率及IgA为拮抗
作用。生殖激素、甲状腺激素和免疫指标之间存在相对的独立性和稳定性，它们之间的联系
主要是对机体产生直接效应的生物学指标上相关程度较大(如几、FSH和T3)。性别、单
独使用氛氛菊酷和甲基对硫磷和抓氛菊酷混配影响大鼠的体重增长。
Objective: To identify the interaction of reproductive hormone, thyroid hormone and immunological function in rats after exposure to combined pesticides of cypermethrin and methylparathion. It is purpose to provide science evidence to identify, evaluate and control the sub-risk and risk assessment of pesticides.
Method: In this study, 80 2-month-old Wistar rats are divided randomly into 8 groups according to the factorial design (3 factors and 2 levels). Each group is force-fed the l/30LD50 of cypermethrion equivalent dose of methyl-parathion (cypermethrion is 0.23mg/kg and methyl-parathion is 8mg/kg) once two days for 30 days. The control group is force-fed vegetable seed oil. Pesticides are dissolved in vegetable seed oil. The rats are killed after the one month treatment and the viscera relative weights are measured. The serum genital hormone that are Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), Estradiol (E2) and Testosterone (T) , the serum thyroid hormone including Triiodothyronine (T3) , Tetraiodothyronine (T4) and Thyroid stimulating hormone (TSH), IgG and IgA level are measured by using Radioimmunoassay(RIA). Lymphocyte translation rates and ambivert grainy cell phagocytosis rates, phagocytosis index and compositive index are measured by the mid-stream blood. The change of rats' weight is a
nalyzed via generalized estimating equations (GEE) and mixed linear model and the order is sex > cypermethrin > methylparathion.
Results: Our results show:
(a) Regarding immunological function, we find the interaction of combined pesticides is
antagonistic effect in Lymphocyte translation rates and IgA. Using of cypermethrin and methylparathion separately can decrease Lymphocyte translation rates and the serum level of IgG.
(b) Regarding thyroid hormone, the level of T3 can decrease and that of T4 can show the trend of increasing on exposure to methylparathion.
(c) Regarding the reproductive hormone, the effect of E2 in female rats is synergism effect. The pesticides of cypermethrin can increase the level of E2 reaching 1.44 times on the condition of using methylparathion, while the pesticides of methylparathion can increase the level of E2 amount to 1.21 times on condition of cypermethrin. The level of FSH can go up on exposure to methylparathion. The level of serum E2 in male can increase on exposure to pesticides of cypermethrin.
(d)The interaction of combined pesticides is antagonistic effect in the relative weight of kidney ovary and the pesticide of cypermethrin can reduce the relative weight of epididymis. The interaction of combined pesticides is additive-effect in other signs. (e)The correlation coefficient of thyroid hormone and reproductive hormone is 0.53363. The correlation coefficient of thyroid hormone and immunological function is 0.589456. The correlation coefficient of reproductive hormone and immunological function is 0.841428. (f) It is sex, using pesticides of cypermethrin alone and combined pesticides that have effect
on the development weight of rats.
Conclusion: From data in the experimentation, we can infer that E2 is a sensitive sign in the reproductive hormone, especially in female rats. The combined pesticides make it increase and the interaction is synergistic effect. The serum FSH level on the exposure to methyl parathion can be affected. All results indicate that these two pesticides perhaps belong to EDCs and have estrogen-like effect. The female rats are sensitive to combined pesticides. In the thyroid hormone, the level of T3 can decrease and that of T4 can show the trend of increasing on exposure to methylparathion. We find that the immunological function of rats is suspended by combined pesticides. Especially the effect Of lymphocyte translation rates and IgG level in serum are synergism. It is indicates that these three systems have partial independency and stabilization. The relationship between them only is represented in active bio-substance(such as E FSH and TS). Our results suggest that the weight of rats can be affected by exposure to
combined pesti
引文
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48. John A Mclachlan. Environmental Signaling: what Embryos and Evolution Teach Us About Endocrin Disrupting Chemicals. Endocrine Reviews, 2001, 22(3):319-341.
49. WHO-IPCS. Cypermethrin. In: Environmental health criteria, vol. 82. Geneva: WHO, 1989.85-112.
50. Repetto R,BAliga SS. Pesticides and the system: the public health risks [Z]. World Resources institute,1996: 17-58.
51. Charlotte Madsen, Mogens H. Claesson, Carsten R(?)pke, et al. Immunotoxicity of the pyrethroid insecticides deltametrin and alpha-cypermetrin. Toxicology, 19,96, 107(3): 219-227.
52. GM waen, C vanVliet, JJ Slangen, et al. Cancer Mortality along licensed herbicide applicators. Scand Jwork Env Hith 1992,18(3):201-204.
53．陈峰．现代医学统计方法与Stata应用(第二版)．北京：中国统计出版社．2003年11月．237～238
54．周衍椒 张镜如．生理学．第三版．北京：人民卫生出版社．1991年9月．476～477，486～496
55. Evamarie Straube, Wolfgang Straube, Egon Kr(?)ger, et al. Disruption of male sex hormones with regard to pesticides:pathophysiological and regulatory aspects. Toxicology Letters, 1999, 107(3): 225-231.
56. Institoris L, Undeger U, Siroki O,et al. Comparison of detection sensitivity of immuno- and genotoxicological effects of subacute cypermethrin and permethrin exposure in rats. 1999, 137 (1):47-55.
57. 34. Institoris L, Siroki O,Desi I. Immunotoxicity study of repeated small doses of dimethoate and thylparathion administered to rats over three generations. Hum Exp Toxicol, 1995, 14(11): 879-83.
58．曹素华．实用医学多因素统计方法．上海：上海医科大学出版社．1～20，174～186
59．贺佳 陆健．医学统计学中的SAS统计分析．上海：第二军医大学出版社．146
60．方积乾 医学统计学与电脑实验(第二版)．上海：上海科学技术出版社．2001年7月．361～369，465～470
61．陈峰．任仁泉．非独立数据的组内相关与广义估计方程．江苏：南通医学院学报．1999，19(4)．359～361
62. Liang KY, Zeger ST. Longitudinal data analysis using generalized linear models. Biometrika, 1986, 73(1):13
63. Sudha khurana, Sejal ranmak. Exposure of Newborn Male and Female Rats to Environmental Estrogens: Delayed and Sustained Hyperprolactinemia and Alterations in Estrogen Receptor Expression, 2000, 141(12), 4512-4517
64. Gina Solomon, Pesticides and Human Health. A Resource for health care proessionals, 2000.42-47
65. Sergio Koifman, Rosalina Jorge Koifman, Human reproductive system disturbances and pesticide exposure in Brazil,Sergio Koifman, Rosalina Jorge Koifman. Human reproductive system disturbances and pesticide exposure in Brazil. Cad. Sa(?)de P(?)blica, Rio de Janeiro, 2002, 18(2):435-445, mar-abr
66. Lora E. Fleming, Fangchao. National Health interview Survey Mortality Among US Farmers and Pesticide Applicators. 2003, American journal of industrial medicine. 43:227-233
67. Stephen A. Martin, Jr. Pesticide use and pesticide-related symptoms among black farmers in the agricultural health study. 2002, 41:202-209
68．陈长生．徐勇勇．重复观测资料的轮廓分析．中国卫生统计．1997，14(6)，1-3
69．杨珉．多水平统计模型在生长发育研究中的应用(一)．中国卫生统计．1997，14(3)，58-60
70．杨珉．多水平统计模型在生_长发育研究中的应用(二)．中国卫生统计．1997，14(4)，61-64
71. Straube E. Straube W, Krueger E. Proceedings of the Internatinal Symposium on Health Aspects of Environmental and Occupational ,Pesticide Exposure. 1998, Germany 28 September-1 October
72. Blizzard D; sueyoshi T; Negishi M. Mechanism of induction of cytochrome P450 enzymes by the proestrogenic endocrine disruptor pesticide-methoxychlor : Interactions of methoxychlor metabolites with the constitutive androstane receptor system Drug metabolism and disposition, 2001 , Volume: 29, Number: 6, Page: 781-785
73. Tully,-D-B; Cox,-V-T; Mumtaz,-M-M; Six high-priority organochlorine pesticides, either singly or in combination, are nonestrogenic in transfected HeLa cells. Reprod-Toxicoi. 2000 Mar-Apr; 14(2): 95-102