有机磷农药—敌敌畏的发育生殖毒性及其机制的实验研究
摘要
目的：建立并确证有机磷农药的代表-敌敌畏诱导先天性尿道下裂的大鼠模型，探讨雄性哺乳动物先天性尿道下裂的病因，并研究广泛使用的有机磷农药具有的发育生殖毒性进行研究。
方法：(1)敌敌畏(DDVP)诱导雄性大鼠先天性尿道下裂模型的建立和确定：初孕清洁级大鼠40只随机分成4组：生理盐水对照组10只，敌敌畏高、中、低剂量组各10只。根据预实验指导，设敌敌畏5mg／kg／d、1.25mg／kg／d和0.625mg／kg/d三个剂量组。各组孕大鼠均在孕11天～18天，每晨管喂相应药物1.5ml～2ml一次，共连续管喂8次；停药后待其孕20天(d20)的下午，从一侧股血管放血处死孕鼠，剖开子宫，剔除胎盘、脐带，在肉眼、解剖显微镜观察雄性胎鼠观察胎鼠外观及外生殖器形态畸形变化，同时测量体长、肛生殖距离(AGD)，检查吸收胎、活胎及晚死胎等，建成尿道下裂动物模型，对实验组畸形、未发现畸形的雄性胎鼠和对照组的生殖腺逐一确定性别并取材，对其生殖结节固定，
Purpose:
The etiology of the worldwide incidence of hypospadias remains unexplained. Data from many Centers for disease control and our epidemic research suggest that maternal orgnaophosphorus (OP) -dichlorvos (DDVP)exposure may be an important risk factor. The development of the rat and human urethra shows significant similarities, so as to justify the use of the rat as a suitable experimental animal model. DDVP may act as hormones disturb directly or alternatively lowering androgenic hormone by unknown way. We describe the effects of DDVP on rat urethral formation rat and take androgenic hormone analysis of maternal rats. Furthermore , immunohistochemistry technology were adopted to explore what influenced in urethral and genital development of male rat.
方法：(1)敌敌畏(DDVP)诱导雄性大鼠先天性尿道下裂模型的建立和确定：初孕清洁级大鼠40只随机分成4组：生理盐水对照组10只，敌敌畏高、中、低剂量组各10只。根据预实验指导，设敌敌畏5mg／kg／d、1.25mg／kg／d和0.625mg／kg/d三个剂量组。各组孕大鼠均在孕11天～18天，每晨管喂相应药物1.5ml～2ml一次，共连续管喂8次；停药后待其孕20天(d20)的下午，从一侧股血管放血处死孕鼠，剖开子宫，剔除胎盘、脐带，在肉眼、解剖显微镜观察雄性胎鼠观察胎鼠外观及外生殖器形态畸形变化，同时测量体长、肛生殖距离(AGD)，检查吸收胎、活胎及晚死胎等，建成尿道下裂动物模型，对实验组畸形、未发现畸形的雄性胎鼠和对照组的生殖腺逐一确定性别并取材，对其生殖结节固定，
Purpose:
The etiology of the worldwide incidence of hypospadias remains unexplained. Data from many Centers for disease control and our epidemic research suggest that maternal orgnaophosphorus (OP) -dichlorvos (DDVP)exposure may be an important risk factor. The development of the rat and human urethra shows significant similarities, so as to justify the use of the rat as a suitable experimental animal model. DDVP may act as hormones disturb directly or alternatively lowering androgenic hormone by unknown way. We describe the effects of DDVP on rat urethral formation rat and take androgenic hormone analysis of maternal rats. Furthermore , immunohistochemistry technology were adopted to explore what influenced in urethral and genital development of male rat.
引文
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4. Miyagawa S, Buchanan DL, Sato T, et al. Characterization of diethylstilbestrol-induced hypospadias in female mice. The Anatomical record, 2002, 266 : 43-50.
5. Wilson JD, Lasnitzki I. Dihydrotestosterone formation in fetal tissues of the rabbit and rat. Endocrinology, 1971,89:659.
6. Prahalada S, Tarantal A F, Harris GS, et al. Effects of finasteride, a type 2 5 -alpha-reductase inhibitor on fetal development in the rhesus monkey (Macaca mulatta). Teratology, 1997,55:119.
7. McIntyre BS, Barlow NJ, Foster PM. Androgen-mediated development in male rat offspring exposed to flutamide in utero: permanence and correlation of early postnatal changes in anogenital distance and nipple retention with malformations in androgen-dependent tissues. Toxicology, 2001,62:236-49.
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14．龚春雨，黄鲁刚，李虹，等．己烯雌酚建立尿道下裂大鼠模型的实验研究．中华小儿外科杂志，2004；25(2)：180～181．
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3．边新安，江皓．职业接触有机磷农药对男工生殖机能影响的初探．劳动医学，2000；17(1)：27～28．
4．黄菊香，戚桂芬．有机磷农药作业女工生殖功能及子代健康影响调查。劳动医学．1994；(11)增刊84-86．
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17. Rawings N C, Cook S J, Waldbiling D. Effects of the pesticides carbofuran, chlorpyrifos, dimethoate, lindane, triallate, trifluralin, 2,4-D, and pentachlorophenol on the metabolic endocrine and reproductive endocrine system in ewes. J Toxicol Environ Health A. 1998 May 8;54(1):21-36.
18. Andersen HR; Vinggaard AM; Rasmussen TH; Gjermandsen IM; Bonefeld, Jorgensen EC.Effects of currently used pesticides in assays for estrogenicity, androgenicity, and aromatase activity in vitro. Toxicol Appl Pharmacol. 2002 Feb 15; 179(1): 1-12.
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21．吴艳乔，王艳萍，朱军，等．国人尿道下裂的流行病特征．中华泌尿外科杂志，1997，1218：753-757．
2．龚春雨，黄鲁刚，李虹，等．己烯雌酚建立尿道下裂大鼠模型的实验研究．中华小儿外科杂志，2004，25(2)：180～181．
3. Baskin. L S, Hypospadias and urethral development. J Urol, 2000, 163:951-6.
4. Gupta C, Goldman AS. The arachidonic acid cascade is involved in the masculinizing action of testosterone on embryonic external genitania in mice. Proc NatlAcad Sci USA, 1986, 83:4346.
5. Silversides DW, Price CA, Cooke GM, et al. Effects of short-term exposure to hydroxyflutamide in utero on the development of the reproductive tract in male mice. Can J Physiol Pharmacol, 1995, 73:1582.
6. Miyagawa S, Buchanan DL, Sato T, et al. Characterization of diethylstilbestrol induced hypospadias in female mice. The Anatomical record, 2002, 266 : 43-50.
7. Kurzrock EA, Jegatheesan P, Cunha GR, et al. Urethral development in the fetal rabbit and induction of hypospadias: a model for human development. J Urol, 2000, 164 : 1786-92.
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10. Bianea S, Li Volti G, Caruso Nicoletti M, et al. Elevated incidence of hypospadias in two sicilian towns where exposure to industrial and agricultural pollutants is high. Reprod-Toxicol. 2003, 17(5): 539-45.
11. Paulozzi LJ . International trends in rates of hypospadias and cryptochidism. Environ Health Perspect, 1999, 107(4): 297-302.
12．吴艳乔，王艳萍，朱军，等．国人尿道下裂的流行病特征．中华泌尿外科杂志，1997，1218：753-757．
13. Caleb PN, John M P, Julian W, et al. The increasing incidence of cogenital penile anomalies in the United states. J Urol, 2005, 174 (10) : 1573-6.
14. Iguchi T. Environmental endocrine disruptors. Nippon rinsho, 1998, 56(11) : 2953-62.
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17. Whiting J. Craniofacial abnormalities induced by the ectopic expression ofhomeobox genes. Mutat Res, 1997, 396(1-2): 97-112.
18. Muroya K, Sasagawa I, Suzuki Y, et al. Hypospadias and androgen receptor gene: Mutation screening and CAG repeat length analysis. Mol Hum Reprod. 2001, 7(5):409-13.
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1. Allen TD, Griffin JE. Endocrine studies in patients with advanced hypospadias . J Urol, 1984,131:310.
2. Kurzrock EA, Jegatheesan P, Cunha GR, et al. Urethral development in the fetal rabbit and induction of hypospadias: a model for human development. J Urol, 2000, 164 : 1786-92.
3. Gupta C, Goldman AS. The arachidonic acid cascade is involved in the masculinizing action of testosterone on embryonic external genitania in mice . Proc Natl Acad Sci USA, 1986,83:4346.
4. Miyagawa S, Buchanan DL, Sato T, et al. Characterization of diethylstilbestrol-induced hypospadias in female mice. The Anatomical record, 2002, 266 : 43-50.
5. Wilson JD, Lasnitzki I. Dihydrotestosterone formation in fetal tissues of the rabbit and rat. Endocrinology, 1971,89:659.
6. Prahalada S, Tarantal A F, Harris GS, et al. Effects of finasteride, a type 2 5 -alpha-reductase inhibitor on fetal development in the rhesus monkey (Macaca mulatta). Teratology, 1997,55:119.
7. McIntyre BS, Barlow NJ, Foster PM. Androgen-mediated development in male rat offspring exposed to flutamide in utero: permanence and correlation of early postnatal changes in anogenital distance and nipple retention with malformations in androgen-dependent tissues. Toxicology, 2001,62:236-49.
8. Baskin. L S, Hypospadias and urethral development. J Urol, 2000, 163:954-5.
9. Baskin LS, Erol A, Jegatheesan P, et al. Urethral seam formation and hypospadias. Cell-Tissue-Res, 2001,305: 379-87.
10. Francoise Paris, Claire Jeandel, Nade' ge Serva, et al, Increased serum estrogenic bioactivity in three male newborns with ambiguous genitalia: A potential consequence of prenatal exposure to environmental endocrine disruptors Environmental Research.2006, 100 : 39-43.
11. Rawings N C, Cook S J, Waldbiling D. Effects of the pesticides carbofuran, chlorpyrifos, dimethoate, lindane, triallate, trifluralin, 2,4-D, and pentachlorophenol on the metabolic endocrine and reproductive endocrine system in ewes. J Toxicol Environ Health A. 1998 May 8; 54(1):21-36.
12. Andersen HR, Vinggaard AM, Rasmussen TH, et al. Bonefeld, Jorgensen EC.Effects of currently used pesticides in assays for estrogenicity, androgenicity, and aromatase activity in vitro. Toxicol Appl Pharmacol. 2002 Feb 15; 179(1): 1-12.
13. Kitamura S, Suzuki T, Ohta S, Fujimoto N, et al. Antiandrogenic activity and metabolism of the organophosphorus pesticide fenthion and related compounds. Environ-Health-Perspect. 2003 Apr; 111 (4): 503-8
14．龚春雨，黄鲁刚，李虹，等．己烯雌酚建立尿道下裂大鼠模型的实验研究．中华小儿外科杂志，2004；25(2)：180～181．
15. Iguchi T. Environmental endocrine disruptors. Nippon rinsho, 1998, 56: 2953-62.
16. Semenza JC, Tolbert PE, Rubin CH, et al: Reproductive toxins and alligator abnormalities at Lake Apopka. Florida. Environ Health Perspect,1997,105: 1030.
17. Foster PM, Mylchreest E, Gaido KW, et al. Effects ofphthalate esters on the developing reproductive tract of male rats . Human reproduction update, 2001, 7:231-5.
18. Gray LE, Ostby J, Furr J, et al. Effects of environmental antiandrogens on reproductive development in experimental animals. Human reproduction update, 2001, 7: 248-64.
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4．李春英．敌敌畏生殖毒性及小柴胡汤拮抗作用的实验研究．山西医科大学学报 2000，31(1)：39-40．
5. Pant N, Shankar R, Srivastava S P. In utero and lactational exposure of carbofuran to rats: effect on testes and sperm. Hum Exp Toxicol. 1997 May;16(5):267-72.
6．边新安，江皓．职业接触有机磷农药对男工生殖机能影响的初探．劳动医学，2000；17(1)：27～28．
7．黄菊香，戚桂芬．有机磷农药作业女工生殖功能及子代健康影响调查。劳动医学．1994；(11)增刊84-86．
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9. Schwetz BA, Ioset HD,Leong BKJ, et al. Teratogenic potential of dichlorvors given by inhalation and gavage to mice and rabbits. Teratology, 1979,20:383-388.
10. Andersen HR; Vinggaard AM; Rasmussen TH; Gjermandsen IM; Bonefeld, Jorgensen EC. Effects of currently used pesticides in assays for estrogenicity, androgenicity, and aromatase activity in vitro. Toxicol Appl Pharmacol. 2002 Feb 15; 179(1): 1-12.
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23. Lehmann Kim P, Phillips Suzanne, Sar Madhabananda, et al. Dose-Dependent Alterations in Gene Expression and Testosterone Synthesis in the Fetal Testes of Male Rats Exposed to Di (n-butyl) phthalate. Endocrine toxicology, 2004, 81(1):60-68.
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13. Allen TD, Griffin JE. Endocrine studies in patients with advanced hypospadias . J Urol, 1984,131:310.
14. Gearhart JP, Linhard HR, Berkovitz GD, et al: Androgen receptor levels and 5 alpha-reductase activities in preputial skin and chordee tissue of boys with isolated hypospadias . J Urol, 1988,part 2,140:1243.
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3．边新安，江皓．职业接触有机磷农药对男工生殖机能影响的初探．劳动医学，2000；17(1)：27～28．
4．黄菊香，戚桂芬．有机磷农药作业女工生殖功能及子代健康影响调查。劳动医学．1994；(11)增刊84-86．
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17. Rawings N C, Cook S J, Waldbiling D. Effects of the pesticides carbofuran, chlorpyrifos, dimethoate, lindane, triallate, trifluralin, 2,4-D, and pentachlorophenol on the metabolic endocrine and reproductive endocrine system in ewes. J Toxicol Environ Health A. 1998 May 8;54(1):21-36.
18. Andersen HR; Vinggaard AM; Rasmussen TH; Gjermandsen IM; Bonefeld, Jorgensen EC.Effects of currently used pesticides in assays for estrogenicity, androgenicity, and aromatase activity in vitro. Toxicol Appl Pharmacol. 2002 Feb 15; 179(1): 1-12.
19. Kitamura, S; Suzuki, T; Ohta, S; Fujimoto, N. Antiandrogenic activity and metabolism of the organophosphorus pesticide fenthion and related compounds. Environ-Health-Perspect. 2003 Apr; 111 (4): 503-8.
20. Caleb PN, John M P, Julian W, et al. The increasing incidence of cogenital penile anomalies in the United states. J Urol, 2005, 174 (10) : 1573-6.
21．吴艳乔，王艳萍，朱军，等．国人尿道下裂的流行病特征．中华泌尿外科杂志，1997，1218：753-757．