Kiss-1mRNA在雌性性早熟大鼠下丘脑中的表达及意义
摘要
目的通过检测Kiss-1mRNA在雌性性早熟大鼠不同时期(青春期早期﹑青春期中期及正常青春前期﹑正常青春期早期)下丘脑中的表达,探讨Kiss-1在中枢性性早熟发生发展中的作用。
方法1、建立动物模型:正常5日龄清洁级Sprague-Dawley雌性大鼠40只,随机分为4组,对照1组,对照2组,模型1组,模型2组,每组10只。模型1组、模型2组大鼠于5日龄每只皮下注射300μg达那唑以诱导中枢性性早熟。对照1组、对照2组大鼠每只皮下注射等体积的生理盐水。出生后25天开始每天检查阴道开口情况,如动物在第一次检查时阴门已经开口,则阴门开口时间记为25天,直至大鼠建立正常的性周期。2、模型1组大鼠在阴道口开放后第一个发情间期被处死,对照1组与其1:1比例同时处死,对照2组大鼠是在进入青春期后(第一个发情间期)处死,模型2组在第二个发情间期处死;处死前大鼠称重,处死后留取子宫和卵巢标本并称重,计算子宫指数和卵巢指数;同时切取下丘脑组织100mg,冷藏备用;。3、化学发光法检测大鼠不同时期血清LH的浓度。5、采用逆转录聚合酶链式反应(RT-PCR)检测对照1组,对照2组,模型1组,模型2组下丘脑的Kiss-1和GnRH mRNA的表达。
结果1、模型1组,模型2组大鼠阴道口开放时间和第一个发情间期时间较对照1组提前(P<0.05),提示模型组大鼠青春期启动提前发生;模型1组,模型2组(D1)的LH水平及GnRH mRNA的水平与对照1组比较有显著差异(P<0.05),但与对照2组比较无显著性;以上结果表明中枢性性早熟模型建立成功。2、模型1组大鼠血清LH、GnRHmRNA水平及卵巢、子宫的重量与对照2组比较差异均无显著性,但均大于对照1组(P<0.05),模型2组大鼠血清LH(D2)均大于模型1组,差异有显著性(P<0.05),结果提示LH及GnRH mRNA在青春前期组﹑性早熟青春期早期组﹑性早熟青春期中期组的水平逐渐增高。3、与对照1组(正常青春前期)相比,模型1组(性早熟青春期早期)和模型2组(性早熟青春期中期)的Kiss-1mRNA的水平分别增加1.39和2.77倍,差异具有显著性意义(P<0.05),对照2组(正常青春期早期)与模型1组(性早熟青春期早期)的Kiss-1mRNA的表达无统计学意义(P>0.05)。
结论Kiss-1mRNA的表达与生长发育的时期密切相关,提示Kiss-1可能与中枢性性早熟的发生有关。
Objective To investigate the gene expression of Kiss-1 in the hypothalamus of central precocious female rats at various stages of development.
Methods Forty 5-day-old normal female Sprague-Dawley rats were randomly assigned into four groups of 10 rats: Control group 1, Control group 2, Model group 1 and Model group 2. The rats from the two model groups were injected with 300 ug of danazol at 5 days of age to induce central precocious puberty. The two control groups were injected with normal saline instead .Rats were used to observe the day of vaginal opening and the day setup regular estrous cycle on day 25. For the determination of Kiss-1 mRNA expression in the hypothalamus, the rats of the Model group 1 were sacrificed during the first diestrus (early puberty) and meanwhile the rats of the Control group 1 were sacrificed when they were at prepuberty; the Control group 2 rats were sacrificed at the first diestrus (early puberty); the rats of the Model group 2 were sacrificed during the second diestrus (middle puberty). The expression of Kiss-1 mRNA and GnRH mRNA in the hypothalamus in the four groups was detected using semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). The weights of body, uterus and ovary were measured and the serum LH concentrations were measures by chemiluminescentassay (CLIA).
Results 1. The day of vaginal and first diestrus in Model group 1 and Model group 2 significantly advance , respectively, compared with that of Control group 1 (p<0.05). It showed the onset of puberty advances; The serum LH concentrations in Model group 1 and Model group 2(D1) were significantly differences, respectively, compared with that of Control group 1 (p<0.05).There were no statistical differences between Model groups and Control groups; That illustrated the model coincident with the demand of the experiment. 2. The serum LH concentrations and the weights of uterus and ovary in Model group 2 showed significantly higher than Model group 1 (p<0.05). There were no statistical differences between Control group 2 and Model group 1.
3. Kiss-1 mRNA expression in the hypothalamus in Model group 1 and Model group 2 increased by 1.4-fold and 2.8-fold, respectively, compared with that of Control group 1 (p<0.05). Model group 2 showed significantly higher Kiss-1 mRNA levels than Model group 1 (p<0.05). There were no statistical differences in the Kiss-1 mRNA expression between Control group 2 and Model group 1.
Conclusion Gene expression of Kiss-1 is associated with the developmental period of central precocious puberty, suggesting that Kiss-1 might play a role in the pathogenesis of this disorder.
方法1、建立动物模型:正常5日龄清洁级Sprague-Dawley雌性大鼠40只,随机分为4组,对照1组,对照2组,模型1组,模型2组,每组10只。模型1组、模型2组大鼠于5日龄每只皮下注射300μg达那唑以诱导中枢性性早熟。对照1组、对照2组大鼠每只皮下注射等体积的生理盐水。出生后25天开始每天检查阴道开口情况,如动物在第一次检查时阴门已经开口,则阴门开口时间记为25天,直至大鼠建立正常的性周期。2、模型1组大鼠在阴道口开放后第一个发情间期被处死,对照1组与其1:1比例同时处死,对照2组大鼠是在进入青春期后(第一个发情间期)处死,模型2组在第二个发情间期处死;处死前大鼠称重,处死后留取子宫和卵巢标本并称重,计算子宫指数和卵巢指数;同时切取下丘脑组织100mg,冷藏备用;。3、化学发光法检测大鼠不同时期血清LH的浓度。5、采用逆转录聚合酶链式反应(RT-PCR)检测对照1组,对照2组,模型1组,模型2组下丘脑的Kiss-1和GnRH mRNA的表达。
结果1、模型1组,模型2组大鼠阴道口开放时间和第一个发情间期时间较对照1组提前(P<0.05),提示模型组大鼠青春期启动提前发生;模型1组,模型2组(D1)的LH水平及GnRH mRNA的水平与对照1组比较有显著差异(P<0.05),但与对照2组比较无显著性;以上结果表明中枢性性早熟模型建立成功。2、模型1组大鼠血清LH、GnRHmRNA水平及卵巢、子宫的重量与对照2组比较差异均无显著性,但均大于对照1组(P<0.05),模型2组大鼠血清LH(D2)均大于模型1组,差异有显著性(P<0.05),结果提示LH及GnRH mRNA在青春前期组﹑性早熟青春期早期组﹑性早熟青春期中期组的水平逐渐增高。3、与对照1组(正常青春前期)相比,模型1组(性早熟青春期早期)和模型2组(性早熟青春期中期)的Kiss-1mRNA的水平分别增加1.39和2.77倍,差异具有显著性意义(P<0.05),对照2组(正常青春期早期)与模型1组(性早熟青春期早期)的Kiss-1mRNA的表达无统计学意义(P>0.05)。
结论Kiss-1mRNA的表达与生长发育的时期密切相关,提示Kiss-1可能与中枢性性早熟的发生有关。
Objective To investigate the gene expression of Kiss-1 in the hypothalamus of central precocious female rats at various stages of development.
Methods Forty 5-day-old normal female Sprague-Dawley rats were randomly assigned into four groups of 10 rats: Control group 1, Control group 2, Model group 1 and Model group 2. The rats from the two model groups were injected with 300 ug of danazol at 5 days of age to induce central precocious puberty. The two control groups were injected with normal saline instead .Rats were used to observe the day of vaginal opening and the day setup regular estrous cycle on day 25. For the determination of Kiss-1 mRNA expression in the hypothalamus, the rats of the Model group 1 were sacrificed during the first diestrus (early puberty) and meanwhile the rats of the Control group 1 were sacrificed when they were at prepuberty; the Control group 2 rats were sacrificed at the first diestrus (early puberty); the rats of the Model group 2 were sacrificed during the second diestrus (middle puberty). The expression of Kiss-1 mRNA and GnRH mRNA in the hypothalamus in the four groups was detected using semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). The weights of body, uterus and ovary were measured and the serum LH concentrations were measures by chemiluminescentassay (CLIA).
Results 1. The day of vaginal and first diestrus in Model group 1 and Model group 2 significantly advance , respectively, compared with that of Control group 1 (p<0.05). It showed the onset of puberty advances; The serum LH concentrations in Model group 1 and Model group 2(D1) were significantly differences, respectively, compared with that of Control group 1 (p<0.05).There were no statistical differences between Model groups and Control groups; That illustrated the model coincident with the demand of the experiment. 2. The serum LH concentrations and the weights of uterus and ovary in Model group 2 showed significantly higher than Model group 1 (p<0.05). There were no statistical differences between Control group 2 and Model group 1.
3. Kiss-1 mRNA expression in the hypothalamus in Model group 1 and Model group 2 increased by 1.4-fold and 2.8-fold, respectively, compared with that of Control group 1 (p<0.05). Model group 2 showed significantly higher Kiss-1 mRNA levels than Model group 1 (p<0.05). There were no statistical differences in the Kiss-1 mRNA expression between Control group 2 and Model group 1.
Conclusion Gene expression of Kiss-1 is associated with the developmental period of central precocious puberty, suggesting that Kiss-1 might play a role in the pathogenesis of this disorder.
引文
1、Rogo A,Blizzard RM,Variations and disorders of puberty development In: Kappy MS, Blizzard RM, Migeon CJ, eds Wilkins’the diagnosis and treatment of endocrine disorders in childhood and adolescence [J]. Springfield, L: Charles C Thomas , 1994:857-917
2、Lee PA, Central precocious puberty . An overview of diagnosis treatment and outcome [J]. Endocrinol Metab Clin North Am, 1999, 28:901-908
3、Lebrethon MC, Bourguingnon JP. Central and peripheral isosexual precocious puberty [J].Current opin Endocrinol Diabet, 2001, 8:17-22
4、Tato L, Savage MO, Antoniazzi F, et al. Optinal therapy of pubertal disorders in precocious/early puberty [J].Pediatric Endocrinol Metab,2001,2:985-995
5、Kadlubar FF, Berkowitz GS, et al. The CYP3A4*1B variant is related to the onset of puberty ,a known risk factor the development of breast cancer [J] Cancer-Epidemiol-Biomarkers-Prev. 2003, 12(4):327-331
6、Tony M. Plant and Mandi L. Barker-Gibb. Neurobiological mechanisms Of puberty in higher primates [J].Human Reproduction update 2004, 10(1):67-77
7、EI Terasawa ,David I, Fernades J.Neurobiological mechanism of the onset of puberty in primates [J].Endocrine Reviews, 2001, 22(1):111-151
8、Bourguignon JP, Ge’rard A, Mathieu J, et al. Maturation of the hypothalamic control of pulsatile gonadotropin-releasing hormone secretion at the onset of puberty.I.Increased activation of N-methyl-D-aspartate receptors [J].Endocrinology,1990, 127:873-881
9、Jain MR, Pu S, Kalra PS, et al.Evidence that stimulation of two modalities of pituitary luteinizing hormone release in ovarian steroid-primed ovariectomized rats may involve neuropeptide Y1 and Y4 receptors[J].Endocrinology,1999,140(11):5172-5177
10、Bianca Marchetti. Cross-Talk signals in the cns: Role of Neurotrophic and hormonal factors,Adhesion molecules and intercellurlar signaling Agents in luteinzinghormone-releasing Hormone(LHRH)-Astroglial interactive network [J].Frontiers in Bioscience 1997,2:88-125
11、Stephanie BS, Sophie Messager, Emmanouella EC, et al. The GPR54Gene as a regulation of puberty [J].N Eng1. J Med 2003,349:1614-1627
12、Ahmed MR, Ong KKL, David J, et al. Longitudinal study of leptin concentrations during puberty. sex difference and relationship to changes in body composition[J].J Clin Endocrinol metab 1999,84:899-905
13、Smith JT, Clifton DK, Steiner RA. Regulation of the neuroendocrine reproductiveaxis by kisspeptin-GPR54 signaling[J]. Reproduction, 2006, 131(4): 623-30.
14、Navarro VM, Fernandez R, Castellano J.M, Roa J, Mayen A, Barreiro ML, et al. Advanced vaginal opening and precocious activation of the reproductive axis by KISS-1 peptide, the endogenous ligand of GPR54[J] .Physiol,2004, 561(2):379-386
15、MurphyK.Gz. Kisspepetins: regulationof metastasis and the hypothalamic-pituitery-gonadaaxis[J].Neuroendocrinol2005,17(8):519-525
16、田占庄,赵宏,陈伯英.达那唑诱导的雌性性早熟大鼠GnRH及其受体mRNA的表达.中华内分泌代谢杂志,2003,19(5):399-401
17、Morishito H, Takemoto M,Kondo H,Higuchi K,Aono T. Induction of true precocious puberty by neonatal treatment with danazol in femal rats.[J] .Neuroscience Lett, 1993, 157: 33-36
18、Ebling, Francis JP , Cronin,Anna S. The neurobiology of reproductive development[J].NeuroReport,2000,11(16):23-33
19、苗明三.常用实验动物:大鼠.见:苗明三,主编.实验动物和动物实验技术,北京:中国中医药出版社,1997,97.
20、Navarro VM, Castellano JM, Fernández-Fernández R, Barreiro M L, Roa J, Sanchez-Criado JE. Developmental and Hormonally Regulated Messenger Ribonucleic Acid Expression of KiSS-1 and Its Putative Receptor, GPR54, in Rat Hypothalamus and Potent Luteinizing Hormone-Releasing Activity of KiSS-1 Peptide[J]. Endocrinology Vol.145, No. 10 4565-4574
21、Olazabal DE,Kalinichev M,Morrell JI,Rosenblatt JS. MPOA cytotoxic lesions and maternal behavior in the rat: effects of midpubertal lesions on maternal behavior and the role of ovarian hormones in maturation of MPOA control of maternal behavior.[J]. Horm Behaw.2002 Mar;41(2):126-138
1、Ebling,F.J.& Cronin,A.S.(2000)NeuroReport 11,R23-R24
2、Navarro V.M, Fernandez R, Castellano J.M, Roa J, Mayen A, Barreiro ML, et al. Advanced vaginal opening and precocious activation of the reproductive axis by KISS-1 peptide, the endogenous ligand of GPR54[J] .Physiol,2004, 561(2):379-386
3、MurphyGZ.Kisspeptin:regulationofmetastasisandthehypothalamic-pituitery-gonadaaxis [J]. Neuroendocrinol 2005,17(8):519-525
4、Lee JH, Welch DR. Indentification of highly expressed genes in metastasis suppressed chromosome 6/human malignant melanoma Hybrid cells using subtractivehybridizationand differential display. [J ].Cancer,1997,71(6):1035-1044
5、West A, Vojta PJ, Welch DR, et al.chromosome location and genomic strcture of the Kiss-1 metastasis suppressor gene (Kiss1). [J].Genomics,1998, 54(1):145-148
6、Ohtaki T, Shintani Y, Honda S, et al. Metasis suppressor gene Kiss-1 encodes peptideligand of a G-protein-coupled receptor[J].Nature,2001, 411(6837):613-617
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21、Bliban M, Ghaffari-Tabrizin N, Hintemann E, et al. Kisspeptin-10, a KISS-1/metastin-derived decapeptide, is a physiological invasion in hibitor of primary human trophoblasts [J]. Cell Sci ,2004, 117(8):1319-1328
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24、Smith JT, Dungan HM, Stoll EA, et al. Differential regulation of Kiss-1mRNA expression by sex steroids in the brain of the male mouse.[J]. Endocrinology 2005,146(7):2976-84
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29、陈少科,郭先鸣.醋酸亮丙瑞林缓冲剂对中枢性性早熟女童生长和成年终身高预测的影响[J].中国当代儿科杂志,2002,4(6):506-508
2、Lee PA, Central precocious puberty . An overview of diagnosis treatment and outcome [J]. Endocrinol Metab Clin North Am, 1999, 28:901-908
3、Lebrethon MC, Bourguingnon JP. Central and peripheral isosexual precocious puberty [J].Current opin Endocrinol Diabet, 2001, 8:17-22
4、Tato L, Savage MO, Antoniazzi F, et al. Optinal therapy of pubertal disorders in precocious/early puberty [J].Pediatric Endocrinol Metab,2001,2:985-995
5、Kadlubar FF, Berkowitz GS, et al. The CYP3A4*1B variant is related to the onset of puberty ,a known risk factor the development of breast cancer [J] Cancer-Epidemiol-Biomarkers-Prev. 2003, 12(4):327-331
6、Tony M. Plant and Mandi L. Barker-Gibb. Neurobiological mechanisms Of puberty in higher primates [J].Human Reproduction update 2004, 10(1):67-77
7、EI Terasawa ,David I, Fernades J.Neurobiological mechanism of the onset of puberty in primates [J].Endocrine Reviews, 2001, 22(1):111-151
8、Bourguignon JP, Ge’rard A, Mathieu J, et al. Maturation of the hypothalamic control of pulsatile gonadotropin-releasing hormone secretion at the onset of puberty.I.Increased activation of N-methyl-D-aspartate receptors [J].Endocrinology,1990, 127:873-881
9、Jain MR, Pu S, Kalra PS, et al.Evidence that stimulation of two modalities of pituitary luteinizing hormone release in ovarian steroid-primed ovariectomized rats may involve neuropeptide Y1 and Y4 receptors[J].Endocrinology,1999,140(11):5172-5177
10、Bianca Marchetti. Cross-Talk signals in the cns: Role of Neurotrophic and hormonal factors,Adhesion molecules and intercellurlar signaling Agents in luteinzinghormone-releasing Hormone(LHRH)-Astroglial interactive network [J].Frontiers in Bioscience 1997,2:88-125
11、Stephanie BS, Sophie Messager, Emmanouella EC, et al. The GPR54Gene as a regulation of puberty [J].N Eng1. J Med 2003,349:1614-1627
12、Ahmed MR, Ong KKL, David J, et al. Longitudinal study of leptin concentrations during puberty. sex difference and relationship to changes in body composition[J].J Clin Endocrinol metab 1999,84:899-905
13、Smith JT, Clifton DK, Steiner RA. Regulation of the neuroendocrine reproductiveaxis by kisspeptin-GPR54 signaling[J]. Reproduction, 2006, 131(4): 623-30.
14、Navarro VM, Fernandez R, Castellano J.M, Roa J, Mayen A, Barreiro ML, et al. Advanced vaginal opening and precocious activation of the reproductive axis by KISS-1 peptide, the endogenous ligand of GPR54[J] .Physiol,2004, 561(2):379-386
15、MurphyK.Gz. Kisspepetins: regulationof metastasis and the hypothalamic-pituitery-gonadaaxis[J].Neuroendocrinol2005,17(8):519-525
16、田占庄,赵宏,陈伯英.达那唑诱导的雌性性早熟大鼠GnRH及其受体mRNA的表达.中华内分泌代谢杂志,2003,19(5):399-401
17、Morishito H, Takemoto M,Kondo H,Higuchi K,Aono T. Induction of true precocious puberty by neonatal treatment with danazol in femal rats.[J] .Neuroscience Lett, 1993, 157: 33-36
18、Ebling, Francis JP , Cronin,Anna S. The neurobiology of reproductive development[J].NeuroReport,2000,11(16):23-33
19、苗明三.常用实验动物:大鼠.见:苗明三,主编.实验动物和动物实验技术,北京:中国中医药出版社,1997,97.
20、Navarro VM, Castellano JM, Fernández-Fernández R, Barreiro M L, Roa J, Sanchez-Criado JE. Developmental and Hormonally Regulated Messenger Ribonucleic Acid Expression of KiSS-1 and Its Putative Receptor, GPR54, in Rat Hypothalamus and Potent Luteinizing Hormone-Releasing Activity of KiSS-1 Peptide[J]. Endocrinology Vol.145, No. 10 4565-4574
21、Olazabal DE,Kalinichev M,Morrell JI,Rosenblatt JS. MPOA cytotoxic lesions and maternal behavior in the rat: effects of midpubertal lesions on maternal behavior and the role of ovarian hormones in maturation of MPOA control of maternal behavior.[J]. Horm Behaw.2002 Mar;41(2):126-138
1、Ebling,F.J.& Cronin,A.S.(2000)NeuroReport 11,R23-R24
2、Navarro V.M, Fernandez R, Castellano J.M, Roa J, Mayen A, Barreiro ML, et al. Advanced vaginal opening and precocious activation of the reproductive axis by KISS-1 peptide, the endogenous ligand of GPR54[J] .Physiol,2004, 561(2):379-386
3、MurphyGZ.Kisspeptin:regulationofmetastasisandthehypothalamic-pituitery-gonadaaxis [J]. Neuroendocrinol 2005,17(8):519-525
4、Lee JH, Welch DR. Indentification of highly expressed genes in metastasis suppressed chromosome 6/human malignant melanoma Hybrid cells using subtractivehybridizationand differential display. [J ].Cancer,1997,71(6):1035-1044
5、West A, Vojta PJ, Welch DR, et al.chromosome location and genomic strcture of the Kiss-1 metastasis suppressor gene (Kiss1). [J].Genomics,1998, 54(1):145-148
6、Ohtaki T, Shintani Y, Honda S, et al. Metasis suppressor gene Kiss-1 encodes peptideligand of a G-protein-coupled receptor[J].Nature,2001, 411(6837):613-617
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