,, 狄冉,中国农业科学院北京畜牧兽医研究所,农业部动物遗传育种与繁殖重点实验室,北京 100193The molecular mechanism of sheep seasonal breeding and artificial regulatory techniques for estrus and mating in anestrus
Qing Xia, Qiuyue Liu, Xiangyu Wang, Wenping Hu, Chunyan Li, Xiaoyun He, Mingxing Chu,, Ran Di,Key Laboratory of Animal Genetics and Breeding and Reproduction of Ministry of Agriculture, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China通讯作者:
编委: 赵要风
收稿日期:2017-12-23修回日期:2018-02-28网络出版日期:2018-05-20
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Received:2017-12-23Revised:2018-02-28Online:2018-05-20
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夏青,硕士研究生,专业方向：动物分子育种E-mail:
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夏青, 刘秋月, 王翔宇, 胡文萍, 李春艳, 贺小云, 储明星, 狄冉. 绵羊季节性繁殖分子机制及休情季节诱导绵羊发情配种技术. 遗传[J], 2018, 40(5): 369-377 doi:10.16288/j.yczz.17-423
Qing Xia, Qiuyue Liu, Xiangyu Wang, Wenping Hu, Chunyan Li, Xiaoyun He, Mingxing Chu, Ran Di.
地球的自转和公转致使地球环境出现了昼夜间以及季节的变化,这种周期性变化导致动物逐渐进化出与外界环境相适应的生理机制。例如在温带地区,季节性繁殖是动物顺应环境进化出的一种重要生理行为,这一性状受外界光照调控,最终保障幼畜在最适宜的季节出生[1]。按照繁殖季节光照时间长短可将季节性繁殖动物分为长光照繁殖动物和短光照繁殖动物,其中绵羊(Ovis aries)为短光照繁殖动物,主要在秋季和冬季进行繁殖[2]。目前已有许多关于哺乳动物的季节性繁殖分子机制方面的研究报道,其大致通路是：视交叉上核神经将接收的外界光照信号传至垂体,垂体内的光照信号因子可探测外界光照时长,并通过神经内分泌通路调控动物机体的繁殖生理活动以适应外界环境的季节性变 化[3,4,5]。已有科研人员利用季节性繁殖分子机制研制出几种在休情季节诱导母羊发情的配种技术,但是实践证明这些技术应用效率低,并存在环境安全隐患[6]。因此,本文重点总结了长光照与短光照条件下绵羊季节性繁殖通路中一系列相关信号分子及细胞形态学的变化特征,分析了肉羊生产中几种休情季节诱导母羊发情配种常用方法的利弊,有助于生产者在养殖场中根据实际情况对以上技术进行单独或联合应用,可提高母羊繁殖率,对促进农业动物生产具有重要意义。为了避免某些弊端,近几年研究发现的新型神经肽在提高休情季节母羊繁殖效率方面具有广泛的应用前景。同时,本文深入解析了绵羊季节性繁殖的分子调控机制,为开发可提高母羊繁殖效率的新方法提供了科学依据和新思路。
1 绵羊季节性繁殖分子调控机制
自然环境的季节性改变通过不同时长的光照信号刺激动物,最终使动物表现出季节性繁殖的特征。在绵羊中,光照信号由视网膜接收,经视交叉上核(hypothalamic suprachiasmatic nuclei, SCN)传至松果体(pineal gland),引起夜间松果体中褪黑素(melatonin, MEL)分泌时长的改变。垂体结节部(pars tuberalis, PT)表达的褪黑素受体(melatonin receptor 1, MT1)感知到MEL的变化后,PT区一系列光照信号分子发生改变,导致下丘脑中四碘甲状腺原氨酸(tetraiodothyronine, T4)与三碘甲状腺原氨酸(triodothyronine, T3)发生相互转化[7],从而对下丘脑中GnRH的释放进行调控。在上述过程中,外界不同的光照条件可导致绵羊PT的促甲状腺细胞表现出两元状态,这种不同状态致使机体分泌截然不同的光照信号分子。例如长光照条件下,PT中促甲状腺细胞(thyrotroph)分泌长光照信号分子,如眼缺失基因3(eyes absent 3, EYA3)与促甲状腺激素β亚基(thyrotrophin β subunit, TSHβ);短光照条件下,促甲状腺细胞分泌短光照信号分子,如嗜铬粒蛋白A基因(chromogranin A, CGA)。不同的光照信号分子导致通路下游信号分子变化的差异[8]。长光照信号分子的作用机制主要由EYA3和TSHβ介导,两种分子的作用机制如下：(1) EYA3作用机制。在长光照下,EYA3在红头白颊鸟(Penelopides exarhatus)和绵羊垂体中表达上调,下丘脑中T3表达量也随之升高[9,10,11];对日本鹌鹑(Coturnix japonica)的研究发现,EYA3是长光照第一天首先被激活诱导表达的分子[5]。以上结果表明,EYA3在鸟类与绵羊等季节性繁殖动物中对长光照响应强烈,暗示该分子属于长光照信号分子,其感应外界光照时长的分子机制是：在短光照和长光照下EYA3均在天黑后12 h达到表达高峰,MEL在天黑时开始分泌,在短光照下,EYA3峰值出现在夜晚,受MEL抑制其峰值较小;在长光照下,EYA3峰值出现在早上,而MEL浓度低无法抑制,因此EYA3峰值较高[7]。综上所述,EYA3是长光照信号分子,外界不同光照时长导致其表达水平出现差异,进而调控下游基因TSHβ的变化。(2) TSHβ作用机制。鸟类在由短光照转至长光照后EYA3与TSHβ的表达水平平行增加,在同样的光照转换过程中,绵羊PT中的EYA3早于TSHβ 4 h达到表达高峰,暗示绵羊中EYA3可能是TSHβ上游的转录激活因子[12]。TSHβ基因的启动子包括一个高度保守的D元件及MEF3位点两部分。在长光照下,EYA3可与促甲状腺细胞胚胎因子(thyrotroph embryonic factor, TEF)及Six1(sine oculis-related homeobox 1)形成复合体,与TSH β启动子D元件结合后协同促进TSHβ的转录[12]。由上述过程产生的TSHβ与下丘脑基底部(mediobasal hypothalamus, MBH)室管膜细胞(ependymal cells, EC)中的促甲状腺激素受体(thyroid-stimulating hormone receptor, TSHR)结合,使PT中的第二信使环磷酸腺苷(cyclic adenosine monophosphate, cAMP)水平升高,TSHR与cAMP藕联形成正反馈循环,同样使长光照下TSHβ转录水平升高[13, 14]。因此,TSHβ表现为长光照信号分子特征。在长光照下,高水平的 TSH β与TSHR结合后通过cAMP信号通路使EC中的Ⅲ型脱碘酶(type Ⅲ thyroid hormone deiodinase, DIO3)转化为Ⅱ型脱碘酶(type Ⅱ thyroid hormone deiodinase, DIO2)[11, 13, 15, 16]。此时,高水平的DIO2促进无活性的T4转化为有活性的T3,T3浓度升高并且作用于下丘脑基底部的GnRH神经元,GnRH神经元末梢被室管膜细胞包围,无法与PT细胞接触,阻碍了GnRH的释放,最终绵羊进入休情状态[17, 18]。
短光照信号分子的作用机制主要由CGA介导。绵羊PT可表达短光照信号分子CGA。CGA是神经肽类家族中的一种分泌蛋白,广泛存在于神经内分泌细胞的分泌颗粒中,与粗面内质网、高尔基体中的分泌颗粒协同表达[19]。研究发现,绵羊PT中的促甲状腺细胞节律性表达CGA。在短光照下,CGA在前4周的表达水平逐渐升高,高水平的CGA导致促甲状腺细胞被星形滤泡细胞(folliculostellate)包围,因而促甲状腺细胞无法分泌EYA3与TSHβ;在长光照下,CGA在前4周的表达水平逐渐下降,低水平的CGA引起星形滤泡细胞排布分散,而促甲状腺细胞间出现紧密连接,因而促甲状腺细胞中EYA3与TSHβ表达水平升高[5]。上述结果暗示CGA为短光照信号分子,可通过绵羊PT中促甲状腺细胞的形态学变化来调控季节性繁殖通路下游生理机制。在短光照下,高浓度的CGA使促甲状腺细胞分泌的EYA3与TSHβ水平下降,进而导致下丘脑中T3浓度下降,低浓度的T3 解除室管膜细胞对GnRH神经元末梢的包围,下丘脑释放的GnRH增多,引起腺垂体中FSH和LH的释放,进而影响卵泡发育和排卵,绵羊进入发情状态[20, 21]。
下丘脑中T3除了直接驱动GnRH神经元,还可以通过下丘脑中的亲吻促动素1(Kisspeptin-1, KISS1)与RF氨酸相关肽(RFamide-related peptides, RFRP)作用于GnRH神经元从而影响季节性发情。KISS1与RFRP参与哺乳动物中性腺轴的调控。在繁殖季节,绵羊下丘脑中的KISS1表达水平升高[22],KISS1与G蛋白藕联受体54(G protein-coupled receptor 54, GPR54)结合后刺激GnRH神经元释放GnRH,从而激活HPG轴[23]。RFRP与促性腺激素抑制激素(GnIH)同源,包括RFRP1、RFRP2和RFRP3,其中RFRP3发挥主要调控作用。该神经肽对不同物种繁殖的调控作用是不同的,它在两种不同季节繁殖的动物(如：短光照繁殖动物—绵羊与长光照繁殖动物—仓鼠)中,均表现为长光照下表达水平高：即在休情季节,绵羊下丘脑中RFRP3表达水平升高,抑制GnRH的释放,关闭HPG轴[24, 25];而仓鼠刚好相反。研究发现,休情状态下的仓鼠经TSHβ处理可转变为发情状态[26],且用外源T3注射休情状态仓鼠会使KISS1与RFRP免疫反应发生改变[27]。因此,我们推测在绵羊中KISS1与RFRP可能受MEL-TSHβ-T3的调控,从而影响动物的季节性发情性状。KISS1与RFRP作为可调控季节性繁殖的神经肽,在畜牧生产中具有良好的应用前景。综上所述,长光照与短光照诱导信号分子调控通路见图1。
图1
新窗口打开|下载原图ZIP|生成PPT图1绵羊季节性繁殖分子机制示意图
视交叉上核神经接收光照信号并传至垂体,垂体结节部的光照信号因子及细胞形态学发生转变,导致下丘脑GnRH神经元形态学变化,最终垂体远侧部分泌的性腺激素水平发生改变。MEL：褪黑素;MT1：褪黑素受体;EYA3：眼缺失基因3;TEF：促甲状腺细胞胚胎因子;SIX1：sine oculis-related homeobox 1;TSH：促甲状腺激素;DIO2：脱碘酶 2;DIO3：脱碘酶3;T3：三碘原氨酸;T4：四碘原氨酸;KISS1：亲吻促动素1;RFRP：RF氨酸相关肽;NKA：神经激肽;PRL：催乳素;FSH：促卵泡素;LH：促黄体素;CGA：嗜铬粒蛋白;GnRH neuron：GnRH神经元;3 V-CSF：第三脑室;ME：正中隆起;PT：垂体结节部;PD：垂体远侧部。参考文献[8, 9, 26, 27]修改并绘制。
Fig. 1A schematic diagram of molecular mechanism for sheep seasonal reproduction
2 休情季节诱导母羊发情配种技术
动物季节性繁殖是养殖业高效发展的一大瓶颈,为了解决这一问题,近些年来人们开发了几项诱导动物在休情季节发情配种的技术并将其应用在生产实践中,旨在提高休情季节的繁殖率。目前,在休情季节激活绵羊HPG轴、提高产羔率的技术有以下几种：公羊效应利用、激素处理技术、光照处理技术和新型分子技术。在生产中根据实际情况对上述方法进行单独或联合使用,联合使用这些方法有许多优点：可实现母羊同期发情,集中产羔,方便生产管理;缩短母羊休情季节时间(如：青春期、季节性乏情、产后乏情);根据特定需求,可在特定时间有计划地实施人工繁育方法;可充分利用人工授精技术。2.1 公羊效应
将性欲旺盛的公羊赶入母羊圈舍,可刺激休情季节母羊分泌LH,并且引起母羊群同步排卵,这种现象称为公羊效应[28]。用性欲旺盛的公羊刺激母羊,激活母羊HPG轴,提高排卵率。该技术不仅使母羊从休情状态转换为发情状态,还可以使青春期母羊提前进入性成熟期[28, 29]。公羊效应的效果受品种、季节等因素影响[6],该技术可诱导休情季节任意时刻的Ile de France母羊、阿尔勒美利奴母羊、克里奥山羊、西班牙Murciano-Granadina山羊排卵[30, 31],但难以诱导休情季节中期的澳大利亚、阿尔派和墨西哥克里奥山羊产生发情行为,但是能够使它们在休情季节后期提前进入繁殖状态[32, 33]。公羊效应不使用孕激素,通过休情季节的自然交配使绵羊或山羊同步产羔。在人工授精(artificial insemination, AI)中使用公羊效应可刺激母羊首先产生一个不能繁殖的排卵周期,接着产生第二个正常的排卵周期,导致母畜在两周内出现两次受精峰。因此使用AI技术需要提前检查母羊是否处于发情期,并且需要在几天内多次重复运用AI。用雌激素或黄体酮预处理母畜是公羊效应中获得单个可受精排卵高峰的唯一方法,这种预处理方法在山羊上得到了很好发展,不需提前检查发情期仅进行单次AI即可获得高妊娠率(60%~70%)。
2.2 光照处理技术单独或联合使用
光照处理技术可应用于AI中心和休情季节养殖场公羊精液的生产中。精液生产方法主要是：使公羊先暴露在长光照下1~2个月,之后转移至短光照下饲养1~2个月,如此交替循环处理,可使公羊全年显示出高性欲并生产出高质量的精液[34]。此外,还可以在晚春或初夏前使用褪黑素(模拟短光照条件)使公羊提前进入繁殖状态,为公羊效应技术提供性活跃的公羊[6]。单独用光照处理技术还可以缩短母羊的休情时间。在休情季节前将拉卡恩母羊长光照(16 h光照∶8 h黑暗)处理77天后转为自然光照(3月初)或用孕酮栓塞处理,发现自然光照组中产羔母羊的比率比孕酮处理组更高[35]。将法国Ile de France母羊在休情季节开始后的第二个月(15 h光照∶9 h黑暗)用短光照(8 h光照∶16 h黑暗)处理,40天后血液中促黄体素(luteinizing hormone, LH)水平升高[36]。在绵羊休情季节可以采用光照处理与激素联合技术：首先进行先长后短的光照处理,之后用前列烯醇激素注射母羊,结果表明两种技术联合使用能显著提高试验组绵羊发情率(91.7%)及排卵效果(90.9%)(P<0.05)[37]。综上所述,仅通过光照处理技术不能使绵羊集中发情,单独使用该方案对提高绵羊繁殖率意义不大,但联合激素处理技术效果得到明显增强。
2.3 激素处理技术
使用激素处理动物提高繁殖率的方法开始于20世纪70年代,激素处理技术可促使母羊同期发情,便于大规模配种,大幅度增加产羔数。目前生产中应用的激素主要是孕激素(如醋酸氟孕酮),可使母羊进入黄体期,并联合eCG(又称PMSG)刺激卵泡成熟。尤其对山羊使用氯前列醇(F2a前列腺素类似物)可诱导其黄体溶解[38]。在繁殖季节或休情季节使用该技术均能高度同步绵羊排卵。由此,AI中的单次受精技术效率也得到提高,产羔率达到60% [39]。激素处理技术最适用于休情季节配种及同期产羔。3 休情季节诱导反刍动物发情配种传统方法存在的问题
公羊效应和光照处理等方法在提高动物繁殖率方面有一定的作用,但总体效率不高。而目前最有效的外源激素方法对环境和人类存在安全隐患：eCG是从动物组织中纯化的,因此商业eCG提取物中可能存在动物病原体;另外,若反复使用eCG会使动物产生eCG抗体,导致母畜生育能力下降。例如欧洲已有相关法律规定“在农场养殖中,禁止使用外源性激素如雌激素等”[40],此外,使用孕激素处理过的肉类和牛奶也被禁止销售。因此,亟待研究者研发一种新型方法或技术,在增加动物产品产量的同时,具有生态友好、可持续等优点。因此,了解动物季节性繁殖的分子机制不仅是基础研究面临的挑战,而且对提高动物繁殖率也有重大意义。4 新型繁殖调控方法
目前使用的外源激素作用的靶标位置主要集中在卵巢(如eCG)或者垂体(如LH)部位。但是,下丘脑神经元可分泌多种神经递质(如多巴胺、谷氨酸、GABA)和神经肽(如强啡肽和神经激肽B),参与调控HPG轴,对季节性繁殖有重要调控作用。最近已发现两种调控动物季节性繁殖的新型神经肽—— KISS1和RFRP3。有研究发现,使用RFRP3受体拮抗剂同时也是KISS1受体(KISS 1 receptor, KISS1R)激活剂的RF9处理母羊,可引起LH分泌上升[41]。若使用仅对RFRP3受体拮抗但不激活KISS1R的选择特异性拮抗剂GJ14处理母羊,LH分泌未发生显著变化[42, 43],这暗示LH的释放主要通过KISS1R介导。因此,RFRP3在季节性繁殖性状中的作用有待进一步评估。
与RFRP3相反,KISS1是哺乳动物HPG轴的一种有效刺激剂[44]。目前,KISS1在绵羊和山羊季节性繁殖中的调控作用研究的最为深入。用KISS1处理繁殖季节母羊可实现同步排卵;对休情季节母羊持续24 h灌注KISS1可使75%的母羊排卵[45]; 24 h内每小时注射一次KISS1可刺激青春期前母羊出现LH脉冲,并且在LH峰后黄体酮短暂性增加[46]。KISS1也可刺激保姆山羊和雄鹿分泌LH/FSH。在母马中,KISS1虽然可刺激LH和 FSH的分泌,但用它诱发排卵的实验并未成功[47]。在其他非季节性繁殖动物(如牛和猪)中,KISS1也能够促进LH 和 FSH的分泌[48]。
综上所述,KISS1是休情季节诱导母羊发情配种的重要靶标分子之一。但是,也存在限制其广泛应用的障碍,如内源性KISS1在体内会被迅速降解并排出体外,长时间静脉灌注才可产生引起排卵所需的LH峰。因此,有必要开发一种新型KISS1类似物,进行单次肌肉注射即可发挥作用。内源性KISS1(Kp10)的主要降解位点已经被鉴定,在此基础上有研究者设计了一系列Kp10类似物以治疗激素依赖性前列腺癌[49]。KISS1类似物的主要研究对象是啮齿类动物和人,同时也有关于对山羊的研究,如对山羊静脉注射Kp10类似物TAK-683 12 h后,LH和FSH分泌水平上升,但第一个排卵期不正常,第二个排卵期卵泡直径小于正常山羊卵泡直径,这暗示处理的山羊会过早排卵[50]。此外,PGF2a和氟尿酸醋酸盐混合后制成的海绵栓处理母羊,并在海绵栓插入后第3天或去除海绵栓12 h后分别注射TAK-683,均有LH峰和排卵出现[51]。以上研究表明,KISS1类似物可以发挥预期的作用。
近来有****研究出新型KISS1类似物,专用于诱导休情季节反刍动物发情配种。肌肉注射该KISS1类似物后可促进休情季节母羊分泌LH和FSH[52]。KISS1类似物与醋酸氟孕酮海绵栓联合处理母羊可刺激LH分泌,绝大多数母羊实现同期发情。最重要的是,由此产生的LH峰可引起正常排卵[44]。之后该****及其课题组计划进一步评估这些类似物是否能够引发休情季节母羊排卵。综上所述,KISS1类似物诱发母羊同期发情效果可能优于eCG,且用KISS1类似物替代eCG将消除相关的安全隐患。新型KISS1类似物存在一个半衰期,当其实现所需效果后会自动降解。一旦降解,它们的基础构架及天然氨基酸会被迅速回收再利用,不产生废弃物。总之,KISS1对于有效提高休情季节反刍动物发情配种效率前景较为乐观,是一种具有潜力的新型神经肽。除了季节性繁殖的反刍动物外,还需对马、猪等动物展开KISS1类似物效果测试实验,可辅助人们管理哺乳动物繁育体系,其中对治疗人类不孕症同样具有很大的应用价值。
综上所述,本文对休情季节几种诱导母羊发情配种技术的应用效果及优缺点进行了总结(表1)。从表1中可以看出,新型技术的繁殖效率最高,在繁殖季节和休情季节均适用。
Table 1
表1
表1 休情季节几种诱导母羊发情配种技术的应用效果及优缺点
Table 1
| 繁育技术 | 应用效果 | 优点 | 缺点 | |||
|---|---|---|---|---|---|---|
| 过渡时期 (9 ~10月) | 繁殖季节 (11 ~2月) | 过渡时期 (3 ~4月) | 休情期 (5 ~8月) | |||
| 自然繁育 | 繁殖性能中, 分散出生 | 繁殖性能中, 分散出生 | 繁殖性能低 | 不繁殖 | 环保 | 效率不高 |
| 公羊效应 | 繁殖性能优, 同期出生 | 繁殖性能低 | 不繁殖 | 可促进发情;环保 | 不可控因素多, 效率不高 | |
| 光照处理 | 繁殖性能优, 分散出生 | 繁殖性能优, 分散出生 | 可提高发情率;环保 | 发情时间不集中 | ||
| 公羊效应+ 光照处理 | 繁殖性能优, 同期出生 | 繁殖性能优, 同期出生 | 提高发情率, 可实现同期发情 | 操作复杂,非 繁殖状态时间长 | ||
| 激素处理 | 繁殖性能优, 同期出生 | 繁殖性能优, 同期出生 | 繁殖性能优, 同期出生 | 繁殖性能优, 同期出生 | 提高排卵率, 可实现同期发情 | 不利于环保 |
| 激素处理+ 光照处理 | 繁殖性能优, 同期出生 | 繁殖性能优, 同期出生 | 提高同期发情率, 便于集约化管理 | 不利于环保 | ||
| 新型技术 | 繁殖性能优, 同期出生 | 繁殖性能优, 同期出生 | 繁殖性能优, 同期出生 | 繁殖性能优, 同期出生 | 提高同期发情率, 提高排卵率,环保 | |
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5 结语与展望
哺乳动物为适应外界环境的季节性变化逐渐进化出季节性繁殖性状,绵羊通过长光照与短光照信号分子调控下游因子发生改变,导致下丘脑中T3浓度出现季节性差异,最终T3通过直接驱动GnRH或经KISS1间接驱动GnRH来激活或关闭HPG轴,从而调控绵羊季节性繁殖行为。目前,基于绵羊季节性繁殖的分子机制,已开发出多种人工诱导休情季节母羊发情配种的技术。从实际应用来看,公羊效应与光照处理技术操作简单,成本低,安全环保,但这些环保方法整体效率不高。因此,外源激素的使用目前十分普遍,但绝大多数外源激素对环境存在安全隐患,亟需开发新型技术。目前,KISS1类似物单次肌肉注射即可发挥作用,诱导母羊发情效果好,操作简便,发挥效应后立刻被降解并重新回收利用。与传统外源激素相比更加安全环保,提高繁殖率效果更优,是休情季节诱导反刍动物发情配种最具潜力的分子工具。参考文献 原文顺序
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被引期刊影响因子
URLPMID:6820053 [本文引用: 1]
Abstract Seasonal variations of reproductive ability have been demonstrated in male and female sheep and goats. For the female, there is a distinct breeding season. Whilst there are large breed differences in the duration of the sexual season, oestrous cycles generally start when daylength is decreasing and end when daylength is increasing. In some breeds, ovulation without oestrus occurs during the non-breeding season. Although males are able to mate all the year round, seasonal variations occur in the weight of the testis and seminal vesicles and in the fructose concentration of the seminal vesicles. Sexual behaviour and semen characteristics also show seasonal variations. These seasonal variations in males and females are related to hormonal levels. FSH and LH concentrations in the pituitary are reduced to 50% during the non-breeding season. In the peripheral blood, LH concentrations vary throughout the year whilst prolactin concentrations follow the pattern of daylength. Steroid hormones and their feedback actions at the hypothalamo-pituitary axis play a role in the regulation of seasonal reproduction. Three different ways are proposed to overcome these seasonal variations. (1) Males can be introduced into a flock of females before the onset of the breeding season. This leads to induction of ovulation and oestrus, although the first ovulation is frequently followed by a short luteal phase. Teasing does not necessitate contact or sight and is only effective after a period of isolation of the females from the males. (2) Oestrus and ovulation may be induced during the anoestrous period by hormonal treatments. Inducers of LH release have to be associated with a progestagen treatment; PMSG is still the most efficient inducer of LH release. Artificial insemination is useful in this context to avoid subfertility due to seasonal variations of the male. (3) The period of reproduction may be controlled by artificial light regimens. There is a photoinducible period in the circadian cycle of the ewe and it may soon be practical to breed out of season by timed exposure of ewes to short periods of light during the normal hours of darkness.
URLPMID:25004363 [本文引用: 1]
Deep hibernators that spend winter in a hypothermic coma below ground can still emerge and reproduce in spring at the right moment. A recent study shows that specific cells of the pituitary may harbor the internal calendar responsible for this.
URL [本文引用: 1]
URLPMID:21129973 [本文引用: 1]
Abstract Living organisms detect seasonal changes in day length (photoperiod) [1-3] and alter their physiological functions accordingly to fit seasonal environmental changes. TSHβ, induced in the pars tuberalis (PT), plays a key role in the pathway that regulates vertebrate photoperiodism [4, 5]. However, the upstream inducers of TSHβ expression remain unknown. Here we performed genome-wide expression analysis of the PT under chronic short-day and long-day conditions in melatonin-proficient CBA/N mice, in which the photoperiodic TSHβ expression response is preserved [6]. This analysis identified "short-day" and "long-day" genes, including TSHβ, and further predicted the acute induction of long-day genes by late-night light stimulation. We verified this by advancing and extending the light period by 802hr, which induced TSHβ expression within one day. In the following genome-wide expression analysis under this acute long-day condition, we searched for candidate upstream genes by looking for expression that preceded TSHβ's, and we identified the Eya3 gene. We demonstrated that Eya3 and its partner Six1 synergistically activate TSHβ expression and that this activation is further enhanced by Tef and Hlf. These results elucidate the comprehensive transcriptional photoperiodic response in the PT, revealing the complex regulation of TSHβ expression and unexpectedly rapid response to light changes in the mammalian photoperiodic system.
URLPMID:18354476 [本文引用: 3]
Nature is the international weekly journal of science: a magazine style journal that publishes full-length research papers in all disciplines of science, as well as News and Views, reviews, news, features, commentaries, web focuses and more, covering all branches of science and how science impacts upon all aspects of society and life.
URLPMID:27173960 [本文引用: 3]
Seasonal breeding is a remarkable adaptive feature, which allows animals to coordinate physiological functions throughout the year. However, in the context of animal production, it becomes an undesirable complication, which needs to be circumvented. Therefore, eco-friendly methods based on photoperiodic treatments and the use of the male effect have been developed to control seasonal reproduction in small ruminants. In practice, such treatments are hardly used and hormonal treatments constitute the benchmark, but practicality of hormonal treatments comes at a high cost for human health and the environment. Here, we summarize our current understanding of the molecular and neuroendocrine mechanisms underlying seasonal breeding in small ruminants. We then move on to describe current methods to control reproduction and detail why such methods are not sustainable. Finally, using the neuropeptide kisspeptin as an example, we show that an improved understanding of the molecular and neuroendocrine mechanisms that underlie photoperiodism might help design novel strategies for the development of improved and sustainable breeding schemes.
URLPMID:22365553 [本文引用: 2]
Abstract Multimodal objects and events activate many sensory cortical areas simultaneously. This is possibly reflected in reciprocal modulations of neuronal activity, even at the level of primary cortical areas. However, the synaptic character of these interareal interactions, and their impact on synaptic and behavioral sensory responses are unclear. Here, we found that activation of auditory cortex by a noise burst drove local GABAergic inhibition on supragranular pyramids of the mouse primary visual cortex, via cortico-cortical connections. This inhibition was generated by sound-driven excitation of a limited number of cells in infragranular visual cortical neurons. Consequently, visually driven synaptic and spike responses were reduced upon bimodal stimulation. Also, acoustic stimulation suppressed conditioned behavioral responses to a dim flash, an effect that was prevented by acute blockade of GABAergic transmission in visual cortex. Thus, auditory cortex activation by salient stimuli degrades potentially distracting sensory processing in visual cortex by recruiting local, translaminar, inhibitory circuits. Copyright 2012 Elsevier Inc. All rights reserved.
URLPMID:4612467 [本文引用: 1]
Circannual rhythms have evolved to regulate and time annual changes in physiology. Wood et al. report that the pars tuberalis generates the circannual rhythm in mammals through the digital switching of EYA3 expression. A recapitulated developmental pathway is used by the circannual clock to drive a morphogenic cycle in the PT and hypothalamus.
URLPMID:21129971 [本文引用: 1]
Seasonal synchronization based on day length (photoperiod) allows organisms to anticipate environmental change. Photoperiodic decoding relies on circadian clocks, but theunderlying molecular pathways have remained elusive [ 1 ]. In mammals and birds, photoperiodic responses depend crucially on expression of thyrotrophin β subunit RNA ( TSH β) in the pars tuberalis (PT) of the pituitary gland [ 2 , 3 02and02 4 ]. Now, using our well-characterized Soay sheep model [ 2 ], we describe a molecular switch governing TSHβ transcription through the circadian clock. Central to this is a conserved D element in the TSH β promoter, controlled by the circadian transcription factor thyrotroph embryonic factor ( Tef ). In the PT, long-day exposure rapidly induces expression of the coactivator eyes absent 3 ( Eya3 ), which synergizes with Tef to maximize TSH β transcription. The pineal hormone melatonin, secreted nocturnally, sets the phase of rhythmic Eya3 expression in the PT to peak 12hr after nightfall. Additionally, nocturnal melatonin levels directly suppress Eya3 expression. Together, these effects form a switch triggering a strong morning peak of Eya3 expression under long days. Species variability in the TSH β D element influences sensitivity to TEF, reflecting species variability in photoperiodic responsiveness. Our findings define a molecular pathway linking the circadian clock to the evolution of seasonal timing in mammals.
URLPMID:27789391 [本文引用: 1]
61Photoperiod-induced gene expressions parallel physiological responses.61Concurrent hypothalamic expression of gonadostimulatory and steroidogenic genes.61Differential expression ofeya3, cgaandtshβunder acute and chronic long days.61Positive correlation ofcyp19onerαsuggestserα-mediated photoperiod signalling.61Induction and maintenance of photoresponse involve different molecular processes.
URLPMID:26765957 [本文引用: 2]
Management of neoangiogenesis remains a high-value therapeutic goal. A recently uncovered association between the DNA damage repair pathway and pathological angiogenesis could open previously unexplored possibilities for intervention. An attractive and novel target is the Eyes absent (EYA) tyrosine phosphatase, which plays a critical role in the repair versus apoptosis decision after DNA damage. This study examines the role of EYA in the postnatal development of the retinal vasculature and under conditions of ischemia-reperfusion encountered in proliferative retinopathies. We find that the ability of the EYA proteins to promote endothelial cell (EC) migration contributes to a delay in postnatal development of the retinal vasculature whenEya3is deleted specifically in ECs. By using genetic and chemical biology tools, we show that EYA contributes to pathological angiogenesis in a model of oxygen-induced retinopathy. Bothin vivoandin vitro, loss of EYA tyrosine phosphatase activity leads to defective assembly of -H2AX foci and thus to DNA damage repair in ECs under oxidative stress. These data reveal the potential utility of EYA tyrosine phosphatase inhibitors as therapeutic agents in inhibiting pathological neovascularization with a range of clinical applications.
[本文引用: 2]
URLPMID:18674911 [本文引用: 2]
Abstract In mammals, day-length-sensitive (photoperiodic) seasonal breeding cycles depend on the pineal hormone melatonin, which modulates secretion of reproductive hormones by the anterior pituitary gland [1]. It is thought that melatonin acts in the hypothalamus to control reproduction through the release of neurosecretory signals into the pituitary portal blood supply, where they act on pituitary endocrine cells [2]. Contrastingly, we show here that during the reproductive response of Soay sheep exposed to summer day lengths, the reverse applies: Melatonin acts directly on anterior-pituitary cells, and these then relay the photoperiodic message back into the hypothalamus to control neuroendocrine output. The switch to long days causes melatonin-responsive cells in the pars tuberalis (PT) of the anterior pituitary to increase production of thyrotrophin (TSH). This acts locally on TSH-receptor-expressing cells in the adjacent mediobasal hypothalamus, leading to increased expression of type II thyroid hormone deiodinase (DIO2). DIO2 initiates the summer response by increasing hypothalamic tri-iodothyronine (T3) levels. These data and recent findings in quail [3] indicate that the TSH-expressing cells of the PT play an ancestral role in seasonal reproductive control in vertebrates. In mammals this provides the missing link between the pineal melatonin signal and thyroid-dependent seasonal biology.
URLPMID:27033929 [本文引用: 1]
61Leptin affects KiSS-1/GPR54 system expression in pituitary cells of pubertal ewes.61Leptin (106110–10617M) stimulates KiSS-10 secretion and KiSS-1 expressionin vitro.6110615M of leptin reduces KiSS-10 secretion and KiSS-1 expression in ewesin vitro.61The addition of KiSS-10 changes TSH secretion from pituitary cells only after 2h.61KiSS-10 does not influence TSH secretion after 6, 12, 18, 24 or 30hin vitro.
URLPMID:25878058 [本文引用: 1]
Tanycytes play multiple roles in hypothalamic functions, including sensing peripheral nutrients and metabolic hormones, regulating neurosecretion and mediating seasonal cycles of reproduction and metabolic physiology. This last function reflects the expression of TSH receptors in tanycytes, which detect photoperiod-regulated changes in TSH secretion from the neighbouring pars tuberalis. The present overall aim was to determine the signal transduction pathway by which TSH signals in tanycytes. Expression of the TSH receptor in tanycytes of 10-day-old Sprague Dawley rats was observed by in situ hybridisation. Primary ependymal cell cultures prepared from 10-day-old rats were found by immunohistochemistry to express vimentin but not GFAP and by PCR to express mRNA for Dio2, Gpr50, Darpp-32 and Tsh receptors that are characteristic of tanycytes. Treatment of primary tanycyte/ependymal cultures with TSH (10066IU/l) increased cAMP as assessed by ELISA and induced a cAMP-independent increase in the phosphorylation of ERK1/2 as assessed by western blot analysis. Furthermore, TSH (10066IU/l) stimulated a 2.17-fold increase in Dio2 mRNA expression. We conclude that TSH signal transduction in cultured tanycytes signals via Gαs to increase cAMP and via an alternative G protein to increase phosphorylation of ERK1/2.
URLPMID:2587639 [本文引用: 1]
Local thyroid hormone catabolism within the mediobasal hypothalamus (MBH) by thyroid hormone-activating (DIO2) and -inactivating (DIO3) enzymes regulates seasonal reproduction in birds and mammals. Recent functional genomics analysis in birds has shown that long days induce thyroid-stimulating hormone production in the pars tuberalis (PT) of the pituitary gland, which triggers DIO2 expression in the ependymal cells (EC) of the MBH. In mammals, nocturnal melatonin secretion provides an endocrine signal of the photoperiod to the PT that contains melatonin receptors in high density, but the interface between the melatonin signal perceived in the PT and the thyroid hormone levels in the MBH remains unclear. Here we provide evidence in mice that TSH participates in this photoperiodic signal transduction. Although most mouse strains are considered to be nonseasonal, a robust photoperiodic response comprising induced expression of TSHB (TSH 尾 subunit), CGA (TSH 伪 subunit), and DIO2, and reduced expression of DIO3, was observed in melatonin-proficient CBA/N mice. These responses could not be elicited in melatonin-deficient C57BL/6J, but treatment of C57BL/6J mice with exogenous melatonin elicited similar effects on the expression of the above-mentioned genes as observed in CBA/N after transfer to short-day conditions. The EC was found to express TSH receptor (TSHR), and ICV injection of TSH induced DIO2 expression. Finally, we show that melatonin administration did not affect the expression of TSHB, DIO2, and DIO3 in TSHR-null mice. Taken together, our findings suggest that melatonin-dependent regulation of thyroid hormone levels in the MBH appears to involve TSH in mammals.
URLPMID:23282080 [本文引用: 1]
At temperate latitudes, many mammals and birds show internally timed, long-term changes in seasonal physiology, synchronised to the seasons by changing day length (photoperiod). Photoperiodic control of thyroid hormone levels in the hypothalamus dictates the timing. This is effected through reciprocal regulation of thyroid hormone deiodinase gene expression. The local synthesis of type 2 deiodinase (Dio2) promotes triiodothyronine (T3) production and summer biology, whereas type 3 deiodinase (Dio3) promotes T3 degradation and winter biology. In the present study, we investigated the extent to which the hypothalamic expression of Dio2 and Dio3 is circannually regulated in the Soay sheep, a short-day breeding mammal. Male sheep were exposed to a long photoperiod (LP; 16 : 24 h light/dark cycle) or a short photoperiod (SP; 8 : 24 h light/dark cycle), for up to 28 weeks to establish four different endocrine states: (i) LP animals in a spring/summer-like state of reproductive arrest; (ii) LP refractory (LPR) animals showing spontaneous reproductive reactivation; (iii) SP animals showing autumn/winter-like reproductive activation; and (iv) SP refractory (SPR) animals showing spontaneous reproductive arrest. A complex pattern of hypothalamic Dio2 and Dio3 expression was observed, revealing distinctive photoperiod-driven and internally timed effects for both genes. The patterns of expression differed both spatially and temporally, with phases of peak Dio2 expression in the median eminence and tuberoinfundibular sulcus, as well as in the paraventricular zone (PVZ) (maximal under LP), whereas Dio3 expression was always confined to the PVZ (maximal under SP). These effects likely reflect the distinct roles of these enzymes in the localised control of hypothalamic T3 levels. The spontaneous decline in Dio2 and spontaneous increase in Dio3 in LPR animals occurred with a corresponding decline in thyroid-stimulating hormone 脦虏 expression in the neighbouring pars tuberalis (PT), although this relationship did not hold for the corresponding Dio2 increase/Dio3 decrease seen in SPR animals. We conclude that internally timed and spatially regulated changes in Dio2 and Dio3 expression may drive the cycling between breeding and nonbreeding states in long-lived seasonal species, and may be either PT-dependent or PT-independent at different phases of the circannual cycle.
URLPMID:25062803 [本文引用: 1]
The first ovulation induced by male effect in sheep during seasonal anoestrus usually results in the development of a short cycle that can be avoided by progesterone priming before ram introduction. In elucidating the involvement of the hypothalamic-pituitary-gonadal axis on the occurrence of short cycles, the effects of progesterone and the time of anoestrus on the development of male-induced preovulatory follicles were investigated in anoestrus ewes using morphological, endocrine and molecular approaches. Ewes were primed with progesterone for 2 (CIDR-2) or 12 days (CIDR-12) and untreated ewes used as controls during early (April) and late (June) anoestrus. The duration of follicular growth and the lifespan of the male-induced preovulatory follicles were prolonged by about 1.6 days in CIDR-12 ewes compared to the controls. These changes were accompanied by a delay in the preovulatory LH and FSH surges and ovulation. Intrafollicular oestradiol concentration and mRNA levels of LHCGR and STAR in the granulosa and theca cells of the preovulatory follicles were higher in CIDR-12 than the control ewes. The expression of mRNA levels of CYP11A1 and CYP17A1 also increased in theca cells of CIDR-12 ewes. CIDR-2 ewes gave intermediate results. Moreover, ewes ovulated earlier in June than April, without changes in the duration of follicular growth, but these effects were unrelated to the lifespan of corpus luteum. Our results give the first evidence supporting the positive effect of progesterone priming on the completion of growth and maturation of preovulatory follicles induced by male effect in seasonal anoestrus ewes, thereby preventing short cycles.
URLPMID:12812778 [本文引用: 1]
In the course of producing monoclonal antibodies to turkey prolactin, three monoclonal antibodies to turkey chromogranin A (CgA) were also produced, apparently arising from minor contamination of the turkey prolactin immunogen with peptide fragments of CgA. The identity of the antigen recognized by these antibodies was established by tandem mass spectrometry de novo sequencing of seven tryptic peptides from a turkey pituitary protein purified by immunoaffinity chromatography. These peptides showed high homology with distinctly separate regions of mammalian and ostrich CgA, and in silico cloned chicken CgA sequences. Chromogranin A immunostaining patterns on Western blots and pituitary tissue sections differed from those of prolactin, growth hormone, or luteinizing hormone (LH). Dual-label fluorescent immunohistochemistry revealed that CgA was co-localized with LH in most avian gonadotrophs in young chickens and turkeys, but not in adult, laying birds. Conversely, CgA was found in a majority of somatotrophs in laying birds but was absent from somatotrophs in young, growing chickens and turkeys. Lactotrophs contained no detectable CgA immunoreactivity in the tissues studied. These results suggest that CgA may modulate hormone secretion by gonadotrophs and somatotrophs in a manner that differs between cell type with age or reproductive state.
URLPMID:15178649 [本文引用: 1]
In a previous study we showed that photoperiodically generated T3 in the hypothalamus is critical for the photoperiodic response of gonads in Japanese quail. The expression of thyroid hormone receptors in the median eminence (ME) suggested that photoperiodically generated T3 acts on the ME. Because thyroid hormone is known to play a critical role in the development and plasticity of the central nervous system, in the present study we have examined ultrastructure of the ME in Japanese quail kept in short-day and long-day environments. Immunoelectron microscopy revealed that GnRH nerve terminals are in close proximity to the basal lamina under long-day conditions, and conventional transmission electron microscopy demonstrated the encasement of the terminals by the endfeet of glia under short-day conditions. These morphological changes may regulate photoperiodic GnRH secretion.
URLPMID:24616714 [本文引用: 1]
Abstract Living organisms show seasonality in a wide array of functions such as reproduction, fattening, hibernation, and migration. At temperate latitudes, changes in photoperiod maintain the alignment of annual rhythms with predictable changes in the environment. The appropriate physiological response to changing photoperiod in mammals requires retinal detection of light and pineal secretion of melatonin, but extraretinal detection of light occurs in birds. A common mechanism across all vertebrates is that these photoperiod-regulated systems alter hypothalamic thyroid hormone (TH) conversion. Here, we review the evidence that a circadian clock within the pars tuberalis of the adenohypophysis links photoperiod decoding to local changes of TH signaling within the medio-basal hypothalamus (MBH) through a conserved thyrotropin/deiodinase axis. We also focus on recent findings which indicate that, beyond the photoperiodic control of its conversion, TH might also be involved in longer-term timing processes of seasonal programs. Finally, we examine the potential implication of kisspeptin and RFRP3, two RF-amide peptides expressed within the MBH, in seasonal rhythmicity.
URL [本文引用: 1]
URLPMID:27491513 [本文引用: 1]
Contents Ovulation rate and litter size are important reproduction traits in sheep and are of high economic value. Reproduction traits typically have low to medium heritabilities and do not exhibit a noticeable response to phenotypic selection. Therefore, inclusion of genetic information of the genes associated with reproductive ability could efficiently enhance the selection response. The most important major genes affecting prolificacy and their genetic diversities in different sheep breeds were reviewed. Different causative mutations with major effects on reproductive traits including ovulation rate and litter size have been found in various sheep breeds around the world. A general overview of the studies on main prolificacy genes showed that some alleles may express different phenotypic effects in different breeds, and thus, further studies on epistatic effects are necessary for more understanding of genetic control of reproductivity in sheep. Regarding the polygenic control of fertility traits, application of new high-throughput technologies to find new variants is essential for future studies. Moreover, genomewide association studies and genomic best linear unbiased predictions of breeding values are likely to be effective tools for genetic improvement of sheep reproductive performance traits.
URLMagsci [本文引用: 1]
动物季节性发情繁殖涉及下丘脑-垂体-性腺轴系统复杂的神经内分泌过程, 并受光照周期等环境因素的影响。褪黑激素则作为光周期信号分子调控动物季节性繁殖活动。近年来研究发现, 对GnRH分泌有重要影响的Kiss1/GPR54系统既受褪黑激素的调控又受到性腺类固醇激素反馈调节, Kiss1/GPR54系统很可能是调控动物季节性繁殖的关键因子; 同时动物季节性繁殖很可能还存在一条涉及TSH-DIO2/DIO3系统的逆向调控通路, 该系统同样显著影响GnRH合成释放并受褪黑激素调控。文章就褪黑激素中心信号, 特别是Kiss1/GPR54和TSH-DIO2/DIO3系统对繁殖季节性调控的最新研究进展进行综述。
URLMagsci [本文引用: 1]
动物季节性发情繁殖涉及下丘脑-垂体-性腺轴系统复杂的神经内分泌过程, 并受光照周期等环境因素的影响。褪黑激素则作为光周期信号分子调控动物季节性繁殖活动。近年来研究发现, 对GnRH分泌有重要影响的Kiss1/GPR54系统既受褪黑激素的调控又受到性腺类固醇激素反馈调节, Kiss1/GPR54系统很可能是调控动物季节性繁殖的关键因子; 同时动物季节性繁殖很可能还存在一条涉及TSH-DIO2/DIO3系统的逆向调控通路, 该系统同样显著影响GnRH合成释放并受褪黑激素调控。文章就褪黑激素中心信号, 特别是Kiss1/GPR54和TSH-DIO2/DIO3系统对繁殖季节性调控的最新研究进展进行综述。
URLPMID:29019791 [本文引用: 1]
Abstract This study aimed to explain how prolonged inhibition of central dopaminergic activity affects the cellular processes governing gonadotrophin-releasing hormone (GnRH) and LH secretion in anoestrous sheep. For this purpose, the study included two experimental approaches: first, we investigated the effect of infusion of sulpiride, a dopaminergic D2 receptor antagonist (D2R), on GnRH and GnRH receptor (GnRHR) biosynthesis in the hypothalamus and on GnRHR in the anterior pituitary using an immunoassay. This analysis was supplemented by analysis of plasma LH levels by radioimmunoassay. Second, we used real-time polymerase chain reaction to analyse the influence of sulpiride on the levels of kisspeptin (Kiss1) mRNA in the preoptic area and ventromedial hypothalamus including arcuate nucleus (VMH/ARC), and RFamide-related peptide-3 (RFRP-3) mRNA in the paraventricular nucleus (PVN) and dorsomedial hypothalamic nucleus. Sulpiride significantly increased plasma LH concentration and the levels of GnRH and GnRHR in the hypothalamic-pituitary unit. The abolition of dopaminergic activity resulted in a significant increase in transcript level of Kiss1 in VMH/ARC and a decrease of RFRP-3 in PVN. The study demonstrates that dopaminergic neurotransmission through D2R is involved in the regulatory pathways of GnRH and GnRHR biosynthesis in the hypothalamic-pituitary unit of anoestrous sheep, conceivably via mechanisms in which Kiss1 and RFRP-3 participate.
URLPMID:23538709 [本文引用: 1]
In mammals, melatonin is the pivotal messenger synchronizing biological functions, notably reproductive activity, with annual daylength changes. Recently, two major findings clarified melatonin's mode of action. First, melatonin controls the production of thyroid stimulating hormone (TSH) by the pars tuberalis of the adenohypophysis. This TSH regulates local thyroid hormone availability in the mediobasal hypothalamus. Second, the RF-amides kisspeptin and RFRP-3, recently discovered regulators of the gonadotropic axis, are involved in the melatonin control of reproduction. This study aims to establish a mechanistic link between the melatonin-driven TSH and the RF-amide control of reproduction. We treated short-day-adapted male Djungarian and Syrian hamsters with a chronic central infusion of TSH. In both hamster species, the central administration of 5 mIU/d TSH for 4 to 6 wk restored the summer phenotype of both testicular activity and kisspeptin and RFRP expression. Vehicle treated hamsters remain sexually inactive. Furthermore, the TSH treatment increased the body weight of lean short-day-adapted Djungarian hamsters and reduced hypothalamic somatostatin expression to the summer phenotype. In summary, our study demonstrates the pivotal role of melatonin-driven TSH for the seasonal regulation of reproduction and body weight, and uncovers the neuropeptides relaying this signal within the hypothalamus.Klosen, P., Sebert, M.-E., Rasri, K., Laran-Chich, M.-P., Simonneaux, V. TSH restores a summer phenotype in photoinhibited mammals via the RF-amides RFRP3 and kisspeptin.
URLPMID:23735498 [本文引用: 1]
Siberian hamsters (Phodopus sungorus) exhibit robust seasonal rhythms of reproduction driven by changes in day length. Day length is encoded endogenously by the duration of nocturnal melatonin (Mel) secretion from the pineal gland. Short duration Mel signals stimulate whereas long duration Mel signals inhibit reproduction. The mechanism by which Mel regulates the reproductive axis has not been fully characterized. In Siberian hamsters, the thyroid hormone triiodothyronine (T61) is thought to be part of the photoperiodic mechanism. The availability of T61 is decreased in hamsters housed in short day lengths, and injections of exogenous T61 stimulate testicular growth in short-day (SD) Siberian hamsters. Thus, T61 acts as a neuroendocrine intermediate between the Mel rhythm and the reproductive axis. The RFamides kisspeptin (Kiss1) and gonadotropin-inhibitory hormone (GnIH) also act as a link between the Mel rhythm and the reproductive axis. Expression of both of these neuropeptides is regulated by photoperiod and Mel. Kiss1 stimulates, and GnIH inhibits, the reproductive axis in long-day housed hamsters. It remains unknown whether T61 acts through changes in RFamide expression in the regulation of reproduction or whether these molecules act independently of one another. We tested the hypothesis that exogenous T61 administered to SD hamsters, a treatment that stimulates testicular growth, would also result in alterations in the patterns of Kiss1- and GnIH-immunoreactivity. Administration of T61 to SD hamsters resulted in significant testicular growth as well as a long day-like pattern of RFamide peptide expression. Thus, exogenous T61 elicited increased numbers of Kiss1-positive cells in the hypothalamic anteroventral periventricular nucleus, decreased numbers of Kiss1-positive cells in the arcuate nucleus, and a greater number of GnIH-positive cells in the dorsomedial hypothalamus compared with SD controls. The results are consistent with the hypothesis that T61 elicits alterations in the reproductive axis through alterations in RFamide peptide expression.
URLPMID:25914614 [本文引用: 2]
Reproduction in mammals is controlled by the hypothalamo-pituitary-gonadal (HPG) axis under the influence of external and internal factors such as photoperiod, stress, nutrition, and social interactions. Sheep are seasonal breeders and stop mating when day length is increasing (anestrus). However, interactions with a sexually active ram during this period can override the steroid negative feedback responsible for the anoestrus state, stimulate luteinizing hormone (LH) secretion and eventually reinstate cyclicity. This is known as the "ram effect" and research into the mechanisms underlying it is shedding new light on HPG axis regulation. The first step in the ram effect is increased LH pulsatile secretion in anestrus ewes exposed to a sexually active male or only to its fleece, the latter finding indicating a "pheromone-like" effect. Estradiol secretion increases in all ewes and this eventually induces a LH surge and ovulation, just as during the breeding season. An exception is a minority of ewes that exhibit a precocious LH surge (within 4 h) with no prior increase in estradiol. The main olfactory system and the cortical nucleus of the amygdala are critical brain structures in mediating the ram effect since it is blocked by their inactivation. Sexual experience is also important since activation (increased c-fos expression) in these and other regions is greatly reduced in sexually na茂ve ewes. In adult ewes kisspeptin neurons in both arcuate and preoptic regions and some preoptic GnRH neurons are activated 2 h after exposure to a ram. Exposure to rams also activates noradrenergic neurons in the locus coeruleus and A1 nucleus and increased noradrenalin release occurs in the posterior preoptic area. Pharmacological modulation of this system modifies LH secretion in response to the male or his odor. Together these results show that the ram effect can be a fruitful model to promote both a better understanding of the neural and hormonal regulation of the HPG axis in general and also the specific mechanisms by which male cues can overcome negative steroid feedback and trigger LH release and ovulatory cycles.
URLPMID:28460678 [本文引用: 1]
It has been suggested that female goats in permanent contact with males become refractory to their presence, and need to be previously separated from them for 40 45 days if the presence of bucks is to induce reproductive activity, ovulation and oestrous during seasonal anoestrous. The present study examines the reproductive response (ovulation and oestrus) and reproductive performance of does isolated from bucks for different periods before their reintroduction to male company. A total of 103 Payoya and Blanca Andaluza does were distributed into six treatment groups that required their isolation from males for different periods: 0 days (N=29), 5 days (N=15), 10 days (N=14), 20 days (N=16), 30 days (N=14) and 39 days (N=15). After this period they were introduced to sexually active bucks (ensured to be in this condition by keeping them under long days light treatment for three months), and oestrous activity was recorded daily by direct visual observation of the marks left by the marking harnesses worn by these males. Ovulation was confirmed via the plasma progesterone concentration (measured in blood samples taken twice per week). The ovulation rate was assessed by transrectal ultrasonography. Fecundity, fertility, prolificacy and productivity were also determined. The sexual behaviour of the males towards the females was also monitored on Days 0, 1, 2, 3, 4, 8 and 9 after their meeting with the latter. The length of the female isolation period had no effect on the percentage of does that responded to contact with the males, nor did it affect the oestrous response, fecundity, fertility or productivity. The males, however, undertook more ano-genital sniffing and nudging with the 5 day group females compared to those of the other groups (P<0.05). However, the sexual behaviour of the males changed as the days passed, with ano-genital sniffing becoming less common, and nudging, licking, sneezing and mounts with intromission more frequent on Days 8 and 9 than on Day 0, 1 and 2 after the sexes were reunited (P<0.05). These results show that the isolation of females is not necessary for an efficient male effect if the bucks used are sexually active. In addition, the sexual behaviour of the bucks changes as the time in contact with the does increases, but in general is not affected by the duration of female isolation.
URL [本文引用: 1]
Exposure of anoestrous ewes to rams induces an increase in LH secretion, eventually leading to ovulation. This technique therefore is an effective, low-cost and hormone-free way of mating sheep outside the breeding season. However, the use of this technique is limited by the variability of the ewesram effectrinos d'Arles and Romane), one highly seasonal (Mouton Vendle-de-France) breeds. Anoestrus was longer and deeper in Mouton Vendle-de-France than in Romane or Mram effectram effectram effectrinos d'Arles at the end of anoestrus. However, there was no relationship between the proportion of females in the flock showing spontaneous ovulation and the response to the of anoestrous ewes from the same flock.
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URLPMID:25497417 [本文引用: 1]
Abstract A well-defined season of sexual rest controlled by photoperiod is observed in female sheep and goats during spring and summer, delineating their "anestrous season"; bucks also decrease sexual activity at about the same time. Nutrition and/or socio-sexual stimuli play only secondary roles. However, the presence of sexually active males can reduce the length of seasonal anestrus. Whether it can also completely suppress anestrus has not been investigated. Here we tested this in goats in 3 experiments, using bucks rendered sexually active out of season by exposure to long days. The continuous presence of these males prevented goats to display seasonal anestrus: 12/14 females cycled the year round, vs. 0/13 and 0/11 for females with un-treated bucks or without bucks (experiment 1). When active bucks were removed, females immediately entered anestrus (7/7 stopped ovulating vs. 1/7 if maintained with active bucks; experiment 2). Finally, 7/7 anestrous does with bucks in sexual rest since 1.5months commenced cycling rapidly during mid-anestrous, when these bucks became sexually active following a treatment with artificial long days, vs. 0/7 with un-treated bucks or no bucks (experiment 3). The presence/withdrawal of active bucks had a highly significant effect in the three experiments (P 0.002). Therefore, the presence of a mating opportunity can completely override the photoperiodic inhibition of reproduction of females throughout the anestrous season. Results suggest that we must re-evaluate the relative contributions of photoperiod vs. other external cues in controlling seasonal reproduction, thus offering new non-pharmaceutical ways for controlling out-of-season reproduction in small ruminants. Copyright 2014. Published by Elsevier Inc.
URLPMID:28708495 [本文引用: 1]
Abstract Sheep breeds from Mediterranean area show reproductive seasonal patterns of oestrous behaviour and ovulatory activity, mainly regulated by variation in the photoperiod. Maximal reproductive activity is associated with short days from August to March. The aim of this study therefore was, to identify new SNPs and genes associated to reproductive seasonality in sheep by using the Illumina OvineSNP50 Beadchip. A total of 239 adult Rasa Aragonesa breed ewes from one flock were controlled from January to August. Three reproductive seasonality traits were considered: the total days of anoestrus (TDA), based on weekly individual plasma progesterone levels and defined as the sum of days in anoestrus, considering anoestrus those periods with three or more consecutive P4 concentrations lower than 0.50002ng/ml; the progesterone cycling months (P4CM), defined for each ewe as the rate of cycling months between January and August based on progesterone determinations and the oestrus cycling months (OCM), defined for each ewe as the rate of months cycling between January and August based on oestrus records. Genotyping of 123 ewes was performed with the OvineSNP50 Infinium Beadchip. After the quality control (QC) performed on the raw genotypes, a total of 47,206 SNPs distributed over the 27 ovine chromosomes and 110 ewes were included in subsequent analyses. Principal component analysis revealed a substructure within the total dataset and identified 4 principal clusters in the experimental flock. None of the SNPs overcame the genome-wide significance level (P0002=00021.0600020103000210 -6 ). However, the SNPs OAR4_66002395 (9.41E-6), and OAR8_25877010 (1.86E-5) reached the genome-wide suggestive significance level (set to 2.3200020103000210 -5 ) for TDA and P4CM traits, respectively, while OAR23_14608581 was significant for both TDA (2.02E-5) and P4CM (1.05E-5) traits. Five SNPs evidenced association at chromosome-wise level: SNPs OAR4_66002395, OAR23_14608581 and s20800 (DTA), and OAR8_25877010, OAR23_14608581 and s48474 (P4CM). Several genes related to circadian and circannual rhythms were found close to these SNPs: NPSR1 (SNP OAR4_66002395), HS3ST5 (SNP OAR8_25877010), RPTOR (SNP s48474), and NPTX1 (SNP s48474) and could be considered as candidate gene related to TDA and P4CM traits. Copyright 0008 2017 Elsevier Inc. All rights reserved.
URLPMID:8142042 [本文引用: 1]
We have previously shown that reproductive seasonality of bucks was prevented for 2 consecutive years by short photoperiodic cycles. To determine the effect of the length of treatment time on bucks subjected to the same photoperiod conditions, experiments were continued for a third consecutive year on 3 groups of 6 Alpine and Saanen bucks. The control group was kept under natural photoperiodic conditions, while the experimental groups were exposed alternately to 1 month of long days and 1 month of short days (group 2M) or to 2 months of long days and 2 months of short days (group, 4M). Prolactin profiles indicated that bucks from both experimental groups responded adequately to rapid photoperiod changes as their plasma prolactin levels were significantly higher in long days (mean +/- SEM; 2M: 61.1 +/- 15.9 ng/ml; 4M: 102.2 +/- 13.5 ng/ml) than in short days (2M: 35.3 +/- 8.2 ng/ml; 4M: 46.1 +/- 9.0 ng/ml). Testosterone secretion was also dependent on day length (P < 0.0001), since testosterone concentrations of experimental animals were higher during long days (2M: 7.0 +/- 0.7 ng/ml; 4M: 10.2 +/- 1.1 ng/ml) than during short days (2M: 4.3 +/- 0.4 ng/ml; 4M: 5.0 +/- 0.9 ng/ml). Furthermore, controls displayed a high level of sexual behavior (always higher than 10%) and the proportion of bucks unable to ejaculate was significantly lower (P < 0.01) than the experimental animals (2M: 25.6%; 4M: 28.1%).(ABSTRACT TRUNCATED AT 250 WORDS)
URLPMID:25468556 [本文引用: 1]
Abstract This study compared the reproductive performance of Lacaune dairy ewes exposed to a light program and subsequent male introduction without (n02=0236) or with (n02=0236) an additional 6-day progestagen treatment during the nonbreeding season. All ewes were exposed to extended day length (1602hours light and 802hours darkness) for 7702days during winter (December 15 until March 2) followed by increasing natural photoperiod. At the end of the photoperiodic treatment, three blood samples were collected 602days apart for progesterone (P4) analysis to determine cyclic activity. One half of the ewes were additionally subjected to a 6-day progestagen treatment in combination with PGF2α and eCG at insert withdrawal. Rams fitted with marking harnesses were introduced to females for 4502days and marked ewes recorded. Ewes exposed to the light program only were joined 4002days after the end of photoperiodic treatment, and ewes with additional progestagen treatment were joined 102day after insert removal (40-4402days after the end of photostimulation). Lambing data were recorded and fertility (percentage of ewes lambing, lambing rate, and litter size) assessed to the first service period and overall. Mean serum P4 concentrations were similarly (P02>020.05) low in both groups (0.4-0.702ng/mL vs. 0.4-0.602ng/mL). On the basis of elevated P4 levels (>102ng/mL), evidence of luteal activity was found in 27.8% of the ewes at the end of the light program. Estrus response was equally high (97.2%) and estrus distribution highly synchronized in progestagen-treated ewes (91.7% within 402days). In ewes exposed to the light program only, estrous activity was recorded within 402days (six ewes), from Day 8 to Day 17 (17 ewes) and from Day 19 to Day 25 (12 ewes) after joining. The percentage of ewes that lambed to the first service period was higher (P02020.05) by the treatment. In conclusion, this study reports that exposition of Lacaune ewes to artificial long days followed by natural day length and male introduction is highly effective to induce fertile estrous activity during the nonbreeding season and offers a reliable and practical alternative to hormonal manipulation for out-of-season breeding in sheep. Copyright 08 2015 Elsevier Inc. All rights reserved.
URLPMID:22053094 [本文引用: 1]
ABSTRACT In sheep, the seasonal patterns of reproductive activity are driven primarily by the annual photoperiodic cycle, but can also respond to other environmental factors, such as nutrition, yet little is known about the mechanisms underlying this interaction. This study was designed to define the interaction between photoperiodic and nutritional cues on seasonal patterns of ovarian activity, and to determine if there is a central interaction between these cues. Groups of Ile-de-France ewes were maintained in two nutritional states (restricted and well fed) under a simulated annual photoperiod of 8鈥16 h of light per day over two breeding seasons. At the end of the first breeding season, half of the animals of each group were ovariectomized (OVX) and fitted subcutaneously with estradiol implants. Low nutritional status shortened the season of ovarian activity, determined from the pattern of progesterone concentrations, by modifying the timing of seasonal transitions between periods of ovarian activity a...
URL [本文引用: 1]
试验通过模拟绵羊繁殖季节前后 的光照条件,对蒙古绵羊进行非繁殖季节诱导发情。试验采用先长后短的光照处理方案,开始时每天逐渐增加光照0.5～16h后恒定并保持1个月,然后每天逐 渐缩短光照0.5～8h后恒定直至试验结束。结果表明:光照控制对蒙古羊体重增长无显著影响,采取光照控制处理的母羊发情率91.7%,而对照组为 16.7%。发情母羊的排卵率达到90.7%。
URL [本文引用: 1]
Des essais ont également été conduits en vue d'adapter les traitements hormonaux d'induction de l'ovulation et les conditions d'insémination à la physiologie et à l'anatomie des chevrettes. L'administration vaginale de progestérone naturelle à partir d'un support en silastic a permis d'obtenir des niveaux de fertilité comparables à ceux obtenus après administration d'acétate de fluorogestone au moyen d'éponges vaginales. L'insémination de doses de semences de 0,2 ml contenant 100 × 10 6 spermatozoides a été suivie de pourcentages de mises bas supérieurs à 60% et non différents de ceux obtenus avec des paillettes de 0,5 ml contenant 150 ou 200 millions de spermatozoides.
URLPMID:14511789 [本文引用: 1]
In small ruminants, progestagen-impregnated vaginal devices (sponges) are useful tools to manage reproduction irrespective of season and to the application of timed artificial insemination (AI). A novel progestagen releasing vaginal-controlled release device (Chronogest CR), loaded with less (2002mg) cronolone using proprietary procedures, was developed and its efficacy (synchronising ability, fertility and prolificacy following sponge removal) evaluated versus the existing Chronogest sponge containing 4502mg of cronolone in goats. Females ( n =199) were maintained in field conditions and inseminated with graded amounts of spermatozoa at two stages of the year (breeding and non-breeding seasons). The use of the new Chronogest CR sponge was associated with an earlier initiation of the LH surge (28.702h versus 30.802h following sponge removal, P <0.01). A similar degree of synchronisation of the LH surge was obtained with both types of sponges. In both treatment groups, a longer time interval between sponge removal and the LH surge was noted in females with high milk production. Fertility and prolificacy were high and unaffected by the type of sponge used or the amount of spermatozoa inseminated. It is concluded that the new Chronogest CR sponge allows a reduction of the progestagen load from 45 to 2002mg without detrimental effects on synchronisation, fertility and prolificacy.
URLPMID:15271456 [本文引用: 1]
Abstract This paper describes three strategies to improve the reproductive performance of small ruminants in ways that lead to "clean, green and ethical" animal production. The first is aimed at control of the timing of reproductive events for which we turn to the socio-sexual inputs of the "male effect" to induce synchronised ovulation in females that would otherwise be anovulatory. The second strategy, "focussed feeding", is based on our knowledge of the responses to nutrition and aims to develop short programs of nutritional supplements that are precisely timed and specifically designed for individual events in the reproductive process, such as gamete production, embryo survival, fetal programming and colostrum production. The third strategy aims to maximise offspring survival by a combination of management, nutrition and genetic selection for behavior (temperament). All of these approaches involve non-pharmacological manipulation of the endogenous control systems of the animals and complement the detailed information from ultrasound that is now becoming available. The use of such clean, green and ethical tools in the management of our animals can be cost-effective, increase productivity and, at the same time, greatly improve the image of meat and milk industries in society and the marketplace.
URLPMID:22283564 [本文引用: 1]
Abstract GPR147 and its endogenous ligands, RFRPs, are emerging as important actors in hypothalamic-pituitary axis control. The role of this system would be to inhibit gonadotrophin secretion. However, data on the subject are contradictory. The discovery of RF9 (adamantanecarbonyl-RF-2-NH(2)), a GPR147 antagonist, prompted us to use this new tool to further investigate this system in the ewe. Accordingly, we tested the effect of i.c.v. administration of RF9 on gonadotrophin secretion in the ewe during anoestrous and the breeding season. Intracerebroventricular injections of RF9 (from 50-450 nmol) caused a clear elevation in peripheral blood plasma luteinising hormone (LH) concentrations. The effect of RF9 on LH was more pronounced during the anoestrous season. Furthermore, peripheral administration of RF9 as a bolus (2.1, 6.2 and 12.4 mol per ewe) or as a constant i.v. infusion (2.1, 6.2, 12.4 and 18.6 mol/h per ewe) to anoestrous acyclic ewes induced a sustained increase in LH plasma concentrations. A pharmacokinetic study showed that RF9 (12.4 渭mol bolus i.v.) has an effective half life of 5.5 h in the plasma. Conversely, RF9 is not detectable in the cerebrospinal fluid, suggesting that it does not cross the blood-brain barrier. The increase in LH plasma concentrations induced by RF9 was blocked by previous administration of 1.3 mol per ewe of gondotrophin-releasing hormone (GnRH) antagonist Teverelix. This suggests that GnRH is involved in the stimulatory effect of RF9 on gonadotrophin secretion. Finally, no variation in LH plasma concentrations could be detected in ovariectomised ewes injected either i.c.v. or i.v. with RFRP3 (VPNLPQRF-NH(2)). The lack of effect of RFRP3 in our experimental setting suggests that the mechanisms involved in RF9 action are probably more complex than previously assumed. Our results indicate that delivery of RF9 in the ewe greatly increases gondadotrophin secretion in both the oestrus and anoestrus season, suggesting a potential new way of controlling reproduction in mammals. 2012 The Authors. Journal of Neuroendocrinology 2012 Blackwell Publishing Ltd.
URLPMID:26259035 [本文引用: 1]
RFamide-related peptide-3 (RFRP-3) is a recently discovered neuropeptide that has been proposed to play a role in the stress response. We aimed to elucidate the role of RFRP-3 and its receptor, neuropeptide FF (NPFF1R), in modulation of stress and anxiety responses. To achieve this, we characterized a new NPFF1R antagonist because our results showed that the only commercially available putative antagonist, RF9, is in fact an agonist at both NPFF1R and the kisspeptin receptor (KISS1R). We report here the identification and pharmacological characterization of GJ14, a true NPFFR antagonist. In in vivo tests of hypothalamic-pituitary-adrenal (HPA) axis function, GJ14 completely blocked RFRP-3-induced corticosterone release and neuronal activation in CRH neurons. Furthermore, chronic infusion of GJ14 led to anxiolytic-like behavior, whereas RFRP-3 infusion had anxiogenic effects. Mice receiving chronic RFRP-3 infusion also had higher basal circulating corticosterone levels. These results indicate a stimulatory action of RFRP-3 on the HPA axis, consistent with the dense expression of NPFF1R in the vicinity of CRH neurons. Importantly, coinfusion of RFRP-3 and GJ14 completely reversed the anxiogenic and HPA axis-stimulatory effects of RFRP-3. Here we have established the role of RFRP-3 as a regulator of stress and anxiety. We also show that GJ14 can reverse the effects of RFRP-3 both in vitro and in vivo. Infusion of GJ14 causes anxiolysis, revealing a novel potential target for treating anxiety disorders.
URLPMID:26707385 [本文引用: 1]
Abstract Goat estrous and ovulatory responses to the "male effect" were characterized to determine the time range over which fertile ovulations occur after buck exposure. The results were used to explore the efficacy of different hormone-free artificial insemination (AI) protocols aimed at diminishing the number of inseminations needed to optimize fertility. Adult bucks and does were exposed to artificially long days during winter and then exposed to a natural photoperiod before buck exposure (Day 0). Most goats (>70%) ovulated twice, developing a short cycle followed by a normal cycle over 13 days after buck exposure. Among them, 21% were in estrus at the short cycle and 94% at the normal cycle. This second ovulation occurred within 48 hours of Day 6 and was the target for AI protocols. In protocol A (n = 79), goats were inseminated 12 hours after estrus detection from Day 5 to Day 9. Up to six AI times over 4 days were needed to inseminate goats in estrus. Forty-nine percent of the inseminated goats kidded. In protocol B (n = 145), estrus detection started on Day 5. The earlier (group 1) and later (group 2) buck-marked goats received one single insemination at fixed times on Days 6.5 or 7 and 8, respectively; unmarked goats (group 3) were inseminated along with group 2. In protocol C (n = 153), goats were inseminated twice on Days 6.5 or 7 and 8 without needing to detect estrus. Goats induced to ovulate by hormonal treatment were used as the control (n = 319). Fertility was lower in protocol B than in protocol C and controls (47% vs. 58% and 65% kidding; P 0909¤ 0.05), whereas this was higher in buck-marked goats than in unmarked ones (64% vs. 33%; P 0909¤ 0.05). In protocol B, fertility can increase (>60%) when only goats coming into estrus are inseminated. The best kidding rate (09080470%) was achieved when does were inseminated within 24 hours of the LH surge. Protocols involving insemination on Day 7 instead of Day 6.5 led to more goats being inseminated during this favorable time. Copyright 0008 2016 Elsevier Inc. All rights reserved.
URLPMID:24145132 [本文引用: 2]
The hypothalamus integrates endogenous and exogenous inputs to control the pituitary-gonadal axis. The ultimate hypothalamic influence on reproductive activity is mediated through timely secretion of GnRH in the portal blood, which modulates the release of gonadotropins from the pituitary. In this context neurons expressing the RF-amide neuropeptide kisspeptin present required features to fulfill the role of the long sought-after hypothalamic integrative centre governing the stimulation of GnRH neurons. Here we focus on the intracellular signaling pathways triggered by kisspeptin through its cognate receptor KISS1R and on the potential role of proteins interacting with this receptor. We then review evidence implicating both kisspeptin and RFRP3 - another RF-amide neuropeptide - in the temporal orchestration of both the pre-ovulatory LH surge in female rodents and the organization of seasonal breeding in photoperiodic species.
URLPMID:20097511 [本文引用: 1]
We have previously demonstrated that a constant intravenous infusion of kisspeptin (Kp) for 4802h in anestrous ewes induces a preovulatory luteinizing hormone (LH) surge followed by ovulation in approximately 75% of animals. The mechanisms underlying this effect are unknown. In this study, we investigated whether Kp-induced preovulatory LH surges in anestrous ewes were the result of the general activation of the whole gonadotropic axis or of the direct activation of central GnRH neurons required for the GnRH/LH surge. In the first experiment, a constant iv infusion of ovine kisspeptin 10 (Kp; 15.2 nmol/h) was given to 11 seasonally acyclic ewes over 4302h. Blood samples were taken every 1002min for 1502h, starting 502h before the infusion, and then hourly until the end of the infusion. We found that the infusion of Kp induced a well-synchronized LH surge (around 2202h after the start of the Kp infusion) in 82% of the animals. In all ewes with an LH surge, there was an immediate but transient increase in the plasma concentrations of LH, follicle-stimulating hormone (FSH), and growth hormone (GH) at the start of the Kp infusion. Mean (± SEM) concentrations for the 5-h periods preceding and following the start of the Kp infusion were, respectively, 0.33 ± 0.09 vs 2.83 ± 0.49 ng/mL ( = 0.004) for LH, 0.43 ± 0.05 vs 0.55 ± 0.03 ng/mL ( = 0.015) for FSH, and 9.34 ± 1.01 vs 11.51 ± 0.92 ng/mL ( = 0.004) for GH. In the first experiment, surges of LH were observed only in ewes that also had a sustained rise in plasma concentrations of estradiol (E) in response to Kp. Therefore, a second experiment was undertaken to determine the minimum duration of Kp infusion necessary to induce such a pronounced and prolonged increase in plasma E concentration. Kisspeptin (15.2 nmol/h) was infused for 6, 12, or 2402h in seasonally acyclic ewes (N = 8), and blood samples were collected hourly for 2802h (beginning 502h before the start of infusion), then every 202h for the following 2202h. Kisspeptin infused for 2402h induced LH surges in 75% of animals, and this percentage decreased with the duration of the infusion (1202h = 50%; 602h = 12.5%). The plasma concentration of E was greater in ewes with an LH surge compared to those without LH surges; mean (± SEM) concentrations for the 5-h period following the Kp infusion were, respectively, 2.23 ± 0.16 vs 1.27 ± 0.13 pg/mL ( -positive feedback on gonadotropin secretion in acyclic ewes.
URLPMID:21273366 [本文引用: 1]
Abstract The onset of puberty in mammals involves an increase in the pulsatile release of GNRH and LH. The KISS1 gene is essential for pubertal development, and its product, kisspeptin, stimulates the release of LH. The objective of this study was to determine the effects of kisspeptin in the hypothalamic-adenohypophyseal-gonadal axis of prepubertal ewe lambs. Ewe lambs (28 weeks of age) were treated intravenously with saline (control, n=6) or kisspeptin (20 渭g kisspeptin; n=6) every hour for 24 h. Kisspeptin stimulated pulse-like release of LH within 15 min following injections, and increased the frequency and amplitude of LH pulses, and mean circulating concentrations of LH and estradiol. A surge-like release of LH was observed in four kisspeptin-treated lambs beginning 17 h after the onset of treatment, and all four lambs had elevated circulating concentrations of progesterone within 5 days post-treatment. However, circulating concentrations of progesterone decreased within 2 days after the initial rise in three of the four ewe lambs, indicating that induced luteal activity was of short duration. The proportion of lambs that were pubertal (defined by circulating concentrations of progesterone above 1 ng/ml for at least 7 days) by 35 weeks of age (8/11) and the mean age at puberty (32 卤 1 weeks) for those reaching puberty within the experimental period did not differ between treatments. Results support a role for kisspeptin in the activation of the hypothalamic-adenohypophyseal axis leading to the onset of puberty in ewe lambs.
URLPMID:24429215 [本文引用: 1]
Kisspeptin has emerged as the most potent gonadotropin-releasing hormone (GnRH) secretagogue and appears to represent the penultimate step in the central control of reproduction. In the sheep, we...
URL [本文引用: 1]
Background/Aims: Growth hormone (GH) is necessary for optimal reproductive efficiency and its secretion is influenced by sex steroids. This study was designed to determine whether kisspeptin-10 (Kp10) could stimulate GH and if gonadal steroids enhance the GH response to Kp10 in cows. Methods and Results: Intravenous injection of Kp10 at 100 or 200 pmol/kg body weight with or without treatment with estradiol cypionate and/or progesterone increased luteinizing hormone (p < 0.01) plasma concentrations. Plasma concentrations of GH were increased following Kp10 in cows treated with estradiol cypionate and/or progesterone (p < 0.05) but not in cows treated with Kp10 without gonadal steroids. Conclusions: These data suggest that reproductive steroids enhance the sensitivity of the somatotropic axis to physiologically relevant doses of Kp10, and support the possibility that Kp10 is an integrator of luteinizing hormone and GH release.
URLPMID:24047141 [本文引用: 1]
Metastin/kisspeptin is a 54 amino acid peptide ligand of the KISS1R receptor and is a critical regulator of GnRH secretion. The N-terminally truncated peptide, metastin(45-54), possesses a 10-fold higher receptor-binding affinity than full-length metastin and agonistic KISS1R activity but is rapidly inactivated in rodent plasma. We have developed a decapeptide analog [D-Tyr(45),D-Trp(47),azaGly(51),Arg(Me)(53)]metastin(45-54) with improved serum stability compared with metastin(45-54) but with decreased KISS1R agonistic activity. Amino acid replacements at positions 45-47 led to an enhancement of KISS1R agonistic activity and metabolic stability. N-terminal truncation resulted in a stable nonapeptide, [D-Tyr(46),D-Pya(4)(47),azaGly(51),Arg(Me)(53)]metastin(46-54), compound 26, which displayed KISS1R binding affinities comparable to metastin(45-54) and had improved serum stability. Compound 26 reduced plasma testosterone in male rats and is the first short-length metastin analog to possess testosterone suppressive activities. Compound 26 has led to the elucidation of investigational analogs TAK-683 and TAK-448, both of which have undergone clinical evaluation for hormone-dependent diseases such as prostate cancer.
URLPMID:24484509 [本文引用: 1]
ContentsThis study evaluated the effects of follicular phase administration of TAK-683, an investigational metastin/kisspeptin analog, on follicular growth, ovulation, luteal function and reproductive hormones in goats. After confirmation of ovulation by transrectal ultrasonography (Day 0), PGF2 (2 mg/head of dinoprost) was administered intramuscularly on Day 10 to induce luteal regression. At 12 h after PGF2 administration, intravenous administration of vehicle or 35 nmol (50 0204g)/head of TAK-683 was performed in control (n = 4) and treatment (n = 4) groups, respectively. Blood samples were collected at 6-h intervals for 96 h and then daily until the detection of subsequent ovulation (second ovulation). After the second ovulation, ultrasound examinations and blood sampling were performed every other day or daily until the subsequent ovulation (third ovulation). Mean concentrations of LH and FSH in the treatment group were significantly higher 6 h after TAK-683 treatment than those in the control group (12.0 00± 10.7 vs 1.0 00± 0.7 ng/ml for LH, 47.5 00± 28.2 vs 15.1 00± 3.4 ng/ml for FSH, p < 0.05), whereas mean concentrations of oestradiol in the treatment group decreased immediately after treatment (p < 0.05) as compared with the control group. Ovulation tended to be delayed (n = 2) or occurred early (n = 1) in the treatment group as compared with the control group. For the second ovulation, ovulatory follicles in the treatment group were significantly smaller in maximal diameter than in the control group (3.8 00± 0.5 vs 5.4 00± 0.2 mm, p < 0.05, n = 3). Administration of TAK-683 in the follicular phase stimulates gonadotropin secretion and may have resulted in ovulation of premature follicles in goats.
URLPMID:26051610 [本文引用: 1]
This study aimed to evaluate the hormonal and ovarian responses to the administration of a metastin/kisspeptin analog (TAK-683) under the endocrine environments of luteal and follicular phases in goats. Five estrous cycling goats received a prostaglandin F2α injection followed by 10 days of progesterone treatment by CIDR. The TAK-683 (35nmol) was intravenously administered (Hour 0) on 3 days after CIDR insertion (luteal phase condition; LC) and at 12h after CIDR removal (follicular phase condition; FC). Blood samples were collected at 10min (612 to 6h), 2h (6–24h) or 6h intervals (24–48h). In the LC, small increases in the basal concentrations of LH were observed after TAK-683 administration from 0 to 6h, which were associated with an increase in estradiol concentration, followed by a surge-like release of LH with a peak at 12.5±1.0h (n=4) after TAK-683 administration. In the FC, a surge-like release of LH occurred immediately after TAK-683 administration with a peak at 6.0±3.5h (n=5), which was earlier than that in the LC (P<0.01). The peak concentration of estradiol did not differ between the two conditions, whereas the time interval from TAK-683 treatment to estradiol peak in the LC was longer than that in the FC (12.0±0.0 compared with 6.0±4.2h, P<0.05). These findings suggest that the timing of surge-like release of LH after TAK-683 administration is associated with blood estradiol concentration at the time of treatment.
URLPMID:25811530 [本文引用: 1]
New potent and selective KISS1R agonists were designed using a combination of rational chemical modifications of the endogenous neuropeptide kisspeptin 10 (KP10). Improved resistance to degradation and presumably reduced renal clearance were obtained by introducing a 1,4-disubstituted 1,2,3-triazole as a proteolysis-resistant amide mimic and a serum albumin-binding motif, respectively. These triazololipopeptides are highly potent full agonists of KISS1R and are >100 selective over the closely related NPFF1R. When injected in ewes with a quiescent reproductive system, the best compound of our series induced a much prolonged increase of luteinizing hormone release compared to KP10 and increased follicle-stimulating hormone plasma concentration. Hence, this KISS1R agonist is a new valuable pharmacological tool to explore the potential of KP system in reproduction control. Furthermore, it represents the first step to develop drugs treating reproductive system disorders due to a reduced activity of the hypothalamo–pituitary–gonadal axis such as delayed puberty, hypothalamic amenorrhea, and hypogonadotropic hypogonadism.
