繁殖效率是决定一个牛场经济效益高低的重要因素,它直接影响奶牛场的奶产量和犊牛数量。妊娠母牛的高胚胎死亡率是造成养牛业经济损失的主要原因。奶牛的胚胎期从受孕到分化结束(约42 d),胎儿期是从妊娠第42天到分娩。早期胚胎丢失传统上是指妊娠不足12周时宫内发生的妊娠丢失[1]。奶牛胚胎丢失可发生在妊娠的各个阶段,但主要发生在配种后42 d内,即胚胎阶段[2]。有学者对1980年和2006年英国荷斯坦奶牛早期胚胎丢失的情况进行了统计,发现奶牛在正常配种后约有10%受精失败,早期胚胎丢失率从1980年的25%上升到2006年的55%,而配种28 d后的胚胎丢失率没有发生显著变化,一直稳定在7%左右[3-4]。Dailey等[5]研究发现,胚胎存活率在配种后1~4 d内为78%,20 d为38%,28~29 d为36%,36~42 d为31%,最终成功产犊的奶牛仅占30%。Santos等[6]也研究发现,在配种后的1~4 d内,胚胎存活率为76%,6 d为50%,28~29 d为40%,36~42 d为35%,最终成功产犊的奶牛仅占28%。由此可知,配种后约有10%的奶牛会发生受精失败,1~7 d内胚胎丢失率约为30%~40%,8~17 d内的胚胎丢失率约为10%~20%,40 d之后胚胎丢失率一般不超过10%。
内分泌环境和外源性因素决定着妊娠能否建立和维持。因此,造成早期胚胎丢失的原因有多种,奶牛自身的患病和免疫情况、双胎妊娠、染色体异常、热应激等因素均会导致奶牛早期胚胎丢失。此外,B族维生素在奶牛早期胚胎发育过程中也起着重要作用。
1 染色体畸变对早期胚胎丢失的影响染色体畸变是导致早期胚胎丢失最常见的原因,超过一半的自发性流产是由染色体缺陷导致的,大多数是非整倍体。其中最常见的畸变是常染色体三倍体(60%),其次是X染色体单体(20%)和多倍体(20%)[7]。染色体易位在所有染色体畸变中发生比例最高,尤其是非同源染色体之间的交互易位,它会因为染色体分配不平衡而产生染色体不平衡的配子,这些配子在受精后产生胚胎,而这些胚胎往往带有不平衡核型, 这对胚胎发育都是致死性的[8]。一般情况下,染色体畸变携带者在表型上是正常的,但是在减数分裂时发生平衡易位的染色体及其同源染色体会发生联会互换,生成配子时发生遗传物质变化[9]。如果配子的染色体数目平衡,发生易位的动物可能会正常妊娠[10]。然而,大约2/3的配子在遗传上是不平衡的, 这些不平衡的配子将会引起早期胚胎丢失。
排卵延迟的奶牛受精后,由于精子或卵子异常等自身缺陷导致胚胎发育停滞,或近亲繁殖导致受精卵成活率低,在胚胎附植后不能正常发育导致死亡[11]。有研究报道,鸟苷酸合成酶缺乏也会导致早期胚胎丢失,且这一现象存在品种差异,夏洛来牛和荷斯坦牛的早期胚胎丢失率高于其他品种牛[12]。
2 激素对早期胚胎丢失的影响高产奶牛肝脏代谢旺盛,高的代谢率使血浆中孕酮(P4)等类固醇激素在肝中被代谢,血液循环中P4浓度也随之降低,这不仅对生育能力有影响,而且对早期胚胎发育也有一定的危害。Puget等[13]研究报道,母畜排卵后,P4浓度上升的速度与胚胎发育密切相关,如果P4浓度的上升速度较慢, 则胚胎的存活力就会降低。有研究发现,在配种后4~5 d,P4水平较低会导致胚胎丢失率上升。Ferguson等[14]对14头经过3次或多次人工授精未能怀孕的母牛在配种后第3、4和5天分别肌肉注射含15 mg P4的乙醇3 mL,发现14头中有6头妊娠,妊娠率为43%(6/14),并且在第5天时,妊娠牛的P4浓度((1.87±0.20) ng·mL-1)显著高于未妊娠牛((0.89±0.20) ng·mL-1),说明在此期间补充P4可以提高有繁殖障碍牛的妊娠率。Forde等[15]在授精后3~7 d对小母牛埋置含1.55 g P4的孕酮栓,然后采用荧光定量PCR对多个基因(FABP、DGAT2、MSTN、CRYGS)进行研究,发现补充P4可以改变胚胎发育阶段子宫内膜关键基因的表达模式,这可能有助于子宫内膜第13和16天晚期孕体的发育,对预防早期胚胎丢失具有重要意义。所以在黄体形成期补充P4可以降低早期胚胎丢失率。
奶牛在没有配种的情况下,大约在发情周期的第15天左右,子宫内膜产生的前列腺素(PGF2α)溶解黄体,导致P4水平下降,动物开始新的发情周期。配种后,反刍动物滋养层细胞会分泌一类糖基化的酸性低分子量蛋白质干扰素τ(interferon tau,IFN-τ),它在反刍动物妊娠识别过程中起重要作用[16]。妊娠识别大约发生在奶牛授精后的第15天,并且母体接纳孕体的时间最晚不能超过第17天,IFN-τ重要的生物学功能主要表现在黄体维持和妊娠建立阶段[17]。IFN-τ在孕体发育到囊胚期时开始表达,在胚胎附着开始前达到最高水平。IFN-τ的分泌量随着囊胚的不断延伸而逐渐增加,并于孕体附着于子宫上皮之前达到峰值,着床后其分泌量逐渐减退[18]。IFN-τ可作为旁分泌因子,与子宫内膜细胞上的相关受体结合下调催产素受体的表达,使PGF2a脉冲释放遭到破坏,黄体溶解被阻止,从而使P4正常分泌来维持妊娠[19-20]。Garcia-Ispierto等[17]对授精后15~17 d的高产奶牛埋置含1.55 g P4的孕酮栓,发现该阶段埋置孕酮栓可使奶牛在授精后28~34 d的妊娠率增加1.6倍,说明在妊娠识别阶段外源性补充P4有益于提高奶牛的妊娠率。
附植期一直被认为是牛和其他物种发生胚胎丢失的关键时期。有研究发现,奶牛在此阶段胚胎丢失率为25%~30%[21]。胚胎附植是一个复杂的过程,包括母体和胚胎之间复杂信号的相互作用,除了子宫内膜基质的变化外,胚胎还经历了包括血管生成在内的巨大形态学变化,这是胎盘子叶形成的先决条件[22]。在妊娠第19天,胚胎滋养层细胞与子宫内膜上皮细胞之间开始附植;大约从21~22 d,上皮层开始通过微绒毛的相互作用而黏附,这个黏附过程大约会持续1~2周[23-24]。有研究报道,IFN-τ在小母牛胚胎中的表达量高于经产母牛,并且它受奶牛胚胎附植期雌二醇(E2)和P4联合作用的影响。P4可使IFN-τ的表达显著上调,E2可使其表达显著下调[25]。Ferguson等[26]研究表明,P4可以促进体外受精牛的胚胎发育, 并且能够促进子宫内膜基质细胞分化为蜕膜细胞,对胚胎附植和早期胚胎发育起重要作用。
附植前后,P4和其他生殖激素的不平衡也是导致胚胎死亡的原因,通常雌激素分泌过多或者孕激素分泌不足,均会影响胚胎附植,导致早期胚胎丢失[27]。有研究报道,在授精21~24 d后,P4水平低于2 ng·mL-1会导致胚胎附植失败[28]。在妊娠诊断后(授精后36~42 d),补充P4可降低母体早期胚胎丢失[29-30]。López-Gatius等[31]对授精36~42 d的奶牛进行为期28 d的孕酮栓处理,在妊娠第90天时发现,无孕酮栓处理组有12%的奶牛发生胚胎丢失,而孕酮栓处理组只有5.3%的奶牛发生胚胎丢失,说明补充外源性孕酮可以降低早期胚胎丢失率。因此,P4对母体支持孕体生长发育必不可少。
3 双胎妊娠对早期胚胎丢失的影响双胎妊娠对奶牛的生殖周期有很大的负面影响,它会增加整个妊娠期妊娠失败的风险。García-Ispierto等[32]对妊娠90 d内无临床疾病、怀双胎的荷斯坦奶牛进行研究,发现有22%的奶牛发生了妊娠丢失,并且妊娠早期双胎妊娠丢失的风险是单胎妊娠的3.4倍。黄体数目超过胚胎数目的奶牛,其妊娠丢失率会降低32%,并且额外黄体的存在是预防早期胚胎丢失的一个重要因素[32-33]。减少奶牛的胚胎数量可以降低双胎妊娠对奶牛生殖的负面影响。目前,多胎妊娠减胎术已被用于人类辅助生殖和母马双胎妊娠治疗[34-35]。有研究报道,对妊娠第34天的双胎奶牛进行人工按压使羊膜囊破裂,随后对一部分进行孕酮治疗,发现孕酮治疗可以降低奶牛的双胎率,这为减少奶牛双胎妊娠,提高胚胎存活率提供了一个较好的方法[36]。这些研究都说明,双胎妊娠对早期胚胎丢失有很大的负面影响。
4 免疫对早期胚胎丢失的影响有研究报道,T、B淋巴细胞和自然杀伤细胞(NK细胞)在妊娠期起的作用可能微不足道,然而非特异性先天免疫机制对妊娠早期奶牛的生殖有明显的影响[37]。在适当的刺激下,局部胎盘激活NK细胞,使NK细胞产生大量的IFN-γ,而后IFN-γ激活巨噬细胞,使巨噬细胞产生大量的肿瘤坏死因子(TNF-α),这些因子的大量产生会导致胚胎死亡[38-39]。
临床乳腺炎是奶牛常患的疾病之一,它会引起奶牛体温升高,黄体受损,前列腺素合成增加,并且还会通过上调各种细胞因子的浓度影响促黄体素的水平,从而导致奶牛发情推迟,影响受胎和胚胎发育[40]。Romano等[41]研究表明,在配种后第45天患有乳腺炎的奶牛,在90 d内早期胚胎丢失是未患乳腺炎奶牛的2.7倍。
5 疾病对早期胚胎丢失的影响肢蹄病会引起奶牛行动不便、活动量减少,从而引起奶牛发情鉴定困难、发情强度下降、受胎率降低、授精次数增加;同时,也会加大奶牛患卵巢囊肿的风险,引起卵子质量下降,导致奶牛早期胚胎丢失[42]。Melendez等[43]对195头奶牛产后30 d内的患病情况进行统计分析,发现65头患肢蹄病的奶牛卵巢囊肿发病率(25%)显著高于130头健康奶牛的发病率(11.1%)。Olechnowicz和Ja s ′ kowski[44]研究报道,患肢蹄病奶牛的平均受孕率为31%,低于健康奶牛的40%。这进一步说明肢蹄病可能会导致部分奶牛不排卵, 从而降低奶牛的受孕率。
奶牛产后患子宫内膜炎也是导致早期胚胎丢失的一个重要原因。奶牛患子宫内膜炎时,子宫腺体的正常功能被破坏,阻断供给早期胚泡发育所需的营养物质,从而使胚胎附植和发育受到影响,引起早期胚胎丢失[22]。Gilbert等[45]对5个商业荷斯坦奶牛群体进行了研究,采用细胞学诊断后发现患子宫内膜炎的奶牛生殖能力严重受损,并且Kaplan-Meier生存分析显示妊娠率总体较低。
6 叶酸和维生素B12对早期胚胎丢失的影响叶酸在维持胚胎发育和表观遗传过程中起重要作用,它在妊娠期间对胎儿组织和胎盘的快速生长是必不可少的。叶酸还是许多生物反应的底物或辅助因子,参与能量与蛋白质代谢、嘌呤与DNA的合成,并且在DNA和RNA的合成中起重要作用;它能为奶牛体组织提供一碳基团参与几种氨基酸的代谢、转甲基化和转硫酸化,也可被孕体用于维持细胞的快速分裂[46-48]。叶酸在参与机体反应时,高水平的维生素B12起重要的协同作用,它能够促进叶酸被更好的吸收利用[49]。同时,叶酸和维生素B12还是同型半胱氨酸(Hcy)代谢的辅助因子,它们的缺乏会导致Hcy水平升高。MTHFR酶是叶酸和Hcy代谢通路的重要酶,参与许多生理过程,如影响基因组稳定性、印迹、表达和维持血液中适当的Hcy水平[50]。编码MTHFR酶基因的多态性是评价早期复发性流产风险的重要生物标志物[51]。
随着胚胎发育,孕体对B族维生素的需求量增加,由于B族维生素在体内不易储存,又不能自身合成;而叶酸在体外极不稳定,见光容易分解[52]。饲料中B族维生素供给不足会导致叶酸和维生素B12缺乏,进而影响雌性动物的卵泡和胚胎发育[53]。当妊娠母牛的叶酸和维生素B12浓度过低时,则会导致Hcy浓度升高及DNA低甲基化,从而引起胚胎发育异常[54]。常见的异常有胚胎附植障碍、胎儿神经管缺陷(NTDs)、胎盘早剥或梗死以及不明原因的复发性胚胎丢失[55-56]。
Li等[57]对4组胎次和产奶量相近的荷斯坦奶牛从产前3周到产后15周的饲粮中添加不同剂量的过瘤胃叶酸(RPFA),发现RPFA的剂量与产后150 d内的妊娠率呈正相关,随着RPFA剂量的增大(0~3 g),妊娠率从对照组(0 g)的73.4%逐渐增加到高剂量组(3 g)的76.9%,低添加组(1 g)和中添加组(2 g)妊娠率分别为74.5%、76.2%;说明补充不同剂量的RPFA能够改善奶牛的生殖性能。Gagnon等[58]对产前24 d到产后56 d的经产荷斯坦奶牛肌肉注射叶酸(每周320 mg)和VB12(每周10 mg),发现在此期间奶牛的采食量没有发生变化,但血液中的尿素水平下降,叶酸和VB12的水平升高;并且在排卵前与颗粒细胞分化有关的基因表达也升高了,产后第一次配种的时间也提前了3.8 d,说明这种处理对促进卵泡发育、提前产后配种时间非常有利。此外,在其他物种上也有叶酸和VB12联合补充提高胚胎存活率的报道[59]。因此,叶酸和VB12在早期奶牛胚胎发育中起重要作用,适时补充有利于降低早期胚胎丢失率。
7 热应激对早期胚胎丢失的影响热应激是奶牛夏季不可避免的危害之一。温湿度指数(THI)是一种评价热舒适度的常用指标,用于估计泌乳奶牛所遭受的热应激程度[60]。Santolaria等[61]研究了奶牛人工授精后1~40 d的气候条件与早期胚胎丢失之间的可能关系;在妊娠后1~20 d,THI值高于85时会导致妊娠丢失增加1.57倍。García-Ispierto等[32]也研究了高产奶牛人工授精后1~40 d THI值与早期胚胎丢失的关系,发现妊娠后21~30 d,平均最大THI每增加一个单位,胚胎丢失的可能性就增加1.05倍。综上所述,热应激可能会影响着床前后的妊娠成功,在人工授精后1~30 d内,THI过大是导致早期胚胎丢失的危险因素。
8 小结与展望影响奶牛早期胚胎丢失的因素有很多,染色体异常、妊娠早期P4分泌不足、胚胎附植异常、妊娠识别失败、叶酸和维生素B12缺乏、热应激等因素均会导致奶牛早期胚胎丢失,只有了解其原因和发生机理,更好地做好防治工作,才能避免因饲养管理失误导致的早期胚胎丢失。因此,牧场在妊娠早期适量补充P4、叶酸和维生素B12等物质、减少双胎妊娠、关注牧场环境、降低疾病发生率、提高奶牛的免疫力、预防热应激等均可以降低奶牛早期胚胎丢失率,提高妊娠率,降低牧场经济损失。
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