TNFα对小鼠卵泡发育的影响
摘要
卵巢是雌性生殖器官的一部分,动物卵巢发育是一个复杂的过程,包括从早期胚胎发育一直到卵巢衰老。而且卵巢是一个在整个生命周期中不断进行连续修复的动态系统,细胞凋亡是维持这个动态修复系统的重要机制。卵泡是卵巢的结构功能单位,卵泡的发育依次经历了原始卵泡(primordial follicle)、初级卵泡(primary follicle)、次级卵泡(secondary follicle)和成熟卵泡(mature follicle)四个阶段。卵巢卵泡的发育是一个由内分泌、自分泌和旁分泌因子所调控的一系列复杂的过程。
肿瘤坏死因子α(TNFα)是卵巢卵泡发育中的一个重要的调节因子。它是由激活的巨噬细胞产生的17.3 kDa的蛋白。TNFα的作用十分复杂,既能提升细胞存活,又能导致细胞凋亡。TNFα的多样的作用是通过细胞表面的专门的受体所介导的,包括TNFRⅠ和TNFRⅡ。许多报道指出,TNFα的大多数生物学作用是通过TNFRⅠ来介导的。TNFα具有广泛的生物学活性,具有强大的抗肿瘤作用,是迄今发现的抗肿瘤作用最强的细胞因子,此外,TNFα也参与了一些疾病如心血管病和自身免疫性疾病的发生、发展。在哺乳动物卵巢中,已有体外实验表明,TNFα在卵泡发育、排卵、甾类生成、黄体化、生殖和闭锁等方面发挥着重要的作用,但是目前利用体内实验来研究TNFα在卵巢内的作用的报道还很少。
本实验是首次利用TNFα敲除的小鼠模型来进一步研究其在卵泡发育和繁殖力方面的作用。并在分子水平和细胞水平上对敲除TNFα后卵泡发育和繁殖力的相关参数进行了检测。本实验将为在正常卵巢中进一步研究TNFα作用的分子机制打下基础。
本实验结果显示:
1. TNFα-/-小鼠的阴道开口时间与WT小鼠的阴道开口时间相似。小鼠2个月龄时,TNFα-/-与WT小鼠的发情周期长度基本没有明显变化,但是TNFα-/-的小鼠与野生型的小鼠相比,处于发情期的时间要明显延长,而处于间情期的时间要短。所以,TNFα-/-的小鼠在21天中发情周期的个数要比野生型的小鼠多。但当小鼠6个月大时,TNFα-/-的小鼠仅有50%的表现出发情周期,而在这些有发情周期的小鼠中,大部分时间也都处于间情期,很少时间处于发情期。所以,在衰老期的小鼠中,TNFα-/-的小鼠在21天中发情周期的个数要比野生型的小鼠要少。
2.21天时,TNFα-/-的小鼠超排所得的卵明显比野生型的小鼠排的卵多。而且,在随后的孕酮检测实验中,TNFα-/-的小鼠的孕酮含量明显要比野生型的小鼠中的多。
3.对出生后4,18,42,90天的两种类型的小鼠进行的卵泡检测实验表明,总体上来说,TNFα-/-的小鼠中的卵泡总数、各级卵泡数特别是腔前和有腔卵泡数都要比处于同一时期的野生型的小鼠中的多。
4.对两种类型的小鼠卵巢卵泡进行的增殖与凋亡检测实验表明,在蛋白水平上来看,在小鼠90天时,TNFα-/-的小鼠卵巢的颗粒细胞、膜细胞和间质细胞中CDK4蛋白的水平要比野生型小鼠中的高很多。而TNFα-/-的小鼠卵巢卵母细胞中CASPASE 3蛋白的水平明显要比野生型小鼠的卵巢卵母细胞中的低很多。在分子水平上来看,在小鼠90天时,TNFα-/-小鼠卵巢内Cdk 4和Cyclin D2的表达水平明显要高于野生型的小鼠卵巢内的相应基因表达量。而TNFα-/-小鼠卵巢内促凋亡因子Bad和Bax的表达水平明显要低于野生型的小鼠卵巢内的基因表达量。
5. TNFα-/-小鼠和WT小鼠的繁殖力比较是通过检测小鼠每窝的产仔数和12个月连续的产仔累积量来实现的。TNFα-/-的小鼠平均每窝产仔量要比野生型的小鼠多30%,而且TNFα-/-小鼠产仔的累积量要比野生型的小鼠多21%。
6.当小鼠12个月龄时,TNFα敲除的小鼠卵巢内的卵泡要比野生型小鼠卵巢内的卵泡要多。
总之,敲除TNFα后,能够通过影响与卵巢功能相关的一些因子来提高小鼠的繁殖力。
Ovary is one part of the female reproductive organs, the ovarian development of the animal is a complicate process, which from embryonic development to ovarian senescence. Furthermore, the ovary is a dynamic system which is continue to be repaired in the whole life period. The follicle is the functional unit of ovary, and follicles develop through the primordial, primary, secondary and mature stages. Follicle development in ovary is a series of complex processes governed by endocrine, autocrine and paracrine factors.
One potential regulator of ovarian follicular development is tumor necrosis factorα(TNFα), which is a 17.3 kDa protein product of activated macrophages. The roles of TNFαare quite complex ranging from promoting cell survival to initiating cell death. The multiple activities of TNFαare mediated by specific cell surface receptors, the TNF receptorⅠ(TNFRⅠ) and TNF receptorⅡ(TNFRⅡ). Several reports have shown that the signal through TNFRⅠis necessary for many biological functions of TNFα. TNFαhas wide biologic activity, in addition, it also participate in the nosogenesis of some disease, such as angiocardiopathy and autoimmune disease. In the ovary of the mammal, several in vitro studies have indicated that TNFαplays an important role in follicular development, ovulation, steroidogenesis, luteinization, fertility and atresia, but the in vivo role of TNFαin ovary remains an enigma.
The purpose of present study was using TNFαdeleted model for the first time to further elucidate the biological roles of this cytokine in the regulation of follicular development and female fertility, and studied the parameters of the fertility after deletion of the TNFαon molecular level and cellular level. This study may establish foundation for dentifying molecular mechanisms of TNFαin normal ovarian function.
The results show:
1. Vaginal opening was similar in TNFα-/- females when compared with WT females. At two months of age, cycle length was not significantly different between TNFαknockout and WT mice, but TNFα-/- mice spent more time in estrus and significantly less time in diestrus than did controls. Consequently, the number of cycles per mouse in a 21 day period was more in TNFα-/- mice than in controls. At six months of age, only 50% of TNFαnull mice exhibited estrous cycles, of those TNFαnull mice exhibiting estrous cycles, significantly more time in diestrus and relatively less time were spent in estrus. Thus, in aged animals, the number of cycles in a 21 day period was significantly reduced in TNFαnull mice compared to controls.
2. On day of 21, TNFαknockout mice shed significantly more ova compared with WT controls of the same age. Furthermore, the greater number of ovulations by TNFаknockout mice was followed by higher serum levels of progesterone on day 21.
3.The follicular detect experiment of the two types mice on postnatal 4,18,42,90 indicated that, the TNFα-/- ovaries contained more total follicles, more each stage follicles especially preantral and antral follicles than did wild type animals contemporaneity.
4. The follicular proliferation and apoptosis detect experiment of the ovary of the two types of mice indicated that, on proteinum level, granulosa cells, theca cells and interstitial cells of TNFαknockout mice demonstrated higher levels of proliferation than WT ovaries did based on immunohistochemistry for CDK 4 on day 90, but TNFαknockout ovaries appeared to have lower levels of CASPASE 3 in oocytes than WT ovaries did. On molecular level, a significantly higher abundance of of Cdk 4 and Cyclin D2 transcripts was detected in TNFαdeficient ovaries compared with WT ovaries on PD 90, but a significantly lower expression of Bad and Bax (a proapoptotic factor) was detected in TNFαdeficient ovaries compared with WT ovaries.
5. Fertility of TNFαnull mice was compared to that of controls by determining the number of pups per litter and the cumulative number of pups per female during a 12 month breeding period. The TNFα-/- females produced 30% more pups per litter than the wild type mice. Moreover, the TNFα-/- mice gave birth to 21% more pups than control mice did during a 12 month breeding period.
6. At one year of age, the follicular reserve in TNFα-/- mice was more than that in WT mice.
In a word, deletion of the TNFαcan improve overall reproductive capacity of the mice through affecting some factor related to the function of the ovary.
肿瘤坏死因子α(TNFα)是卵巢卵泡发育中的一个重要的调节因子。它是由激活的巨噬细胞产生的17.3 kDa的蛋白。TNFα的作用十分复杂,既能提升细胞存活,又能导致细胞凋亡。TNFα的多样的作用是通过细胞表面的专门的受体所介导的,包括TNFRⅠ和TNFRⅡ。许多报道指出,TNFα的大多数生物学作用是通过TNFRⅠ来介导的。TNFα具有广泛的生物学活性,具有强大的抗肿瘤作用,是迄今发现的抗肿瘤作用最强的细胞因子,此外,TNFα也参与了一些疾病如心血管病和自身免疫性疾病的发生、发展。在哺乳动物卵巢中,已有体外实验表明,TNFα在卵泡发育、排卵、甾类生成、黄体化、生殖和闭锁等方面发挥着重要的作用,但是目前利用体内实验来研究TNFα在卵巢内的作用的报道还很少。
本实验是首次利用TNFα敲除的小鼠模型来进一步研究其在卵泡发育和繁殖力方面的作用。并在分子水平和细胞水平上对敲除TNFα后卵泡发育和繁殖力的相关参数进行了检测。本实验将为在正常卵巢中进一步研究TNFα作用的分子机制打下基础。
本实验结果显示:
1. TNFα-/-小鼠的阴道开口时间与WT小鼠的阴道开口时间相似。小鼠2个月龄时,TNFα-/-与WT小鼠的发情周期长度基本没有明显变化,但是TNFα-/-的小鼠与野生型的小鼠相比,处于发情期的时间要明显延长,而处于间情期的时间要短。所以,TNFα-/-的小鼠在21天中发情周期的个数要比野生型的小鼠多。但当小鼠6个月大时,TNFα-/-的小鼠仅有50%的表现出发情周期,而在这些有发情周期的小鼠中,大部分时间也都处于间情期,很少时间处于发情期。所以,在衰老期的小鼠中,TNFα-/-的小鼠在21天中发情周期的个数要比野生型的小鼠要少。
2.21天时,TNFα-/-的小鼠超排所得的卵明显比野生型的小鼠排的卵多。而且,在随后的孕酮检测实验中,TNFα-/-的小鼠的孕酮含量明显要比野生型的小鼠中的多。
3.对出生后4,18,42,90天的两种类型的小鼠进行的卵泡检测实验表明,总体上来说,TNFα-/-的小鼠中的卵泡总数、各级卵泡数特别是腔前和有腔卵泡数都要比处于同一时期的野生型的小鼠中的多。
4.对两种类型的小鼠卵巢卵泡进行的增殖与凋亡检测实验表明,在蛋白水平上来看,在小鼠90天时,TNFα-/-的小鼠卵巢的颗粒细胞、膜细胞和间质细胞中CDK4蛋白的水平要比野生型小鼠中的高很多。而TNFα-/-的小鼠卵巢卵母细胞中CASPASE 3蛋白的水平明显要比野生型小鼠的卵巢卵母细胞中的低很多。在分子水平上来看,在小鼠90天时,TNFα-/-小鼠卵巢内Cdk 4和Cyclin D2的表达水平明显要高于野生型的小鼠卵巢内的相应基因表达量。而TNFα-/-小鼠卵巢内促凋亡因子Bad和Bax的表达水平明显要低于野生型的小鼠卵巢内的基因表达量。
5. TNFα-/-小鼠和WT小鼠的繁殖力比较是通过检测小鼠每窝的产仔数和12个月连续的产仔累积量来实现的。TNFα-/-的小鼠平均每窝产仔量要比野生型的小鼠多30%,而且TNFα-/-小鼠产仔的累积量要比野生型的小鼠多21%。
6.当小鼠12个月龄时,TNFα敲除的小鼠卵巢内的卵泡要比野生型小鼠卵巢内的卵泡要多。
总之,敲除TNFα后,能够通过影响与卵巢功能相关的一些因子来提高小鼠的繁殖力。
Ovary is one part of the female reproductive organs, the ovarian development of the animal is a complicate process, which from embryonic development to ovarian senescence. Furthermore, the ovary is a dynamic system which is continue to be repaired in the whole life period. The follicle is the functional unit of ovary, and follicles develop through the primordial, primary, secondary and mature stages. Follicle development in ovary is a series of complex processes governed by endocrine, autocrine and paracrine factors.
One potential regulator of ovarian follicular development is tumor necrosis factorα(TNFα), which is a 17.3 kDa protein product of activated macrophages. The roles of TNFαare quite complex ranging from promoting cell survival to initiating cell death. The multiple activities of TNFαare mediated by specific cell surface receptors, the TNF receptorⅠ(TNFRⅠ) and TNF receptorⅡ(TNFRⅡ). Several reports have shown that the signal through TNFRⅠis necessary for many biological functions of TNFα. TNFαhas wide biologic activity, in addition, it also participate in the nosogenesis of some disease, such as angiocardiopathy and autoimmune disease. In the ovary of the mammal, several in vitro studies have indicated that TNFαplays an important role in follicular development, ovulation, steroidogenesis, luteinization, fertility and atresia, but the in vivo role of TNFαin ovary remains an enigma.
The purpose of present study was using TNFαdeleted model for the first time to further elucidate the biological roles of this cytokine in the regulation of follicular development and female fertility, and studied the parameters of the fertility after deletion of the TNFαon molecular level and cellular level. This study may establish foundation for dentifying molecular mechanisms of TNFαin normal ovarian function.
The results show:
1. Vaginal opening was similar in TNFα-/- females when compared with WT females. At two months of age, cycle length was not significantly different between TNFαknockout and WT mice, but TNFα-/- mice spent more time in estrus and significantly less time in diestrus than did controls. Consequently, the number of cycles per mouse in a 21 day period was more in TNFα-/- mice than in controls. At six months of age, only 50% of TNFαnull mice exhibited estrous cycles, of those TNFαnull mice exhibiting estrous cycles, significantly more time in diestrus and relatively less time were spent in estrus. Thus, in aged animals, the number of cycles in a 21 day period was significantly reduced in TNFαnull mice compared to controls.
2. On day of 21, TNFαknockout mice shed significantly more ova compared with WT controls of the same age. Furthermore, the greater number of ovulations by TNFаknockout mice was followed by higher serum levels of progesterone on day 21.
3.The follicular detect experiment of the two types mice on postnatal 4,18,42,90 indicated that, the TNFα-/- ovaries contained more total follicles, more each stage follicles especially preantral and antral follicles than did wild type animals contemporaneity.
4. The follicular proliferation and apoptosis detect experiment of the ovary of the two types of mice indicated that, on proteinum level, granulosa cells, theca cells and interstitial cells of TNFαknockout mice demonstrated higher levels of proliferation than WT ovaries did based on immunohistochemistry for CDK 4 on day 90, but TNFαknockout ovaries appeared to have lower levels of CASPASE 3 in oocytes than WT ovaries did. On molecular level, a significantly higher abundance of of Cdk 4 and Cyclin D2 transcripts was detected in TNFαdeficient ovaries compared with WT ovaries on PD 90, but a significantly lower expression of Bad and Bax (a proapoptotic factor) was detected in TNFαdeficient ovaries compared with WT ovaries.
5. Fertility of TNFαnull mice was compared to that of controls by determining the number of pups per litter and the cumulative number of pups per female during a 12 month breeding period. The TNFα-/- females produced 30% more pups per litter than the wild type mice. Moreover, the TNFα-/- mice gave birth to 21% more pups than control mice did during a 12 month breeding period.
6. At one year of age, the follicular reserve in TNFα-/- mice was more than that in WT mice.
In a word, deletion of the TNFαcan improve overall reproductive capacity of the mice through affecting some factor related to the function of the ovary.
引文
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