Reproductive abnormalities in human insulin-like growth factor-binding protein-1 transgenic male mice
Reproductive abnormalities in human insulin-like growth factor-binding protein-1 transgenic male mice
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DOI：
10.1210/en.2003-0956
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发表时间：
2004-04-01
期刊：
影响因子：
4.8
通讯作者：
Monget, P
中科院分区：
文献类型：
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作者：
Froment, P;Staub, C;Monget, P
在肝脏中过度表达人胰岛素样生长因子结合蛋白-1的成年转基因小鼠在两性中都表现出生殖异常。在目前的工作中，我们研究了导致这些转基因雄性小鼠繁殖能力受限的机制。纯合子成年转基因雄性小鼠(3-6个月大)表现出不规则的交配行为，每只雌性小鼠的怀孕次数和每次怀孕的小鼠数量都减少了。与非转基因小鼠相比，纯合子转基因小鼠的生殖道重量，更具体地说是附睾囊和精囊重量减少了45%。纯合子转基因小鼠的生精小管长度减少了30%(P=0.007)，每天每个睾丸的精子产量减少了30%(P=0.019)，睾丸内的精子数量减少了50%(P=0.037)，并伴随着精子头的形态异常，导致交配后第5.5天受精的双细胞卵子减少了约50%(P=0.002)，植入的胚胎减少了约50%(P=0.004)。圆形精子细胞的形态也发生了变化。此外，纯合子转基因小鼠的间质细胞外观发生了改变，细胞质中的脂滴增加了1.8%(P<；0.001)。此外，转基因小鼠睾丸中3β-羟基类固醇脱氢酶的浓度比正常小鼠低66%(P=0.01)，导致血浆睾酮水平下降(P=0.1)。有趣的是，转基因小鼠脑垂体提取液中的黄体生成素浓度比正常小鼠增加了40%(P=0.02)，体外培养的小鼠脑垂体组织中黄体生成素的基础分泌量比正常小鼠增加了60%(P=0.04)，提示体内黄体生成素的分泌发生了变化。综上所述，这些数据表明，人类胰岛素样生长因子结合蛋白-1转基因男性的繁殖障碍至少部分是由于精子发生过程的改变，导致精子产量和质量下降。类固醇合成的轻微损害也可能导致这些动物的生殖能力下降。我们的观察结果与以下观点是一致的，即正常的精子发生以及类固醇的发生都依赖于足够浓度的未结合IGF-I的作用。
Adult transgenic mice overexpressing human insulin-like growth factor-binding protein-1 in the liver present reproductive abnormalities in both sexes. In the present work, we have investigated the mechanisms responsible for limiting breeding capacity in these transgenic male mice. Homozygous adult transgenic male mice (3-6 months old) exhibited irregular copulatory behavior and a reduction of the number of pregnancies per female as well as of litter size per pregnancy. Genital tract weight, more specifically epididymal and seminal vesicle weights, were reduced by 45% in homozygous transgenic vs. nontransgenic mice. Homozygous transgenic mice exhibited a 30% reduction of the length of seminiferous tubules (P = 0.007), a 30% decrease in daily sperm production per testis (P = 0.019), and a 50% decrease in the number of spermatozoa in testis (P = 0.037), associated with morphological abnormalities of the sperm heads leading to an approximately 50% reduction of fertilized two-cell eggs (P = 0.002) and of implanted embryos on d 5.5 after mating (P = 0.004). The round spermatids also appeared altered in their morphology. In addition, Leydig cells in homozygous transgenic mice exhibited an altered appearance, with a 1.8-fold increase in lipid droplets in their cytoplasm (P < 0.001). Moreover, the concentration of 3 beta-hydroxysteroid dehydrogenase was 66% lower in testis from transgenics compared with those from normal mice (P = 0.01), leading to a tendency toward lower plasma testosterone levels (P = 0.1). Interestingly, LH concentrations were increased by 40% in transgenic pituitary extracts (P = 0.02), and basal LH secretion by pituitary explants in vitro was increased by 60% in homozygous transgenic vs. normal mice (P = 0.04), suggesting an alteration of LH pulsatile secretion in vivo. In conclusion, these data suggest that the breeding impairment of human insulin-like growth factor-binding protein-1 transgenic males is due at least in part to an alteration of the process of spermatogenesis, leading to a diminution of sperm production and of its quality. Minor impairment of steroidogenesis may also contribute to the reduced reproductive capacity of these animals. Our observations are consistent with the idea that normal spermatogenesis and perhaps also steroidogenesis are dependent on the actions of sufficient concentrations of unbound IGF-I.