Gonadal pathologies in transgenic mice expressing the rat inhibin α-subunit
Gonadal pathologies in transgenic mice expressing the rat inhibin α-subunit
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DOI：
10.1210/en.142.11.5005
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发表时间：
2001-11-01
期刊：
影响因子：
4.8
通讯作者：
Mayo, KE
中科院分区：
文献类型：
--
作者：
McMullen, ML;Cho, BN;Mayo, KE
抑制素和激活素是结构上相关的二聚体多肽激素，是转化生长因子-β超家族蛋白质的成员。在随附的论文中，我们描述了过表达金属硫蛋白-I启动子(MT-α)抑制素α亚单位基因的转基因小鼠，并检测了MT-α转基因对促性腺激素水平和生育能力的影响。为了研究抑制素α亚基增加对性腺形态和功能的影响，本报告研究了MT-α转基因小鼠的性腺组织学、类固醇激素水平和卵巢囊肿形成的基础。MT-α转基因雌性小鼠在3个月大的时候就形成了巨大的充满液体的卵泡起源的卵巢囊肿。到12个月大时，超过92%的MT-α转基因雌性小鼠会出现卵巢囊肿，而野生型小鼠的这一比例不到25%。卵巢囊肿单侧或双侧形成，囊性卵巢通常有一个大大扩张的法氏囊。此外，MT-α转基因小鼠的卵巢含有多卵泡，成熟的有腔卵泡和黄体较少。MT-Alpha雌性小鼠表现出异常的类固醇激素分泌，血清T水平升高，血清E水平降低，子宫重量相应减少。在MT-α转基因雄鼠中，与对照雄鼠相比，睾丸大小减小了20%-40%，生精管体积也相应减少。在用促性腺激素释放激素拮抗剂进行慢性治疗后，MT-α雌性小鼠继续发展为卵巢囊和囊泡扩张，尽管囊的大小明显减小。这些结果表明，大鼠抑制素α亚基的表达导致了显著的卵巢病理，缩小了睾丸，并改变了卵巢类固醇的生成。拮抗剂研究与阿尔法亚单位转基因产物在这些小鼠中通过抑制素/激活素比率的变化介导的直接卵巢效应是一致的。
Inhibin and activin are structurally related dimeric peptide hormones and are members of the TGF-beta superfamily of proteins. In the accompanying paper, we describe transgenic mice that overexpress the inhibin alpha -subunit gene from a metallothionein-I promoter (MT-alpha) and examine the effects of the MT-alpha transgene on gonadotropin levels and fertility. To characterize the effects of increased inhibin alpha -subunit on gonadal morphology and function, in this report we investigate gonadal histology, steroid hormone levels, and the basis of ovarian cyst formation in MT-alpha transgenic mice. MT-alpha transgenic female mice develop large fluid-filled ovarian cysts of follicular origin as early as 3 months of age. By 12 months of age, more than 92% of female MT-alpha transgenic mice develop ovarian cysts compared with less than 25% of wild-type littermates. Ovarian cysts form unilaterally or bilaterally, and cystic ovaries often have a greatly expanded bursal sac. Additionally, the ovaries of MT-alpha transgenic mice contain polyovular follicles and have fewer mature antral follicles and corpora lutea. MT-alpha female mice exhibit abnormal steroid hormone production, with increased serum T levels and reductions in serum E with corresponding reductions in uterine mass. In the MT-alpha transgenic males, testis size was decreased by 20-40% compared with control males, and there is a corresponding reduction in seminiferous tubule volume. After a chronic treatment with a GnRH antagonist, MT-alpha female mice continued to develop ovarian cysts and bursal sac expansions, although the cysts were markedly reduced in size. These results indicate that the expression of the rat inhibin alpha -subunit in mice results in significant ovarian pathology, reduced testicular size, and altered ovarian steroidogenesis. The antagonist studies are consistent with a direct ovarian effect of the alpha -subunit transgene product mediated by changes in the inhibin-to-activin ratio in these mice.