White spotting variant mouse as an experimental model for ovarian aging and menopausal biology.
White spotting variant mouse as an experimental model for ovarian aging and menopausal biology.
复制标题
白斑变异小鼠作为卵巢衰老和更年期生物学的实验模型。
DOI：
10.1097/gme.0b013e318239cc53
复制
发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Xu,Xiang-Xi
中科院分区：
文献类型：
--
作者：
Smith,ElizabethR;Yeasky,Toni;Wei,JainQin;Miki,RobertoA;Cai,KathyQ;Smedberg,JenniferL;Yang,Wan-Lin;Xu,Xiang-Xi
绝经是现代女性特有的现象，因为大多数哺乳动物都有与其寿命相当的生殖期。更年期是由含有生殖细胞的卵泡耗尽引起的，在实验室研究中，通常是通过卵巢切除或生殖细胞化学中毒来消除卵巢功能的动物。我们的目的是探索和鉴定由c-kit基因点突变导致的卵巢生殖细胞丰度降低的白色斑点变异(WV)小鼠，作为用于更年期研究的遗传模型。方法与年龄匹配的野生型对照小鼠比较雌性WV/WV小鼠与绝经相关的生理和形态特征。免疫组织化学方法检测石蜡包埋卵巢中卵泡的存在和数量。使用PIXImus X射线密度计评估骨密度和身体成分，并使用抗原特异性酶免疫分析法检测血清中的血脂、钙和激素水平。结果与野生型小鼠相比，WV/WV雌性小鼠出生时卵巢内正常生殖细胞数量明显减少。剩余的卵泡大约2个月就会耗尽，卵巢会出现良性的上皮性病变，类似于卵巢老化过程中的形态变化，而正常小鼠的卵巢在发育的各个阶段都有大量的卵泡，即使在老年也会保留一些卵泡。WV小鼠血浆促性腺激素水平升高，雌激素和孕激素水平降低，骨密度显著降低，血清胆固醇和脂蛋白水平升高。结论WV小鼠c-kit活性降低导致新生小鼠卵泡捐赠能力显著降低，幼年小鼠卵泡过早耗竭，尽管突变雌性小鼠在卵巢功能停止后仍有正常寿命。WV雌性小鼠表现出一致的生理变化，类似于绝经后女性的常见特征。这些变化包括卵泡枯竭、卵巢形态老化、血清胆固醇、促性腺激素和类固醇激素水平改变、骨密度下降和心脏功能下降。无论是年龄匹配的雄性WV/WV小鼠还是野生型小鼠，这些变化都没有在雄性小鼠中观察到，而且不太可能是由c-kit功能的全面丧失引起的。WV小鼠可能是一种遗传的、完整的卵巢模型，它非常接近人类更年期的表型，用于进一步研究了解更年期生物学的机制。
ObjectiveMenopause is a unique phenomenon in modern women, as most mammalian species possess a reproductive period comparable with their life span. Menopause is caused by the depletion of germ cell–containing ovarian follicles and in laboratory studies is usually modeled in animals in which the ovarian function is removed through ovariectomy or chemical poisoning of the germ cells. Our objective was to explore and characterize the white spotting variant (Wv) mice that have reduced ovarian germ cell abundance, a result of a point mutation in the c-kit gene that decreases kinase activity, as a genetic model for use in menopause studies.MethodsPhysiological and morphological features associated with menopause were determined in female Wv/Wv mice compared with age-matched wildtype controls. Immunohistochemistry was used to evaluate the presence and number of follicles in paraffin-embedded ovaries. Bone density and body composition were evaluated using the PIXImus x-ray densitometer, and lipids, calcium, and hormone levels were determined in serum using antigen-specific enzyme immunoassays. Heart and body weight were measured, and cardiac function was evaluated using transthoracic echocardiography.ResultsThe ovaries of the Wv/Wv females have a greatly reduced number of normal germ cells at birth compared with wildtype mice. The remaining follicles are depleted by around 2 months, and the ovaries develop benign epithelial lesions that resemble morphological changes that occur during ovarian aging, whereas a normal mouse ovary has numerous follicles at all stages of development and retains some follicles even in advanced age. Wv mice have elevated plasma gonadotropins and reduced estrogen and progesterone levels, a significant reduction in bone mass density, and elevated serum cholesterol and lipoprotein levels. Moreover, the Wv female mice have enlarged hearts and reduced cardiac function.ConclusionsThe reduction of c-kit activity in Wv mice leads to a substantially diminished follicular endowment in newborn mice and premature depletion of follicles in young mice, although mutant females have a normal life span after cessation of ovarian function. The Wv female mice exhibit consistent physiological changes that resemble common features of postmenopausal women. These alterations include follicle depletion, morphological aging of the ovary, altered serum levels of cholesterol, gonadotropins and steroid hormones, decreased bone density, and reduced cardiac function. These changes were not observed in male mice, either age-matched male Wv/Wv or wildtype mice, and are improbably caused by global loss of c-kit function. The Wv mouse may be a genetic, intact-ovary model that mimics closely the phenotypes of human menopause to be used for further studies to understand the mechanisms of menopausal biology.