Zinc depletion causes multiple defects in ovarian function during the periovulatory period in mice.
Zinc depletion causes multiple defects in ovarian function during the periovulatory period in mice.
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DOI：
10.1210/en.2011-1599
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发表时间：
2012-02
期刊：
影响因子：
4.8
通讯作者：
X. Tian;Francisco Javier Diaz
中科院分区：
文献类型：
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作者：
X. Tian;Francisco Javier Diaz
排卵前不久，卵母细胞获得发育能力，颗粒细胞发生巨大变化，包括卵丘扩张和黄素化。锌是体外减数分裂的关键调节因子，但对锌在排卵期介导的作用缺乏完整的了解。本研究揭示了以前未知的锌在维持排卵前减数分裂停滞的作用。锌螯合剂[N，N，N '，N'-四（2-吡啶基甲基）乙二胺（TPEN）]即使在磷酸二酯酶3A抑制剂（米力农）存在下也能引起裸露卵母细胞中的早期萌发囊泡破裂和相关的纺锤体缺陷。TPEN还通过阻断扩张相关转录物Has 2、Ptx 3、Ptgs 2和Tnfaip 6 mRNA的诱导而有效地阻断卵丘扩张。外源锌对减数分裂停滞和积云扩展都有一定的拯救作用。缺乏积云扩展是由于几乎完全抑制磷酸-Sma-和Mad-related蛋白2/3信号。与磷酸-Sma-和Mad-related蛋白2/3信号传导的减少一致，TPEN也减少卵丘转录物（Ar和Slc 38 a3），并引起卵丘细胞中壁转录物（Lhcgr和Cyp 11 a1）的惊人增加。在体内，喂养缺锌饮食10天完全阻断排卵和损害卵丘扩张。然而，42.5%的卵母细胞在注射人绒毛膜促性腺激素前过早恢复减数分裂，强调了排卵前锌的重要性。用缺锌饮食进行更急性的3-d治疗并没有阻止排卵，但确实增加了黄体化卵泡中捕获的卵母细胞数量。此外，23%的排卵卵母细胞没有达到中期II由于严重的纺锤体缺陷。因此，急性缺锌导致排卵期严重缺陷，影响卵母细胞成熟、卵丘扩张和排卵。
Shortly before ovulation, the oocyte acquires developmental competence and granulosa cells undergo tremendous changes including cumulus expansion and luteinization. Zinc is emerging as a key regulator of meiosis in vitro, but a complete understanding of zinc-mediated effects during the periovulatory period is lacking. The present study uncovers the previously unknown role of zinc in maintaining meiotic arrest before ovulation. A zinc chelator [N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN)] caused premature germinal vesicle breakdown and associated spindle defects in denuded oocytes even in the presence of a phosphodiesterase 3A inhibitor (milrinone). TPEN also potently blocked cumulus expansion by blocking induction of expansion-related transcripts Has2, Ptx3, Ptgs2, and Tnfaip6 mRNA. Both meiotic arrest and cumulus expansion were rescued by exogenous zinc. Lack of cumulus expansion is due to an almost complete suppression of phospho-Sma- and Mad-related protein 2/3 signaling. Consistent with a decrease in phospho-Sma- and Mad-related protein 2/3 signaling, TPEN also decreased cumulus transcripts (Ar and Slc38a3) and caused a surprising increase in mural transcripts (Lhcgr and Cyp11a1) in cumulus cells. In vivo, feeding a zinc-deficient diet for 10 d completely blocked ovulation and compromised cumulus expansion. However, 42.5% of oocytes had prematurely resumed meiosis before human chorionic gonadotropin injection, underscoring the importance of zinc before ovulation. A more acute 3-d treatment with a zinc-deficient diet did not block ovulation but did increase the number of oocytes trapped in luteinizing follicles. Moreover, 23% of ovulated oocytes did not reach metaphase II due to severe spindle defects. Thus, acute zinc deficiency causes profound defects during the periovulatory period with consequences for oocyte maturation, cumulus expansion, and ovulation.