Center for Reproductive Biology and Health, Department of Poultry Science, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Endocrinology. 2012 Feb;153(2):873-86. doi: 10.1210/en.2011-1599. Epub 2011 Dec 6.
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.
在排卵前不久，卵母细胞获得发育能力，颗粒细胞发生巨大变化，包括卵丘扩展和黄体化。锌作为体外减数分裂的关键调节剂而出现，但对排卵期间锌介导的作用还缺乏全面了解。本研究揭示了锌在维持排卵前减数分裂阻滞中的先前未知作用。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）存在的情况下，也会导致裸卵母细胞过早发生生发泡破裂和相关的纺锤体缺陷。TPEN 还通过阻断与扩展相关的转录物 Has2、Ptx3、Ptgs2 和 Tnfaip6mRNA 的诱导，有效地阻止卵丘扩展。外源性锌可挽救减数分裂阻滞和卵丘扩展。卵丘扩展的缺失是由于磷酸化 Smad 和 Mad 相关蛋白 2/3 信号的几乎完全抑制。与磷酸化 Smad 和 Mad 相关蛋白 2/3 信号的减少一致，TPEN 还降低了卵丘细胞中的转录物（Ar 和 Slc38a3），并导致壁细胞中的转录物（Lhcgr 和 Cyp11a1）出人意料地增加。在体内，用缺锌饮食喂养 10 天完全阻断排卵并损害卵丘扩展。然而，在人绒毛膜促性腺激素注射前，42.5%的卵母细胞过早恢复减数分裂，强调了排卵前锌的重要性。更急性的缺锌饮食 3 天处理不会阻止排卵，但会增加被束缚在黄体化卵泡中的卵母细胞数量。此外，由于严重的纺锤体缺陷，23%的排卵卵母细胞未能达到中期 II 期。因此，急性锌缺乏症在排卵期间会导致严重缺陷，对卵母细胞成熟、卵丘扩展和排卵产生影响。
