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Gonadotropin-Releasing Hormone I Analog Acts as an Antiapoptotic Factor in Mouse Blastocysts

Departments of Obstetrics and Gynecology (K.K, J.F., J.K., Y.S., T.T.) and Information Science (A.N.) and Faculty of Health Science (H.K.), Akita University School of Medicine, Akita 010-8543, Japan

Address all correspondence and requests for reprints to: Kazuhiro Kawamura, Department of Obstetrics and Gynecology, Akita University School of Medicine, Hondo 1-1-1, Akita 010-8543, Japan. E-mail: kawamura{at}yf7.so-net.ne.jp.

Both GnRH-I and its receptor (GnRHR)-I have been shown to be expressed in the mammalian preimplantation embryo. In this study, we investigated the molecular mechanisms of GnRH-I in the regulation of early embryonic development in mouse. We found that GnRH-I and GnRHR-I mRNAs were detectable throughout early embryonic stages and that expression levels of both increased significantly after the early blastocyst stage. In blastocysts, GnRH-I and GnRHR-I expression was detected in both inner cell mass and trophectoderm cells. The pregnant uterus also expressed both genes, suggesting that preimplantation embryos could be affected by GnRH through both paracrine and autocrine signaling. Treatment with GnRH-I agonist, buserelin, promoted development of two-cell-stage embryos to the expanded and hatched blastocyst stages and inhibited apoptosis in a dose-dependent manner. In contrast, treatment with GnRH-I antagonist, ganirelix acetate, inhibited development of preimplantation embryos beyond the expanded blastocyst stage and induced apoptosis; both effects could be reversed by cotreatment with GnRH-I agonist. GnRH-I antagonist-induced cell death was mediated by disruption of mitochondrial function, release of cytochrome c, and activation of caspase-3. Furthermore, treatment with GnRH-I antagonist decreased expression of two antiapoptotic growth factors, epidermal growth factor and IGF-II, in blastocysts. These results indicate that GnRH-I, acting as an antiapoptotic factor, is an important growth factor in development of mouse blastocysts.

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