Division of Endocrinology, Department of Medicine, Los Angeles Biomedical Research Institute and Harbor-UCLA Medical Center, Torrance, California 90502, USA.
Endocrinology. 2010 Jan;151(1):350-7. doi: 10.1210/en.2009-0577. Epub 2009 Dec 1.
Modulating germ cell death and survival have significant therapeutic potential for male infertility and contraception. We have shown previously that IGF binding protein 3 (IGFBP3) gene expression is up-regulated in human testis when germ cell apoptosis is induced by intratesticular hormonal deprivation created by testosterone administration. Humanin (HN) is a binding partner of IGFBP3, and both are expressed in rat testes. We therefore hypothesized that IGFBP3, a proapoptotic factor, and HN, an antiapoptotic factor, are important regulators of male germ cell apoptosis. Whereas baseline apoptosis in the testis was equivalent between Igfbp3 knockout and wild-type mice, treatment with GnRH antagonist (GnRH-A) for 2 wk induced germ cell apoptosis in wild type, which was dramatically reduced in Igfbp3 knockout mice. To investigate the direct effects of IGFBP3 and HN on germ cell apoptosis, intratesticular administration of IGFBP3 for 5 d in rats induced a 4.2- and 3.8-fold increase in apoptosis at stages VII-VIII and XIV-I of the seminiferous epithelium cycle, respectively. GnRH-A treatment for 5 d increased apoptosis, mainly at stages VII-VIII. Addition of IGFBP3 to GnRH-A treatment enhanced apoptosis to 39.3-fold at stages VII-VIII, which was higher than either treatment alone. Intratesticular injection of HN significantly decreased GnRH-A-induced apoptosis at stages XIV-I but not stages VII-VIII. We conclude that IGFBP3 and HN play key roles in the coordinated regulation of testicular germ cell homeostasis. Perturbation of this interaction is important in enhancing or preventing germ cell death, providing new targets for future therapies.
调节生殖细胞的死亡和存活对男性不育和避孕具有重要的治疗潜力。我们之前已经表明，当通过睾丸内激素剥夺（通过给予睾酮来实现）诱导生殖细胞凋亡时，人 IGF 结合蛋白 3（IGFBP3）基因在人睾丸中表达上调。人源神经调节蛋白（HN）是 IGFBP3 的结合伴侣，两者均在大鼠睾丸中表达。因此，我们假设 IGFBP3（促凋亡因子）和 HN（抗凋亡因子）是男性生殖细胞凋亡的重要调节因子。虽然 Igfbp3 基因敲除和野生型小鼠的睾丸基础凋亡相当，但用 GnRH 拮抗剂（GnRH-A）处理 2 周会诱导野生型小鼠的生殖细胞凋亡，而 Igfbp3 基因敲除小鼠的生殖细胞凋亡则明显减少。为了研究 IGFBP3 和 HN 对生殖细胞凋亡的直接影响，我们在大鼠睾丸内给予 IGFBP3 5 天，分别导致生精上皮周期的 VII-VIII 期和 XIV-I 期的凋亡增加 4.2 倍和 3.8 倍。GnRH-A 处理 5 天会增加凋亡，主要发生在 VII-VIII 期。在 GnRH-A 处理中添加 IGFBP3 会使 VII-VIII 期的凋亡增加到 39.3 倍，高于任何单一处理。HN 向 GnRH-A 处理的睾丸内注射显著降低了 XIV-I 期但不降低 VII-VIII 期的凋亡。我们得出结论，IGFBP3 和 HN 在睾丸生殖细胞动态平衡的协调调节中发挥关键作用。这种相互作用的破坏对于增强或预防生殖细胞死亡很重要，为未来的治疗提供了新的靶点。
