DNA damage of spermatozoa and its influence on embryonal development

研究表明，男性不育症患者的精子基因组DNA受损可遗传给后代，并可能抑制胚胎发育。我们最近的研究表明，高水平的氧化应激导致精子DNA损伤，这种应激诱导睾丸生殖细胞凋亡损失。在本研究中，我们研究了睾丸生殖细胞DNA损伤和凋亡的机制，并研究了早期人和大鼠胚胎的凋亡信号。得到的结果如下：1。热休克蛋白105 （HSP105）特异性定位于生殖细胞，并可能在热休克后转运到细胞核中。HSP105在阴囊温度下与p53形成复合物，在阴囊上温度下与p53分离。在手术诱导的未成熟大鼠隐睾症中，黄嘌呤氧化酶抑制剂减轻了隐睾的重量减轻和生殖细胞的凋亡损失。在培养的睾丸细胞中，黄嘌呤氧化酶抑制剂可以阻止DNA分裂成低分子量的细胞凋亡阶梯。在大鼠胚胎中，Fas mRNA仅在2细胞期表达，而Fas配体（Fas L） mRNA在卵母细胞、原核（1细胞）和2细胞期均有表达。在人胚胎中，Fas mRNA仅在4细胞阶段表达，而Fas L mRNA在2细胞和4细胞阶段均有表达。综上所述，1)HSP105可能有助于阴囊温度下生殖细胞细胞质中p53蛋白的稳定，2)黄嘌呤氧化酶抑制剂可抑制热应激诱导的生殖细胞凋亡，3)大鼠2细胞胚胎和人4细胞胚胎中Fas和Fas L mrna的同时表达可能与早期胚胎凋亡有关。

It has been suggested that damaged genomic DNA of the spermatozoa in patients with male infertility can be transmitted to the progeny, and may inhibit embryonal development. Recent our studies have demonstrated that a high level of oxidative stress causes DNA damages of the spermatozoa, and such stress induce apoptotic loss of testicular germ cells. In this study, we investigated the mechanism of DNA damage and apoptosis in the testicular germ cells, and investigate the apoptotic signals of early human and rat embryos. The results obtained are as follows.1. Heat shock protein 105 (HSP105) is specifically localized in the germ cells, and may translocate into the nucleus after heat shock. HSP105 is suggested to form a complex with p53 at scrotal temperature, and dissociate from it at suprascrotal temperature.2. In the surgically induced cryptorchidism in immature rats, xanthine oxidase inhibitors attenuated weight reduction of the cryptorchid testis and apoptotic loss of germ cells. In cultured testicular cells, treatment with xanthine oxidase inhibitors prevented DNA cleavage into low molecular weight ladders characteristic of apoptosis.3. In rat embryos, Fas mRNA was expressed at 2-cell stage only, whereas Fas ligand (Fas L) mRNA was expressed at oocytes, pronuclear (1-cell) and 2-cell stages. In human embryos, Fas mRNA was expressed at the 4-cell stage only, whereas Fas L mRNA was expressed at both 2-and 4-cell stages.In conclusions, 1)HSP105 may contribution to stabilization of p53 proteins in the cytoplasm in the germ cells at scrotal temperature, 2)Xanthine oxidase inhibitors inhibit apoptotic death of germ cell induced by heat stress, and 3) Simultaneous expression of Fas and Fas L mRNAs at 2-cell embryos in rats and 4-cell embryos in human may be associated with apoptosis of the early embryos.