Reproductive Science Group, Priority Research Centre in Reproductive Science, School of Environmental and Life Sciences, Discipline of Biological Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.
TRG Gynecology & Andrology and Male Health Care Research, Bayer Schering Pharma AG, Berlin, Germany.
Free Radic Biol Med. 2013 Dec;65:872-881. doi: 10.1016/j.freeradbiomed.2013.05.021. Epub 2013 May 23.
Oxidative stress in the male germ line is known to be a key factor in both the etiology of male infertility and the high levels of DNA damage encountered in human spermatozoa. Because the latter has been associated with a variety of adverse clinical outcomes, including miscarriage and developmental abnormalities in the offspring, the mechanisms that spermatozoa use to defend themselves against oxidative stress are of great interest. In this context, the male germ line expresses three unique forms of thioredoxin, known as thioredoxin domain-containing proteins (Txndc2, Txndc3, and Txndc8). Two of these proteins, Txndc2 and Txndc3, retain association with the spermatozoa after spermiation and potentially play an important role in regulating the redox status of the mature gamete. To address this area, we have functionally deleted the sperm-specific thioredoxins from the male germ line of mice by either exon deletion (Txndc2) or mutation of the bioactive cysteines (Txndc3). The combined inactivation of these Txndc isoforms did not have an overall impact on spermatogenesis, epididymal sperm maturation, or fertility. However, Txndc deficiency in spermatozoa did lead to age-dependent changes in these cells as reflected by accelerated motility loss, high rates of DNA damage, increases in reactive oxygen species generation, enhanced formation of lipid aldehyde-protein adducts, and impaired protamination of the sperm chromatin. These results suggest that although there is considerable redundancy in the systems employed by spermatozoa to defend themselves against oxidative stress, the sperm-specific thioredoxins, Txndc2 and Txndc3, are critically important in protecting these cells against the increases in oxidative stress associated with paternal age.
已知雄性生殖细胞中的氧化应激是男性不育症的病因和人类精子中高水平 DNA 损伤的关键因素。由于后者与多种不良临床结局相关，包括流产和后代发育异常，因此精子用来抵御氧化应激的机制引起了极大的关注。在这种情况下，雄性生殖细胞表达三种独特的硫氧还蛋白形式，称为硫氧还蛋白结构域蛋白（Txndc2、Txndc3 和 Txndc8）。这两种蛋白质，Txndc2 和 Txndc3，在精子发生后仍与精子结合，并可能在调节成熟配子的氧化还原状态方面发挥重要作用。为了解决这一问题，我们通过外显子缺失（Txndc2）或生物活性半胱氨酸突变（Txndc3）从雄性生殖细胞中功能性缺失了精子特异性硫氧还蛋白。这些 Txndc 同工型的联合失活对精子发生、附睾精子成熟或生育能力没有总体影响。然而，精子中 Txndc 的缺失确实导致这些细胞发生年龄依赖性变化，表现为运动能力丧失加速、DNA 损伤率高、活性氧生成增加、脂质醛蛋白加合物形成增强以及精子染色质的鱼精蛋白化受损。这些结果表明，尽管精子用来抵御氧化应激的系统存在相当大的冗余，但精子特异性硫氧还蛋白 Txndc2 和 Txndc3 对于保护这些细胞免受与父系年龄相关的氧化应激增加至关重要。
