Aitken Robert J, Gibb Zamira
Priority Research Center for Reproductive Science, Discipline of Biological Sciences, University of Newcastle, Callaghan, Australia -
Priority Research Center for Reproductive Science, Discipline of Biological Sciences, University of Newcastle, Callaghan, Australia.
Minerva Endocrinol (Torino). 2022 Mar;47(1):38-57. doi: 10.23736/S2724-6507.21.03630-7. Epub 2022 Feb 15.
Male infertility is a relatively common condition responsible for around 30% of all infertility cases and contributing to another 20%. Although the traditional semen profile is used to diagnose this condition, the criteria at the heart of this analysis are purely descriptive and shed no light on the underlying etiology. Recent research on the causes of male infertility have revealed the importance of three major factors including genetic and epigenetic mutations and a state of oxidative stress. The fundamental complexity of spermatogenesis, involving the coordinated action of over 2000 genes, plus the fact that any gene defect causing infertility will be heavily selected against, means that the genetic landscape for male infertility is characterized by a large number of different mutations each one of which is extremely rare. Such mutations can only remain within the population as a result of passage through the female germ line or transmission via heterozygous males. However, the most common genetic cause of male infertility, Y-chromosome deletions, cannot be propagated by either of these mechanisms and arises de novo in every instance. The presence of Y chromosome mutation in around 5% of severely oligozoospermic males suggests that the male germ line is under a great deal of stress, one form of which is oxidative stress. The latter impairs all aspects of sperm function and also disrupts the integrity of DNA in the sperm nucleus. An oxidative attack on sperm DNA not only generates strand breaks but, more importantly, oxidative base adducts that are extremely mutagenic. It is proposed that the persistence of these lesions into S-phase of the first mitotic division generates de novo mutations that are potentially capable of impacting the long-term health and wellbeing of the offspring including the latter's fertility. To address this issue, the field desperately needs simple validated tests of oxidative stress in the male germ line, that can then be used to direct the appropriate management of these patients.
男性不育是一种相对常见的病症，约占所有不育病例的30%，另有20%的不育病例与之相关。虽然传统的精液分析用于诊断这种病症，但该分析核心的标准纯粹是描述性的，无法揭示潜在病因。最近对男性不育原因的研究揭示了三个主要因素的重要性，包括基因和表观遗传突变以及氧化应激状态。精子发生的基本复杂性涉及2000多个基因的协同作用，再加上任何导致不育的基因缺陷都会受到强烈的自然选择，这意味着男性不育的基因图谱具有大量不同的突变，每个突变都极为罕见。这些突变只能通过雌性生殖系传递或通过杂合子男性遗传才能在种群中保留。然而，男性不育最常见的遗传原因——Y染色体缺失，不能通过这两种机制传播，每次都是从头发生。约5%的严重少精子症男性中存在Y染色体突变，这表明雄性生殖系承受着巨大压力，其中一种形式就是氧化应激。氧化应激会损害精子功能的各个方面，还会破坏精子细胞核中DNA的完整性。对精子DNA的氧化攻击不仅会产生链断裂，更重要的是会产生极具诱变性的氧化碱基加合物。有人提出，这些损伤持续到第一次有丝分裂的S期会产生新的突变，这些突变可能会影响后代的长期健康和幸福，包括后代的生育能力。为了解决这个问题，该领域迫切需要简单且经过验证的雄性生殖系氧化应激检测方法，以便用于指导这些患者的适当治疗。
