Sperm oxidative stress in the context of male infertility: current evidence, links with genetic and epigenetic factors and future clinical needs.

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.