The Role of Genetics and Oxidative Stress in the Etiology of Male Infertility-A Unifying Hypothesis?

Robert John Aitken,Mark A Baker

doi:10.3389/fendo.2020.581838

Abstract

Despite the high prevalence of male infertility, very little is known about its etiology. In recent years however, advances in gene sequencing technology have enabled us to identify a large number of rare single point mutations responsible for impeding all aspects of male reproduction from its embryonic origins, through the endocrine regulation of spermatogenesis to germ cell differentiation and sperm function. Such monogenic mutations aside, the most common genetic causes of male infertility are aneuploidies such as Klinefelter syndrome and Y-chromosome mutations which together account for around 20–25% of all cases of non-obstructive azoospermia. Oxidative stress has also emerged as a major cause of male fertility with at least 40% of patients exhibiting some evidence of redox attack, resulting in high levels of lipid peroxidation and oxidative DNA damage in the form of 8-hydroxy-2'-deoxyguanosine (8OHdG). The latter is highly mutagenic and may contribute to de novo mutations in our species, 75% of which are known to occur in the male germ line. An examination of 8OHdG lesions in the human sperm genome has revealed ~9,000 genomic regions vulnerable to oxidative attack in spermatozoa. While these oxidized bases are generally spread widely across the genome, a particular region on chromosome 15 appears to be a hot spot for oxidative attack. This locus maps to a genetic location which has linkages to male infertility, cancer, imprinting disorders and a variety of behavioral conditions (autism, bipolar disease, spontaneous schizophrenia) which have been linked to the age of the father at the moment of conception. We present a hypothesis whereby a number of environmental, lifestyle and clinical factors conspire to induce oxidative DNA damage in the male germ line which then triggers the formation de novo mutations which can have a major impact on the health of the offspring including their subsequent fertility.

Highlights

Spermatogenesis is an immensely complicated process involving the coordinated action of thousands of genes in order to generate one of the most complex, specialized cell types in human biology, the spermatozoon
A majority of such cells are diploid and the etiology involves mutations in the AURKC gene [16]. The incidence of these mutations varies from population to population but a recent analysis of North African males suggested that AURKC mutations were the most common, comprising 2.7% of the infertile male population compared with 1.2% exhibiting DPY19L2-dependent globozoospermia and anticipated rates of 1.6% exhibiting Klinefelter syndrome and 0.23% with Y-chromosome deletion [19]
Just as we saw with mutations affecting sperm structure and function, gene mutations leading to primary testicular failure are many, varied and infrequent, reflecting the underlying complexity of the spermatogenic process and the inability of any particular mutation to become anything other than rare, given: [1] the negative selection pressure associated with male infertility, [2] the fact that many of these mutations cause infertility in women and so cannot find refuge in the female germ line [67], and [3] the absence of any particular reproductive advantage in the heterozygous form

Summary

INTRODUCTION

Spermatogenesis is an immensely complicated process involving the coordinated action of thousands of genes in order to generate one of the most complex, specialized cell types in human biology, the spermatozoon. Just as we saw with mutations affecting sperm structure and function, gene mutations leading to primary testicular failure are many, varied and infrequent, reflecting the underlying complexity of the spermatogenic process and the inability of any particular mutation to become anything other than rare, given: [1] the negative selection pressure associated with male infertility, [2] the fact that many of these mutations cause infertility in women and so cannot find refuge in the female germ line [67], and [3] the absence of any particular reproductive advantage in the heterozygous form These mutations are generally autosomal recessive and inherited from fertile parents in homozygous, compound heterozygous or hemizygous form. This oxidatively damaged DNA is brought into the oocyte by the fertilizing sperm, overwhelming the latter’s capacity for effective DNA repair and stimulating the creation of de novo mutations that impact the health and well-being, and potentially the fertility, of the offspring

A Unifying Concept

Findings

CONCLUSION