Molecular Biology of Spermatogenesis: Novel Targets of Apparently Idiopathic Male Infertility

Abstract

Male infertility affects half of infertile couples and, currently, a relevant percentage of cases of male infertility is considered as idiopathic. Although the male contribution to human fertilization has traditionally been restricted to sperm DNA, current evidence suggest that a relevant number of sperm transcripts and proteins are involved in acrosome reactions, sperm‒oocyte fusion and, once released into the oocyte, embryo growth and development. The aim of this review is to provide updated and comprehensive insight into the molecular biology of spermatogenesis, including evidence on spermatogenetic failure and underlining the role of the sperm-carried molecular factors involved in oocyte fertilization and embryo growth. This represents the first step in the identification of new possible diagnostic and, possibly, therapeutic markers in the field of apparently idiopathic male infertility.

Keywords: DNA fragmentation; embryo growth; male infertility; recurrent pregnancy loss; sperm proteome; sperm transcriptome; spermatogenesis; spermatogenetic failure.

Figure 1

Molecular factors involved in human spermatogenesis. Spermatogenesis is a 74-day-long process required to differentiate spermatogonial stem cells in spermatozoa, divided in three functional steps: spermatogonia proliferation, spermatocyte meiotic division and spermiogenesis. Several factors are specifically involved in each of these steps. Their absence results in the failure of spermatogenesis in a specific phase.

Figure 2

Sperm contribution in fertilization and preimplantation embryo development. Several sperm-carried proteins are involved in acrosome reaction, binding to the zona pellucida (ZP), sperm‒oocyte fusion, and oocyte activation. Soon after sperm penetration into the oocyte, the sperm genome undergoes to global demethylation, much faster than the maternal genome. Embryonic Genome Activation (EGA), a process by which the embryo starts to produce its own transcripts, starts between the four-cell and eight-cell embryo stages. Before this phase, the embryo is sustained by the gametes’ transcriptome and proteome. A list of sperm-specific proteins has been identified in the embryo, in the up to eight-cell, morula, and blastocyst phases.