Sperm-Derived Dysfunction of Human Embryos: Molecular Mechanisms and Clinical Resolution

Apart from the male genome, the fertilizing spermatozoon delivers to the oocyte several factors that are needed for embryonic development and whose deficiency can cause human embryo dysfunction. Sperm oocyte-activating factor, identified as phoshoplipase C zeta (PLCζ), drives oocyte exit from meiotic arrest and preparation for the first mitotic division by a signaling pathway initiated by periodic rises of free cytosolic Ca2+ concentration (calcium oscillations). Sperm centrioles together with oocyte proteins form centrosomes that are responsible for aster formation, pronuclear migration and DNA polarization before nuclear syngamy and subsequent mitotic divisions. Sperm DNA fragmentation can be at the origin of aneuploidies arising from mistakes of zygote mechanisms of DNA repair, while epigenetic issues, mainly abnormal methylation of DNA-associated histones, causes asynchronies of zygotic gene activation among embryonic cells. Sperm long and short noncoding RNAs, mainly, microRNAs, are important epigenetic regulators affecting genes involved in critical developmental processes. Dysfunction of sperm PLCζ, centrioles, DNA and RNA converge to serious impediments of embryo development which ultimately result in aneuploidy, developmental arrest or implantation failure, when manifested early in embryo development, but they may also emerge after implantation and cause miscarriage, abortion or offspring disease. With the exception of DNA fragmentation, the other sperm issues are more difficult to diagnose. Specific tests, including heterologous human intracytoplasmic sperm injection (ICSI) into animal oocytes, genetic testing for mutations in PLCZ1 (the gene coding for PLCζ in humans) and associated genes, and next-generation sequencing of sperm DNA and RNA and currently available. Customized treatment of sperm DNA damage and in vitro selection of healthy spermatozoa can be used in cases of sperm DNA fragmentation, while ICSI with assisted oocyte activation is useful to overcome oocyte-activation defects. No specific and clinically confirmed treatments for problems derived from sperm centrioles, DNA (except fragmentation) and RNA are available yet.