Apoptosis and DNA damage in human spermatozoa

DNA damage is frequently encountered in spermatozoa of subfertile males and is correlated with a range of adverse clinical outcomes including impaired fertilization, disrupted preimplantation embryonic development, increased rates of miscarriage and an enhanced risk of disease in the progeny. The etiology of DNA fragmentation in human spermatozoa is closely correlated with the appearance of oxidative base adducts and evidence of impaired spermiogenesis. We hypothesize that oxidative stress impedes spermiogenesis, resulting in the generation of spermatozoa with poorly remodelled chromatin. These defective cells have a tendency to default to an apeptotic pathway associated with motility loss, caspase activation, phosphatidylserine exteriorization and the activation of free radical generation by the mitochondria. The latter induces lipid peroxidation and oxidative DNA damage, which then leads to DNA fragmentation and cell death. The physical architecture of spermatozoa prevents any nucleases activated as a result of this apoptotic process from gaining access to the nuclear DNA and inducing its fragmentation. It is for this reason that a majority of the DNA damage encountered in human spermatozoa seems to be oxidative. Given the important role that oxidative stress seems to have in the etiology of DNA damage, there should be an important role for antioxidants in the treatment of this condition. If oxidative DNA damage in spermatozoa is providing a sensitive readout of systemic oxidative stress, the implications of these findings could stretch beyond our immediate goal of trying to minimize DNA damage in spermatozoa as a prelude to assisted conception therapy.

Cellular mechanisms regulating sperm-zona pellucida interaction

For mammalian spermatozoa to exhibit the ability to bind the zona pellucida （ZP） they must undergo three distinct phases of maturation, namely, spermatogenesis （testis）, epididymal maturation （epididymis） and capacitation （female reproductive tract）. An impressive array of spermatozoa surface remodeling events accompany these phases of maturation and appear critical for recognition and adhesion of the outer vestments of the oocyte, a structure known as the ZP. It is becoming increasingly apparent that species-specific zona adhesion is not mediated by a single receptor. Instead, compelling evidence now points toward models implicating a multiplicity of receptor-ligand interactions. This notion is in keeping with emerging research that has shown that there is a dynamic aggregation of proteins believed to be important in sperm-ZP recognition to the regions of sperm that mediate this binding event. Such remodeling may in turn facilitate the assembly of a multimeric zona recognition complex （MZRC）. Though formation of MZRCs raises questions regarding the nature of the block to polyspermy, formation and assembly of such a structure would no doubt explain the strenuous maturation process that sperm endure on their sojourn to functional maturity.

Falling sperm counts twenty years on： where are we now？

Poor semen quality is an attribute of the human condition that we sharewith our closest primate ancestors and may be part of our evolutionary inheritance. This characteristic may also reflect the lack of selection pressure on male fertility in advanced societies that have gone through the demographic transition. In the future, such trends may be further exacerbated by the widespread use of ART, which will impair the elimination of low fecundity genotypes from the human gene pool. Environmental pollutants may also be influencing male fertility, however, neither the chemical identity of these factors nor their mechanism-of-action are fully understood.

Sperm cell biology： current perspectives and future prospects

Major advances in biomolecular techniques as well as in the sensitivity and accuracy of mass spectrometers are transforming the scientific landscape by fueling unprecedented advances in analytical biochemistry--the ＇omics revolution, which refers to the study of genes （genomics）,

The role of the molecular chaperone heat shock protein A2 （HSPA2） in regulating human sperm-egg recognition

One of the most common lesions present in the spermatozoa of human infertility patients is an idiopathic failure of sperm-egg recognition. Although this unique cellular interaction can now be readily by-passed by assisted reproductive strategies such as intracytoplasmic sperm injection （ICSI）, recent large-scale epidemiological studies have encouraged the cautious use of this technology and highlighted the need for further research into the mechanisms responsible for defective sperm-egg recognition. Previous work in this field has established that the sperm domains responsible for oocyte interaction are formed during spermatogenesis prior to being dynamically modified during epididymal maturation and capacitation in female reproductive tract. While the factors responsible for the regulation of these sequential maturational events are undoubtedly complex, emerging research has identified the molecular chaperone, heat shock protein A2 （HSPA2）, as a key regulator of these events in human spermatozoa. HSPA2 is a testis-enriched member of the 70 kDa heat shock protein family that promotes the folding, transport, and assembly of protein complexes and has been positively correlated with in vitro fertilization （IVF） success. Furthermore, reduced expression of HSPA2 from the human sperm proteome leads to an impaired capacity for cumulus matrix dispersal, sperm-egg recognition and fertilization following both IVF and ICSI. In this review, we consider the evidence supporting the role of HSPA2 in sperm function and explore the potential mechanisms by which it is depleted in the spermatozoa of infertile patients. Such information offers novel insights into the molecular mechanisms governing sperm function.

Advantages of using the CRISPR/Cas9 system of genome editing to investigate male reproductive mechanisms using mouse models

Gene disruption technology has long been beneficial for the study of male reproductive biology. However, because of the time and cost involved, this technology was not a viable method except in specialist laboratories. The advent of the CRISPR/Cas9 system ofgene disruption has ushered in a new era of genetic investigation. Now, it is possible to generate gene-disrupted mouse models in very tittle time and at very little cost. 1his Highlight article discusses the application of this technology to study the genetics of male fertility and looks at some of the future uses of this system that could be used to reveal the essential and nonessential genetic components of male reproductive mechanisms.

Remodeling of the plasma for sperm-egg recognition： proteins membrane in preparation roles of acrosomal

The interaction of sperm with the egg＇s extracellular matrix, the zona pellucida （ZP） is the first step of the union between male and female gametes. The molecular mechanisms of this process have been studied for the past six decades with the results obtained being both interesting and confusing. In this article, we describe our recent work, which attempts to address two lines of questions from previous studies. First, because there are numerous ZP binding proteins reported byvarious researchers, how do these proteins act together in sperm-ZP interaction？ Second, why do a number of acrosomal proteins have ZP affinity？ Are they involved mainly in the initial sperm-ZP binding or rather in anchoring acrosome reacting/reacted spermatozoa to the ZP？ Our studies reveal that a number of ZP binding proteins and chaperones, extracted from the anterior sperm head plasma membrane, coexist as high molecular weight （HMW） complexes, and that these complexes in capacitated spermatozoa have preferential ability to bind to the ZP. Zonadhesin （ZAN）, known as an acrosomal protein with ZP affinity, is one of these proteins in the HMW complexes. Immunoprecipitation indicates that ZAN interacts with other acrosomal proteins, proacrosin/acrosin and sp32 （ACRBP）, also present in the HMW complexes. Immunodetection of ZAN and proacrosin/acrosin on spermatozoa further indicates that both proteins traffic to the sperm head surface during capacitation where the sperm acrosomal matrix is still intact, and therefore they are likely involved in the initial sperm-ZP binding step.

The 12th International Symposium on Spermatology

The 12th International Symposium of Spermatology continued the excellent tradition of this meeting since its inception in 1969 when the first Symposium was held in Italy under the Chairmanship of Professor Baccio Baccetti. This unique Symposium is held every 4 years and serves as a beacon for sperm cell biologists from all over the world, regardless of which species, animal or plant, they are working on. This willingness to embrace the fundamental biology of this distinctive cell type without species limitations is one of the hallmarks of this Symposium. For sperm biologists - it is our Olympics. The meeting in Newcastle, NSW brought together around 300 biologists from more than 22 different countries covering North and South America, Africa, Europe, Asia and Australia. Given the considerable distances and high cost involved in travelling to the East Coast of NSW, this was an outstanding outcome. The Symposium featured a series of 31 plenary lectures culminating in the prestigious Thaddeus Mann Memorial Lecture, which was delivered with typical grace and brilliance by Professor Masaru Okabe.