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Apoptosis and DNA damage in human spermatozoa

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Asian Journal of Andrology 2011年第1期13卷 36-42页

作者： r john aitken Adam J Koppers ArC Centre of Excellence in Biotechnology and Development Priority Research Centre in Reproductive Science Discipline of Biological Sciences School of Environmental and Life Sciences University of Newcastle Callaghan NSW 2308 Australia Department of Anatomy and Developmental Biology School of Biomedical Sciences Monash University Clayton VIC 3800 Australia

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.

关键词： apoptosis DNA damage oxidative stress spermatozoa

Sperm cell biology： current perspectives and future prospects

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Asian Journal of Andrology 2011年第1期13卷 3-5页

作者： r john aitken ralf r Henkel Discipline of Biological Sciences University of Newcastle Newcastle NSW 2308 Australia Department of Medical Biosdences University of the Western Cape Bellville 7535 South Africa

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 ＇... 详细信息

关键词： Sperm cell biology perspectives

Cellular mechanisms regulating sperm-zona pellucida interaction

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Asian Journal of Andrology 2011年第1期13卷 88-96页

作者： Andrew T reid Kate redgrove r john aitken Brett Nixon reproductive Science Group Discipline of Biological Sciences School of Environmental and Life Sciences University of Newcastle Callaghan NSW 2308 Australia ArC Centre of Excellence in Biotechnology and Development Discipline of Biological Sciences School of Environmental and Life Sciences University of Newcastle CaUaghan NSW 2308 Australia

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.

关键词： capacitation fertilization spermatozoa sperm-zona pellucida interaction

The 12th International Symposium on Spermatology

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Asian Journal of Andrology 2015年第4期17卷 519-520页

作者： r john aitken Jim M Cummins Brett Nixon Priority research Centre in reproductive Science Discipline of Biological Sciences and HunterMedical Research Institute University of NewcastleNSW 2308 Australia Division of Veterinary andBiomedical Sciences Murdoch University MurdochWA. Australia.

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.

关键词： International Symposium Spermatology

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

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Asian Journal of Andrology 2015年第4期17卷 623-627页

作者： Samantha AM Young r john aitken Masahito Ikawa Priority research Centre in reproductive Science Discipline of Biological Sciences Faculty of Scienceand IT University of Newcastle Callaghan NSWAustralia Animal resource Centre for InfectiousDiseases Research Institute for Microbial DiseasesOsaka University Suita Osaka Japan.Correspondence: Prof. M Ikawa

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.

关键词： Advantages investigate mechanisms

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

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Asian Journal of Andrology 2015年第4期17卷 568-573页

作者： Brett Nixon Elizabeth G Bromfield Matthew D Dun Kate A redgrove Eileen A McLaughlin r john aitken priority research Centre in reproductive Science School of Environmental and Life Sciences Discipline of Biological Sciences University of Newcastle CallaghanNSW 2308 Australia Priority research Centre in Chemical Biology School of Environmental and Life Sciences Discipline of Biological Sciences University of NewcastleCallaghan NSW 2308 Australia Hunter Cancer research Alliance School of Biomedical Sciences and Pharmacy Faculty of Health and Medicine NSW Australia

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.

关键词： egg fertilization heat shock protein A2 molecular chaperone sperm sperm-egg interactions

Proteomic changes in mammalian spermatozoa during epididymal maturation

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Asian Journal of Andrology 2007年第4期9卷 554-564页

作者： r. john aitken Brett Nixon Minjie Lin Adam J. Koppers Yun H. Lee Mark A. Baker The ArC Centre of Excellence in Biotechnology and Development University of Newcastle Newcastle NSW 2308Australia Discipline of Biological Sciences University of Newcastle Newcastle NSW 2308 Australia

Epididymal maturation is associated with the activation of a cAMP-induced tyrosine phosphorylation cascade, which is ultimately associated with the expression of capacitation-dependent sperm functions, such as hyperactivated movement and acrosomal exocytosis. As spermatozoa progress through the epididymis they first acquire the capacity to phosphorylate tyrosine on targets on the principal piece, followed by the midpiece. By the time these cells have reached the cauda epididymidis they can phosphorylate the entire tail from neck to endpiece. This particular pattern of phosphorylation is associated with the ontogeny of fully functional spermatozoa that are capable of fertilizing the oocyte. Proteomic analyses indicate that this change is associated with the phosphorylation of several mitochondrial proteins, creation of a mitochondrial membrane potential and activation of mitochondrial free radical generation. At least in rodent species, activation of sperm mitochondria appears to be a particularly important part of epididymal maturation. （Asian J Androl 2007 July; 9： 554-564）

关键词： epididymis mitochondria spermatozoa tyrosine phosphorylation

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

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Asian Journal of Andrology 2015年第4期17卷 574-582页

作者： Nongnuj Tanphaichitr Kessiri Kongmanas Hathairat Kruevaisayawan Arpornrad Saewu Clarissa Sugeng Jason Fernandes Puneet Souda Jonathan B Angel Kym F Faull r john aitken Julian Whitelegge Daniel Hardy Trish Berger Mark Baker Chronic Disease Program Ottawa Hospital ResearchInstitute Ottawa Ontario Canada Department ofObstetrics and Gynaecology University of OttawaOntario Canada Department of Biochemistry Microbiology and Immunology University of OttawaOntario Canada Department of Anatomy Faculty ofMedical Sciences Naresuan University PhitsanulokThailand Division of Infectious Diseases OttawaHospital - General Campus Ottawa Ontario Canada Pasarow Mass Spectrometry Laboratory Universityof California Los Angeles California USA TheArC Centre of Excellence in Biotechnology andDevelopment School of Environmental and LifeSciences University of Newcastle Callaghan NewSouth Wales Australia Department of Cell Biologyand Biochemistry Health Sciences Center Texas TechUniversity Texas USA Department of Animal ScienceUniversity of California Davis California USA

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.

关键词： SPErM CAPACITATION ANDSPErM-ZONA PELLUCIDAINTErACTION- BACKGrOUND ANDCONFUSION IN THE FIELDS

Phosphorylation of Izumo1 and its role in male nfertility

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Asian Journal of Andrology 2015年第5期17卷 708-710,I0005页

作者： Samantha AM Young john aitken Mark A Baker priority research Centre in reproductive Science Discipline of Biological Sciences Faculty of Science and IT University of Newcastle Callaghan NSW Australia Animal resource Centre for Infectious Diseases Research Institute for Microbial Diseases Osaka University Suita Osaka Japan

Izumol is a testis-specific gene product, whose function is essential for sperm-egg fusion. Throughout its lifespan, Izumol is posttranslationally modified, being both N-linked glycosylated on its extracellular domain and phosphorylated on the intracellular C-terminal tail. Within the caput regions of the rat epididymis, two phosphorylation events have been documented. However, as sperm pass through the epididymis, this cytoplasmic portion of Izumol has been shown to contain up to seven phosphorylation sites. remarkably, in the rat, in correlation with these events, Izumol undergoes sub-cellular re-location, moving from the head/tail regions of the spermatozoa, to a predominantly equatorial segment location once they have reached the caudal end of the epididymis.

关键词： epididymis Izumol LC-MS phosphorylation proteomics