Sperm cell biology: current perspectives and future prospects.

M ajor 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), transcripts (transcriptomics), proteins (proteomics) and the various metabolites (metabolomics). It is now possible to secure inventories of lipids, proteins, metabolites and RNA species in purified cell populations and to determine how these entities change in relation to cellular function. The humble spermatozoon is an ideal target for these new technologies because these cells can be obtained in large numbers, in an absolutely pure state and can be routinely and robustly induced to perform their major biological function—fertilization–in vitro. The spermatozoon is also an excellent target for proteomics because the functional transformation of these cells during their journey from the seminiferous tubules of the testes to the surface of the oocyte, takes place in the complete absence of contemporaneous gene transcription. Rather, functionality is conferred upon these cells by post-translational changes to their protein complement that, in turn, induce critical changes in sperm metabolism. Integrating the ’omics profiles of spermatozoa holds the key to understanding the molecular mechanisms that regulate their biology. The development of these powerful new analytical tools that include DNA sequencing, DNA microarrays, mass spectrometry and protein arrays, with user interfaces that encourage their incorporation into gamete biology laboratories, will ensure that we learn more about the cell biology of mammalian spermatozoa in the next 5 years than we have learnt in the previous 50. In this Special Issue of Asian Journal of Andrology, we acknowledge these technical developments by highlighting contributions that have been made by some of the pioneers of sperm cell ’omics. Mark Baker, for example, has been responsible for developing the first detailed proteomic profiles of human, rat and mouse spermatozoa and, in so doing, has created a resource that can be used by all gamete biologists to further their research on the cell biology of spermatozoa. Mark has also pioneered the use of label free proteomics to determine how the protein structure of mammalian spermatozoa changes in concert with their physiological status during epididymal transit or capacitation. These studies have opened up new avenues of research on the roles played by membrane receptors, kinases and specific chaperones in the control of sperm function. Moreover, technologies are now available that allow us to drill down into specific subsets of proteins such as the phosphoproteome or the glycome that will further elucidate the molecular underpinnings of normal and pathological sperm function. Of course, not all aspects of sperm function are driven by changes in the proteome, and lipid biochemistry is also an extremely important facet of the regulatory process. The chapter from Joel Drevet’s group illustrates this point beautifully. Using genetically modified mice these researchers show that the regulation of cholesterol homeostasis in the epididymis is absolutely critical in the expression of normal sperm function. While Mark Baker has focused largely on the proteomic analyses of isolated spermatozoa, Xiaoyan Huang has concentrated on the proteomic analysis of testes and precursor germ cells, again generating inventories of proteins that will be of immense value to the entire community of scientists trying to understand the molecular regulation of male fertility. Raphael Oliva follows this theme by expertly summarizing the avalanche of data that is now being generated on the proteomic changes associated with spermatogenesis, epididymal maturation and capacitation, and focuses our attention on sperm chromatin. The evolution of chromatin structure is clearly a key aspect of sperm cell biology. It begins with chromatin remodeling during spermiogenesis to create a highly compacted, crosslinked nucleus that is absolutely unique to this cell type and extends to the subsequent unraveling of this structure in the oocyte, following fertilization. The mechanisms that control the remodeling of sperm chromatin during spermiogenesis and epididymal maturation are clearly extremely complex and are only now being resolved. Steven Ward is an international authority on this topic and has prepared an authoritative summary of current concepts and, specifically, emerging evidence suggesting an important role for the nuclear matrix in the functional organization of sperm chromatin. According to this model, points of attachment between the DNA linker regions and the nuclear matrix may be important for the initiation of DNA cleavage during apoptosis by topoisomerase II. It would indeed be interesting to know whether the factors that induce apoptosis in human spermatozoa consistently generate 50-kb fragments typical of nuclear toroids. Additionally, DNA can also be damaged by reactive oxygen species (ROS) that induce oxidized base adduct formation (largely 8-hydroxy-2’-deoxyguanosine), leading to the creation of abasic sites, destabilization of the DNA backbone and fragmentation. In this case, however, the DNA fragmentation will not be into discrete 50-kb toroid fragments, but into much smaller fragments in the 20–25 kb range. In the review of DNA damage, John Aitken points out the possible involvement of ROS generated during sperm apoptosis in the etiology of defective sperm function and DNA damage. Ralf Henkel also provides a very comprehensive discussion of the importance of oxidative stress in the impairment of sperm function and the chemical principles that underpin these negative effects. In this chapter, the nature of the ROS source Asian Journal of Andrology (2011) 13, 3–5 2011 AJA, SIMM & SJTU. All rights reserved 1008-682X/11 $32.00