Summaries of new peer-reviewed publications
Reviews
“It is apparent that the scientific community in the past few decades has witnessed impressive progress in understanding the basics of male physiology, the knowledge necessary for developing new contraceptive methods for men… The diverse approaches that are at various stages of development and/or in clinical trials include: 1) administration of hormones, herbal extracts or chemicals to suppress/arrest sperm production in the testes (spermatogenesis); 2) interference with the delivery of spermatozoa during ejaculation by targeted blockage of vas deferens with plugs or chemicals (polymers) that prevent flow of sperm through the vas duct; 3) active or passive immunization of males with well characterized antigens/antibodies which are intended to block sperm function; and 4) administration of site-directed antagonists to block specific sperm function(s) necessary for normal fertilization.”
Male contraception: an overview of the potential target events.
Tulsiani DR, Abou-Haila A.
Endocr Metab Immune Disord Drug Targets. 2008 Jun;8(2):122-31.
PMID: 18537698
Endocinological supporting research
“For hormone replacement in men, administration of C19 androgens such as testosterone (T) may lead to elevations in circulating levels of estrogens due to aromatization. As several reports have suggested that certain 19-norandrogens may serve as substrates for the aromatase enzyme and are converted to the corresponding aromatic A-ring products, it was important to investigate whether DMA, the related compound, 11beta-methyl-19-nortestosterone (11beta-MNT), also being tested for hormonal therapy in men, and other 19-norandrogens can be converted to aromatic A-ring products by human aromatase… [There] was no detectable conversion of DMA, 11beta-MNT, or NET to their respective hypothetical aromatic A-ring products during incubation times up to 180min. Aromatization of MENT and 19-NT proceeded slowly and was limited.”
Dimethandrolone (7alpha,11beta-dimethyl-19-nortestosterone) and 11beta-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase.
Attardi BJ, Pham TC, Radler LM, Burgenson J, Hild SA, Reel JR.
J Steroid Biochem Mol Biol. 2008 May 28;110(3-5):212-220. [Epub ahead of print]
PMID: 18555683
“This novel lanthanide-coordinated, DTPA-labeled INSL3 has excellent sensitivity, stability, and high specific activity, properties that will be particularly beneficial in high-throughput screening of INSL3 analogues in structure-activity studies.”
Solid-Phase Synthesis of Europium-Labeled Human INSL3 as a Novel Probe for the Study of Ligand-Receptor Interactions.
Shabanpoor F, Hughes RA, Bathgate RA, Zhang S, Scanlon DB, Lin F, Hossain MA, Separovic F, Wade JD.
Bioconjug Chem. 2008 Jun 5. [Epub ahead of print]
PMID: 18529069
Genomic / proteomic supporting research
A report of the gene expression controlling the “coordinated maturation of spermatogonia, spermatocytes, and spermatids... Microarray analysis using Rat Genome 230 2.0 arrays identified 16,971 probe sets that recognized testicular transcripts, and 398 of these were identified as testis-specific. Expression of 1,286 probe sets were found to differ at least 4-fold between two cell types and also across the stages of the cycle. Pathway and annotated cluster analyses of those probe sets predicted that entire biological pathways and processes are regulated cyclically in specific cells. Important among these are the cell cycle, DNA repair, and embryonic neuron development. Taken together, these data indicate that stage-regulated gene expression is a widespread and fundamental characteristic of spermatogenic cells and Sertoli cells.”
Stage-specific gene expression is a fundamental characteristic of rat spermatogenic cells and Sertoli cells.
Johnston DS, Wright WW, Dicandeloro P, Wilson E, Kopf GS, Jelinsky SA.
Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8315-20. Epub 2008 Jun 10.
PMID: 18544648
The authors have “identified eight members of the ADAM family, seven of which have previously been detected in spermatozoa (ADAM2, -3, -4, -5, -6, -7, and -30) while ADAM34 has been identified in the sperm proteome for the first time. Approximately 21 gene products were found to possess isomerase activity including peptidylprolyl cis/trans isomerases that are known to be involved in germ cell differentiation and protein disulfide isomerases that have been implicated in sperm-oocyte fusion. Furthermore, 51 gene products clustered into ion-transporter activity. This inventory of gene products, the first ever 2-D LC-MS/MS analysis of rat spermatozoa, will be invaluable in directing future research into the molecular mechanisms that drive these highly specialized cells.”
The rat sperm proteome characterized via IPG strip prefractionation and LC-MS/MS identification.
Baker MA, Hetherington L, Reeves G, Müller J, Aitken RJ.
Proteomics. 2008 Jun;8(11):2312-21.
PMID: 18528845
Glycolipid metabolism targets
“In all recipient mice, irrespective of reproductive phenotype, NB-DNJ has a similar biochemical effect: inhibition of the glucosylceramidase beta-glucosidase 2 and subsequent elevation of glucosylceramide, a glycosphingolipid. The questions that we now need to address are: how can glucosylceramide specifically affect early acrosome formation, and why is this contingent on genetic factors? Here we discuss relevant aspects of reproductive biology, the metabolism and cell biology of sphingolipids, and complex trait analysis; we also present a speculative model that takes our observations into account.”
Differential sensitivity of mouse strains to an N-alkylated imino sugar: glycosphingolipid metabolism and acrosome formation.
van der Spoel AC, Mott R, Platt FM.
Pharmacogenomics. 2008 Jun;9(6):717-31.
PMID: 18518850
Gamete binding / fusion targets
“Caltrin is a small and basic protein of the seminal vesicle secretion which inhibits sperm calcium uptake… The present data suggest that rat caltrin molecules bound to the sperm head during ejaculation prevent the occurrence of the spontaneous acrosomal exocytosis along the female reproductive tract.”
Rat Caltrin Protein Modulates the Acrosomal Exocytosis During Sperm Capacitation.
Dematteis A, Miranda SD, Novella ML, Maldonado C, Ponce RH, Maldera JA, Cuasnicu PS, Coronel CE.
Biol Reprod. 2008 Jun 11. [Epub ahead of print]
PMID: 18550793
“Sperm motility and the ability to undergo a spontaneous or progesterone-induced acrosome reaction were neither affected in Crisp1(-/-) mice. However, the level of protein tyrosine phosphorylation during capacitation was clearly lower in mutant sperm than in controls. In vitro fertilization assays showed that Crisp1(-/-) sperm also exhibited a significantly reduced ability to penetrate both ZP-intact and ZP-free eggs… [The] finding that the fusion ability of Crisp1(-/-) sperm was further inhibited by the presence of CRISP1 or CRISP2 during gamete co-incubation, supports that another CRISP cooperates with CRISP1 during fertilization and might compensate for its lack in the mutant mice.”
Impaired sperm fertilizing ability in mice lacking Cysteine-RIch Secretory Protein 1 (CRISP1).
Da Ros VG, Maldera JA, Willis WD, Cohen DJ, Goulding EH, Gelman DM, Rubinstein M, Eddy EM, Cuasnicu PS.
Dev Biol. 2008 Mar 20. [Epub ahead of print]
PMID: 18571638
“This paper aims to overview recent insights in sperm surface remodeling pertinent to fertilization. A basic understanding of this remodeling is required to interpret the high amount of data appearing from high-throughput identification techniques for proteins presently applied in reproductive biology. From the extensive lists of protein candidates identified by proteomics, only a few are recognized to be directly involved in fertilization.”
Sperm membrane physiology and relevance for fertilization.
Gadella BM.
Anim Reprod Sci. 2008 May 14. [Epub ahead of print]
PMID: 18556155
“Here, we present the first studies of this crucial and complex event occurring in real-time in individual live sperm using time-lapse fluorescence microscopy. Simultaneous imaging of separate probes for acrosomal content and inner acrosomal membrane show that rapid membrane fusion, initiated at the cell apex, is followed by exceptionally slow dispersal of acrosomal content (up to 12 minutes).”
Dynamic resolution of acrosomal exocytosis in human sperm.
Harper CV, Cummerson JA, White MR, Publicover SJ, Johnson PM.
J Cell Sci. 2008 Jul 1;121(Pt 13):2130-5. Epub 2008 Jun 3.
PMID: 18522990
Immunological approaches
“One of these [local immunoregulatory] mechanisms involves targeting T-cells for inactivation and destruction within the testicular environment. Although the fluids of the testis and ovary surrounding the developing gametes contain soluble factors that inhibit T-cells, the identity of the molecule(s) responsible for this activity has been unknown… The active molecules were identified, using capillary electrophoresis electrospray ionization mass spectroscopy, as lyso-glycerophosphocholines (lyso-GPCs)… The emergence of gonadal lyso-GPCs as potential regulators of critical immune events opens up new avenues of inquiry into the origins of autoimmune infertility, and more generally into mechanisms of peripheral immunoregulation and the development of novel immunosuppressives.”
Molecular Identification of Lyso-Glycerophosphocholines as Endogenous Immunosuppressives in Bovine and Rat Gonadal Fluids.
Foulds LM, Boysen RI, Crane M, Yuanzhong Y, Muir JA, Smith AI, de Kretser DM, Hearn MT, Hedger MP.
Biol Reprod. 2008 May 28. [Epub ahead of print]
PMID: 18509166
Motility / capacitation targets
“Glycolysis is the primary source of the ATP necessary for [sperm] motility in the mouse and several novel glycolytic enzymes have been identified that are localized to the principal piece region of the flagellum. One of these is the spermatogenic cell-specific type 1 hexokinase isozyme (HK1S), the only member of the hexokinase enzyme family detected in sperm… HK1S was present in dimer and monomer forms in extracts of quiescent sperm but mainly as a monomer in motile sperm… [Our] results strongly suggest that cleavage of disulfide bonds in HK1S dimers contributes to the increases in HK activity and motility that occur when mouse sperm become activated.”
Cleavage of Disulfide Bonds in Mouse Spermatogenic Cell-Specific Type 1 Hexokinase Isozyme Is Associated with Increased Hexokinase Activity and Initiation of Sperm Motility.
Nakamura N, Miranda-Vizuete A, Miki K, Mori C, Eddy EM.
Biol Reprod. 2008 May 28. [Epub ahead of print]
PMID: 18509164
