Summaries of new peer-reviewed publications
Epididymal targets and supporting research
This month’s entire issue of the Asian Journal of Andrology is dedicated to original research on the stucture and function of the epididymis.
“[At] least two different signaling processes are important in regulating the rat epididymis in addition to endocrine regulation: (i) a paracrine signaling process wherein growth factors or other signaling molecules traffic between interstitial and epithelial cells within a given segment, signaling limited to individual segments by the CTS forming the segment borders; and (ii) a lumicrine signaling process wherein intra-luminal molecules can pass from segment to segment, yet are still required for the direct or indirect regulation of thousands of gene expressions in a segment-specific manner.”
Segment boundaries of the adult rat epididymis limit interstitial signaling by potential paracrine factors and segments lose differential gene expression after efferent duct ligation.
Turner TT, Johnston DS, Jelinsky SA, Tomsig JL, Finger JN.
Asian J Androl. 2007 Jul;9(4):565-73.
PMID: 17589796
“As part of our efforts to identify novel contraceptive targets in the epididymis we performed transcriptional profiling on each of the 10 and 19 segments of the mouse and rat epididymidis… Defensin 22 (E3 epididymal protein) was shown to be completely specific for the epididymis.”
Identification of epididymis-specific transcripts in the mouse and rat by transcriptional profiling.
Johnston DS, Turner TT, Finger JN, Owtscharuk TL, Kopf GS, Jelinsky SA.
Asian J Androl. 2007 Jul;9(4):522-7.
PMID: 17589790
“These studies demonstrate that the more abundant D form interacts with spermatozoa transiently, possibly with a specific receptor on the sperm surface, consistent with a capacitation-suppressing function during sperm transit and storage in the epididymis, and also confirm a tightly bound population of the E form that could act in the female reproductive tract.”
Structure and function of epididymal protein cysteine-rich secretory protein-1.
Roberts KP, Johnston DS, Nolan MA, Wooters JL, Waxmonsky NC, Piehl LB, Ensrud-Bowlin KM, Hamilton DW.
Asian J Androl. 2007 Jul;9(4):508-14.
PMID: 17589788
A summary of androgens’ molecular-level actions in the epididymis. We “[determined] the sequence of responses that occur in an androgen deprived tissue upon re-administration of the two metabolites of T, DHT and E2… [and studied] the effects of androgen withdrawal and re-administration on gene expression in immortalized murine caput epididymidal principal cells.”
Androgenic regulation of novel genes in the epididymis.
Robaire B, Seenundun S, Hamzeh M, Lamour SA.
Asian J Androl. 2007 Jul;9(4):545-53.
PMID: 17589794
Discussion of the possible role of the epididymis in the regulatory volume decrease capacity of mature sperm.
Sperm maturation in the epididymis: a new look at an old problem.
Cooper TG.
Asian J Androl. 2007 Jul;9(4):533-9.
PMID: 17589792
“Proteomic analyses indicate that this change [– progressive acquisition of the capacity to phosphorylate tyrosine –] is associated with the phosphorylation of several mitochondrial proteins, creation of a mitochondrial membrane potential and activation of mitochondrial free radical generation.”
Proteomic changes in mammalian spermatozoa during epididymal maturation.
Aitken RJ, Nixon B, Lin M, Koppers AJ, Lee YH, Baker MA.
Asian J Androl. 2007 Jul;9(4):554-64.
PMID: 17589795
Immunological approaches
“[We] localized eppin, lactotransferrin and clusterin in human Sertoli cells and on human testicular and ejaculate spermatozoa, implying that the eppin protein complex (EPC) is present on spermatozoa from the time they leave the seminiferous tubule. On ejaculate spermatozoa eppin, lactotransferrin and clusterin co-localize on the tail. The identification of the EPC components suggests that lactotransferrin, clusterin and/or eppin receptors may function as sperm plasma membrane receptors for the EPC, implicating the complex as a central player in a network of protein-protein interactions on the human sperm surface.”
Characterization of an eppin Protein Complex from Human Semen and Spermatozoa.
Wang Z, Widgren EE, Richardson RT, O'rand MG.
Biol Reprod. 2007 Jun 13; [Epub ahead of print]
PMID: 17567961
“Higher MIF [macrophage Migration Inhibitory Factor] levels determined in men with azoospermia or severe oligozoospermia might be associated with adverse effects of this molecule related to reduced sperm motility… We consistently found that MIF (1 to 20 μg/mL) treatment of healthy spermatozoa dose-dependently decreased sperm total and progressive motility… Low MIF concentrations are indicative of impaired fertilizing ability, which corresponds with the finding that MIF is required for sperm maturation.”
Imbalance in seminal fluid MIF indicates male infertility.
Aljabari B, Calogero AE, Perdichizzi A, Vicari E, Karaki R, Lahloub T, Zatari R, El-Abed K, Nicoletti F, Miller EJ, Pavlov VA, Al-Abed Y.
Mol Med. 2007 Mar-Apr;13(3-4):199-202.
PMID: 17592555
“While there is no doubt that TLRs are important in providing protection against infection in the reproductive tract, there is increasing evidence for the involvement of TLRs in more basic pathology and physiology of reproduction… In the male, toll-like receptors (TLRs) appear to play a role in the control of testicular steroidogenesis and spermatogenesis in disease and, potentially, during normal function, as well.”
Toll-like receptors in the gonads and reproductive tract: emerging roles in reproductive physiology and pathology.
Girling JE, Hedger MP.
Immunol Cell Biol. 2007 Jun 26; [Epub ahead of print]
PMID: 17592495
Genomic/proteomic supporting research
“[A] number of different classes of receptor have also been detected in these cells and are potential regulators of sperm function. This list includes at least six seven-pass transmembrane receptors, six tyrosine kinase receptors, a tyrosine phosphatase receptor, glutamate-gated ion channel receptors, transient receptor potential cation channels, and a non-genomic progesterone receptor. This is the first published list of identified proteins in human spermatozoa using LC-MS/MS analysis.”
Identification of gene products present in Triton X-100 soluble and insoluble fractions of human spermatozoa lysates using LC-MS/MS analysis.
Baker MA, Reeves G, Hetherington L, Müller J, Baur I, Aitken RJ.
Proteomics Clin. Appl. 2007 1(5):524–532.
DOI 10.1002/prca.200601013
“There are many possible causes of such DNA damage, including abortive apoptosis, the oxidative stress associated with male genital tract infection, exposure to redox cycling chemicals, and defects of spermiogenesis associated with the retention of excess residual cytoplasm. Physical factors such as exposure to radiofrequency electromagnetic radiation or mild scrotal heating can also induce DNA damage in mammalian spermatozoa, although the underlying mechanisms are unclear.”
Origins and consequences of DNA damage in male germ cells.
Aitken RJ, De Iuliis GN.
Reprod Biomed Online. 2007 Jun;14(6):727-33.
PMID: 17579989
“[INSL3] Receptor expression was markedly increased after birth and readily detectable in the epididymis, Leydig and germ cells of the testis. The strongest expression was detected in adult mouse cremaster muscle. INSL3 treatment increased cell proliferation of embryonic gubernacular and TM3 embryonic Leydig cells implicating active INSL3-mediated autocrine signaling in these cells and identifying TM3 as a novel in vitro model to study the effects of RXFP2 signaling.”
Developmental Expression and Gene Regulation of Insulin-like 3 Receptor RXFP2 in Mouse Male Reproductive Organs.
Feng S, Bogatcheva NV, Truong A, Korchin B, Bishop CE, Klonisch T, Agoulnik IU, Agoulnik AI.
Biol Reprod. 2007 Jul 5; [Epub ahead of print]
PMID: 17615407
“The common INSL3 G178A polymorphism was not statistically significantly associated with male infertility (P>.05), even though INSL3 is essential for the occurrence of bilateral cryptorchidism.”
Preliminary analysis of the G178A polymorphism of insulin-like factor 3 in male infertility.
Yun YJ, Lee HC, Kim JE, Song SH, Lee S.
Fertil Steril. 2007 Jun 6; [Epub ahead of print]
PMID: 17559848
In an examination of the sperm of 13 infertile men presenting for ICSI, the researchers found no evidence of inner acrosome IZUMO absence. They speculate that “men with dysfunction of IZUMO would only be able to leave a descendant by the use of ICSI, which has been performed in infertility treatments for only the past 15 years. Prior to 15 years ago, they would have been lost from the population because of their infertile phenotype. As this would make such individuals quite rare, our sample size was likely insufficient to identify them.”
Positive expression of the immunoglobulin superfamily protein IZUMO on human sperm of severely infertile male patients.
Hayasaka S, Terada Y, Inoue N, Okabe M, Yaegashi N, Okamura K.
Fertil Steril. 2007 Jul;88(1):214-6. Epub 2007 Feb 12.
PMID: 17296188
“[We] describe a procedure to cryopreserve the postnatal members of the Leydig cell lineage, including progenitor (PLC), immature (ILC) and adult (ALC) Leydig cells from, respectively 21-, 35- and 90-day-old rats… This study demonstrates that purified rat Leydig cells at a range of developmental stages can be frozen and that the cryopreserved cells retain normal function.”
Development of a cryopreservation protocol for Leydig cells.
Chen GR, Ge RS, Lin H, Dong L, Sottas CM, Hardy MP.
Hum Reprod. 2007 Jun 27; [Epub ahead of print]
PMID: 17596277
Fusion targets
“That anti-DE and anti-Tpx-1 inhibit sperm-egg fusion while recognizing only the corresponding proteins, suggests functional cooperation between these homologous CRISP to ensure fertilization success. These results increase our understanding of the molecular mechanisms of gamete fusion and contribute to the development of new and safer fertility regulating methods.”
Participation of epididymal cysteine-rich secretory proteins in sperm-egg fusion and their potential use for male fertility regulation.
Cohen DJ, Da Ros VG, Busso D, Ellerman DA, Maldera JA, Goldweic N, Cuasnicu PS.
Asian J Androl. 2007 Jul;9(4):528-32.
PMID: 17589791
Capacitation & binding targets
“By imaging the calcium responses generated in individual [sperm] cells, we have demonstrated that… spermatozoa exhibit a series of asynchronous secondary calcium oscillations… The oscillations were dependent upon the influx of extracellular calcium via mechanisms that were insensitive to inhibitors of L-type voltage operated calcium channels (nifedipine, verapamil, diltiazem), G-proteins (pertussis toxin) or the GABA (A) receptor (bicuculline). However, treatment with an inhibitor of the GABA-associated chloride channel (picrotoxin) significantly suppressed the incidence of secondary calcium oscillations in pentoxifylline-treated cells, as did two inhibitors of T-type calcium channels (pimozide and amiloride).”
Molecular mechanisms of sperm capacitation: progesterone-induced secondary calcium oscillations the attainment of a capacitated state.
Aitken RJ, McLaughlin EA.
Soc Reprod Fertil Suppl. 2007;63:273-93.
PMID: 17566279
“[Capacitation] is associated with an increase in both [human] sperm-zona binding and an increase in tyrosine phosphorylation over the sperm tail. However, we could not detect the surface expression of phosphotyrosine residues over the sperm head, as observed with murine spermatozoa… [Strong] species-specific differences exist in the molecular mechanisms that drive sperm-egg recognition and that alternative, chaperone-independent, mechanisms must underpin sperm-zona interaction in the human.”
Analysis of chaperone proteins associated with human spermatozoa during capacitation.
Mitchell LA, Nixon B, Aitken RJ.
Mol Hum Reprod. 2007 Jun 26; [Epub ahead of print]
PMID: 17595329
“Interestingly, addition of a CFTR [cystic fibrosis transmembrane conductance regulator] inhibitor (DPC 250 microM) inhibited the capacitation-associated hyperpolarization, prevented ENaC [epithelial sodium channel] closure and decreased the zona pellucida-induced acrosome reaction without affecting the increase in tyrosine phosphorylation… These results suggest that cAMP-dependent Cl- fluxes through CFTR are involved in the regulation of ENaC during capacitation and thus contribute to the observed hyperpolarization associated to this process.”
Involvement of cystic fibrosis transmembrane conductance regulator in mouse sperm capacitation.
Hernández-González EO, Treviño CL, Castellano LE, de la Vega-Beltran JL, Ocampo AY, Wertheimer E, Visconti PE, Darszon A.
J Biol Chem. 2007 Jun 22; [Epub ahead of print]
PMID: 17588945
Heat-based approach supporting research
“The mRNA of the mitochondrial uncoupling protein 2 (UCP2) was up-regulated by cryptorchidism, a testicular hyperthermic condition under which germ cells undergo severe apoptosis. We investigated whether UCP2 was able to protect germ cells from hyperthermia-induced apoptosis.” UCP2 had a protective effect after 5 minutes of 43˚C treatment, but not after 15 minutes.
Uncoupling protein 2 protects testicular germ cells from hyperthermia-induced apoptosis.
Zhang K, Shang Y, Liao S, Zhang W, Nian H, Liu Y, Chen Q, Han C.
Biochem Biophys Res Commun. 2007 Jun 21; [Epub ahead of print]
PMID: 17603020
Review
Current status and future perspectives in male contraception.
Costantino A, Cerpolini S, Perrone AM, Ghi T, Pelusi C, Pelusi G, Meriggiola MC.
Minerva Ginecol. 2007 Jun;59(3):299-310.
PMID: 17576406
