Summaries of new peer-reviewed publications
Heat-based methods
“Treatment [of Cynomolgus monkeys] with T, heat, or both led to sustained activation of both mitogen-activated protein kinase (MAPK) 1/3 and MAPK14,” although the rate of onset, duration and extent of the germ cell death varied between the treatment groups. The authors concluded that “the serine phosphorylation of BCL2 and activation of the MAPK14-mediated mitochondria-dependent pathway are critical for male germ cell death in monkeys.”
Signaling Pathways for Germ Cell Death in Adult Cynomolgus Monkeys (Macaca fascicularis) Induced by Mild Testicular Hyperthermia and Exogenous Testosterone Treatment.
Jia Y, Sinha-Hikim AP, Lue YH, Swerdloff RS, Vera Y, Zhang XS, Hu ZY, Li YC, Liu YX, Wang C.
Biol Reprod. 2007 Mar 21; [Epub ahead of print]
PMID: 17377139
A small-scale test (n = 11 men) of the effect of wet heat on fertility parameters. Men with “known hyperthermic exposure to hot tubs, hot baths or whirlpool baths” stopped these exposures, with “semen parameters analyzed before and after”. Half the men responded favorably, with “statistically significant increase in sperm motility, from a mean of 12% at baseline to 34% post-intervention,” being the largest parameter rebound.
Wet heat exposure: a potentially reversible cause of low semen quality in infertile men.
Shefi S, Tarapore PE, Walsh TJ, Croughan M, Turek PJ.
Int Braz J Urol. 2007 Jan-Feb;33(1):50-7.
PMID: 17335598
RISUG
Light microscopy, scanning, and TEM study of the in vivo effect of various doses of RISUG on primate and human sperm viability and vasa deferentia morphology after 3 hours to 6 months of treatment. The first human samples were collected 3 hours after injection. Sectioned samples of the entire length of primate vasa were collected after 6 months. The study found that RISUG became hydrated and anchored to the vasa 3 days post-injection. Disassembly of sperm chromatin was noted only in sperm which had already acrosome-reacted. “As the sperm membranes are damaged first with a consequent loss of sperm fertility, a non-obstructive contraception can be achieved without the risk of damaged sperms passing into the ejaculated sperm causing teratogenic effects. This is because before the nucleus is affected the sperms have been rendered infertile.”
Biophysical mechanism-mediated time-dependent effect on sperm of human and monkey vas implanted polyelectrolyte contraceptive.
Guha SK.
Asian J Androl. 2007 Mar;9(2):221-7.
PMID: 17334590
Genomic / proteomic supporting research
Study of the disruption of rat epididymal lumicrine regulation by efferent duct ligation (EDL). “Over 2,000 genes responded significantly to EDL in segment 1… In the absence of lumicrine factors, the 4 segments regressed to a transcriptionally undifferentiated state… Such results reveal a higher complexity to the regulation of rat epididymal segments than heretofore appreciated.”
Differential Gene Expression among the Proximal Segments of the Rat Epididymis Is Lost after Efferent Duct Ligation.
Turner TT, Johnson DS, Finger JN, Jelinsky SA.
Biol Reprod. 2007 Mar 21; [Epub ahead of print]
PMID: 17377138
A review of the known roles of cyclic nucleotide phosphodiesterases (PDEs). “It also has been proposed that PDEs themselves may function as scaffolds for other proteins... PDE4A interacts with a specialized AKAP present in the flagellum of spermatozoa.”
Biochemistry and Physiology of Cyclic Nucleotide Phosphodiesterases: Essential Components in Cyclic Nucleotide Signaling.
Conti M, Beavo J.
Annu Rev Biochem. 2007 Mar 21; [Epub ahead of print]
PMID: 17376027
“PP1gamma2 is the most abundant [serine/threonine protein phosphatase 1 (PP1)] isoform in the testis, and a key regulator of sperm motility… Targeted disruption of the Ppp1cc gene causes male infertility in mice due to impaired spermiogenesis… Testicular sperm tails from Ppp1cc-null mice showed malformed mitochondrial sheaths and extra outer dense fibers in both the middle and principal pieces. These data suggest that, in addition to its previously documented role in motility, PP1gamma2 is involved in sperm tail morphogenesis.”
Analysis of Ppp1cc-Null Mice Suggests a Role for PP1gamma2 in Sperm Morphogenesis.
Chakrabarti R, Kline D, Lu J, Orth J, Pilder S, Vijayaraghavan S.
Biol Reprod. 2007 Feb 14; [Epub ahead of print]
PMID: 17301292
“Selenium is a micronutrient that is essential for production of normal spermatozoa. The selenium-rich plasma protein, selenoprotein P (Sepp1), is required for maintenance of testis selenium and for fertility of the male mouse… [We] identified apolipoprotein E receptor 2 (ApoER2) as a candidate testis Sepp1 receptor… [and showed] that Sertoli cell ApoER2 is a Sepp1 receptor and a component of the selenium delivery pathway to spermatogenic cells.”
Apolipoprotein E receptor-2 (ApoER2) mediates selenium uptake from selenoprotein P by the mouse testis.
Olson GE, Winfrey VP, Nagdas SK, Hill KE, Burk RF.
J Biol Chem. 2007 Feb 21; [Epub ahead of print]
PMID: 17314095
The novel rat testis-specific gene, LM23, “encodes a putative protein including 312 amino acids, which shares no significant homology with any known gene” (GenBank Accession No. AF492385). The gene is testis-specific, and RTPCR “showed that the expression level of LM23 was highest in spermatocytes and very low in spermatogonia,” with strong cytoplasmic in situ hybridization signals in spermatocytes. Authors conclude that the gene may be involved in rat spermatogenesis.
Identification and characterization of a novel spermatogenesis related gene LM23 in rat testis.
Liu ML, Pei KY, Shi XQ, Liu DY, Jia MC.
Biochem Biophys Res Commun. 2007 Mar 12; [Epub ahead of print]
PMID: 17376406
“CRISP2 (previously TPX1) is a testis-enriched member of the cysteine-rich secretory protein (CRISP) family and has been localized to both the sperm acrosome and tail.” This study sought to “determine the biochemical pathways within which CRISP2 is a component… One of the most frequently identified interacting partners was mitogen activated protein kinase kinase kinase 11 (MAP3K11).” Both proteins occurred at “the acrosome of the developing spermatids and epididymal spermatozoa, [suggesting] the possibility that CRISP2 is a MAP3K11 modifying protein, or alternatively that MAP3K11 acts to phosphorylate CRISP2 during acrosome development.”
Cysteine-Rich Secretory Protein 2 Binds to Mitogen-Activated Protein Kinase Kinase Kinase 11 in Mouse Sperm.
Gibbs GM, Bianco DM, Jamsai D, Herlihy A, Aitken RJ, de Kretser DM, O'bryan MK.
Biol Reprod. 2007 Mar 21; [Epub ahead of print]
PMID: 17377140
In mice “CDC25B transcripts were found to be mainly located in the testicular interstitium and nondividing Sertoli cells”; male null mice have normal fertility. In human sperm, four CDC25B isoforms were found in multiple cellular compartments: the midpiece of spermatozoa, the principal piece and cytosol of the head. The widespread expression of CDC25B isoforms in human spermatozoa “suggests that there are diverse noncell-cycle-related functions of CDC25B in terminally differentiated human germ cells.”
Expression of various CDC25B isoforms in human spermatozoa.
Teng YN, Chung CL, Lin YM, Pan HA, Liao RW, Kuo PL.
Fertil Steril. 2007 Mar 3; [Epub ahead of print]
PMID: 17336969
“Possible cell autonomous and paracrine mechanisms for the spermatogenic defects in mice lacking p18(Ink4c) or p19(Ink4d) are supported by expression of these CKIs [cyclin-dependent kinase inhibitors] in spermatogenic cells and in somatic cells of the testis and pituitary.”
p19(Ink4d) and p18(Ink4c) cyclin-dependent kinase inhibitors in the male reproductive axis.
Buchold GM, Magyar PL, Arumugam R, Lee MM, O'brien DA.
Mol Reprod Dev. 2007 Mar 6; [Epub ahead of print]
PMID: 17342741
“LXRalpha-deficient mice had lower levels of testicular testosterone that correlated with a higher apoptotic rate of the germ cells. LXRbeta-deficient mice showed increased lipid accumulation in the Sertoli cells and a lower proliferation rate of the germ cells…All together, these data identify new roles of each LXR, collaborating to maintain both integrity and functions of the testis.”
Multiple roles of the nuclear receptors for oxysterols LXR to maintain male fertility.
Volle DH, Mouzat K, Duggavathi R, Siddeek B, Dechelotte P, Sion B, Veyssiere G, Benahmed M, Lobaccaro JM.
Mol Endocrinol. 2007 Mar 6; [Epub ahead of print]
PMID: 17341595
“We previously showed that in live murine and bovine sperm heads, the ganglioside GM1 localizes to the sterol-rich plasma membrane overlying the acrosome (APM)… incubation of sperm of both species with specific stimuli for capacitation, followed by the use of specific fixation conditions, induced reproducible, stimulus-specific patterns of GM1 distribution.”
GM1 dynamics as a marker for membrane changes associated with the process of capacitation in murine and bovine spermatozoa.
Selvaraj V, Buttke DE, Asano A, McElwee JL, Wolff CA, Nelson JL, Klaus AV, Hunnicutt GR, Travis AJ.
J Androl. 2007 Mar 21; [Epub ahead of print]
PMID: 17377143
Cell adhesion targets
“In this report, C-type natriuretic peptide (CNP) was shown to be a regulator of BTB [blood-testis barrier] dynamics.” The CNP-receptor, “natriuretic peptide receptor B, resided almost exclusively in Sertoli cells… A synthetic CNP-22 peptide, when added to Sertoli cell cultures, was shown to perturb Sertoli cell tight junction in vitro, causing disappearance of BTB-associated proteins (JAM-A, occludin, N-cadherin, and beta-catenin) from the cell-cell interface,” and this effect was confirmed in vivo. “In summary, CNP secreted by Sertoli and germ cells into the BTB microenvironment regulates BTB dynamics during spermatogenesis.”
C-type natriuretic peptide regulates blood-testis barrier dynamics in adult rat testes.
Xia W, Mruk DD, Cheng CY.
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):3841-6. Epub 2007 Feb 27.
PMID: 17360440
“The coxsackie and adenovirus receptor (CAR), a putative cell-cell adhesion molecule, has attracted wide interest due to its importance in viral pathogenesis and in mediating adenoviral gene delivery… we identified CAR in Sertoli cells and germ cells of rats,” localizing it to the blood-testis barrier and the ectoplasmic specialization. “we propose that CAR functions as an adhesion molecule in maintaining the inter-Sertoli cell junctions at the basal compartment of the seminiferous epithelium. In addition, CAR may confer adhesion between Sertoli and germ cells at the Sertoli-germ cell interface. It is possible that the receptor utilized by viral pathogens to breakthrough the epithelial barrier was also employed by developing germ cells to migrate through the inter-Sertoli cell junctions.”
Coxsackie and adenovirus receptor (CAR) is a product of Sertoli and germ cells in rat testes which is localized at the Sertoli-Sertoli and Sertoli-germ cell interface.
Wang CQ, Mruk DD, Lee WM, Cheng CY.
Exp Cell Res. 2007 Feb 3; [Epub ahead of print]
PMID: 17359973
TEX14 is a protein required during spermatogenesis for germ cell intercellular bridge formation. “We show that TEX14 co-localizes with the centralspindlin complex, mitotic kinesin-like protein 1 (MKLP1) and male germ cell Rac GTPase-activating protein (MgcRacGAP) and converts these midbody matrix proteins into stable intercellular bridge components… In cultured somatic cells, TEX14 can localize to the midbody in the absence of other germ cell-specific factors, suggesting that TEX14 serves to bridge the somatic cytokinesis machinery to other germ cell proteins to form a stable intercellular bridge essential for male reproduction.”
Conversion of midbodies into germ cell intercellular bridges.
Greenbaum MP, Ma L, Matzuk MM.
Dev Biol. 2007 Feb 24; [Epub ahead of print]
PMID: 17383626
Endocrinological supporting research
“[Postnatal] androgen exposure has a profound effect on the development of excitatory transmission in vas deferens smooth muscle, primarily by a postjunctional action, but is not essential for development of the structural innervation of this organ.”
Postnatal androgen deprivation dissociates the development of smooth muscle innervation from functional neurotransmission in mouse vas deferens.
Brock JA, Handelsman DJ, Keast JR.
J Physiol. 2007 Mar 22; [Epub ahead of print]
PMID: 17379637
Immunological approaches
Immunization of male rats with CD46, a membrane complement regulator present in the inner acrosome, had no effect on fertility. There was no CD46 immunoglobin on sperm precursors in the testis, and 5-10% staining in epididymal sperm. These sperm may have already undergone a spontaneous acrosome reaction. The authors suggest CD46 immunization had little contraceptive effect due to functional redundancy of CD46 in murine fertilization.
Immunization with autologous CD46 generates a strong autoantibody response in rats that targets spermatozoa
Mizuno M, Harris CL, Morgan BP.
J Reprod Immunol. 2007 Apr;73(2):135-47.
PMID: 16950517
Review
A summary of the effective formulations of hormonal male contraception approaching the market. “Recent trials with newer, long-acting forms of injectable testosterone, such as testosterone undecanoate, which can be administered every 8-10 weeks, combined with progestogens, administered either orally or by long-acting implant, have yielded promising results and may soon result in the marketing of a safe, reversible and effective hormonal contraceptive for men.”
Contraceptive developments for men.
Amory JK.
Drugs Today (Barc). 2007 Mar;43(3):179-92.
PMID: 17380214
