327 results on '"De Kretser D.M."'
Search Results
2. Progesterone stimulates expression of follistatin splice variants Fst288 and Fst315 in the mouse uterus
- Author
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Craythorn, R.G., Winnall, W.R., Lederman, F., Gold, E.J., O’Connor, A.E., de Kretser, D.M., Hedger, M.P., Rogers, P.A.W., and Girling, J.E.
- Published
- 2012
- Full Text
- View/download PDF
3. Polymorphisms in the human cysteine-rich secretory protein 2 (CRISP2) gene in Australian men
- Author
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Jamsai, D., Reilly, A., Smith, S.J., Gibbs, G.M., Baker, H.W.G., McLachlan, R.I., de Kretser, D.M., and OʼBryan, M.K.
- Published
- 2008
4. Histological evaluation of the human testis—approaches to optimizing the clinical value of the assessment: Mini Review
- Author
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McLachlan, R.I., Rajpert-De Meyts, E., Hoei-Hansen, C.E., de Kretser, D.M., and Skakkebaek, N.E.
- Published
- 2007
5. Male infertility
- Author
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de Kretser, D.M.
- Subjects
Infertility, Male -- Care and treatment ,Genetic disorders -- Physiological aspects ,Artificial insemination, Human -- Innovations - Published
- 1997
6. A repository of ENU mutant mouse lines and their potential for male fertility research
- Author
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Kennedy, C.L., OʼConnor, A.E., Sanchez-Partida, L.G., Holland, M.K., Goodnow, C.C., de Kretser, D.M., and OʼBryan, M.K.
- Published
- 2005
7. Sexual activity, fertility and contraceptive use in middle-aged and older men: Men in Australia, Telephone Survey (MATeS)
- Author
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Holden, C.A., McLachlan, R.I., Cumming, R., Wittert, G., Handelsman, D.J., de Kretser, D.M., and Pitts, M.
- Published
- 2005
8. The Y chromosome gr/gr subdeletion is associated with male infertility
- Author
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Lynch, M., Cram, D.S., Reilly, A., O’Bryan, M.K., Baker, H.W.G., de Kretser, D.M., and McLachlan, R.I.
- Published
- 2005
9. The role of activin, follistatin and inhibin in testicular physiology
- Author
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de Kretser, D.M., Buzzard, J.J., Okuma, Y., O’Connor, A.E., Hayashi, T., Lin, Shyr-Yeu, Morrison, J.R., Loveland, K.L., and Hedger, M.P.
- Published
- 2004
- Full Text
- View/download PDF
10. Inhibins, activins and follistatin: actions on the testis
- Author
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de Kretser, D.M., Loveland, K.L., Meehan, T., O'Bryan, M.K., Phillips, D.J., and Wreford, N.G.
- Published
- 2001
- Full Text
- View/download PDF
11. The roles of inhibin and related peptides in gonadal function
- Author
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de Kretser, D.M, Meinhardt, A, Meehan, T, Phillips, D.J, O’Bryan, M.K, and Loveland, K.A
- Published
- 2000
- Full Text
- View/download PDF
12. Inhibition of activin signaling in lung adenocarcinoma increases the therapeutic index of platinum chemotherapy.
- Author
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Boolell V., Vaghjiani V., Gonzalez-Rajal A., Hastings J.F., Chin V., Szczepny A., Kostyrko K., Marquez C., Samantha W., Jayasekara N., McCloy R.A., Han J.Z.R., Waugh T., Lee H.C., Oakes S.R., Harrison C.A., Hedger M.P., Lorensuhewa N., Kita B., Barrow R., Robinson B.W., De Kretser D.M., Wu J., Ganju V., Alejandro Sweet-Cordero E., Burgess A., Martelotto L.G., Rossello F.J., Cain J.E., Neil Watkins D., Kumar B., Alamgeer M., Marini K.D., Croucher D.R., Boolell V., Vaghjiani V., Gonzalez-Rajal A., Hastings J.F., Chin V., Szczepny A., Kostyrko K., Marquez C., Samantha W., Jayasekara N., McCloy R.A., Han J.Z.R., Waugh T., Lee H.C., Oakes S.R., Harrison C.A., Hedger M.P., Lorensuhewa N., Kita B., Barrow R., Robinson B.W., De Kretser D.M., Wu J., Ganju V., Alejandro Sweet-Cordero E., Burgess A., Martelotto L.G., Rossello F.J., Cain J.E., Neil Watkins D., Kumar B., Alamgeer M., Marini K.D., and Croucher D.R.
- Abstract
Resistance to platinum chemotherapy is a long-standing problem in the management of lung adenocarcinoma. Using a whole-genome synthetic lethal RNA interference screen, we identified activin signaling as a critical mediator of innate platinum resistance. The transforming growth factor- (TGF) superfamily ligands activin A and growth differentiation factor 11 (GDF11) mediated resistance via their cognate receptors through TGF-activated kinase 1 (TAK1), rather than through the SMAD family of transcription factors. Inhibition of activin receptor signaling or blockade of activin A and GDF11 by the endogenous protein follistatin overcame this resistance. Consistent with the role of activin signaling in acute renal injury, both therapeutic interventions attenuated acute cisplatin-induced nephrotoxicity, its major dose-limiting side effect. This cancer-specific enhancement of platinum-induced cell death has the potential to dramatically improve the safety and efficacy of chemotherapy in lung cancer patients.Copyright © 2018 The Authors, some rights reserved.
- Published
- 2018
13. Differences in the prevalence of cryptorchidism
- Author
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de Kretser, D.M.
- Subjects
Cryptorchism -- Comparative analysis ,Cryptorchism -- Research - Published
- 2004
14. Activin and follistatin interactions in the male reproductive tract: activin expression and morphological abnormalities in mice lacking follistatin 288.
- Author
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Wijayarathna R., Hedger M.P., de Kretser D.M., Meinhardt A., Loveland K.L., Ludlow H., Michel V., Girling J.E., Genovese R., Sarraj M.A., Wijayarathna R., Hedger M.P., de Kretser D.M., Meinhardt A., Loveland K.L., Ludlow H., Michel V., Girling J.E., Genovese R., and Sarraj M.A.
- Abstract
Activin A is an important regulator of testicular and epididymal development and function, as well as inflammation and immunity. In the adult murine reproductive tract, activin A mRNA (Inhba) expression levels are highest in the caput epididymis and decrease progressively towards the distal vas deferens. The activin-binding protein, follistatin (FST), shows the opposite expression pattern, with exceptionally high levels of the Fst288 mRNA variant in the vas deferens. This unique pattern of expression suggests that activin A and follistatin, in particular FST288, play region-specific roles in regulating the epididymis and vas deferens. The cellular distribution of activin and follistatin and structural organization of the male reproductive tract was examined in wild-type and transgenic (TghFST315) mice lacking FST288. Compared to wild-type littermates, TghFST315 mice showed a 50% reduction in serum follistatin and a significant elevation of both activin A and B. Testicular, epididymal and seminal vesicle weights were reduced, but intra-testicular testosterone was normal. A decrease in the epididymal duct diameter in the corpus and thickening of the peritubular smooth muscle in the cauda, together with increased coiling of the proximal vas deferens, were observed in TghFST315 mice. No immune cell infiltrates were detected. Immunohistochemistry indicated that epithelial cells are the main source of activins and follistatin in the epididymis and vas deferens. Activin A, but not activin B, was also localized to sperm heads in the lumen of the epididymis and vas deferens. Expression of Inhba and another immunoregulatory gene, indoleamine-2,3-dioxygenase (Ido-1), was increased approximately twofold in the TghFST315 caput epididymis, but several other genes associated with immunoregulation, inflammation or fibrosis were unaffected. Our novel data indicate that disruption of follistatin expression has significant effects on the testis and epididymis, and suggest an associati
- Published
- 2017
15. A mouse model of spinal bulbar muscular atrophy (SBMA)
- Author
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Morrison, J.R., McManamny, P., O'Bryan, M.K., Cimdins, K.L., Kola, I., Cheema, S., and de Kretser, D.M.
- Subjects
Spinal muscular atrophy -- Genetic aspects ,Androgens -- Genetic aspects ,Biological sciences - Published
- 2000
16. Activins in reproductive biology and beyond
- Author
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Wijayarathna, R., primary and de Kretser, D.M., additional
- Published
- 2016
- Full Text
- View/download PDF
17. LRGUK-1 Is Required for Basal Body and Manchette Function during Spermatogenesis and Male Fertility.
- Author
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Jamsai D., Efthymiadis A., McLachlan R.I., Ormandy C.J., Goodnow C.C., O'Bryan M.K., Liu Y., DeBoer K., de Kretser D.M., O'Donnell L., O'Connor A.E., Merriner D.J., Okuda H., Whittle B., Jans D.A., Jamsai D., Efthymiadis A., McLachlan R.I., Ormandy C.J., Goodnow C.C., O'Bryan M.K., Liu Y., DeBoer K., de Kretser D.M., O'Donnell L., O'Connor A.E., Merriner D.J., Okuda H., Whittle B., and Jans D.A.
- Abstract
Male infertility affects at least 5% of reproductive age males. The most common pathology is a complex presentation of decreased sperm output and abnormal sperm shape and motility referred to as oligoasthenoteratospermia (OAT). For the majority of OAT men a precise diagnosis cannot be provided. Here we demonstrate that leucine-rich repeats and guanylate kinase-domain containing isoform 1 (LRGUK-1) is required for multiple aspects of sperm assembly, including acrosome attachment, sperm head shaping and the initiation of the axoneme growth to form the core of the sperm tail. Specifically, LRGUK-1 is required for basal body attachment to the plasma membrane, the appropriate formation of the sub-distal appendages, the extension of axoneme microtubules and for microtubule movement and organisation within the manchette. Manchette dysfunction leads to abnormal sperm head shaping. Several of these functions may be achieved in association with the LRGUK-1 binding partner HOOK2. Collectively, these data establish LRGUK-1 as a major determinant of microtubule structure within the male germ line.Copyright © 2015 Liu et al.
- Published
- 2015
18. Testicular Control of Follicle-Stimulating Hormone Secretion
- Author
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BAKER, H.W.G., primary, BREMNER, W.J., additional, BURGER, H.G., additional, DE KRETSER, D.M., additional, DULMANIS, AUSMA, additional, EDDIE, L.W., additional, HUDSON, B., additional, KEOGH, E.J., additional, LEE, V.W.K., additional, and RENNIE, G.C., additional
- Published
- 1976
- Full Text
- View/download PDF
19. RHYTHMS IN THE SECRETION OF GONADOTROPINS AND GONADAL STEROIDS
- Author
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BAKER, H.W.G., primary, SANTEN, R.J., additional, BURGER, H.G., additional, DE KRETSER, D.M., additional, HUDSON, B., additional, PEPPERELL, R.J., additional, and BARDIN, C.W., additional
- Published
- 1976
- Full Text
- View/download PDF
20. Local Regulation of Testicular Function
- Author
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de Kretser, D.M., primary
- Published
- 1987
- Full Text
- View/download PDF
21. LIST OF CONTRIBUTORS AND DISCUSSANTS
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Aiyer, M.S., primary, Albert, A., additional, Alexander, R.W., additional, Anderson, H.J., additional, Aubert, M., additional, Aurbach, G.D., additional, Baker, H.W.G., additional, Bardin, C.W., additional, Bartke, A., additional, Bartter, F.C., additional, Bennett, P.H., additional, Bernstein, R.S., additional, Bitensky, L., additional, Boucher, R., additional, Bourne, H., additional, Braunstein, G.D., additional, Bravo, E.L., additional, Bremner, W.J., additional, Brown, E.M., additional, Brunton, L.L., additional, Burger, H.G., additional, Burrow, G.N., additional, Campbell, G.T., additional, Caron, M.G., additional, Carter, A.C., additional, Chatterton, R.T., additional, Chayen, J., additional, Coffino, P., additional, Cohen, S.L., additional, Constantopoulos, G., additional, Daly, J.R., additional, de Kretser, D.M., additional, DiGirolamo, M., additional, Dillmann, W.H., additional, Dominguez, O.V., additional, Duax, W.L., additional, Dulmanis, A., additional, Earll, J.M., additional, Eddie, L.W., additional, Edelman, I.S., additional, Edgren, R.A., additional, Faiman, C., additional, Fakunding, J.L., additional, Friedrich, U., additional, Friesen, H.G., additional, Frisch, R.E., additional, Frohman, L.A., additional, Furth, J., additional, Ganten, D., additional, Gardner, J.D., additional, Gehring, U., additional, Geller, J., additional, Gendrich, R., additional, Genest, J., additional, George, J.M., additional, Gill, J.R., additional, Gilman, A.G., additional, Goodman, H.M., additional, Gross, G., additional, Grumbach, M., additional, Hembree, W., additional, Hochman, J., additional, Huckins, C., additional, Hudson, B., additional, Insel, P.A., additional, Jacobs, L.S., additional, Jewelewicz, R., additional, Kaplan, S., additional, Kennedy, T., additional, Kenny, A.D., additional, Keogh, E.J., additional, Kirschner, M.A., additional, Knobil, E., additional, Koerner, D., additional, Kowal, J., additional, Krieger, D.T., additional, Kuchel, O., additional, Kulin, H.E., additional, LeCompte, P.M., additional, Lee, V.W.K., additional, Lefkowitz, R.J., additional, Lemaire, I., additional, Lequin, R.M., additional, Limbird, L.E., additional, Lin, Y.C., additional, Lindner, H.R., additional, Lipsett, M.B., additional, Little, B., additional, Loveridge, N., additional, McArthur, J.W., additional, McKenzie, J.M., additional, Maguire, M.E., additional, Martin, J.B., additional, Means, A.R., additional, Melby, J.C., additional, Melmon, K.L., additional, Messerli, F., additional, Mickey, J.V., additional, Miller, M., additional, Montoya, E., additional, Mukherjee, C., additional, Murphy, B.E.P., additional, Naftolin, F., additional, Niswender, G.D., additional, Nowaczynski, W., additional, Nureddin, A., additional, Odell, W.D., additional, Oliver, J.T., additional, Oppenheimer, J.H., additional, O'Riordan, J.L.H., additional, Orr, J., additional, Osathanondh, R., additional, Papkoff, H., additional, Parsons, J.A., additional, Pasqualini, J.R., additional, Paulsen, C.A., additional, Pearlman, W.H., additional, Pearson, O.H., additional, Perón, F.G., additional, Plotnikoff, N.P., additional, Raiti, S., additional, Ramaley, J.A., additional, Rayford, P.L., additional, Renaud, L., additional, Rennie, G.C., additional, Rice, B.F., additional, Rodbard, D., additional, Rodgers, C.H., additional, Rohrer, D.C., additional, Rojo-Ortega, J.M., additional, Rosemberg, E., additional, Rosenqvist, U., additional, Ross, G.T., additional, Rushford, N.B., additional, Ryan, R.J., additional, Saffran, M., additional, Sairam, M.R., additional, Samuels, H.H., additional, Santen, R.J., additional, Schwartz, H.L., additional, Schwartz, N.B., additional, Segaloff, A., additional, Sherins, R.J., additional, Sherman, M.R., additional, Sibley, C.H., additional, Spiegel, A.M., additional, Stampfer, M.R., additional, Steinetz, B.G., additional, Sterling, K., additional, Surks, M.I., additional, Swerdloff, R.S., additional, Swislocki, N.I., additional, Tate, R., additional, Tindall, D.J., additional, Tomkins, G.S., additional, Vaitukaitis, J.L., additional, Van Arsdale, P.M., additional, Vitale, R., additional, Waldhäusl, W., additional, Weeks, C.M., additional, Weisz, J., additional, White, W.F., additional, Wiklund, R.A., additional, Wilber, J.F., additional, Williams, L.T., additional, Winter, J., additional, and Yamamoto, K.R., additional
- Published
- 1976
- Full Text
- View/download PDF
22. REGULATION OF GONADAL FUNCTION IN THE MALE BY GONADOTROPINS
- Author
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Burger, H.G., primary, Baker, H.W.G., additional, de Kretser, D.M., additional, Hudson, B., additional, Franchimont, P., additional, and Pepperell, R.J., additional
- Published
- 1974
- Full Text
- View/download PDF
23. Semen analysis: Its place in modern reproductive medical practice.
- Author
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De Kretser D.M., McLachlan R.I., Baker H.W.G., Clarke G.N., Harrison K.L., Matson P.L., Holden C.A., De Kretser D.M., McLachlan R.I., Baker H.W.G., Clarke G.N., Harrison K.L., Matson P.L., and Holden C.A.
- Abstract
Semen analysis is the most important laboratory investigation for men when assessing the infertile couple. Advances in in vitro fertilisation (IVF) techniques, particularly intracytoplasmic sperm injection (ICSI) involving the direct injection of a single spermatozoon into an egg, have not diminished the role of semen analysis in modern reproductive practice. Semen analysis is the most basic laboratory investigation undertaken and is descriptive in terms of semen volume, appearance, viscosity, sperm concentration, sperm motility and morphology. Since the results are used by clinicians to choose appropriate treatment options, a reliable service is imperative. It is crucial that the laboratory is experienced in the performance of semen analyses to ensure an accurate result. To ensure a quality semen analysis service, laboratories must participate in internal and external quality assurance activities, incorporate rigorous training protocols for technical staff and use reliable procedures. The World Health Organization laboratory manual for the examination of human semen and sperm cervical mucous interaction, clearly describes the variables that need to be assessed and the methods of analysis and quality assurance to be used.
- Published
- 2012
24. Cloning and regulation of the rat activin beta(E) subunit.
- Author
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De Kretser D.M., O'Bryan M.K., Sebire K.L., Gerdprasert O., Hedger M.P., Hearn M.T.W., De Kretser D.M., O'Bryan M.K., Sebire K.L., Gerdprasert O., Hedger M.P., and Hearn M.T.W.
- Abstract
Using a combination of polymerase chain reaction (PCR) procedures, we have cloned and sequenced the rat activin beta(E) subunit cDNA. The putative protein corresponding to the prepro-activin beta(E) subunit was predicted to comprise 350 amino acids which, when cleaved between amino acid residues 236 and 237, would yield a mature polypeptide of approximately M(r) 12 500 with a predicted pI of 5-1. Two cDNA transcripts for activin beta(E) were identified; these differed by 738 bp in the 3'-untranslated region. Activin beta(E) mRNA transcripts were expressed only in rat liver and lung tissue as assessed by Northern blotting and PCR analysis. Relatively higher levels of both transcripts were found in the liver, whereas the lung contained lower levels that were detectable by PCR only. In situ hybridization data showed that, within the liver, activin beta(E) mRNA was localized to hepatocytes. In vivo treatment with lipopolysaccharide as a means of activating the immune system and the hepatic acute-phase response resulted in stimulated activin beta(E) mRNA levels, compared with untreated, control rats. This increased expression was accompanied by a preferential increase in the amount of the long activin beta(E) transcript over the shorter transcript. These findings suggested that the two activin beta(E) mRNA transcripts may be products of alternative splicing events or use alternative polyadenylation sites which are differentially regulated during inflammation. These data provide evidence of a role for activin beta(E) in liver function and inflammation in the rat.
- Published
- 2012
25. Identification of receptor tyrosine kinases in the rat testis.
- Author
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De Kretser D.M., Loveland K.L., Hedger M.P., Risbridger G., Herszfeld D., De Kretser D.M., Loveland K.L., Hedger M.P., Risbridger G., and Herszfeld D.
- Abstract
Evidence of receptor/ligand interactions that regulate testis cell function was sought in order to broaden the current understanding of the molecular basis of testis cell function. Using reverse transcription and the polymerase chain reaction, we have obtained novel evidence for the expression of three mRNAs encoding receptor tyrosine kinases in the adult rat testis: the platelet-derived growth factor type A receptor (PDGF-RA), the basic fibroblast growth factor receptor (flg), and fetal liver kinase 1 (Flk-1). A 6.8 kb transcript encoding the PDGF-RA was observed in RNA prepared from testes of rats aged day 5 through adult, with a decline in relative abundance with increasing age after day 17. Analysis of mRNA from isolated cell preparations (day 21 Sertoli cells, adult Leydig cells, round spermatids, and primary spermatocytes) and testes depleted of specific cell types [ethane dimethane sulfonate (EDS)-treated and cryptorchid] indicated that the Leydig cell was the predominant source of this mRNA in the adult testis. The addition of PDGF-BB to cultures of highly purified adult rat Leydig cell preparations resulted in a 40% increase in LH-stimulated testosterone production, confirming a role for this growth factor in regulation of Leydig cell function. These data indicate that the Leydig cell is a principal site of action of PDGF in the testis.
- Published
- 2012
26. Linkage between male infertility and trinucleotide repeat expansion in the androgen-receptor gene.
- Author
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Yong E.L., Trounson A.O., De Kretser D.M., McLachlan R.I., Clark M., Dowsing A.T., Yong E.L., Trounson A.O., De Kretser D.M., McLachlan R.I., Clark M., and Dowsing A.T.
- Abstract
Background. Androgens acting via the androgen receptor bring about stimulation and maintenance of spermatogenesis. If mutations in the androgen-receptor gene interfere with the receptor's function, this effect may partly account for impaired spermatogenesis. We aimed to find out whether expansion of a trinucleotide repeat in the androgen-receptor gene is associated with male infertility. Methods. We analysed 67 coded semen and blood samples from a predominantly white group of male infertility patients and controls. Clinical analyses included cause of infertility, sperm count, and reproductive hormone concentrations. Analysis of trinucleotide (CAG) repeat length and point mutations in the androgen-receptor gene was done by PCR, single-stranded conformational polymorphism,and DNA sequencing. Findings. Screening and characterisation of the androgen-receptor gene in 35 patients and 32 controls showed no point mutations in the gene. 30 of the infertile patients had idiopathic azoospermia or oligozoospermia, and these men had significantly longer CAG repeat tracts than controls (mean 23.2 [SE 0.7] vs 20.5 [0.3], p = 0.0001). The odds of having CAG repeat lengths of 20 were six-fold higher for fertile men than for men with a spermatogenic disorder. Interpretation. Our results indicate a relation between CAG repeat length in the androgen-receptor gene and the risk of defective spermatogenesis. With the use of intracytoplasmic sperm injection, this mutation could be inherited, possibly leading to an increase in male infertility in future generations. Should further elongation of the CAG repeat occur in these future generations, there is an added risk of increased severity of male infertility, and potentially an increased incidence of neurodegenerative disease.
- Published
- 2012
27. Inhibins, activins and follistatin: Actions on the testis.
- Author
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Phillips D.J., Wreford N.G., De Kretser D.M., Loveland K.L., Meehan T., O'Bryan M.K., Phillips D.J., Wreford N.G., De Kretser D.M., Loveland K.L., Meehan T., and O'Bryan M.K.
- Abstract
While the early studies of the inhibins, activins and follistatins concentrated on their role as endocrine regulators of FSH secretion, recent data has emphasized the local actions of the activins and follistatin. Inhibin, through its capacity to suppress FSH secretion can modulate numerous processes within the testis. However, to date, evidence to support a local role for inhibin is limited. In contrast, activin and its binding protein follistatin are produced by a large number of cell-types within the testis raising the possibility of a range of paracrine and autocrine actions. These include the modulation of androgen production, influence on the proliferation of Sertoli cells and germ cells as well as the capacity to influence the structural and functional features of mitochondria within germ cells. Some of these actions are carefully controlled in a temporal relationship during the development of testicular function in the rat in which there is no separation in time between birth and the onset of spermatogenesis. Given the range of actions of activin in different cell-types, recognition of systems that are designed to modulate its actions are crucial in enhancing our understanding of how these many roles can be compartmentalized. Copyright © 2001 Elsevier Science Ireland Ltd.
- Published
- 2012
28. The 4th Copenhagen Workshop on Carcinoma in situ and Cancer of the Testis: Concluding remarks.
- Author
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De Kretser D.M., Damjanov I., De Kretser D.M., and Damjanov I.
- Abstract
The 4th Copenhagen Workshop 'Carcinoma in situ Germ Cell and Testicular Cancer: Molecular and Endocrine Aspects' was held in Copenhagen, Denmark, May 18-21, 1997. This paper discusses the major themes that emerged during the workshop and summarises the most important contributions.
- Published
- 2012
29. Characterization of serum activin-A and follistatin and their relation to virological and histological determinants in chronic viral hepatitis.
- Author
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Evans L.W., Sievert W., Groome N.P., Patella S., Phillips D.J., De Kretser D.M., Evans L.W., Sievert W., Groome N.P., Patella S., Phillips D.J., and De Kretser D.M.
- Abstract
Background/Methods: Hepatocyte proliferation in viral hepatitis is regulated by a number of growth factors. Activin-A inhibits hepatocyte DNA synthesis while follistatin, a potent activin-A antagonist, promotes liver regeneration. We report the first study of activin-A and follistatin in human viral hepatitis. Sera from 15 normal subjects, 22 hepatitis B and 47 hepatitis C patients were analysed for activin-A and follistatin and correlated with serological and histological markers of liver injury and with specific immunohistochemistry. Result(s): All groups showed immunoreactivity for activin with hepatocyte localisation. Serum activin-A was significantly increased in viral hepatitis patients compared to controls, was greater in hepatitis B compared to hepatitis C, and correlated with serum aminotransferase and hepatitis B viral replication. A concurrent rise in serum follistatin was not observed in either group, but serum follistatin correlated inversely with hepatitis B DNA levels. Although hepatocyte apoptosis in hepatitis C and proliferation in both groups was significantly elevated compared to controls, there was no correlation with serum activin-A or follistatin. Conclusion(s): Activin-A and follistatin are constitutively expressed in human liver and serum concentrations are increased in viral hepatitis. Dysregulation of the activin/follistatin axis may be linked to hepatitis B replication but does not correlate with hepatocyte apoptosis. © 2001 European Association for the Study of the Liver.
- Published
- 2012
30. Evidence that heparin binding autocrine factors modulate testosterone production by the adult rat Leydig cell.
- Author
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De Kretser D.M., Risbridger G.P., McFarlane J.R., Laslett A., De Kretser D.M., Risbridger G.P., McFarlane J.R., and Laslett A.
- Abstract
Androgen production by adult rat Leydig cells is stimulated by pituitary LH but can also be modulated in vitro by paracrine stimulatory and inhibitory factors, many of which belong to growth factor families. Their actions are mediated through cell surface or extracellular matrix proteoglycans and the aim of this study was to determine the role of cell surface heparan sulfate proteoglycans in the regulation of testosterone secretion by adult rat Leydig cells. The presence of sodium chlorate (25 mM) and protamine sulfate (10 mug/ml) inhibited testosterone production by LH stimulated cells by over 50%, but had no effect on unstimulated cells. The LH responsiveness and testosterone production returned to normal after these agents were removed from the culture media. No significant difference in LH receptor numbers at the end of the culture period was seen between sodium chlorate treated and untreated cells. Testosterone production by dibutryl-cAMP stimulated Leydig cells was also inhibited by sodium chlorate. The addition of heparin inhibited testosterone production by LH stimulated cells in a dose-dependent manner, however, in unstimulated Leydig cells heparin stimulated testosterone production to up to 50% of that seen in LH stimulated cells. These data suggest that cell surface heparan sulfate proteoglycans modulate testosterone production by adult Leydig cells in vitro, and that this may involve the autocrine actions of heparin binding growth factors on the Leydig cells.
- Published
- 2012
31. Novel low molecular weight microtubule-associated protein-2 isoforms contain a functional nuclear localization sequence.
- Author
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Herszfeld D., Rames E., Christy E., Briggs L.J., Chu B., Shakri R., De Kretser D.M., Jans D.A., Loveland K.L., Herszfeld D., Rames E., Christy E., Briggs L.J., Chu B., Shakri R., De Kretser D.M., Jans D.A., and Loveland K.L.
- Abstract
Known high and low molecular weight (LMW) MAP2 protein isoforms result from alternative splicing of the MAP2 gene. Contrary to previous reports that MAP2 is neural-specific, we recently identified MAP2 mRNA and protein in somatic and germ cells of rat testis, and showed the predominant testicular isoform is LMW. Although cytoplasmic in neural tissue, MAP2 appeared predominantly nuclear in germ cells using immunohistochemistry. We sought to determine whether this unexpected localization was due to the inclusion of exon 10 within novel LMW MAP2 isoforms. Normally excluded from the LMW MAP2c, exon 10 harbors a putative CcN motif, comprising a nuclear localization sequence (NLS) flanked by regulatory phosphorylation sites for protein kinase CK2 and cdc2 kinase. Characterization of MAP2 mRNA in adult and immature brain and testis, by reverse transcriptase-polymerase chain reaction/Southern analysis and Northern blot, identified novel LMW forms containing exons 10 and 11, previously detected only in high molecular weight MAP2a and 2b. The MAP2 NLS targeted a large heterologous protein to the nucleus, as demonstrated using bacterially expressed MAP2-CcN-beta-galactosidase fusion protein and an in vitro nuclear import assay. Antibodies raised against the fusion protein produced a testicular immunohistochemical staining pattern correlating with MAP2 protein distribution in the nucleus of most germ cells, and precipitated both ~70-kDa and >220-kDa proteins recognized by the commercial MAP2-specific HM2 monoclonal antibody, supporting our hypothesis of a novel LMW MAP2 isoform. These results demonstrate the presence of a functional NLS in MAP2 and indicate that novel LMW MAP2 isoforms may be targeted to the nucleus in both neural and non-neuronal tissues.
- Published
- 2012
32. The effects of lipopolysaccharide on testicular androgen secretion are preceded by changes in the testicular vasculature.
- Author
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De Kretser D.M., Hedger M.P., O'Bryan M.K., Phillips D.J., Schlatt S., De Kretser D.M., Hedger M.P., O'Bryan M.K., Phillips D.J., and Schlatt S.
- Published
- 2012
33. Testosterone effects on spermatogenesis in the gonadotropin-releasing hormone-immunized rat.
- Author
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Tsonis C., Robertson D.M., De Kretser D.M., McLachlan R.I., Wreford N.G., Tsonis C., Robertson D.M., De Kretser D.M., McLachlan R.I., and Wreford N.G.
- Abstract
Active immunization of adult rats with a GnRH fusion protein was used to inhibit gonadotropin secretion and to establish an in vivo model for studying the hormonal control of spermatogenesis. The model was characterized in terms of the efficacy of the immunogen as well as the time course and nature of the immunological and biological responses. To study the reinitiation of spermatogenesis, testosterone (T) was chosen for this initial study as it is known to restore spermatogenesis in gonadotropin-deficient rats. Adult Sprague-Dawley rats were actively immunized with a proprietory GnRH immunogen (BA-11, 100 mug s.c.) every 4 wk. After 12 wk, 58% of animals showed markedly suppressed testicular size, as assessed by scrotal palpation, and were classed as responders. Serum LH, FSH, and T as well as the testicular elongated spermatid count (ESC) and epididymal sperm were undetectable in responding animals. Marked reductions in testicular (29% of control), prostatic (8% of control), and epididymal (32% of control) weights were seen. Spermatogenesis was severely disrupted with no evidence of progression beyond round spermatids. To study the action of T in GnRH-immunized animals, T (defined by lengths of s.c. silastic implant, T3-T24 cm) was given to responding animals. Animals were killed 2, 8, and 12 wk after T24 administration. In response to T24, serum T levels increased to 4 times control levels, serum FSH levels were restored to 65% of control levels by 2 wk, and serum LH remained undetectable. Testicular weight increased to 80% of control levels at 12 wk (p < 0.05 vs. control). Epididymal and prostatic weights were normalized by T. ESC increased to 82% of control values at 12 wk (110 +/- 10 vs. control 134 +/- 8 million/testis, p = 0.001). Spermatogenesis was histologically normal after 8 wk of T24 treatment. To study the time course and dose response of T action, animals were immunized with another GnRH immunogen (BA-17), which yielded an 87% response rate at 12 wk.
- Published
- 2012
34. A switch in the cellular localization of macrophage migration inhibitory factor (MIF) in rat testis after ethane dimethane sulfonate treatment.
- Author
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De Kretser D.M., Mallidis C., Lehmann C., Metz C.N., Bucala R., Hedger M.P., Meinhardt A., Bacher M., McFarlane J.R., De Kretser D.M., Mallidis C., Lehmann C., Metz C.N., Bucala R., Hedger M.P., Meinhardt A., Bacher M., and McFarlane J.R.
- Published
- 2012
35. Testicular cancer and infertility.
- Author
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De Kretser D.M. and De Kretser D.M.
- Published
- 2012
36. Immunoregulatory activity in adult rat testicular interstitial fluid: Roles of interleukin-1 and transforming growth factor beta.
- Author
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Hutchinson P., De Kretser D.M., Hedger M.P., Atkins R.C., Nikolic-Paterson D.J., Hutchinson P., De Kretser D.M., Hedger M.P., Atkins R.C., and Nikolic-Paterson D.J.
- Abstract
Studies on the effect of rat testicular interstitial fluid (IF) on T- cell function have reported both stimulatory and inhibitory actions. Specific cytokines produced within the testis, particularly interleukin-1 (IL-1) and transforming growth factor beta (TGFbeta), may contribute to these apparently conflicting observations. In proliferation assays employing lectin- or antibody-activated thymocytes or mature T cells in vitro, adult rat testicular IF stimulated T-cell activation and/or proliferation at low assay doses and was inhibitory at higher doses. The stimulatory activity was blocked by recombinant IL-1 receptor antagonist. The inhibitory activity was not affected by a polyspecific TGFbeta antiserum. The biological characteristics of the inhibitor were distinct from those of a similar, but considerably less potent, activity in platelet-depleted serum. These data demonstrate that rat testicular IF contains biologically significant concentrations of IL-1 but has a predominantly inhibitory action on T-cell responses. The factor predominantly responsible for this inhibitory activity displays a relatively large apparent molecular weight, is protease sensitive and partially heat labile, but does not appear to be one of the known mammalian TGFbeta isoforms.
- Published
- 2012
37. Clinical male infertility. I. Prevalence of and progress in understanding male infertility.
- Author
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de Kretser D.M. and de Kretser D.M.
- Published
- 2012
38. Activin maintains the condensed type of mitochondria in germ cells.
- Author
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Meinhardt A., De Kretser D.M., Seitz J., McFarlane J.R., Meinhardt A., De Kretser D.M., Seitz J., and McFarlane J.R.
- Abstract
Development of germ cells during spermatogenesis is characterized by a complex series of differentiation events finally leading to the production of spermatozoa. Beside the main hormonal regulators, paracrine interactions are thought to play a major role in this process. Mitochondria in germ cells pass through unique alterations ranging from the 'typical' cristae-rich mitochondria found in spermatogonia to the 'condensed' form in pachytene spermatocytes. This study provides further support that paracrine factors produced by Sertoli cells, most likely activin A, are involved in germ cell differentiation as monitored by the maintenance of the physiological 'condensed' mitochondrial phenotype in primary spennatocytes. Culture of primary spermatocytes in Sertoli cell conditioned medium (SCCM) for 18 h resulted in the maintenance of a high percentage of 'condensed-type' mitochondria in comparison to cells cultured in Dulbecco's minimum essential medium (DMEM). Activin A, a product of Sertoli cells, showed at subnanogram concentrations a similar ability to SCCM to maintain a high percentage of spematocyte mitochondria in the 'condensed' state, while inhibin had no effect. The addition of an antiserum specific for activin A resulted in a neutralization of the effect caused by activin A or SCCM. This strongly suggested that the active substance in SCCM was activin A. Taken together these data indicate that activin A is the first Sertoli cell product that has been identified to influence differentiation of male meiotic germ cells. (C) 2000 Elsevier Science Ireland Ltd.
- Published
- 2012
39. Characterisation of adult Sertoli cell cultures from cryptorchid rats: Inhibin secretion in response to follicle-stimulating hormone stimulation.
- Author
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Simpson B.J.B., De Kretser D.M., Hedger M.P., Simpson B.J.B., De Kretser D.M., and Hedger M.P.
- Abstract
Testes from adult (90-120-day-old) rats, which had been made cryptorchid 28 days previously, were dispersed by successive treatment with trypsin, collagenase and hyaluronidase. The resulting crude cell suspension was fractionated on discontinuous Percoll density gradients to yield five distinct cell bands (1-5), at the interface between successive layers of Percoll. Crude cells and purified fractions were cultured for up to 7 days, and inhibin was subsequently measured in the media by radioimmunoassay and in vitro bioassay. Sertoli cells from density gradient bands 2 (1.03-1.04 g/ml) and 3 (1.04-1.05 g/ml) showed minimal germ cell or peritubular cell contamination, as determined by morphological and histochemical techniques. Cells from these bands secreted significantly higher levels of immunoactive inhibin/mug DNA/48 h under both basal and either follicle-stimulating hormone (FSH)- (100 ng/ml) or dibutyryl cAMP-stimulated (100 mug/ml) conditions than did cells from the other bands. While there was a decline in basal secretion of inhibin with increasing duration of culture, the capacity of the purified Sertoli cells (bands 2 and 3) to respond to both FSH and dibutyryl cAMP increased over the culture period. The addition of dibutyryl cAMP (31.25-500 mug/ml) to the purified Sertoli cells also caused a stimulation of bioactive inhibin. Immunoactive inhibin production by purified Sertoli cells was unaffected by the addition of either rat LH (8 ng/ml) or testosterone (10-6 M). The data describe a method for the isolation of adult Sertoli cells from cryptorchid testes, and demonstrate their responsiveness to both FSH and dibutyryl cAMP in vitro using the measurement of immunoactive inhibin as a marker of Sertoli cell function.
- Published
- 2012
40. Identification of specific sites of hormonal regulation in spermatogenesis in rats, monkeys, and man.
- Author
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Stanton P.G., Robertson D.M., Pratis K., De Kretser D.M., McLachlan R.I., O'Donnell L., Meachem S.J., Stanton P.G., Robertson D.M., Pratis K., De Kretser D.M., McLachlan R.I., O'Donnell L., and Meachem S.J.
- Abstract
A detailed understanding of the hormonal regulation of spermatogenesis is required for the informed assessment and management of male fertility and, conversely, for the development of safe and reversible male hormonal contraception. An approach to the study of these issues is outlined based on the use of well-defined in vivo models of gonadotropin/androgen deprivation and replacement, the quantitative assessment of germ cell number using stereological techniques, and the directed study of specific steps in spermatogenesis shown to be hormone dependent. Drawing together data from rat, monkey, and human models, we identify differences between species and formulate an overview of the hormonal regulation of spermatogenesis. There is good evidence for both separate and synergistic roles for both testosterone and follicle-stimulating hormone (FSH) in achieving quantitatively normal spermatogenesis. Based on relatively selective withdrawal and replacement studies, FSH has key roles in the progression of type A to B spermatogonia and, in synergy with testosterone, in regulating germ cell viability. Testosterone is an absolute requirement for spermatogenesis. In rats, it has been shown to promote the adhesion of round spermatids to Sertoli cells, without which they are sloughed from the epithelium and spermatid elongation fails. The release of mature elongated spermatids from the testis (spermiation) is also under FSH/testosterone control in rats. Data from monkeys and men treated with steroidal contraceptives indicate that impairment of spermiation is a key to achieving azoospermia. The contribution of 5alpha-reduced androgens in the testis to the regulation of spermatogenesis is also relevant, as 5alpha-reduced androgens are maintained during gonadotropin suppression and may act to maintain low levels of germ cell development. These concepts are also discussed in the context of male hormonal contraceptive development.
- Published
- 2012
41. Identification of a novel testis-specific member of the phosphatidylethanolamine binding protein family, pebp-2.
- Author
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Loveland K.L., Hearn M.T.W., De Kretser D.M., O'Bryan M.K., Alter K., Keah H.-H., Edgar K., Sebire K., Morrison J.R., Gibbs G., Hickox D.M., Loveland K.L., Hearn M.T.W., De Kretser D.M., O'Bryan M.K., Alter K., Keah H.-H., Edgar K., Sebire K., Morrison J.R., Gibbs G., and Hickox D.M.
- Abstract
The phosphatidylethanolamine binding proteins (pebps) are an evolutionarily conserved family of proteins recently implicated in mitogen-activated protein (MAP) kinase pathway regulation, where they are called raf kinase inhibitory proteins. Here, we describe the cloning, cellular localization, and partial characterization of a new member, pebp-2, with potential roles in male fertility. Expression data show that pebp-2 is a testis-specific 21-kDa protein found within late meiotic and haploid germ cells in a stage-specific pattern that is temporally distinct from that of pebp-1. Sequence analyses suggest that pebp-2 forms a distinct subset of the pebp family within mammals. Database analyses revealed the existence of a third subset. Analysis suggests that the specificity/regulation of the distinct pebps subsets is likely to be determined by the amino terminal 40 amino acids or the 3' untranslated region, where the majority of sequence differences occur. Protein homology modeling suggests that pebp-2 protein is, however, topologically similar to other pebps and composed of Greek key fold motifs, a dominant beta sheet formed from five anti-parallel beta strands forming a shallow groove associated with a putative phosphatidylethanolamine binding site. The pebp-2 gene is intronless and data suggest that it is a retrogene derived from pebp-1. Further, pebp-2 colocalizes with members of the MAP kinase pathway in late spermatocytes and spermatids and on the midpiece of epididymal sperm. These data raise the possibility that pebp-2 is a novel participant in the MAP kinase signaling pathway, with a role in spermatogenesis or posttesticular sperm maturation.
- Published
- 2012
42. Effects of testosterone plus medroxyprogesterone acetate on semen quality, reproductive hormones, and germ cell populations in normal young men.
- Author
-
De Kretser D.M., Robertson D.M., Frydenberg M., Balourdos G., Stanton P.G., O'Donnell L., McLachlan R.I., De Kretser D.M., Robertson D.M., Frydenberg M., Balourdos G., Stanton P.G., O'Donnell L., and McLachlan R.I.
- Abstract
Testosterone (T) treatment suppresses gonadotropin levels and sperm counts in normal men, but the addition of a progestin may improve the efficacy of hormonal contraception. This study aimed to investigate the speed and extent of suppression of testicular germ cell number induced by T plus or minus progestin treatment and correlate these changes with serum gonadotropins and inhibin B levels, testicular androgens, and sperm output. Thirty normal fertile men (31-46 yr) received either testosterone enanthate (TE, 200 mg im weekly) alone or TE plus depot medroxyprogesterone acetate (DMPA, 300 mg im once) for 2, 6, or 12 wk (n = 5 per group) before vasectomy and testis biopsy. Five men (controls) proceeded directly to surgery. The inclusion of DMPA led to a more rapid fall in serum FSH/LH levels (time to 10% baseline: FSH; 12.6 +/- 2.6 vs. 7.9 +/- 1.4 d; LH, 9.9 +/- 3.4 vs. 3.4 +/- 1.7 d, TE vs. TE+DMPA, respectively, mean +/- SD, both P < 0.0001), yet the mean time to reach a sperm count 10% of baseline was not different (23.7 +/- 7.3 vs. 25.3 +/- 13.9 d, NS). The maximum extent of FSH/LH suppression was identical at 12 wk (mean serum FSH 1.2 and 1.6%, and mean LH 0.3 and 0.2% of baseline: TE vs. TE+ DMPA, respectively) as was sperm count suppression (5 of 5 and 4 of 5 men, respectively, with sperm counts <=0.1 x 106/ml). Serum inhibin decreased to 55% control at 12 wk in the TE+DMPA group (P < 0.05) but was unchanged by TE treatment (86% control, NS). Testicular T levels declined to approximately 2% of control levels, but testicular dihydrotestosterone and 5alpha-androstane-3alpha, 17beta-diol (Adiol) levels were not different to control. Germ cell numbers as determined by stereological methods did not differ between TE and TE+DMPA except at 2 wk when type B spermatogonia and early spermatocytes were significantly lower in the TE+DMPA group (P < 0.05). In all groups, a marked inhibition of Apale->B spermatogonial maturation was seen along with a striking inhibition of
- Published
- 2012
43. Regulated production of activin A and inhibin B throughout the cycle of the seminiferous epithelium in the rat.
- Author
-
O'Connor A.E., Hayashi T., Loveland K.L., de Kretser D.M., Hedger M.P., Okuma Y., O'Connor A.E., Hayashi T., Loveland K.L., de Kretser D.M., Hedger M.P., and Okuma Y.
- Abstract
Production and regulation of activin A and inhibin B during the cycle of the seminiferous epithelium were investigated in adult rats. Immunohistochemistry localised the activin betaA-subunit to the Sertoli cell cytoplasm, with much weaker expression in spermatocytes and spermatids. Both activin A and inhibin B, measured by ELISA were secreted by, seminiferous tubule fragments over 72 h in culture. Activin A was secreted in a cyclic manner with peak secretion from tubules isolated at stage VIII. Tubules collected during stage VI produced the least activin A. Inhibin B secretion was highest from stage IX-I tubules and lowest from stage VII tubules. Addition of interleukin-1beta (IL-1beta) had relatively little effect on activin A or inhibin B secretion in culture. In contrast, the peak secretion of activin A by stage VIII tubules was blocked by co-incubation with an excess of human recombinant IL-1 receptor antagonist, whereas inhibin B secretion increased slightly. Dibutyryl cAMP stimulated activin A secretion by late stage VII and VIII tubules and stimulated inhibin B across all stages. These data indicate that activin A and inhibin B are cyclically regulated within the seminiferous epithelium, with endogenous IL-1 (presumably IL-1alpha produced by the Sertoli cells), responsible for a peak of activin A production subsequent to sperm release at stage VIII. These data provide direct evidence that production of activin A and inhibin B by the Sertoli cell is locally modulated by IL-1alpha, in addition to FSH/ cAMP, under the influence of the developing spermatogenic cells. © 2006 Society for Endocrinology.
- Published
- 2012
44. Inhibin in the male.
- Author
-
De Kretser D.M., McFarlane J.R., De Kretser D.M., and McFarlane J.R.
- Published
- 2012
45. Ovine allantoic fluid contains high concentrations of activin A: Partial dissociation of immunoactivity and bioactivity.
- Author
-
Farnworth P., McFarlane J.R., De Kretser D.M., Buttress D., Jenkin G., Groome N.P., Foulds L.M., Farnworth P., McFarlane J.R., De Kretser D.M., Buttress D., Jenkin G., Groome N.P., and Foulds L.M.
- Abstract
In a preliminary study, allantoic fluid collected from pregnant sheep across gestational ages of 20-124 days contained significantly higher levels of activin bioactivity (189 +/- 74 ng/ml, mean +/- SE) than did amniotic fluid (3.2 +/- 0.6 ng/ml). Using a combination of chromatography steps, we isolated from 5 L of allantoic fluid approximately 612 mug of immunoactive activin, which eluted over 10 fractions from a C8 reversed-phase column. When these fractions were assayed in a rat pituitary cell culture bioassay, in a specific RIA, and in an activin A two-site ELISA, the RIA activity was skewed to the less hydrophobic side of the activin profile, while the bioactivity was skewed to the more hydrophobic forms. The activity measured in the two- site ELISA more closely matched the mass of activin as determined by laser densitometry. Amino-terminal sequencing of fractions containing either peak immunoactivity or bioactivity showed each to be identical to activin A. This was confirmed by internal sequences from a fraction that eluted in the area of overlapping immunoactivity and bioactivity. A peptide containing at least 18 amino acids at its amino terminus, which were identical to the conserved region of the acute-phase protein serum amyloid A, was identified in the most immunoactive activin fractions.
- Published
- 2012
46. Expression of activin betaC subunit mRNA in reproductive tissues.
- Author
-
McFarlane J.R., De Kretser D.M., Loveland K.L., McFarlane J.R., De Kretser D.M., and Loveland K.L.
- Abstract
A cDNA encoding the potential activin betaC subunit was produced from human testis RNA using reverse transcription and PCR and then used as a probe in Northern blot analysis of poly(A)+ RNA. A transcript of ~1.8 kb was evident in human ovary, placenta and testis samples. A transcript of this size was also detected in adult rat caput and cauda epididymis, and adult and day-15 testis and adult spleen, while adult liver contained a single transcript of ~2.1 kb. Poly(A)+ RNA from primary spermatocytes but not from round spermatids contained the 1.8 kb activin betaC mRNA. These findings highlight the need for further studies to determine the physiological role(s) of activin betaC in a wide variety of tissues.
- Published
- 2012
47. Tpx-1 is a component of the outer dense fibers and acrosome of rat spermatozoa.
- Author
-
De Kretser D.M., O'Bryan M.K., Sebire K., Meinhardt A., Edgar K., Keah H.-H., Hearn M.T.W., De Kretser D.M., O'Bryan M.K., Sebire K., Meinhardt A., Edgar K., Keah H.-H., and Hearn M.T.W.
- Abstract
Previously we reported the cloning of a member of the cysteine-rich secretory protein family, tpx-1, from a testis expression library using an outer dense fiber (ODF)-specific antiserum. Using immunohistochemical and immunoelectron microscopic techniques and Western blotting of purified sperm tail components, we have determined that tpx-1 exists as 25 and 27 kDa proteins in two components of rat spermatid: the ODFs and the acrosome. Tpx-1 mRNA is first expressed in the late pachytene spermatocytes, but the production of these tpx-1 proteins is translationally delayed for 4-5 days before being incorporated into the developing sperm acrosome, surrounding the elongating and condensing spermatid nucleus. Concurrent with sperm head formation, tpx-1 protein was incorporated into the developing sperm tail, and specifically the ODFs. The tpx-1 protein was seen within structures resembling granulated bodies in the cytoplasmic lobe of elongating spermatids and was incorporated subsequently into the growing tail in a manner consistent with ODF development. In addition, tpx-1 protein was localized at the ultrastructural level of the connecting piece of the neck and longitudinal columns of the fibrous sheath, suggesting common protein components in these cytoskeletal structures. As such, tpx-1 may have functional significance in the processes of sperm head development and tail function. (C) 2001 Wiley-Liss, Inc.
- Published
- 2012
48. The Y chromosome gr/gr subdeletion is associated with male infertility.
- Author
-
Lynch M., Cram D.S., Reilly A., O'Bryan M.K., Baker H.W.G., de Kretser D.M., McLachlan R.I., Lynch M., Cram D.S., Reilly A., O'Bryan M.K., Baker H.W.G., de Kretser D.M., and McLachlan R.I.
- Abstract
Men with Y chromosome (Yq) AZFc deletions lack all copies of the DAZ gene and have severe spermatogenic failure. A recently described gr/gr subdeletion of AZFc removes two of four copies of DAZ. To better understand the relative frequencies of AZFc and gr/gr deletions and their associated phenotypes, we analysed two large groups of infertile men. A total of 788 men from the Monash Male Infertility (MMI) database with a range of fertility disorders showed similar overall prevalences of AZFc (2.5%) and gr/gr deletions (3.4%). There was no association of gr/gr deletions with sperm density. In 234 control men of known or presumed fertility, only one gr/gr deletion was found. In a further 599 consecutive men presenting for assisted reproductive technologies, we detected 13 (2.2%) AZFc deletions and 28 (4.7%) gr/gr deletions. All AZFc deletions were seen with sperm densities <5 million/ml but again the gr/gr deletion occurred with similar frequency across all sperm density categories. These data show that gr/gr deletions are significantly associated with infertility in the Australian population (P = 0.0015) but not exclusively with reduced sperm density suggesting a complex interaction with other factors important for male fertility. Vertical transmission of gr/gr deletions from father to son by ICSI was demonstrated in four cases. Analysis of 130 ICSI-conceived sons revealed no de novo gr/gr deletions indicating that ICSI is not a risk factor. The data suggest that testing for gr/gr deletions should be considered in the routine genetic assessment of men with idiopathic infertility. © The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
- Published
- 2012
49. A sensitive and specific in vitro bioassay for activin using a mouse plasmacytoma cell line, MPC-11.
- Author
-
Hedger M.P., Phillips D.J., Brauman J.N., Mason A.J., De Kretser D.M., Hedger M.P., Phillips D.J., Brauman J.N., Mason A.J., and De Kretser D.M.
- Abstract
A new in vitro bioassay for activin was developed using the mouse plasmacytoma cell line, MPC-11. Human recombinant (hr) activin A dose- dependently inhibited the proliferation of these cells, whereas a range of other factors, including inhibit, follistatin and transforming growth factor- beta1, -beta2 and -beta3 had no effect. Conditioned medium containing activin B induced an inhibition similar to hr-activin A. The inhibitory influence of activin A could be blocked by follistatin, but not by hr-inhibit A. This bioassay had a sensitivity for activin A of around 0.4 ng/ml, an ED50 response of 3.5 ng/ml, and an intraassay coefficient of variation of <11%. It offers substantial advantages over existing in vitro activin bioassays in terms of ease of use, specificity and throughput. The utility of the MPC-11 bioassay was demonstrated in the purification of activin from amniotic fluid, where an almost identical profile of bioactive activin A was detected compared with the pituitary cell bioassay of activin. Bioactive activin could also be detected in unpurified ovine allantoic and amniotic fluids and bovine follicular fluid. Measuring activin in untreated and heat-treated human sera or seminal plasma was hampered by a non-specific inhibitory effect, so that several serum samples did not run parallel with the hr-activin A standard. This inhibitory effect by serum could not be overcome by addition of follistatin, suggesting it is not activin-like bioactivity. This new bioassay for activin demonstrates widespread applicability for monitoring of purified or partially purified samples during purification procedures, bioactivity measurements, receptor-binding studies and assays of cell culture medium.
- Published
- 2012
50. Functional Analysis of the Cooled Rat Testis.
- Author
-
Zhang Z., Short R.V., Meehan T., De Kretser D.M., Renfree M.B., Loveland K.L., Zhang Z., Short R.V., Meehan T., De Kretser D.M., Renfree M.B., and Loveland K.L.
- Abstract
Direct cooling of the testis results in the depletion of most germ cells in vivo. Germ cell-depleted testes are now commonly used to investigate spermatogenic regeneration and can serve as recipients for germ cell transplantation. The present study explored the effects of cooling rat testes on the depletion of endogenous germ cells, spermatogenic regeneration, and Sertoli cell function. Adult rat testes were cooled with iced Ringer's solution for 60 minutes, which results in the initiation of apoptotic germ cell loss within 8 hours. Pachytene spermatocytes at stages XII-I were the cells most sensitive to cooling. In 46%-67% of seminiferous tubule cross-sections, only Sertoli cells remained in the cooled testes 3-10 weeks after treatment. Germ cell loss was accompanied by a significant decrease in circulating inhibin B and an increase in follicle-stimulating hormone concentrations, which indicated a change in Sertoli cell function. Quantitative analysis of mRNA expression associated with apoptotic signals showed no significant uniform changes among the cooled testes, although some individuals had a distinct up-regulation of FAS mRNA at 24 hours. Attempts to use the cooled testes as recipient testes for mouse-to-rat germ cell transplantation were undertaken, but none of the mouse germ cells transplanted into the testes 15-34 days after cooling appeared to have undergone spermatogenesis 64-92 days after transplantation. These data suggest that modifications to Sertoli cell function resulting from testicular cooling create an environment that is unable to support spermatogenesis by donor germ cells.
- Published
- 2012
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