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Altered testicular development as a consequence of increase number of sertoli cell in male lambs exposed prenatally to excess testosterone

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Abstract

The reprograming effects of prenatal testosterone (T) treatment on postnatal reproductive parameters have been studied extensively in females of several species but similar studies in males are limited. We recently found that prenatal T treatment increases Sertoli cell number and reduced spermatogenesis in adult rams. If such disruptions are manifested early in life and involve changes in testicular paracrine environment remain to be explored. This study addresses the impact of prenatal T excess on testicular parameters in infant males, including Sertoli cell number and expression of critical genes [FSH receptor (FSHR), androgen receptor (AR), transforming growth factor beta 1 (TGFB1), 3 (TGFB3), transforming growth factor beta type 1 receptor, (TGFBR1), and anti-Müllerian hormone (AMH)] modulating testicular function. At 4 week of age, male lambs born to dams treated with 30 mg of T propionate twice weekly from day 30 to 90, followed by 40 mg of T propionate from day 90 to 120 of pregnancy (T-males), had a higher number of Sertoli cells/testis (P = 0.035) than control males (C-males) born to dams treated with the vehicle. While no differences were observed in the expression of FSHR and TGFB3, testicular TGFBR1 expression was found to be lower in T-males (P = 0.03) compared to C-males. Expression level of AMH, TGFB1, and AR also tended to be lower in T-males. These findings provide evidence that impact of fetal exposure to T excess is evident early in postnatal life, mainly characterized by an increase in Sertoli cell number. This could explain the testicular dysfunction observed in adult rams.

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References

  1. S.E. Recabarren, P.P. Rojas-García, M.P. Recabarren, V.H. Alfaro, R. Smith, V. Padmanabhan, T. Sir-Petermann, Prenatal testosterone excess reduces sperm count and motility. Endocrinology 149, 6444–6448 (2008)

    Article  PubMed  CAS  Google Scholar 

  2. P.P. Rojas-García, M.P. Recabarren, L. Sarabia, J. Schön, C. Gabler, R. Einspanier, M. Maliqueo, T. Sir-Petermann, R. Rey, S.E. Recabarren, Prenatal testosterone excess alters Sertoli and germ cell number and testicular FSH receptor expression in rams. Am. J. Physiol. Endocrinol. Metab. 299, E998–E1005 (2010)

    Article  PubMed  Google Scholar 

  3. T. Sir-Petermann, M. Maliqueo, B. Angel, H.E. Lara, F. Pérez-Bravo, S.E. Recabarren, Maternal serum androgens in pregnant women with polycystic ovarian syndrome: possible implications in prenatal androgenization. Hum. Reprod. 17, 2573–2579 (2002)

    Article  PubMed  CAS  Google Scholar 

  4. D. Tran, N. Meusy-Dessolle, N. Josso, Anti-Müllerian hormone is a functional marker of foetal Sertoli cells. Nature 269, 411–412 (1977)

    Article  PubMed  CAS  Google Scholar 

  5. R. Rey, Endocrine, paracrine and cellular regulation of postnatal anti-Mullerian hormone secretion by Sertoli cells. Trends Endocrinol. Metab. 9, 271–276 (1998)

    Article  PubMed  CAS  Google Scholar 

  6. S.E. Recabarren, T. Sir-Petermann, R. Rios, M. Maliqueo, B. Echiburú, R. Smith, P. Rojas-García, M. Recabarren, R.A. Rey, Pituitary and testicular function in sons of women with polycystic ovary syndrome from infancy to adulthood. J. Clin. Endocrinol. Metab. 93, 3318–3324 (2008)

    Article  PubMed  CAS  Google Scholar 

  7. C. West, D.L. Foster, N.P. Evans, J. Robinson, V. Padmanabhan, Intra-follicular activin availability is altered in prenatally-androgenized lambs. Mol. Cell. Endocrinol. 185, 51–59 (2001)

    Article  PubMed  CAS  Google Scholar 

  8. S.E. Recabarren, V. Padmanabhan, E. Codner, A. Lobos, C. Durán, M. Vidal, D.L. Foster, T. Sir-Petermann, Postnatal developmental consequences of altered insulin sensitivity in female sheep treated prenatally with testosterone. Am. J. Physiol. Endocrinol. Metab. 289, E801–E806 (2005)

    Article  PubMed  CAS  Google Scholar 

  9. T.L. Steckler, C. Herkimer, D.A. Dumesic, V. Padmanabhan, Developmental programming: excess weight gain amplifies the effects of prenatal testosterone excess on reproductive cyclicity–implication for polycystic ovary syndrome. Endocrinology 150, 1456–1465 (2009)

    Article  PubMed  Google Scholar 

  10. S. Franks, Animal models and the developmental origins of polycystic ovary syndrome: increasing evidence for the role of androgens in programming reproductive and metabolic dysfunction. Endocrinology 153, 2536–2547 (2012)

    Article  PubMed  CAS  Google Scholar 

  11. B.P. Mullaney, M.K. Skinner, Transforming growth factor-beta (beta 1, beta 2, and beta 3) gene expression and action during pubertal development of the seminiferous tubule: potential role at the onset of spermatogenesis. Mol. Endocrinol. 7, 67–76 (1993)

    Article  PubMed  CAS  Google Scholar 

  12. K.J. Teerds, J.H. Dorrington, Localization of transforming growth factor beta 1 and beta 2 during testicular development in the rat. Biol. Reprod. 48, 40–45 (1993)

    Article  PubMed  CAS  Google Scholar 

  13. C. Belville, S.P. Jamin, J.Y. Picard, N. Josso, N. di Clemente, Role of type I receptors for anti-Müllerian hormone in the SMAT-1 Sertoli cell line. Oncogene 24, 4984–4992 (2005)

    Article  PubMed  CAS  Google Scholar 

  14. S. Hirobe, W.W. He, M.M. Lee, P.K. Donahoe, Mullerian inhibiting substance messenger ribonucleic acid expression in granulosa and Sertoli cells coincides with their mitotic activity. Endocrinology 131, 854–862 (1992)

    Article  PubMed  CAS  Google Scholar 

  15. J. Teixeira, S. Maheswaran, P.K. Donahoe, Müllerian inhibiting substance: an instructive developmental hormone with diagnostic and possible therapeutic applications. Endocr. Rev. 22, 657–674 (2001)

    Article  PubMed  CAS  Google Scholar 

  16. W.Y. Lui, W.M. Lee, C.Y. Cheng, TGF-betas: their role in testicular function and Sertoli cell tight junction dynamics. Int. J. Androl. 26, 147–160 (2003)

    Article  PubMed  CAS  Google Scholar 

  17. W.Y. Lui, W.M. Lee, C.Y. Cheng, Transforming growth factor-beta3 perturbs the inter-Sertoli tight junction permeability barrier in vitro possibly mediated via its effects on occludin, zonula occludens-1, and claudin-11. Endocrinology 142, 1865–1877 (2001)

    Article  PubMed  CAS  Google Scholar 

  18. W.Y. Lui, W.M. Lee, C.Y. Cheng, Transforming growth factor beta3 regulates the dynamics of Sertoli cell tight junctions via the p38 mitogenactivated protein kinase pathway. Biol. Reprod. 68, 1597–1612 (2003)

    Article  PubMed  CAS  Google Scholar 

  19. L. Konrad, G.H. Lüers, E. Völck-Badouin, M.M. Keilani, L. Laible, G. Aumüller, R. Hofmann, Analysis of the mRNA expression of the TGF-Beta family in testicular cells and localization of the splice variant TGF-beta2B in testis. Mol. Reprod. Dev. 73, 1211–1220 (2006)

    Article  PubMed  CAS  Google Scholar 

  20. S.E. Recabarren, P.P. Rojas-García, M.P. Recabarren, K. Norambuena, T. Sir-Petermann, Impact of prenatal exposure to testosterone in biometrics and endocrine parameters of newborn lambs. Arch. Med. Vet. 41, 43–51 (2009)

    Article  CAS  Google Scholar 

  21. R. Rey, S. Campo, P. Bedecarrás, C. Nagle, H. Chemes, Is infancy a quiescent period of testicular development? Histological, morphometric, and functional study of the seminiferous tubules of the Cebus monkey from birth to the end of puberty. J. Clin. Endocrinol. Metab. 76, 1325–1331 (1993)

    Article  PubMed  CAS  Google Scholar 

  22. H. Mori, A.K. Christensen, Morphometric analysis of Leydig cells in the normal rat testis. J. Cell Biol. 84, 340–354 (1980)

    Article  PubMed  CAS  Google Scholar 

  23. R. Rey, C. Nagle, H. Chemes, Morphometric study of the testicular interstitial tissue of the monkey Cebus apella during postnatal development. Tissue Cell 28, 31–42 (1996)

    Article  PubMed  CAS  Google Scholar 

  24. D.J. Handelsman, S. Staraj, Testicular size: the effects of aging, malnutrition, and illness. J. Androl. 6, 144–151 (1985)

    PubMed  CAS  Google Scholar 

  25. W. Muruvi, H.M. Picton, R.G. Rodway, I.M. Joyce, In vitro growth of oocytes from primordial follicles isolated from frozen–thawed lamb ovaries. Theriogenology 64, 1357–1370 (2005)

    Article  PubMed  CAS  Google Scholar 

  26. C.L. Bormann, G.D. Smith, V. Padmanabhan, T.M. Lee, Prenatal testosterone and dihydrotestosterone exposure disrupts ovine testicular development. Reproduction 142, 167–173 (2011)

    Article  PubMed  CAS  Google Scholar 

  27. M. Nistal, M.A. Abaurrea, R. Paniagua, Morphological and histometric study on the human Sertoli cell from birth to the onset of puberty. J. Anat. 134, 351–363 (1982)

    PubMed  CAS  Google Scholar 

  28. J. Müller, N.E. Skakkebæk, Quantification of germ cells and seminiferous tubules by stereological examination of testicles from 50 boys who suffered from sudden death. Int. J. Androl. 6, 143–156 (1983)

    Article  PubMed  Google Scholar 

  29. C. Lukas-Croisier, C. Lasala, J. Nicaud, P. Bedecarrás, T.R. Kumar, M. Dutertre, M.M. Matzuk, J.Y. Picard, N. Josso, R. Rey, Follicle-stimulating hormone increases testicular anti-Müllerian hormone (AMH) production through Sertoli cell proliferation and a nonclassical cyclic adenosine 5′-monophosphate-mediated activation of the AMH gene. Mol. Endocrinol. 17, 550–561 (2003)

    Article  PubMed  CAS  Google Scholar 

  30. H. Johnston, P.J. Baker, M. Abel, H.M. Charlton, G. Jackson, L. Fleming, T.R. Kumar, P.J. O’Shaughnessy, Regulation of Sertoli cell number and activity by follicle-stimulating hormone and androgen during postnatal development in the mouse. Endocrinology 145, 318–329 (2004)

    Article  PubMed  CAS  Google Scholar 

  31. K.A. Tan, K. De Gendt, N. Atanassova, M. Walker, R.M. Sharpe, P.T. Saunders, E. Denolet, G. Verhoeven, The role of androgens in Sertoli cell proliferation and functional maturation: studies in mice with total or Sertoli cell-selective ablation of the androgen receptor. Endocrinology 146, 2674–2683 (2005)

    Article  PubMed  CAS  Google Scholar 

  32. H.M. Scott, G.R. Hutchison, M.S. Jobling, C. McKinnell, A.J. Drake, R.M. Sharpe, Relationship between androgen action in the “male programming window,” fetal Sertoli cell number, and adult testis size in the rat. Endocrinology 149, 5280–5287 (2008)

    Article  PubMed  CAS  Google Scholar 

  33. L. You, M. Sar, Androgen receptor expression in the testes and epididymides of prenatal and postnatal Sprague-Dawley rats. Endocrine 9, 253–261 (1998)

    Article  PubMed  CAS  Google Scholar 

  34. G. Majdic, M.R. Millar, P.T. Saunders, Immunolocalisation of androgen receptor to interstitial cells in fetal rat testes and to mesenchymal and epithelial cells of associated ducts. J. Endocrinol. 147, 285–293 (1995)

    Article  PubMed  CAS  Google Scholar 

  35. L. Al-Attar, K. Noël, M. Dutertre, C. Belville, M.G. Forest, P.S. Burgoyne, N. Josso, R. Rey, Hormonal and cellular regulation of Sertoli cell anti- Müllerian hormone production in the postnatal mouse. J. Clin. Invest. 100, 1335–1343 (1997)

    Article  PubMed  CAS  Google Scholar 

  36. E.B. Berensztein, M.S. Baquedano, C.R. Gonzalez, N.I. Saraco, J. Rodriguez, R. Ponzio, M.A. Rivarola, A. Belgorosky, Expression of aromatase, estrogen receptor alpha and beta, androgen receptor, and cytochrome P-450scc in the human early prepubertal testis. Pediatr. Res. 60, 740–744 (2006)

    Article  PubMed  CAS  Google Scholar 

  37. H.E. Chemes, R.A. Rey, M. Nistal, J. Regadera, M. Musse, P. González-Peramato, A. Serrano, Physiological androgen insensitivity of the fetal, neonatal, and early infantile testis is explained by the ontogeny of the androgen receptor expression in Sertoli cells. J. Clin. Endocrinol. Metab. 93, 4408–4412 (2008)

    Article  PubMed  CAS  Google Scholar 

  38. K. Boukari, G. Meduri, S. Brailly-Tabard, J. Guibourdenche, M.L. Ciampi, N. Massin, L. Martinerie, J.Y. Picard, R. Rey, M. Lombès, Lack of androgen receptor expression in Sertoli cells accounts for the absence of anti-Mullerian hormone repression during early human testis development. J. Clin. Endocrinol. Metab. 94, 1818–1825 (2009)

    Article  PubMed  CAS  Google Scholar 

  39. J.M. Orth, G.L. Gunsalus, A.A. Lamperti, Evidence from Sertoli cell-depleted rats indicates that spermatid number in adults depends on numbers of Sertoli cells produced during perinatal development. Endocrinology 122, 787–794 (1988)

    Article  PubMed  CAS  Google Scholar 

  40. T.A. Yarney, L.M. Sanford, Pubertal changes in the secretion of gonadotropic hormones, testicular gonadotropic receptors and testicular function in the ram. Domest. Anim. Endocrinol. 6, 219–229 (1989)

    Article  PubMed  CAS  Google Scholar 

  41. A. Wagener, J. Fickel, J. Schön, A. Fritzenkötter, F. Göritz, S. Blottner, Seasonal variation in expression and localization of testicular transforming growth factors TGF-{beta}1 and TGF-{beta}3 corresponds with spermatogenic activity in roe deer. J. Endocrinol. 187, 205–215 (2005)

    Article  PubMed  CAS  Google Scholar 

  42. Y.Q. Zhang, X.Z. He, J.S. Zhang, R.A. Wang, J. Zhou, R.J. Xu, Stage-specific localization of transforming growth factor beta1 and beta3 and their receptors during spermatogenesis in men. Asian J. Androl. 6, 105–109 (2004)

    PubMed  CAS  Google Scholar 

  43. L. Su, D.D. Mruk, W.M. Lee, C.Y. Cheng, Differential effects of testosterone and TGF-B3 on endocytic vesicle-mediated protein trafficking events at the blood–testis barrier. Exp. Cell Res. 316, 2945–2960 (2010)

    Article  PubMed  CAS  Google Scholar 

  44. H.H. Yan, D.D. Mruk, W.M. Lee, C.Y. Cheng, Blood–testis barrier dynamics are regulated by testosterone and cytokines via their differential effects on the kinetics of protein endocytosis and recycling in Sertoli cells. FASEB J. 22, 1945–1959 (2008)

    Article  PubMed  CAS  Google Scholar 

  45. V. Caussanel, E. Tabone, J.C. Hendrick, F. Dacheux, M. Benahmed, Cellular distribution of transforming growth factor betas 1, 2, and 3 and their types I and II receptors during postnatal development and spermatogenesis in the boar testis. Biol. Reprod. 56, 357–367 (1997)

    Article  PubMed  CAS  Google Scholar 

  46. C. Gautier, C. Levacher, O. Avallet, M. Vigier, V. Rouiller-Fabre, L. Lecerf, J. Saez, R. Habert, Immunohistochemical localization of transforming growth factor-beta 1 in the fetal and neonatal rat testis. Mol. Cell. Endocrinol. 99, 55–61 (1994)

    Article  PubMed  CAS  Google Scholar 

  47. S.E. Recabarren, A. Lobos, Y. Figueroa, V. Padmanabhan, D.L. Foster, T. Sir-Petermann, Prenatal testosterone treatment alters LH and testosterone responsiveness to GnRH agonist in male sheep. Biol. Res. 40, 329–338 (2007)

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We are grateful to Dr. José F. Cox for the facilities of the Reproductive Biotechnology Laboratory of the Universidad de Concepción; to Dr Gordon E Niswender, Leo Reichert Jr and A. F. Parlow for providing reagents for LH and FSH RIAs, to DAAD (Deutscher Akademischer Austauschdienst) for the donation of the Biophotometer. Participation of Dr Vasantha Padmanabhan and Dr Rodolfo Rey in this project was supported by International Collaboration Agreement with FONDECYT. This work was supported by Fondecyt Grant 1090031. This work was supported by the National Fund for Science and Technology Development (FONDECYT, Grant number 1090031).

Conflict of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

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Authors and Affiliations

  1. Laboratory of Animal Physiology and Endocrinology, Faculty of Veterinary Sciences, University of Concepción, Av. Vicente Mendez 595, Chillán, Chile

    Pedro P. Rojas-García, Mónica P. Recabarren, Sergio Palma, Albert Carrasco & Sergio E. Recabarren

  2. Laboratory of Endocrinology and Metabolism, Department of Internal Medicine, Western Faculty of Medicine, University of Chile, Las Palmeras 299, Interior Quinta Normal, Casilla, 33052, Correo 33, Santiago, Chile

    Teresa Sir-Petermann

  3. Center for Research in Endocrinology Children’s Hospital “R. Gutiérrez” C1425EFD Buenos Aires, Argentina, and Department of Histology, Cell Biology, Embryology, University of Buenos Aires, C1121ABG, Buenos Aires, Argentina

    Rodolfo Rey

  4. Department of Animal Medicine and Surgery, Faculty of Veterinary Medicine, University of Cordoba, 14014, Cordoba, Spain

    Carlos C. Perez-Marin

  5. Departments of Pediatrics and the Reproductive Sciences Program, University of Michigan, Ann Arbor, MI, 48109, USA

    Vasantha Padmanabhan

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  1. Pedro P. Rojas-García
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  2. Mónica P. Recabarren
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  9. Sergio E. Recabarren
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Correspondence to Pedro P. Rojas-García.

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Rojas-García, P.P., Recabarren, M.P., Sir-Petermann, T. et al. Altered testicular development as a consequence of increase number of sertoli cell in male lambs exposed prenatally to excess testosterone. Endocrine 43, 705–713 (2013). https://doi.org/10.1007/s12020-012-9818-5

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