Hostname: page-component-cd9895bd7-lnqnp Total loading time: 0 Render date: 2024-12-19T06:10:01.988Z Has data issue: false hasContentIssue false
  • English
  • Français

In utero betamethasone affects 3β-hydroxysteroid dehydrogenase and inhibin-α immunoexpression during testis development

Published online by Cambridge University Press:  29 March 2016

G. Pedrana Open the ORCID record for G. Pedrana [Opens in a new window] ,
H. Viotti ,
P. Lombide ,
G. Sanguinetti ,
C. Pino ,
D. Cavestany Open the ORCID record for D. Cavestany [Opens in a new window] ,
D. M. Sloboda  and
G. B. Martin Open the ORCID record for G. B. Martin [Opens in a new window]
G. Pedrana*
Affiliation:
Departmento de Morfología y Desarrollo, Facultad de Veterinaria, Universidad de la República Oriental del Uruguay, Uruguay
H. Viotti
Affiliation:
Departmento de Morfología y Desarrollo, Facultad de Veterinaria, Universidad de la República Oriental del Uruguay, Uruguay
P. Lombide
Affiliation:
Departmento de Morfología y Desarrollo, Facultad de Veterinaria, Universidad de la República Oriental del Uruguay, Uruguay
G. Sanguinetti
Affiliation:
Departmento de Morfología y Desarrollo, Facultad de Veterinaria, Universidad de la República Oriental del Uruguay, Uruguay
C. Pino
Affiliation:
Departmento de Morfología y Desarrollo, Facultad de Veterinaria, Universidad de la República Oriental del Uruguay, Uruguay
D. Cavestany
Affiliation:
Departmento de Morfología y Desarrollo, Facultad de Veterinaria, Universidad de la República Oriental del Uruguay, Uruguay
D. M. Sloboda
Affiliation:
Departments of Biochemistry and Biomedical Sciences, Obstetrics and Gynecology, Pediatrics and the Farncombe Digestive Diseases Institute, McMaster University, Hamilton, Canada
G. B. Martin
Affiliation:
UWA School of Animal Biology M092, University of Western Australia, Crawley, Australia Nuffield Department of Obstetrics & Gynaecology, University of Oxford, Oxford, UK
*
*Address for correspondence: G. Pedrana, Departmento de Morfología y Desarrollo, Facultad de Veterinaria, Universidad de la República Oriental del Uruguay, 11600 Uruguay. (Email [email protected])
Get access Rights & Permissions [Opens in a new window]

Abstract

Prenatal glucocorticoids, commonly used in women at risk of preterm delivery, can predispose the newborn to disease in later life. Since male reproductive function is likely to reflect testis development during fetal life, we studied the effects of prenatal glucocorticoids on two key intra-testicular factors that play roles in cellular proliferation and differentiation, 3β-hydroxysteroid dehydrogenase (3β-HSD) and inhibin-α. Pregnant sheep (n=42) were treated with betamethasone (0.5 mg/kg) or saline (control) at 104, 111 and 118 days of gestation (DG). Testicular tissue was sampled from fetuses at 121 and 132DG, and from lambs at 45 and 90 postnatal days (PD). Within the betamethasone treated group, 3β-HSD immunostaining area was greater at 121DG than at 90PD (P=0.04), but the intensity of immunostaining was higher at 90PD than at 121DG (P=0.04), 132DG (P=0.04) and 45PD (P=0.03). Control animals showed no changes in 3β-HSD area or intensity of immunostaining. No significant differences were observed between treated and control animals in immunostaining area, but immunostaining was more intense in the treated group than in the control group at 90PD (P=0.03). For inhibin-α, the proportion of immunostaining area declined in treated offspring from 121DG to 45PD, in contrast to control values, but recovered fully by 90PD, concomitantly with the onset of spermatogenesis. In conclusion, prenatal betamethasone increased the postnatal testicular expression of inhibin-α but reduced the expression of 3β-HSD. These effects could compromise androgen-mediated testicular development and therefore adult capacity for spermatogenesis.

Keywords

fetusmaleglucocorticoidprogrammingreproduction
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 7 , Issue 4 , August 2016 , pp. 342 - 349
Check for updates
Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2016 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Bishop, EH. Acceleration of fetal pulmonary maturity. Obstet Gynecol. 1981; 58(Suppl. 5), 48S–51S.Google Scholar
2. Ward, RM. Pharmacologic enhancement of fetal lung maturation. Clin Perinatol. 1994; 21, 523–542.Google Scholar
3. Dodic, M, Abouantoun, T, O’Connor, A, Wintour, E, Moritz, K. Programming effects of short prenatal exposure to dexamethasone in sheep. Hypertension. 2002; 40, 729–734.Google Scholar
4. O’Regan, D, Kenyon, CJ, Seckl, JR, Holmes, MC. Glucocorticoid exposure in late gestation in the rat permanently programs gender-specific differences in adult cardiovascular and metabolic physiology. Am J Physiol Endocrinol Metab. 2004; 287, E863–E870.Google Scholar
5. Sloboda, DM, Moss, TJ, Gurrin, LC, Newnham, JP, Challis, JRG. The effect of prenatal betamethasone administration on postnatal ovine hypothalamic-pituitary-adrenal function. J Endocrinol. 2002; 172, 71–81.Google Scholar
6. Drake, A, Tang, J, Nyirenda, M. Mechanisms underlying the role of glucocorticoids in the early life programming of adult disease. Clin Sci. 2007; 232, 219–232.Google Scholar
7. Sharpe, RM, Franks, S. Environment, lifestyle and infertility – an inter-generational issue. Nat Cell Biol. 2002; 4(Suppl.), s33–s40.Google Scholar
8. Recabarren, SE, Rojas-García, PP, Recabarren, MP, et al. Prenatal testosterone excess reduces sperm count and motility. Endocrinology. 2008; 149, 6444–6448.Google Scholar
9. Pedrana, G, Viotti, MH, Souza, E, et al. Apoptosis-related protein expression during pre- and post-natal testicular development after administration of glucocorticoid in utero in the sheep. Reprod Domest Anim. 2013; 48, 795–802.Google Scholar
10. Sharpe, RM, Skakkebaek, NE. Testicular dysgenesis syndrome: mechanistic insights and potential new downstream effects. Fertil Steril. 2008; 89(Suppl. 2), e33–e38.Google Scholar
11. Raman, JD, Nobert, CF, Goldstein, M. Increased incidence of testicular cancer in men presenting with infertility and abnormal semen analysis. J Urol. 2005; 174, 1819–1822, discussion 1822.Google Scholar
12. O’Shaughnessy, PJ, Fowler, PA. Endocrinology of the mammalian fetal testis. Reproduction. 2011; 141, 37–46.Google Scholar
13. Hardy, MP, Gao, H-B, Dong, Q, et al. Stress hormone and male reproductive function. Cell Tissue Res. 2005; 322, 147–153.Google Scholar
14. Griswold, MD, Oatley, JM. Concise review: defining characteristics of mammalian spermatogenic stem cells. Stem Cells. 2013; 31, 8–11.Google Scholar
15. Prince, FP. The triphasic nature of Leydig cell development in humans, and comments on nomenclature. J Endocrinol. 2001; 168, 213–216.Google Scholar
16. Bambino, TH, Hsueh, AJ. Direct inhibitory effect of glucocorticoids upon testicular luteinizing hormone receptor and steroidogenesis in vivo and in vitro. Endocrinology. 1981; 108, 2142–2148.Google Scholar
17. Welsh, TH, Bambino, TH, Hsueh, AJ. Mechanism of glucocorticoid-induced suppression of testicular androgen biosynthesis in vitro. Biol Reprod. 1982; 27, 1138–1146.Google Scholar
18. Gao, H-B, Tong, M-H, Hu, Y-Q, et al. Glucocorticoid induces apoptosis in rat Leydig cells. Endocrinology. 2002; 143, 130–138.Google Scholar
19. Pelletier, G, Dupont, E, Simard, J, et al. Ontogeny and subcellular localization of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) in the human and rat adrenal, ovary and testis. J Steroid Biochem Mol Biol. 1992; 43, 451–467.Google Scholar
20. Samuels, LT, Helmreich, ML, Lasater, MB, Reich, H. An enzyme in endocrine tissues which oxidizes 5-3 hydroxy steroids to delta 5-3 unsaturated ketones. Science. 1951; 113, 490–491.CrossRefGoogle ScholarPubMed
21. Simard, J, Durocher, F, Mébarki, F, et al. Molecular biology of the 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase gene family. Endocr Rev. 2005; 150(Suppl.4), 525–582.Google Scholar
22. Orr, TE, Mann, DR. Role of glucocorticoids in the stress-induced suppression of testicular steroidogenesis in adult male rats. Horm Behav. 1992; 26, 350–363.Google Scholar
23. Sweeney, T, Saunders, PT, Millar, MR, Brooks, AN. Ontogeny of anti-müllerian hormone, 3 beta-hydroxysteroid dehydrogenase and androgen receptor expression during ovine total gonadal development. J Endocrinol. 1997; 153, 27–32.CrossRefGoogle ScholarPubMed
24. Quirke, LD, Juengel, JL, Tisdall, DJ, Lun, S, Heath, DA, McNatty, KP. Ontogeny of steroidogenesis in the fetal sheep gonad. Biol Reprod. 2001; 65, 216–228.Google Scholar
25. Feige, J, Chambaz, EM. The auto/paracrine regulation of endocrine functions: a history of tgf-β and the adrenal cortex. Endocrinologia. 2005; 56, 159–164.Google Scholar
26. Anderson, R, Cambray, N. Expression and localization of inhibin alpha, inhibin/activin betaA and betaB and the activin type II and inhibin beta-glycan receptors in the developing human testis. Reproduction. 2002; 123, 779–788.Google Scholar
27. Jarred, RA, Cancilla, B, Richards, M, et al. Differential localization of inhibin subunit proteins in the ovine testis during fetal gonadal development. Endocrinology. 1999; 140, 979–986.Google Scholar
28. Sloboda, DM, Newnham, JP, Challis, JR. Effects of repeated maternal betamethasone administration on growth and hypothalamic-pituitary-adrenal function of the ovine fetus at term. J Endocrinol. 2000; 165, 79–91.Google Scholar
29. Sloboda, DM, Moss, TJM, Li, S, et al. Hepatic glucose regulation and metabolism in adult sheep: effects of prenatal betamethasone. Am J Physiol Endocrinol Metab. 2005; 289, E721–E728.Google Scholar
30. Sloboda, DM, Newnham, JP, Challis, JRG. Repeated maternal glucocorticoid administration and the developing liver in fetal sheep. J Endocrinol. 2002; 175, 535–543.Google Scholar
31. Liggins, GC, Howie, RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics. 1972; 50, 515–525.Google Scholar
32. Braun, T, Meng, W, Shang, H, et al. Early dexamethasone treatment induces placental apoptosis in sheep. Reprod Sci. 2015; 22, 47–59.CrossRefGoogle ScholarPubMed
33. Ceda, GP, Davis, RG, Hoffman, AR. Glucocorticoid modulation of growth hormone secretion in vitro. Evidence for a biphasic effect on GH-releasing hormone mediated release. Acta Endocrinol (Copenh). 1987; 114, 465–469.Google Scholar
34. Tilbrook, AJ, Canny, BJ, Serapiglia, MD, Ambrose, TJ, Clarke, J. Suppression of the secretion of luteinizing hormone due to isolation/restraint stress in gonadectomised rams and ewes is influenced by sex steroids. J Endocrinol. 1999; 160, 469–481.CrossRefGoogle ScholarPubMed
35. Tilbrook, AJ, De Kretser, DM, Clarke, IJ. Changes in the suppressive effects of recombinant inhibin A on FSH secretion in ram lambs during sexual maturation: evidence for alterations in the clearance rate of inhibin. J Endocrinol. 1999; 161, 219–229.Google Scholar
36. Schanbacher, B, Gomes, W, VanDemark, N. Developmental changes in spermatogenesis, testicular carnitine acetyltransferase activity and serum testosterone in the ram. J Anim Sci. 1974; 39, 889–892.Google Scholar
37. Skinner, JD, Rowson, LEA. Puberty in suffolk and cross-bred rams. J Reprod Fertil. 1968; 16, 479–488.Google Scholar
38. Castrillejo, A, Moraña, A, Bielli, A, et al. Onset of spermatogenesis in Corriedale ram lambs under extensive rearing conditions in Uruguay. Acta Vet Scand. 1995; 36, 161–173.CrossRefGoogle ScholarPubMed
39. Bergh, A, Cajander, S. Immunohistochemical localization of inhibin-alpha in the testes of normal men and in men with testicular disorders. Int J Androl. 1990; 13, 463–469.Google Scholar
40. Walsh, LP, McCormick, C, Martin, C, Stocco, DM. Roundup inhibits steroidogenesis by disrupting steroidogenic acute regulatory (StAR) protein expression. Environ Health Perspect. 2000; 108, 769–776.Google Scholar
41. Stocco, DM, McPhaul, MJ. Physiology of testicular steroidogenesis. In Knobil and Neill’s Physiology of Reproduction (eds. Neill JD, Plant TM, Pfaff DW, Challis JRG, de Kretser DM, Richards JS and Wassarman PM), 2006; pp 977–1016. Elsevier: USA.Google Scholar
42. Agular, BM, Vinggaard, AM, Vind, C. Regulation by dexamethasone of the 3 beta-hydroxysteroid dehydrogenase activity in adult rat Leydig cells. J Steroid Biochem Mol Biol. 1992; 43, 565–571.Google Scholar
43. Ward, IL, Weisz, J. Maternal stress alters plasma testosterone in fetal males. Science. 1980; 207, 328–329.Google Scholar