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Does melatonin influence the apoptosis in rat uterus of animals exposed to continuous light?

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Abstract

Melatonin has been described as a protective agent against cell death and oxidative stress in different tissues, including in the reproductive system. However, the information on the action of this hormone in rat uterine apoptosis is low. Our objective was to evaluate the effects of melatonin on mechanisms of cell death in uterus of rats exposed to continuous light stress. Twenty adult Wistar rats were divided into two groups: GContr (vehicle control) and GExp which were treated with melatonin (0.4 mg/mL), both were exposed to continuous light for 90 days. The uterus was removed and processed for quantitative real time PCR (qRT-PCR), using PCR-array plates of the apoptosis pathway; for immunohistochemistry and TUNEL. The results of qRT-PCR of GEXP group showed up-regulation of 13 and 7, pro-apoptotic and anti-apoptotic genes, respectively, compared to GContr group. No difference in pro-apoptotic proteins (Bax, Fas and Faslg) expression was observed by immunohistochemistry, although the number of TUNEL-positive cells was lower in the group treated with melatonin compared to the group not treated with this hormone. Our data suggest that melatonin influences the mechanism and decreases the apoptosis in uterus of rats exposed to continuous light.

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References

  1. Reiter RJ (1993) The melatonin rhythm: both a clock and a calendar. Experientia 49:654–664

    Article  PubMed  CAS  Google Scholar 

  2. Ganguly S, Coon SL, Klein DC (2002) Control of melatonin synthesis in the mammalian pineal gland: the critical role of serotonin acetylation. Cell Tissue Res 309:127–137

    Article  PubMed  CAS  Google Scholar 

  3. Macchi MM, Bruce JN (2004) Human pineal physiology and functional significance of melatonin. Front Neuroendocrinol 25:177–195

    Article  PubMed  CAS  Google Scholar 

  4. Zawilska JB, Skene DJ, Arendt J (2009) Physiology and pharmacology of melatonin in relation to biological rhythms. Pharmacol Rep 61:383–410

    Article  PubMed  CAS  Google Scholar 

  5. Arendt J, Skene DJ (2005) Melatonin as a chronobiotic. Sleep Med Rev 9:25–39

    Article  PubMed  Google Scholar 

  6. Revel FG, Masson-Pevet M, Pevet P, Mikkelsen JD, Simonneaux V (2009) Melatonin controls seasonal breeding by a network of hypothalamic targets. Neuroendocrinology 90:1–14

    Article  PubMed  CAS  Google Scholar 

  7. Carrillo-Vico A, Lardone PJ, Naji L et al (2005) Beneficial pleiotropic actions of melatonin in an experimental model of septic shock in mice: regulation of pro-/anti-inflammatory cytokine network, protection against oxidative damage and anti-apoptotic effects. J Pineal Res 39:400–408

    Article  PubMed  CAS  Google Scholar 

  8. Claustrat B, Brun J, Chazot G (2005) The basic physiology and pathophysiology of melatonin. Sleep Med Rev 9:11–24

    Article  PubMed  Google Scholar 

  9. Hardeland R, Pandi-Perumal SR, Cardinali DP (2006) Melatonin. Int J Biochem Cell Biol 38:313–316

    Article  PubMed  CAS  Google Scholar 

  10. Radogna F, Paternoster L, Albertini MC et al (2006) Melatonin as an apoptosis antagonist. Ann NY Acad Sci 1090:226–233

    Article  PubMed  CAS  Google Scholar 

  11. Sarlak G, Jenwitheesuk A, Chetsawang B, Govitrapong P (2013) Effects of melatonin on nervous system aging: neurogenesis and neurodegeneration. J Pharmacol Sci 123:9–24

    Article  PubMed  CAS  Google Scholar 

  12. Vanecek J (1998) Cellular mechanisms of melatonin action. Physiol Rev 78:687–721

    PubMed  CAS  Google Scholar 

  13. Clemens JW, Jarzynka MJ, Witt-Enderby PA (2001) Down-regulation of mt1 melatonin receptors in rat ovary following estrogen exposure. Life Sci 69:27–35

    Article  PubMed  CAS  Google Scholar 

  14. Ekmekcioglu C (2006) Melatonin receptors in humans: biological role and clinical relevance. Biomed Pharmacother 60:97–108

    Article  PubMed  CAS  Google Scholar 

  15. Tamura H, Takasaki A, Taketani T et al (2014) Melatonin and female reproduction. J Obstet Gynaecol Res 40:1–11

    Article  PubMed  CAS  Google Scholar 

  16. Soares JM Jr, Masana MI, Ersahin C, Dubocovich ML (2003) Functional melatonin receptors in rat ovaries at various stages of the estrous cycle. J Pharmacol Exp Ther 306:694–702

    Article  PubMed  CAS  Google Scholar 

  17. Itoh MT, Hosaka T, Takahashi N, Ishizuka B (2006) Expression of luteinizing hormone/chorionic gonadotropin receptor in the rat pineal gland. J Pineal Res 41:35–41

    Article  PubMed  CAS  Google Scholar 

  18. Bondi CD, Alonso-Gonzalez C, Clafshenkel WP et al (2014) The effect of estradiol, progesterone, and melatonin on estrous cycling and ovarian aromatase expression in intact female mice. Eur J Obstet Gynecol Reprod Biol 174:80–85

    Article  PubMed  CAS  Google Scholar 

  19. Wideman CH, Murphy HM (2009) Constant light induces alterations in melatonin levels, food intake, feed efficiency, visceral adiposity, and circadian rhythms in rats. Nutr Neurosci 12:233–240

    Article  PubMed  CAS  Google Scholar 

  20. Acuna-Castroviejo D, Fernandez B, Castillo JL, del Aguila CM (1993) Similarity between the effects of suprachiasmatic nuclei lesions and of pinealectomy on gonadotropin release in ovariectomized, sulpiride-treated and melatonin-replaced rats. Experientia 49:797–801

    Article  PubMed  CAS  Google Scholar 

  21. Prata Lima MF, Baracat EC, Simoes MJ (2004) Effects of melatonin on the ovarian response to pinealectomy or continuous light in female rats: similarity with polycystic ovary syndrome. Braz J Med Biol Res 37:987–995

    Article  PubMed  CAS  Google Scholar 

  22. Dair EL, Simoes RS, Simoes MJ et al (2008) Effects of melatonin on the endometrial morphology and embryo implantation in rats. Fertil Steril 89:1299–1305

    Article  PubMed  CAS  Google Scholar 

  23. Dardes RC, Baracat EC, Simões MJ (2000) Modulation of estrous cycle and LH, FSH and melatonin levels by pinealectomy and sham-pinealectomy in female rats. Prog Neuropsychopharmacol Biol Psychiatry 24:441–453

    Article  PubMed  CAS  Google Scholar 

  24. Rodriguez C, Martin V, Herrera F et al (2013) Mechanisms involved in the pro-apoptotic effect of melatonin in cancer cells. Int J Mol Sci 14:6597–6613

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Bizzarri M, Proietti S, Cucina A, Reiter RJ (2013) Molecular mechanisms of the pro-apoptotic actions of melatonin in cancer: a review. Expert Opin Ther Targets 17:1483–1496

    Article  PubMed  CAS  Google Scholar 

  26. Sainz RM, Mayo JC, Rodriguez C, Tan DX, Lopez-Burillo S, Reiter RJ (2003) Melatonin and cell death: differential actions on apoptosis in normal and cancer cells. Cell Mol Life Sci 60:1407–1426

    Article  PubMed  CAS  Google Scholar 

  27. Pieri C, Marra M, Moroni F, Recchioni R, Marcheselli F (1994) Melatonin: a peroxyl radical scavenger more effective than vitamin E. Life Sci 55:Pl271–Pl276

    Article  PubMed  CAS  Google Scholar 

  28. Barlow-Walden LR, Reiter RJ, Abe M et al (1995) Melatonin stimulates brain glutathione peroxidase activity. Neurochem Int 26:497–502

    Article  PubMed  CAS  Google Scholar 

  29. Nava M, Romero F, Quiroz Y, Parra G, Bonet L, Rodriguez-Iturbe B (2000) Melatonin attenuates acute renal failure and oxidative stress induced by mercuric chloride in rats. Am J Physiol Renal Physiol 279:F910–918

    PubMed  CAS  Google Scholar 

  30. Hoijman E, Rocha Viegas L, Keller Sarmiento MI, Rosenstein RE, Pecci A (2004) Involvement of Bax protein in the prevention of glucocorticoid-induced thymocytes apoptosis by melatonin. Endocrinology 145:418–425

    Article  PubMed  CAS  Google Scholar 

  31. Baydas G, Koz ST, Tuzcu M, Etem E, Nedzvetsky VS (2007) Melatonin inhibits oxidative stress and apoptosis in fetal brains of hyperhomocysteinemic rat dams. J Pineal Res 43:225–231

    Article  PubMed  CAS  Google Scholar 

  32. Molpeceres V, Mauriz JL, Garcia-Mediavilla MV, Gonzalez P, Barrio JP, Gonzalez-Gallego J (2007) Melatonin is able to reduce the apoptotic liver changes induced by aging via inhibition of the intrinsic pathway of apoptosis. J Gerontol A Biol Sci Med Sci 62:687–695

    Article  PubMed  Google Scholar 

  33. Maestroni GJ (1993) The immunoneuroendocrine role of melatonin. J Pineal Res 14:1–10

    Article  PubMed  CAS  Google Scholar 

  34. Mediavilla MD, Cos S, Sanchez-Barcelo EJ (1999) Melatonin increases p53 and p21WAF1 expression in MCF-7 human breast cancer cells in vitro. Life Sci 65:415–420

    Article  PubMed  CAS  Google Scholar 

  35. Pedreanez A, Rincon J, Romero M, Viera N, Mosquera J (2004) Melatonin decreases apoptosis and expression of apoptosis-associated proteins in acute puromycin aminonucleoside nephrosis. Nephrol Dial Transpl 19:1098–1105

    Article  CAS  Google Scholar 

  36. Voznesenskaya T, Makogon N, Bryzgina T, Sukhina V, Grushka N, Alexeyeva I (2007) Melatonin protects against experimental immune ovarian failure in mice. Reprod Biol 7:207–220

    PubMed  Google Scholar 

  37. Wang SJ, Liu WJ, Wu CJ et al (2012) Melatonin suppresses apoptosis and stimulates progesterone production by bovine granulosa cells via its receptors (MT1 and MT2). Theriogenology 78:1517–1526

    Article  PubMed  CAS  Google Scholar 

  38. Barrezueta LF, Oshima CT, Lima FO et al (2010) The intrinsic apoptotic signaling pathway in gastric adenocarcinomas of Brazilian patients: immunoexpression of the Bcl-2 family (Bcl-2, Bcl-x, Bak, Bax, Bad) determined by tissue microarray analysis. Mol Med Rep 3:261–267

    Article  PubMed  CAS  Google Scholar 

  39. Paiotti AP, Ribeiro DA, Silva RM et al (2012) Effect of COX-2 inhibitor lumiracoxib and the TNF-alpha antagonist etanercept on TNBS-induced colitis in Wistar rats. J Mol Histol 43:307–317

    Article  PubMed  CAS  Google Scholar 

  40. Gavrieli Y, Sherman Y, Ben-Sasson SA (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119:493–501

    Article  PubMed  CAS  Google Scholar 

  41. Beigi Boroujeni M, Salehnia M, Khalatbary AR, Pourbeiranvand S, Beigi Boroujeni N, Ebrahimi S (2010) Effect of ovarian stimulation on the endometrial apoptosis at implantation period. Iran Biomed J 14:171–177

    PubMed  PubMed Central  Google Scholar 

  42. Bubenik GA, Brown GM (1997) Pinealectomy reduces melatonin levels in the serum but not in the gastrointestinal tract of rats. Biol Signals 6:40–44

    Article  PubMed  CAS  Google Scholar 

  43. Maganhin CC, Simoes RS, Fuchs LF et al (2014) Melatonin influences on steroidogenic gene expression in the ovary of pinealectomized rats. Fertil Steril 102:291–298

    Article  PubMed  CAS  Google Scholar 

  44. Siiteri PK (1978) Steroid hormones and endometrial cancer. Cancer Res 38:4360–4366

    PubMed  CAS  Google Scholar 

  45. Konishi I, Koshiyama M, Mandai M et al (1997) Increased expression of LH/hCG receptors in endometrial hyperplasia and carcinoma in anovulatory women. Gynecol Oncol 65:273–280

    Article  PubMed  CAS  Google Scholar 

  46. Grosse J, Maywood ES, Ebling FJ, Hastings MH (1993) Testicular regression in pinealectomized Syrian hamsters following infusions of melatonin delivered on non-circadian schedules. Biol Reprod 49:666–674

    Article  PubMed  CAS  Google Scholar 

  47. Li C, Zhou X (2015) Melatonin and male reproduction. Clin Chim Acta 446:175–180

    Article  PubMed  CAS  Google Scholar 

  48. Aleandri V, Spina V, Morini A (1996) The pineal gland and reproduction. Hum Reprod Update 2:225–235

    Article  PubMed  CAS  Google Scholar 

  49. Romeu LR, da Motta EL, Maganhin CC et al (2011) Effects of melatonin on histomorphology and on the expression of steroid receptors, VEGF, and PCNA in ovaries of pinealectomized female rats. Fertil Steril 95:1379–1384

    Article  PubMed  CAS  Google Scholar 

  50. Tamura H, Nakamura Y, Korkmaz A et al (2009) Melatonin and the ovary: physiological and pathophysiological implications. Fertil Steril 92:328–343

    Article  PubMed  CAS  Google Scholar 

  51. Chuffa LG, Seiva FR, Favaro WJ et al (2011) Melatonin reduces LH, 17 beta-estradiol and induces differential regulation of sex steroid receptors in reproductive tissues during rat ovulation. Reprod Biol Endocrinol 9:108

    Article  PubMed  CAS  Google Scholar 

  52. Slominski RM, Reiter RJ, Schlabritz-Loutsevitch N, Ostrom RS, Slominski AT (2012) Melatonin membrane receptors in peripheral tissues: distribution and functions. Mol Cell Endocrinol 351:152–166

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  53. Kokawa K, Shikone T, Nakano R (1996) Apoptosis in the human uterine endometrium during the menstrual cycle. J Clin Endocrinol Metab 81:4144–4147

    PubMed  CAS  Google Scholar 

  54. Harada T, Kaponis A, Iwabe T et al (2004) Apoptosis in human endometrium and endometriosis. Hum Reprod Update 10:29–38

    Article  PubMed  CAS  Google Scholar 

  55. Vaskivuo TE, Stenback F, Karhumaa P, Risteli J, Dunkel L, Tapanainen JS (2000) Apoptosis and apoptosis-related proteins in human endometrium. Mol Cell Endocrinol 165:75–83

    Article  PubMed  CAS  Google Scholar 

  56. Slayden OD, Hirst JJ, Brenner RM (1993) Estrogen action in the reproductive tract of rhesus monkeys during antiprogestin treatment. Endocrinology 132:1845–1856

    PubMed  CAS  Google Scholar 

  57. Gosden R, Spears N (1997) Programmed cell death in the reproductive system. Br Med Bull 53:644–661

    Article  PubMed  CAS  Google Scholar 

  58. Teixeira C, Reed JC, Pratt MA (1995) Estrogen promotes chemotherapeutic drug resistance by a mechanism involving Bcl-2 proto-oncogene expression in human breast cancer cells. Cancer Res 55:3902–3907

    PubMed  CAS  Google Scholar 

  59. McLaren J, Prentice A, Charnock-Jones DS, Sharkey AM, Smith SK (1997) Immunolocalization of the apoptosis regulating proteins Bcl-2 and Bax in human endometrium and isolated peritoneal fluid macrophages in endometriosis. Hum Reprod 12:146–152

    Article  PubMed  CAS  Google Scholar 

  60. Gompel A, Sabourin JC, Martin A et al (1994) Bcl-2 expression in normal endometrium during the menstrual cycle. Am J Pathol 144:1195–1202

    PubMed  CAS  PubMed Central  Google Scholar 

  61. Castro A, Johnson MC, Anido M, Cortinez A, Gabler F, Vega M (2002) Role of nitric oxide and bcl-2 family genes in the regulation of human endometrial apoptosis. Fertil Steril 78:587–595

    Article  PubMed  Google Scholar 

  62. Otsuki Y, Misaki O, Sugimoto O, Ito Y, Tsujimoto Y, Akao Y (1994) Cyclic bcl-2 gene expression in human uterine endometrium during menstrual cycle. Lancet 344:28–29

    Article  PubMed  CAS  Google Scholar 

  63. Yamashita H, Otsuki Y, Matsumoto K, Ueki K, Ueki M (1999) Fas ligand, Fas antigen and Bcl-2 expression in human endometrium during the menstrual cycle. Mol Hum Reprod 5:358–364

    Article  PubMed  CAS  Google Scholar 

  64. Selam B, Kayisli UA, Mulayim N, Arici A (2001) Regulation of Fas ligand expression by estradiol and progesterone in human endometrium. Biol Reprod 65:979–985

    Article  PubMed  CAS  Google Scholar 

  65. Song J, Rutherford T, Naftolin F, Brown S, Mor G (2002) Hormonal regulation of apoptosis and the Fas and Fas ligand system in human endometrial cells. Mol Hum Reprod 8:447–455

    Article  PubMed  CAS  Google Scholar 

  66. Panzan MQ, Mattar R, Maganhin CC et al (2013) Evaluation of FAS and caspase-3 in the endometrial tissue of patients with idiopathic infertility and recurrent pregnancy loss. Eur J Obstet Gynecol Reprod Biol 167:47–52

    Article  PubMed  CAS  Google Scholar 

  67. Tewari M, Yu M, Ross B, Dean C, Giordano A, Rubin R (1997) AAC-11, a novel cDNA that inhibits apoptosis after growth factor withdrawal. Cancer Res 57:4063–4069

    PubMed  CAS  Google Scholar 

  68. Chau BN, Cheng EH, Kerr DA, Hardwick JM (2000) Aven, a novel inhibitor of caspase activation, binds Bcl-xL and Apaf-1. Mol Cell 6:31–40

    Article  PubMed  CAS  Google Scholar 

  69. Kutuk O, Temel SG, Tolunay S, Basaga H (2010) Aven blocks DNA damage-induced apoptosis by stabilising Bcl-xL. Eur J Cancer 46:2494–2505

    Article  PubMed  CAS  Google Scholar 

  70. Czabotar PE, Lessene G, Strasser A, Adams JM (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15:49–63

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to thank Laboratory of Structural and Molecular Gynecology (LIM - 58), Departamento de Ginecologia e Obstetrícia - Faculdade de Medicina da Universidade de São Paulo and Laboratory of Molecular Pathology, Universidade Federal de São Paulo. This work was supported by São Paulo Research Foundation (FAPESP - Process number: 09/51754-0) and National Council of Technological and Scientific Development (CNPq - Process Number: 137442/2009-2). We also thank Priscilla C. Addios for technical support.

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Correspondence to Cecília S. Ferreira.

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Ferreira, C.S., Carvalho, K.C., Maganhin, C.C. et al. Does melatonin influence the apoptosis in rat uterus of animals exposed to continuous light?. Apoptosis 21, 155–162 (2016). https://doi.org/10.1007/s10495-015-1195-0

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