Bisphenol A'nın Rat Testis Gelişiminde Fonksiyon Gören Notch Sinyal Yolağı Üzerine Etkisi

Öz

Endokrin bozucu kimyasallar arasında Bisphenol A (BPA) her yıl dünyada bir kaç milyon ton üretilmesi ve yaygın olarak kullanılmasıyla en çok dikkat çeken bir ajandır. BPA endokrin bozucu bir ajandır ve insanlar için karsinojen olarak sınıflandırılmaktadır. Fötal ve perinatal dönemde çevredeki dozlarla uyumlu olarak BPA’ya maruz kalmak nesiller boyunca erkek infertilitesinin bozulmasını indüklemektedir. Notch sinyal fonksiyonları hücrelerin farklılaşmasını, çoğalmasını ve canlı kalmasını düzenleyerek hücre kaderini belirler. Notch sinyal sistemi erkek germ hücrelerinin farklılaşması ve yaşamasında önemli bir rol oynamaktadır. Bu çalışmada in vivo embriyonal (E) 18-21, postnatal (P) 0-3 ve P4-7. günlerde BPA uygulamasını takiben rat testislerinde Notch I reseptör protein ekspresyonunun değişip değişmediğini araştırmak amaçlandı. Araştırmadan elde edilen sonuçlar, seçilen zaman dilimlerinde kullanılan BPA dozlarının sıçan testislerinde Notch 1 protein ekspresyonları üzerine etkisi olmadığını ortaya koydu.

Anahtar Kelimeler

• Bisphenol A
• Notch
• sıçan
• testis

The Effect of Bisphenol A on Notch Signaling Pathway in Development of Rat Testis

Öz

Bisphenol A (BPA) is the object of great concerns because of its widespread use, due to several millions of tons its production throughout the world each year. BPA is an endocrine disrupting chemical and is classified as a probable human carcinogen. Fetal and perinatal exposure to environmentally relevant doses of BPA induces multigenerational impairments of male fertility. Notch signaling functions to regulate cell-fate by modulating differentiation, proliferation, and survival of cells. Notch signaling system plays a significant role in male germ cell differentiation and survival. In this study, it was aimed to explore the alterations/changes in protein expression of Notch I receptor following BPA treatments during embriyonal (E) days 18 to 21, postnatal (P) days 0 to 3, and P4 to P7 time intervals in the rat testes in vivo. The results of study revealed that the used doses of BPA had’nt effect on Notch 1 protein expressions in rat testes during selected time preiods.

Anahtar Kelimeler

• Bisphenol A
• Notch
• rat
• testis

Kaynakça

1. Aikawa H, Koyama S, Matsuda M, Nakahashi K, Akazome Y, Mori T. Relief effect of vitamin A on the decreased motility of sperm and the increased incidence of malformed sperm in mice exposed neonatally to bisphenol A. Cell Tissue Res. 2004; 315(1): 119–24.
2. Albert O, Je’gou B. A critical assessment of the endocrine susceptibility of the human testis to phthalates from fetal life to adulthood. Hum. Reprod. Update. 2014; 20(2): 231–49.
3. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: Cell fate control and signal integration in development. Science. 1999; 284(5415): 770–6.
4. Austin J, Kimble J. glp-1 Is required in the germ line for regulation of the decision between mitosis and meiosis in elegans. Cell. 1987; 51(4): 589–99.
5. Baron M, Aslam H, Flasza M, Fostier M, Higgs JE, Mazaleyrat SL, Wilkin MB. Multiple levels of Notch signal regulation (review). Mol. Membr. Biol. 2002; 19:27–38.
6. Besaratinia A, Pfeifer GP. A review of mechanisms of acrylamide carcinogenicity [Internet]. Carcinogenesis. 2007; (28):519–28.
7. Bigsby R, Chapin RE, Daston GP, Davis BJ, Gorski J, Gray LE, Howdeshell KL, Thomas Zoeller R, Vom Saal FS. Evaluating the effects of endocrine disrupters on endocrine function during development. Environ. Health Perspect. 1999; 613–8.
8. Bray SJ. Notch signalling: A simple pathway becomes complex. Nat. Rev. Mol. Cell Biol. 2006; 7(9):678–89.

9. Calafat AM, Kuklenyik Z, Reidy JA, Caudill SP, Ekong J, Needham LL. Urinary concentrations of bisphenol A and 4-Nonylphenol in a human reference population. Environ. Health Perspect. 2005;113(4): 391–5.
10. Calafat AM, Weuve J, Ye X, Jia LT, Hu H, Ringer S, Huttner K, Hauser R. Exposure to bisphenol A and other phenols in neonatal intensive care unit premature infants. Environ. Health Perspect. 2009;117(4): 639–44.
11. Calafat AM, Ye X, Wong LY, Reidy JA, Needham LL. Exposure of the U.S. population to Bisphenol A and 4-tertiary-octylphenol: 2003-2004. Environ. Health Perspect. 2008;116(1): 39–44.
12. Carwile JL, Luu HT, Bassett LS, Driscoll DA, Yuan C, Chang JY, Ye X, Calafat AM, Michels KB. Polycarbonate bottle use and urinary bisphenol A concentrations. Environ. Health Perspect. 2009;117(9): 1368–72.
13. Chen J, Crabbe A, Van Duppen V, Vankelecom H. The Notch signaling system is present in the postnatal pituitary: Marked expression and regulatory activity in the newly discovered side population. Mol. Endocrinol. 2006; 20(12): 3293–307.
14. Crittenden SL, Troemel ER, Evans TC, Kimble J. GLP-1 is localized to the mitotic region of the C. elegans germ line. Development. 1994; 120(10): 2901–11.
15. Delfosse V, Grimaldi M, le Maire A, Bourguet W, Balaguer P. Nuclear Receptor Profiling of Bisphenol-A and Its Halogenated Analogues. 1st ed. Vitam. Horm. Elsevier Inc.; 2014.
16. Dirami G, Ravindranath N, Achi M V., Dym M. Expression of Notch pathway components in spermatogonia and sertoli cells of neonatal mice. J. Androl. [Internet]. John Wiley & Sons, Ltd; 2001; 22(6): 944–52.
17. Ema M, Fujii S, Furukawa M, Kiguchi M, Ikka T, Harazono A. Rat two-generation reproductive toxicity study of bisphenol A. Reprod. Toxicol. 2001;15(5): 505–23.
18. Farabollini F, Porrini S, Dessi-Fulgherit F. Perinatal exposure to the estrogenic pollutant bisphenol A affects behavior in male and female rats. Pharmacol Biochem Behav. 1999; 64:687–694
19. Go MJ, Eastman DS, Spyros AT. Cell proliferation control by Notch signaling in Drosophila development. Development. 1998; 125(11): 2031–40.
20. Goyal HO, Robateau A, Braden TD, Williams CS, Srivastava KK, Ali K. Neonatal estrogen exposure of male rats alters reproductive functions at adulthood. Biol. Reprod. 2003; 68(6):2081–91.
21. Hahn KL, Beres B, Rowton MJ, Skinner MK, Chang Y, Rawls A, Wilson-Rawls J. A deficiency of lunatic fringe is associated with cystic dilation of the rete testis. Reproduction. 2009;137(1):79–93.
22. Hayashi T, Kageyama Y, Ishizaka K, Xia G, Kihara K, Oshima H. Requirement of notch 1 and its ligand jagged 2 expressions for spermatogenesis in rat and human testes. J. Androl. 2001; 22(6):999–1011.
23. Henderson ST, Gao D, Christensen S, Kimble J. Functional domains of LAG-2, a putative signaling ligand for LIN-12 and GLP-1 receptors in Caenorhabditis elegans. Mol. Biol. Cell. 1997; 8(9):1751–62.
24. High FA, Zhang M, Proweller A, Tu LL, Parmacek MS, Pear WS, Epstein JA. An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation. J. Clin. Invest. 2007; 117(2):353–63.
25. Horstman KA, Naciff JM, Overmann GJ, Foertsch LM, Richardson BD, Daston GP. Effects of Transplacental 17-α-Ethynyl Estradiol or Bisphenol A on the Developmental Profile of Steroidogenic Acute Regulatory Protein in the Rat Testis. Birth Defects Res. Part B - Dev. Reprod. Toxicol. 2012; 95(4):318–25.
26. Howdeshell KL, Hotchkiss AK, Thayer KA, Vandenbergh JG, vom Saal FS: Exposure to bisphenol A advances puberty. Nature. 1999; 401:763–764.
27. Huang J, Xu H, Gao Z, Li M, Zhu Y, Li Y. Effects of bisphenol A on testis testosterone synthesis in mouse cultured in vitro. Wei Sheng Yan Jiu. 2013; 42(4):543–9.
28. Ikezuki Y, Tsutsumi O, Takai Y, Kamei Y, Taketani Y. Determination of bisphenol A concentrations in human biological fluids reveals significant early prenatal exposure. academic.oup.com. Hum Reprod. 2002; 17(11):2839–41.
29. Kabuto H, Amakawa M, Shishibori T. Exposure to bisphenol A during embryonic/fetal life and infancy increases oxidative injury and causes underdevelopment of the brain and testis in mice. Life Sci. 2004; 74:2931–40.
30. Kawai K, Nozaki T, Nishikata H, Aou S, Takii M, Kubo C. Aggressive Behavior and Serum Testosterone Concentration during the Maturation Process of Male Mice: The Effects of Fetal Exposure to Bisphenol A. Environ. Heal. Perspect. 2003; 111(2):175–8.
31. Koch U, Radtke F. Notch and cancer: A double-edged sword. Cell. Mol. Life Sci. 2007; 64:2746–62.
32. Lai EC. Notch signaling: Control of cell communication and cell fate. Development. 2004; 965–73.
33. Liu X-L, Chen X-Y, Wang Z-C, Shen T, Zhao H. Effects of exposure to bisphenol A during pregnancy and lactation on the testicular morphology and caspase-3 protein expression of ICR pups. Biomed. Reports. 2013; 1(3):420–4.
34. Lupien M, Diévart A, Morales CR, Hermo L, Calvo E, Kay DG, Hu C, Jolicoeur P. Expression of constitutively active Notch1 in male genital tracts results in ectopic growth and blockage of efferent ducts, epididymal hyperplasia and sterility. Dev. Biol. 2006; 300(2): 497–511.
35. Mitsiadis TA, Hirsinger E, Lendahl U, Goridis C. Delta-Notch signaling in odontogenesis: Correlation with cytodifferentiation and evidence for feedback regulation. Dev. Biol. 1998; 204(2):420–31.
36. Mori S, Kadokawa Y, Hoshinaga K, Marunouchi T. Sequential activation of Notch family receptors during mouse spermatogenesis. Dev. Growth Differ. 2003; 45(1):7–13.
37. Munoz-de-Toro M, Markey C, Wadia PR, Luque EH, Rubin BS, Sonnenschein C, Soto AM. Perinatal exposure to Bisphenol A alters peripubertal mammary gland development in mice. Endocrinology. 2005; 146(9):4138–47.
38. Murta D, Batista M, Silva E, Trindade A, Henrique D, Duarte A, Lopes-da-Costa L. Dynamics of Notch Pathway Expression during Mouse Testis Post-Natal Development and along the Spermatogenic Cycle. PLoS One. 2013; 8(8):72767.
39. Rochester JR. Bisphenol A and human health: A review of the literature. Reprod. Toxicol. 2013; 42:132–55.
40. Romano F, Tripiciano A, Muciaccia B, De Cesaris P, Ziparo E, Palombi F, Filippini A. The contractile phenotype of peritubular smooth muscle cells is locally controlled: Possible implications in male fertility. Contraception. 2005; 294–7.
41. vom Saal FS, Akingbemi BT, Belcher SM, Birnbaum LS, Crain DA, Eriksen M, Farabollini F, Guillette LJ, Hauser R, Heindel JJ, Ho SM, Hunt PA, Iguchi T, Jobling S, Kanno J, Keri RA, Knudsen KE,... Zoeller RT. Chapel Hill bisphenol A expert panel consensus statement: Integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure. Reprod. Toxicol. 2007;24(2): 131–8.
42. Safe SH, Pallaroni L, Yoon K, Gaido K, Ross S, Saville B, McDonnell D. Toxicology of environmental estrogens. Reprod. Fertil. Dev. 2001; (13):307–15.
43. Sahin Z, Bayram Z, Celik-Ozenci C, Akkoyunlu G, Seval Y, Erdogru T, Ustunel I, Baykara M, Demir R. Effect of experimental varicocele on the expressions of notch 1, 2, and 3 in rat testes: An immunohistochemical study. Fertil. Steril. 2005;83(1): 86–94.
44. Schönfelder G, Wittfoht W, Hopp H, Talsness CE, Paul M, Chahoud I. Parent bisphenol a accumulation in the human maternal-fetal-placental unit. Environ. Health Perspect. 2002; 110(11): ):A703-7.
45. Shelly LL, Fuchs C, Miele L. Notch-1 Inhibits Apoptosis in Murine Erythroleukemia Cells and Is Necessary for Differentiation Induced by Hybrid Polar Compounds. J. Cell. Biochem. 1999; 73:164 –75.
46. Shih I-M, Wang T-L. Notch Signaling, Gamma-Secretase Inhibitors, and Cancer Therapy. Cancer Res. 2007; 67(5):1879–82. Staples CA, Dorn PB, Klecka GM, O’Block ST, Branson DR, Harris LR. Bisphenol A concentrations in receiving waters near US manufacturing and processing facilities. Chemosphere. Pergamon; 2000; 40(5):521–5.
47. Takahashi O, Oishi S. Testicular toxicity of dietarily or parenterally administered bisphenol A in rats and mice. Food Chem. Toxicol. 2003; 41(7):1035–44.
48. Tanaka M, Nakaya S, Katayama M, Leffers H, Nozawa S, Nakazawa R, Iwamoto T, Kobayashi S. Effect of prenatal exposure to bisphenol A on the serum testosterone concentration of rats at birth. Hum. Exp. Toxicol. 2006; 25(7):369–73.
49. Thuillier R, Manku G, Wang Y, Culty M. Changes in MAPK pathway in neonatal and adult testis following fetal estrogen exposure and effects on rat testicular cells. Microsc. Res. Tech. 2009; 72(11):773–86.
50. Toyama Y, Suzuki-Toyota F, Maekawa M, Ito C, Toshimori K. Adverse effects of bisphenol A to spermiogenesis in mice and rats. Arch Histol Cytol. 2004; 67:373–381
51. Toyama Y, Yuasa S: Effects of neonatal administration of 17ˇ-estradiol,ˇ-estradiol 3-benzoate or Bisphenol A on mouse and rat spermatogenesis. Reprod. Toxicol 2004; 19:181–188.
52. Vandenberg LN, Maffini M V., Sonnenschein C, Rubin BS, Soto AM. Bisphenol-a and the great divide: A review of controversies in the field of endocrine disruption Endocr. Rev. 2009; 75–95.
53. World Health Organization. FAO/WHO Consultation on the Health Implications of Acrylamide in Food Health Implications of Acrylamide in Food Summary Report. (2002). Geneva, Switzerland, WHO, 1 12, (2002).