Journal of Literature Pharmacy Sciences

Endokrin Bozucu Kimyasalların Prostat Bezi Üzerine Etkileri
The Effects of Endocrine Disrupting Chemicals on Prostate Gland
Özge KÖSEa, Pınar ERKEKOĞLUa, Belma KOÇER GÜMÜŞELb
aHacettepe Üniversitesi Eczacılık Fakültesi, Farmasötik Toksikoloji ABD, Ankara, TÜRKİYE
bLokman Hekim Üniversitesi Eczacılık Fakültesi, Farmasötik Toksikoloji ABD, Ankara, TÜRKİYE
J Lit Pharm Sci. 2020;9(1):18-30
doi: 10.5336/pharmsci.2019-70000
Article Language: TR
Full Text
ÖZET
 Endokrin bozucu kimyasal (EDC)'lar, hormonların sentez, taşınma, metabolizma ve atılımları üzerine etkileri olan ve dolayısıyla potansiyel olarak olumsuz sağlık etkileri gösteren maddelerdir. Bu maddelere prenatal maruziyetin daha ciddi sorunlar oluşturabileceği bilinmektedir; fakat yaşamın tüm evrelerinde de istenmeyen etkiler oluşturmaları mümkündür. EDC'lere tek tek maruziyetin olumsuz etkileri birçok çalışmada incelenmiştir. Ancak, özellikle kombine maruziyetlerin etkilerini değerlendiren çalışmalar sınırlıdır. Son yıllarda, tüm dünya genelinde azalan fertilitenin ve artan endokrin bozuklukların farklı EDC'lere maruziyet ile ilişkilendirildiği pek çok çalışma yapılmaktadır. EDC'lerin başta testis olmak üzere, erkek üreme sistemini ve prostat dâhil tüm aksesuar bezleri etkileyebileceği belirtilmiştir. Özellikle ftalatların 'Testiküler Disgenezis sendromu'na neden olduğu, erkek fertilitisini olumsuz yönde etkilediği bilinmektedir. Epidemiyolojik verilere göre, erkek üreme organlarında neoplazi insidansı son 50 yılda artmıştır. Bu durum, normal hormonal dengeyi engelleyen çevresel kimyasalların, özellikle EDC'lere maruziyetin artmasıyla ilişkili olabilir. EDC'lere, özellikle de ftalatlara maruziyetin erken yaşlarda görülen testis kanserleriyle de ilişkili olabileceği ifade edilmektedir. Spesifik endokrin bozucu kimyasalların, hem in vivo hem de in vitro modellerde erkek üreme sistemi ve endokrinle ilişkili kanserlerin gelişimi üzerindeki etkilerine yönelik birçok araştırma yapılmıştır. Bu derlemede, EDC'ler ile ilgili genel bilgiler verildikten sonra, bu kimyasalların erkek üreme sağlığı üzerindeki olası etkileri değerlendirilecek ve özellikle prostat bezi üzerindeki etkileri ile ilgili hem ampirik hem de epidemiyolojik çalışmalardan elde edilen veriler ile birlikte sunulacaktır.

Anahtar Kelimeler: Endokrin bozucu kimyasal; prostat; erkek üreme sistemi
ABSTRACT
 Endocrine disrupting chemicals (EDCs) are substances that affect the synthesis, transfer, metabolism and excretion of hormones and therefore, they potentially have unwanted health effects. It is well-known that prenatal exposure to these subtances may lead to serious deleterious effects; but exposure in all stages of life may also cause negatory effects. Indivudual exposures to EDCs are being investigated in several studies. However, there is limited number of studies that evaluate combined effects. In recent years, there are many studies that associate EDC exposure to decreasing fertility and increasing endocrine conditions throughout the world. It was stated that EDCs affect male reproductive system particularly testis and also all accessory glands, including prostate. Phthalates are particularly associated with testicular dysgenesis syndrome and negatively affect male fertility. Epidemiological data show that incidence of neoplasia in male reproductive organs has increased over the last 50 years. This instance may be related to the increased exposure of environmental chemicals, particularly EDCs, which interfere with normal hormonal balance. It is expressed that exposure to EDCs, specially to phthalates may be linked to early-life testicular cancers. Several studies have been conducted to investigate effects of specific EDCs on the development of male reproductive organs and endocrine related cancers in both in vivo and in vitro models. In this review, we will give general information on EDCs and then focus on their potential impact on male reproductive health, and in particular on their effects on the prostate gland by presenting data from empirical and epidemiological studies.

Keywords: Endocrine disrupting chemicals; prostate; male reproductive system
REFERENCES:
  1. Colborn T, vom Saal FS, Soto AM. Developmental effects of endocrine-disrupting chemicals in wildlife and humans. Environ Health Perspect. 1993;101(5):378-84. [Crossref]  [PubMed]  [PMC] 
  2. Environmental Protection Agency (EPA). Endocrine Disruption Screening Program (EDSP). EDSP Overview; 2012. https://www.epa.gov/endocrine-disruption/endocrine-disruptor-screening-program-edsp-overview
  3. Rüegg J, Penttinen-Damdimopoulou P, Mäkelä S, Pongratz I, Gustafsson JA. Receptors mediating toxicity and their involvement in endocrine disruption. EXS. 2009;99:289-323. [Crossref]  [PubMed] 
  4. Wuttke W, Jarry H, Seidlova-Wuttke D. Definition, classification and mechanism of action of endocrine disrupting chemicals. Hormones (Athens). 2010;9(1):9-15. [Crossref]  [PubMed] 
  5. Safe S. Endocrine disruptors and falling sperm counts: lessons learned or not! Asian J Androl. 2013;15(2):191-4. [Crossref]  [PubMed]  [PMC] 
  6. Prins GS, Ho SM. Early-life estrogens and prostate cancer in an animal model. J Dev Orig Health Dis. 2010;1(6):365-70. [Crossref]  [PubMed]  [PMC] 
  7. Scott HM, Mason JI, Sharpe RM. Steroidogenesis in the fetal testis and its susceptibility to disruption by exogenous compounds. Endocr Rev. 2009;30(7):883-925. [Crossref]  [PubMed] 
  8. Toppari J, Juul A. Trends in puberty timing in humans and environmental modifiers. Mol Cell Endocrinol. 2010;324(1-2):39-44. [Crossref]  [PubMed] 
  9. Campion S, Catlin N, Heger N, McDonnell EV, Pacheco SE, Saffarini C, et al. Male reprotoxicity and endocrine disruption. EXS Suppl. 2012;101:315-60. [Crossref]  [PubMed]  [PMC] 
  10. Toivanen R, Shen MM. Prostate organogenesis: tissue induction, hormonal regulation and cell type specification. Development. 2017;144(8):1382-98. [Crossref]  [PubMed]  [PMC] 
  11. Cunha GR, Donjacour AA, Cooke PS, Mee S, Bigsby RM, Higgins SJ, et al. The endocrinology and developmental biology of the prostate. Endocr Rev. 1987;8(3):338-62. [Crossref]  [PubMed] 
  12. Ruizeveld de Winter JA, Janssen PJ, Sleddens HM, Verleun-Mooijman MC, Trapman J, Brinkmann AO, et al. Androgen receptor status in localized and locally progressive hormone refractory human prostate cancer. Am J Pathol. 1994;144(4):735-46.
  13. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5-29. [Crossref]  [PubMed] 
  14. Katzenwadel A, Wolf P. Androgen deprivation of prostate cancer: leading to a therapeutic dead end. Cancer Lett. 2015;367(1):12-7. [Crossref]  [PubMed] 
  15. Cowin PA, Foster P, Pedersen J, Hedwards S, McPherson SJ, Risbridger GP. Early-onset endocrine disruptor-induced prostatitis in the rat. Environ Health Perspect. 2008;116(7):923-9. [Crossref]  [PubMed]  [PMC] 
  16. Wang X, Wang J, Liu Y, Zong H, Che X, Zheng W, et al. Alterations in mechanical properties are associated with prostate cancer progression. Med Oncol. 2014;31(3):876. [Crossref]  [PubMed] 
  17. Li D, Zhou Z, Qing D, He Y, Wu T, Miao M, et al. Occupational exposure to bisphenol-A (BPA) and the risk of self-reported male sexual dysfunction. Hum Reprod. 2010;25(2):519-27. [Crossref]  [PubMed] 
  18. Vinggaard AM, Niemelä J, Wedebye EB, Jensen GE. Screening of 397 chemicals and development of a quantitative structure--activity relationship model for androgen receptor antagonism. Chem Res Toxicol. 2008;21(4):813-23. [Crossref]  [PubMed] 
  19. Sakkiah S, Ng HW, Tong W, Hong H. Structures of androgen receptor bound with ligands: advancing understanding of biological functions and drug discovery. Expert Opin Ther Targets. 2016;20(10):1267-82. [Crossref]  [PubMed] 
  20. Marselos M, Tomatis L. Diethylstilboestrol: I, pharmacology, toxicology and carcinogenicity in humans. Eur J Cancer. 1992;28A(6-7):1182-9. [Crossref] 
  21. National Toxicology Program (NTP). Diethylstilbestrol CAS No. 56-53-1. 14th ed. Report on Carcinogens; 2016.
  22. Perdew GH. Xenobiotic receptor-mediated toxicity. In: McQueen CA, ed. Comprehensive Toxicology. 2nd ed. New York: Elsevier Science; 2010. p.202-23. [Crossref] 
  23. Liehr JG, Ballatore AM, McLachlan JA, Sirbasku DA. Mechanism of diethylstilbestrol carcinogenicity as studied with the fluorinated analogue E-3',3",5',5"-tetrafluorodiethylstilbestrol. Cancer Res. 1983;43(6):2678-82.
  24. Qu YQ, Fang ZZ, Yang L, Gao ZM, Liang R, Zhu LL, et al. Reversible inhibition of four important human liver cytochrome P450 enzymes by diethylstilbestrol. Pharmazie. 2011;66(3):216-21.
  25. Yonemura CY, Cunha GR, Sugimura Y, Mee SL. Temporal and spatial factors in diethylstilbestrol-induced squamous metaplasia in the developing human prostate. II. Persistent changes after removal of diethylstilbestrol. Acta Anat (Basel). 1995;153(1):1-11. [Crossref]  [PubMed] 
  26. Virtanen HE, Adamsson A. Cryptorchidism and endocrine disrupting chemicals. Mol Cell Endocrinol. 2012;355(2):208-20. [Crossref]  [PubMed] 
  27. Prins GS, Woodham C, Lepinske M, Birch L. Effects of neonatal estrogen exposure on prostatic secretory genes and their correlation with androgen receptor expression in the separate prostate lobes of the adult rat. Endocrinology. 1993;132(6):2387-98. [Crossref]  [PubMed] 
  28. Nelson KG, Sakai Y, Eitzman B, Steed T, McLachlan J. Exposure to diethylstilbestrol during a critical developmental period of the mouse reproductive tract leads to persistent induction of two estrogen-regulated genes. Cell Growth Differ. 1994;5(6):595-606.
  29. McLachlan JA. Prenatal exposure to diethylstilbestrol in mice: toxicological studies. J Toxicol Environ Health. 1977;2(3):527-37. [Crossref]  [PubMed] 
  30. 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. [Crossref]  [PubMed]  [PMC] 
  31. Molina-Molina JM, Amaya E, Grimaldi M, Sáenz JM, Real M, Fernández MF, et al. In vitro study on the agonistic and antagonistic activities of bisphenol-S and other bisphenol-A congeners and derivatives via nuclear receptors. Toxicol Appl Pharmacol. 2013;272(1):127-36. [Crossref]  [PubMed] 
  32. Rochester JR. Bisphenol A and human health: a review of the literature. Reprod Toxicol. 2013;42:132-55. [Crossref]  [PubMed] 
  33. Tarapore P, Ying J, Ouyang B, Burke B, Bracken B, Ho SM. Exposure to bisphenol A correlates with early-onset prostate cancer and promotes centrosome amplification and anchorage-independent growth in vitro. PLoS One. 2014;9(3):e90332. [Crossref]  [PubMed]  [PMC] 
  34. Hanaoka T, Kawamura N, Hara K, Tsugane S. Urinary bisphenol A and plasma hormone concentrations in male workers exposed to bisphenol A diglycidyl ether and mixed organic solvents. Occup Environ Med. 2002;59(9):625-8. [Crossref]  [PubMed]  [PMC] 
  35. Meeker JD, Calafat AM, Hauser R. Urinary bisphenol A concentrations in relation to serum thyroid and reproductive hormone levels in men from an infertility clinic. Environ Sci Technol. 2010;44(4):1458-63. [Crossref]  [PubMed]  [PMC] 
  36. Brandt JZ, Silveira LT, Grassi TF, Anselmo-Franci JA, Fávaro WJ, Felisbino SL, et al. Indole-3-carbinol attenuates the deleterious gestational effects of bisphenol A exposure on the prostate gland of male F1 rats. Reprod Toxicol. 2014;43:56-66. [Crossref]  [PubMed] 
  37. Prins GS, Ye SH, Birch L, Zhang X, Cheong A, Lin H, et al. Prostate cancer risk and dna methylation signatures in aging rats following developmental BPA exposure: a dose-response analysis. Environ Health Perspect. 2017;125(7):077007. [Crossref]  [PubMed]  [PMC] 
  38. Zhu X, Gao L, Yan C, He Y. A novel role and mechanism of cystic fibrosis transmembrane conductance regulator in bisphenol A‐induced prostate cancer. J Cell Biochem. 2019;120(5):8689-95. [Crossref]  [PubMed] 
  39. Xu LC, Sun H, Chen JF, Bian Q, Qian J, Song L, et al. Evaluation of androgen receptor transcriptional activities of bisphenol A, octylphenol and nonylphenol in vitro. Toxicology. 2005;216(2-3):197-203. [Crossref]  [PubMed] 
  40. Roy P, Salminen H, Koskimies P, Simola J, Smeds A, Saukko P, et al. Screening of some anti-androgenic endocrine disruptors using a recombinant cell-based in vitro bioassay. J Steroid Biochem Mol Biol. 2004;88(2):157-66. [Crossref]  [PubMed] 
  41. Ademollo N, Ferrara F, Delise M, Fabietti F, Funari E. Nonylphenol and octylphenol in human breast milk. Environ Int. 2008;34(7):984-7. [Crossref]  [PubMed] 
  42. Inaguma S, Takahashi S, Imaida K, Suzuki S, Shirai T. p-Nonylphenol pretreatment during the late neonatal period has no effect on 3,2'-dimethyl-4-aminobiphenyl-induced prostate carcinogenesis in male F344 rats. Cancer Lett. 2004;212(2):159-66. [Crossref]  [PubMed] 
  43. Bonefeld-Jørgensen EC, Long M, Hofmeister MV, Vinggaard AM. Endocrine-disrupting potential of bisphenol A, bisphenol A dimethacrylate, 4-n-nonylphenol, and 4-n-octylphenol in vitro: new data and a brief review. Environ Health Perspect. 2007;115 Suppl 1:69-76. [Crossref]  [PubMed]  [PMC] 
  44. Murugesan P, Kanagaraj P, Yuvaraj S, Balasubramanian K, Aruldhas MM, Arunakaran J. The inhibitory effects of polychlorinated biphenyl Aroclor 1254 on Leydig cell LH receptors, steroidogenic enzymes and antioxidant enzymes in adult rats. Reprod Toxicol. 2005;20(1):117-26. [Crossref]  [PubMed] 
  45. Gore AC, Chappell VA, Fenton SE, Flaws JA, Nadal A, Prins GS, et al. EDC-2: the endocrine society's second scientific statement on endocrine-disrupting chemicals. Endocr Rev. 2015;36(6):E1-E150. [Crossref]  [PubMed]  [PMC] 
  46. Kester MH, Bulduk S, Tibboel D, Meinl W, Glatt H, Falany CN, et al. Potent inhibition of estrogen sulfotransferase by hydroxylated PCB metabolites: a novel pathway explaining the estrogenic activity of PCBs. Endocrinology. 2000;141(5):1897-900. [Crossref]  [PubMed] 
  47. Ruder AM, Hein MJ, Hopf NB, Waters MA. Mortality among 24,865 workers exposed to polychlorinated biphenyls (PCBs) in three electrical capacitor manufacturing plants: A ten-year update. Int J Hyg Environ Health. 2014;217(2-3):176-87. [Crossref]  [PubMed]  [PMC] 
  48. Aronson KJ, Wilson JW, Hamel M, Diarsvitri W, Fan W, Woolcott C, et al. Plasma organochlorine levels and prostate cancer risk. J Expo Sci Environ Epidemiol. 2010;20(5):434-45. [Crossref]  [PubMed] 
  49. Endo F, Monsees TK, Akaza H, Schill WB, Pflieger-Bruss S. Effects of single non-ortho, mono-ortho, and di-ortho chlorinated biphenyls on cell functions and proliferation of the human prostatic carcinoma cell line, LNCaP. Reprod Toxicol. 2003;17(2):229-36. [Crossref] 
  50. Selvakumar K, Sheerin Banu L, Krishnamoorthy G, Venkataraman P, Elumalai P, Arunakaran J. Differential expression of androgen and estrogen receptors in PCB (Aroclor 1254)-exposed rat ventral prostate: Impact of alpha-tocopherol. Exp Toxicol Pathol. 2011;63(1-2):105-12. [Crossref]  [PubMed] 
  51. International Agency on Cancer (IARC). Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 98. Painting, Firefighting, & Shiftwork; 2010.
  52. Martin MB, Voeller HJ, Gelmann EP, Lu J, Stoica EG, Hebert EJ, et al. Role of cadmium in the regulation of AR gene expression and activity. Endocrinology. 2002;143(1):263-75. [Crossref]  [PubMed] 
  53. Doolan G, Benke G, Giles G. An update on occupation and prostate cancer. Asian Pac J Cancer Prev. 2014;15(2):501-16. [Crossref]  [PubMed] 
  54. García-Esquinas E, Pollan M, Tellez-Plaza M, Francesconi KA, Goessler W, Guallar E, et al. Cadmium exposure and cancer mortality in a prospective cohort: the strong heart study. Environ Health Perspect. 2014;122(4):363-70. [Crossref]  [PubMed]  [PMC] 
  55. Tokar EJ, Qu W, Waalkes MP. Arsenic, stem cells, and the developmental basis of adult cancer. Toxicol Sci. 2011;120 Suppl 1:S192-203. [Crossref]  [PubMed]  [PMC] 
  56. Latini G, Del Vecchio A, Massaro M, Verrotti A, DE Felice C. In utero exposure to phthalates and fetal development. Curr Med Chem. 2006;13(21):2527-34. [Crossref]  [PubMed] 
  57. Muczynski V, Lecureuil C, Messiaen S, Guerquin MJ, N'tumba-Byn T, Moison D, et al. Cellular and molecular effect of MEHP involving LXRα in human fetal testis and ovary. PLoS One. 2012;7(10):e48266. [Crossref]  [PubMed]  [PMC] 
  58. Swan SH, Main KM, Liu F, Stewart SL, Kruse RL, Calafat AM, et al. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect. 2005;113(8):1056-61.
  59. Pant N, Shukla M, Kumar Patel D, Shukla Y, Mathur N, Kumar Gupta Y, et al. Correlation of phthalate exposures with semen quality. Toxicol Appl Pharmacol. 2008;231(1):112-6. [Crossref]  [PubMed] 
  60. Foster PM. Disruption of reproductive development in male rat offspring following in utero exposure to phthalate esters. Int J Androl. 2006;29(1):140-7. [Crossref]  [PubMed] 
  61. Gray LE Jr, Wilson VS, Stoker T, Lambright C, Furr J, Noriega N, et al. Adverse effects of environmental antiandrogens and androgens on reproductive development in mammals. Int J Androl. 2006;29(1):96-104. [Crossref]  [PubMed] 
  62. Erkekoglu P, Giray BK, Kızilgün M, Rachidi W, Hininger-Favier I, Roussel AM, et al. Di(2-ethylhexyl)phthalate-induced renal oxidative stress in rats and protective effect of selenium. Toxicol Mech Methods. 2012;22(6):415-23. [Crossref]  [PubMed] 
  63. Erkekoglu P, Zeybek ND, Giray B, Asan E, Arnaud J, Hincal F. Reproductive toxicity of di(2-ethylhexyl) phthalate in selenium-supplemented and selenium-deficient rats. Drug Chem Toxicol. 2011;34(4):379-89. [Crossref]  [PubMed] 
  64. Erkekoglu P, Rachidi W, Yuzugullu OG, Giray B, Favier A, Ozturk M, et al. Evaluation of cytotoxicity and oxidative DNA damaging effects of di(2-ethylhexyl)-phthalate (DEHP) and mono(2-ethylhexyl)-phthalate (MEHP) on MA-10 Leydig cells and protection by selenium. Toxicol Appl Pharmacol. 2010;248(1):52-62. [Crossref]  [PubMed] 
  65. Erkekoğlu P, Rachidi W, De Rosa V, Giray B, Favier A, Hincal F. Protective effect of selenium supplementation on the genotoxicity of di(2-ethylhexyl)phthalate and mono(2-ethylhexyl)phthalate treatment in LNCaP cells. Free Radic Biol Med. 2010;49(4):559-66. [Crossref]  [PubMed] 
  66. Erkekoğlu P, Rachidi W, Yüzügüllü OG, Giray B, Oztürk M, Favier A, et al. Induction of ROS, p53, p21 in DEHP- and MEHP-exposed LNCaP cells-protection by selenium compounds. Food Chem Toxicol. 2011;49(7):1565-71. [Crossref]  [PubMed] 
  67. Xu X, Dailey AB, Talbott EO, Ilacqua VA, Kearney G, Asal NR. Associations of serum concentrations of organochlorine pesticides with breast cancer and prostate cancer in U.S. adults. Environ Health Perspect. 2010;118(1):60-6. [Crossref]  [PubMed]  [PMC] 
  68. Turusov V, Rakitsky V, Tomatis L. Dichlorodiphenyltrichloroethane (DDT): ubiquity, persistence, and risks. Environ Health Perspect. 2002;110(2):125-8. [Crossref]  [PubMed]  [PMC] 
  69. Hansen ME, Matsumura F. Effects of heptachlor epoxide on components of various signal transduction pathways important in tumor promotion in mouse hepatoma cells. Determination of the most sensitive tumor promoter related effect induced by heptachlor epoxide. Toxicology. 2001;160(1-3):139-53. [Crossref] 
  70. Ritchie JM, Vial SL, Fuortes LJ, Guo H, Reedy VE, Smith EM. Organochlorines and risk of prostate cancer. J Occup Environ Med. 2003;45(7):692-702. [Crossref]  [PubMed] 
  71. Koutros S, Langseth H, Grimsrud TK, Barr DB, Vermeulen R, Portengen L, et al. Prediagnostic serum organochlorine concentrations and metastatic prostate cancer: a nested case-control study in the norwegian janus serum bank cohort. Environ Health Perspect. 2015;123(9):867-72. [Crossref]  [PubMed]  [PMC] 
  72. Dich J, Wiklund K. Prostate cancer in pesticide applicators in Swedish agriculture. Prostate. 1998;34(2):100-12. [Crossref] 
  73. Settimi L, Masina A, Andrion A, Axelson O. Prostate cancer and exposure to pesticides in agricultural settings. Int J Cancer. 2003;104(4):458-61. [Crossref]  [PubMed] 
  74. Mozzachio AM, Rusiecki JA, Hoppin JA, Mahajan R, Patel R, Beane-Freeman L, et al. Chlorothalonil exposure and cancer incidence among pesticide applicator participants in the agricultural health study. Environ Res. 2008;108(3):400-3. [Crossref]  [PubMed]  [PMC] 
  75. Venkataraman P, Sridhar M, Dhanammal S, Vijayababu MR, Srinivasan N, Arunakaran J. Antioxidant role of zinc in PCB (Aroclor 1254) exposed ventral prostate of albino rats. J Nutr Biochem. 2004;15(10):608-13. [Crossref]  [PubMed] 

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4. GENERAL PROVISIONS

4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com