Journal of Literature Pharmacy Sciences

Otizm Spektrum Bozukluklarında Endokrin Bozucu Kimyasal Maddelerin Olası Rolleri: Sistematik Derleme
Possible Roles of Endocrine Disrupting Chemicals in Autism Spectrum Disorders: Systematic Review
Nigar MERCANa, Selinay Başak ERDEMLİ KÖSEa,b, Anıl YİRÜNa,c, Pınar ERKEKOĞLUa,d
aHacettepe Üniversitesi Eczacılık Fakültesi, Farmasötik Toksikoloji ABD, Ankara, TÜRKİYE
bBurdur Mehmet Akif Ersoy Üniversitesi Fen-Edebiyat Fakültesi, Kimya Bölümü, Burdur, TÜRKİYE
cÇukurova Üniversitesi Eczacılık Fakültesi, Farmasötik Toksikoloji ABD, Adana, TÜRKİYE
dHacettepe Üniversitesi Aşı Enstitüsü, Aşı Teknolojisi ABD, Ankara, TÜRKİYE
J Lit Pharm Sci. 2021;10(3):308-21
doi: 10.5336/pharmsci.2020-79267
Article Language: TR
Full Text
ÖZET
 Otizm spektrum bozukluğu (OSB), tekrar eden davranışlar ve sınırlı dikkatin yanı sıra sosyal fonksiyon eksiklikleri ve iletişim alanlarında bozulmayla karakterize kompleks nörogelişimsel bir bozukluk olarak tanımlanmaktadır. OSB'nin ortaya çıkmasında, çok sayıda mekanizma rol oynamaktadır. Bunlar arasında en önemlileri; oksidatif stres, mitokondriyal disfonksiyon, serotonerjik sistemde anomaliler, beyaz cevher yapısında anormal değişiklikler, anormal sitokin düzeyleri, immün sistem disregülasyonu, beyin dokusuna karşı oluşan fetalmaternal antikorlar ve mikroglial aktivasyondur. Bu bozukluğa sebep olan başlıca etmenler; genetik faktörler, çevresel etkenler ve prenatal faktörlerdir. Erken dönemde çevresel maruziyetler, genetik yatkınlıklarla birlikte otizmin ortaya çıkmasında etkili olabilir. Bireylerin genetik yatkınlığı ve toplumun geneline göre daha duyarlı olmaları da bu çevresel etkenlerin, otizm ve benzeri nörogelişimsel bozuklukları oluşturma riskini artırabilir. Prenatal maruziyet, otizmin ortaya çıkmasının en önemli olası nedeni olarak kabul edilebilir. Ayrıca farklı çevresel maruziyetler ve kalıtsal özellikler arasındaki etkileşimin, otizm fenotipinde gözlemlenen heterojenliği de açıklayabileceği varsayılmaktadır. Endokrin bozucu kimyasal maddeler (EDC) endokrin sistemin işleyişini değiştirerek, organizmada ve doğacak nesillerde olumsuz sağlık etkilerine neden olan ekzojen madde veya madde karışımları olarak tanımlanır. EDC'lere maruziyet sonucu, otizm ve diğer nörogelişimsel hastalıkların riskinin arttığı düşünülmektedir. Bu derleme kapsamında; OSB, belirtileri, ortaya çıkmasında etkili olan faktörler ve çevresel faktörlerden EDC'lerin (ftalatlar, poliklorlu bifeniller, perflorokimyasallar, organoklorlu pestisitler, bisfenol A, ağır metaller) OSB ile olası ilişkisi hakkında bilgi verilmesi amaçlanmıştır.

Anahtar Kelimeler: Otizm spektrum bozukluğu; endokrin bozucu kimyasal madde; ftalat; bisfenol A; ağır metaller
ABSTRACT
 Autism spectrum disorder (ASD) is defined as a complex neurodevelopmental disorder, characterized by recurrent behaviors and limited attention, as well as social function deficiencies and disruption in communication. Many mechanisms play a role in the emergence of ASD. The most important mechanisms are oxidative stress, mitochondrial dysfunction, serotonergic system abnormalities, abnormal changes in white matter structure, abnormal cytokine levels, immune system dysregulation, fetal maternal antibodies against brain tissue and microglial activation. Main factors causing ASD are genetic factors, environmental factors and prenatal factors. Environmental exposures in early stages of life, together with genetic predisposition, might be effective in the emergence of autism. Individuals' genetic predisposition and higher sensitivity compared to general population may also increase the risk of these environmental factors to cause autism and similar neurodevelopmental disorders. Prenatal exposure can be considered as the most important possible cause of autism. It is also assumed that interaction between different environmental exposures and hereditary characteristics may explain the heterogeneity observed in autistic phenotype. Endocrine disrupting chemicals (EDCs) are defined as exogenous substances or mixtures that change the functioning of endocrine system and cause negative health effects in an organism and the future generations. Risk of autism and other neurodevelopmental diseases is thought to increase as a result of exposure to endocrine disruptors. In this study, we aimed to give information about ASD, symptoms, factors that affect its occurrence and the possible association between EDCs (phthalates, polychlorinated biphenyls, perfluorochemicals, organochlorine pesticides, bisphenol A, heavy metals) and ASD.

Keywords: Autism spectrum disorders; endocrine disruptors; phthalate; bisphenol A; heavy metals
REFERENCES:
  1. Özeren GS. Otizm spektrum bozukluğu (OSB) ve hastalığa kanıt penceresinden bakış. Acıbadem Univ Sağlık Bilim Derg. 2013;4(2):57-63. [Link] 
  2. Sacco R, Lintas C, Persico AM. Autism genetics: methodological issues and experimental design. Sci China Life Sci. 2015;58(10):946-57. [Crossref] [PubMed] 
  3. Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med. 1995;25(1):63-77. [Crossref] [PubMed] 
  4. Gupta AR, State MW. Autismo: genética [Autism: genetics]. Braz J Psychiatry. 2006 May;28 Suppl 1:S29-38. [Crossref] [PubMed] 
  5. Otizm Dernekleri Federasyonu [İnternet]. Odfed © 2013. [Erişim tarihi: 20.01.2020]. Otizm nedir? Erişim linki: [Link] 
  6. Tohum Türkiye Otizm Erken Tanı ve Eğitim Vakfı [İnternet]. © 2020 Tohum Otizm Vakfı. [Erişim tarihi: 20.01.2020]. Erişim linki: [Link] 
  7. Landrigan PJ. What causes autism? Exploring the environmental contribution. Curr Opin Pediatr. 2010;22(2):219-25. [Crossref] [PubMed] 
  8. Wilson CE, Gillan N, Spain D, Robertson D, Roberts G, Murphy CM, et al. Comparison of ICD-10R, DSM-IV-TR and DSM-5 in an adult autism spectrum disorder diagnostic clinic. J Autism Dev Disord. 2013;43(11):2515-25. [Crossref]  [PubMed] 
  9. Erdemli-Köse SB, Balcı A, Yirun A, Erkekoğlu P. Tiyomersal maruziyeti ve otizm spektrum bozuklukları arasındaki olası ilişkinin değerlendirilmesi. [Evaluation of the possible association between thiomersal exposure and autism spectrum disorders]. J Lit Pharm Sci. 2020;9(3):304-18. [Crossref] 
  10. Bodur Ş, Soysal AŞ. [Early Diagnosis and Importance of Autism]. Sted. 2004;13(10):394-8. [Link] 
  11. Caglayan AO. Genetic causes of syndromic and non-syndromic autism. Dev Med Child Neurol. 2010;52(2):130-8. [Crossref] [PubMed] 
  12. Tordjman S, Somogyi E, Coulon N, Kermarrec S, Cohen D, Bronsard G, et al. Gene × Environment interactions in autism spectrum disorders: role of epigenetic mechanisms. Front Psychiatry. 2014;5:53. [Crossref] [PubMed] [PMC] 
  13. Dietert RR, Dietert JM, Dewitt JC. Environmental risk factors for autism. Emerg Health Threats J. 2011;4:7111. [Crossref] [PubMed] [PMC] 
  14. Larsson HJ, Eaton WW, Madsen KM, Vestergaard M, Olesen AV, Agerbo E, et al. Risk factors for autism: perinatal factors, parental psychiatric history, and socioeconomic status. Am J Epidemiol. 2005;161(10):916-25; discussion 926-8. [Crossref] [PubMed] 
  15. Erden S, Nalbant K. Autism spectrum disorder and prenatal risk factors. Selçuk Med J. 2019;35(4):282-90. [Crossref] 
  16. Özbaran B. Otizm spektrum bozukluklarında çevresel faktörler etkili midir? [Do environmental factors have ınfluence on autism spectrum disorder?]. Pediatr Res. 2014;1(4):170-3. [Crossref] 
  17. Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, Hauser R, Prins GS, Soto AM, et al. Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev. 2009;30(4):293-342. [Crossref] [PubMed] [PMC] 
  18. Lauretta R, Sansone A, Sansone M, Romanelli F, Appetecchia M. Endocrine disrupting chemicals: effects on endocrine glands. Front Endocrinol (Lausanne). 2019;10:178. [Crossref] [PubMed] [PMC] 
  19. Yeşilkaya E. Endokrin bozucular. [Endocrine disruptors]. J Pediatr. 2008;6(3):76-82. [Link] 
  20. Liang DW, Zhang T, Fang HH, He J. Phthalates biodegradation in the environment. Appl Microbiol Biotechnol. 2008;80(2):183-98. [Crossref]  [PubMed] 
  21. Heudorf U, Mersch-Sundermann V, Angerer J. Phthalates: toxicology and exposure. Int J Hyg Environ Health. 2007;210(5):623-34. [Crossref] [PubMed] 
  22. Frederiksen H, Skakkebaek NE, Andersson AM. Metabolism of phthalates in humans. Mol Nutr Food Res. 2007;51(7):899-911. [Crossref]  [PubMed] 
  23. Jeddi MZ, Janani L, Memari AH, Akhondzadeh S, Yunesian M. The role of phthalate esters in autism development: a systematic review. Environ Res. 2016;151:493-504. [Crossref] [PubMed] 
  24. Carbone S, Ponzo OJ, Gobetto N, Samaniego YA, Reynoso R, Scacchi P, et al. Antiandrogenic effect of perinatal exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate increases anxiety-like behavior in male rats during sexual maturation. Horm Behav. 2013;63(5):692-9. [Crossref] [PubMed] 
  25. Lichtensteiger W, Bassetti-Gaille C, Faass O, Axelstad M, Boberg J, Christiansen S, et al. Differential gene expression patterns in developing sexually dimorphic rat brain regions exposed to antiandrogenic, estrogenic, or complex endocrine disruptor mixtures: glutamatergic synapses as target. Endocrinology. 2015;156(4):1477-93. [Crossref] [PubMed] 
  26. Miodovnik A, Engel SM, Zhu C, Ye X, Soorya LV, Silva MJ, et al. Endocrine disruptors and childhood social impairment. Neurotoxicology. 2011;32(2):261-7. [Crossref] [PubMed] [PMC] 
  27. Testa C, Nuti F, Hayek J, De Felice C, Chelli M, Rovero P, et al. Di-(2-ethylhexyl) phthalate and autism spectrum disorders. ASN Neuro. 2012;4(4):223-9. [Crossref] [PubMed] [PMC] 
  28. Kardas F, Bayram AK, Demirci E, Akin L, Ozmen S, Kendirci M, et al. Increased serum phthalates (MEHP, DEHP) and bisphenol a concentrations in children with autism spectrum disorder: the role of endocrine disruptors in autism etiopathogenesis. J Child Neurol. 2016;31(5):629-35. [Crossref] [PubMed] 
  29. Durmaz E, Koçer Giray B. Çevresel bir endokrin bozucu: bisfenol A ve toksik etkilerinin değerlendirilmesi. [An environmental endocrine disrupter: bisphenol A and evaluation of its toxic effects]. Çocuk Sağlığı ve Hastalıkları Dergisi. 2013;56(4):192-9. [Link] 
  30. Masuno H, Iwanami J, Kidani T, Sakayama K, Honda K. Bisphenol a accelerates terminal differentiation of 3T3-L1 cells into adipocytes through the phosphatidylinositol 3-kinase pathway. Toxicol Sci. 2005;84(2):319-27. [Crossref] [PubMed] 
  31. Braun JM, Kalkbrenner AE, Calafat AM, Yolton K, Ye X, Dietrich KN, et al. Impact of early-life bisphenol A exposure on behavior and executive function in children. Pediatrics. 2011;128(5):873-82. [Crossref] [PubMed] [PMC] 
  32. Wolstenholme JT, Taylor JA, Shetty SR, Edwards M, Connelly JJ, Rissman EF. Gestational exposure to low dose bisphenol A alters social behavior in juvenile mice. PLoS One. 2011;6(9):e25448. [Crossref] [PubMed] [PMC] 
  33. Stein TP, Schluter MD, Steer RA, Guo L, Ming X. Bisphenol A exposure in children with autism spectrum disorders. Autism Res. 2015;8(3):272-83. [Crossref] [PubMed] [PMC] 
  34. Braun JM, Yolton K, Dietrich KN, Hornung R, Ye X, Calafat AM, et al. Prenatal bisphenol A exposure and early childhood behavior. Environ Health Perspect. 2009;117(12):1945-52. [Crossref] [PubMed] [PMC] 
  35. Foresta C, Tescari S, Di Nisio A. Impact of perfluorochemicals on human health and reproduction: a male's perspective. J Endocrinol Invest. 2018;41(6):639-45. [Crossref] [PubMed] 
  36. Liew Z, Ritz B, von Ehrenstein OS, Bech BH, Nohr EA, Fei C, et al. Attention deficit/hyperactivity disorder and childhood autism in association with prenatal exposure to perfluoroalkyl substances: a nested case-control study in the Danish National Birth Cohort. Environ Health Perspect. 2015;123(4):367-73. [Crossref] [PubMed] [PMC] 
  37. Hu Q, Franklin JN, Bryan I, Morris E, Wood A, DeWitt JC. Does developmental exposure to perfluorooctanoic acid (PFOA) induce immunopathologies commonly observed in neurodevelopmental disorders. Neurotoxicology. 2012;33(6):1491-8. [Crossref]  [PubMed] 
  38. Sobolewski M, Conrad K, Allen JL, Weston H, Martin K, Lawrence BP, et al. Sex-specific enhanced behavioral toxicity induced by maternal exposure to a mixture of low dose endocrine-disrupting chemicals. Neurotoxicology. 2014;45:121-30. [Crossref] [PubMed] [PMC] 
  39. Lau C, Thibodeaux JR, Hanson RG, Rogers JM, Grey BE, Stanton ME, et al. Exposure to perfluorooctane sulfonate during pregnancy in rat and mouse. II: postnatal evaluation. Toxicol Sci. 2003;74(2):382-92. [Crossref] [PubMed] 
  40. Johansson N, Fredriksson A, Eriksson P. Neonatal exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) causes neurobehavioural defects in adult mice. Neurotoxicology. 2008;29(1):160-9. [Crossref]  [PubMed] 
  41. Liew Z, Ritz B, Bach CC, Asarnow RF, Bech BH, Nohr EA, et al. Prenatal exposure to perfluoroalkyl substances and IQ scores at age 5; a study in the danish national birth cohort. Environ Health Perspect. 2018;126(6):067004. [Crossref] [PubMed] [PMC] 
  42. Eriksson P, Fredriksson A. Neurotoxic effects in adult mice neonatally exposed to 3,3'4,4'5-pentachlorobiphenyl or 2,3,3'4,4'-pentachlorobiphenyl. Changes in brain nicotinic receptors and behaviour. Environ Toxicol Pharmacol. 1998;5(1):17-27. [Crossref] [PubMed] 
  43. Ghosh S, Mitra PS, Loffredo CA, Trnovec T, Murinova L, Sovcikova E, et al. Transcriptional profiling and biological pathway analysis of human equivalence PCB exposure in vitro: indicator of disease and disorder development in humans. Environ Res. 2015;138:202-16. [Crossref] [PubMed] [PMC] 
  44. Mitchell MM, Woods R, Chi LH, Schmidt RJ, Pessah IN, Kostyniak PJ, et al. Levels of select PCB and PBDE congeners in human postmortem brain reveal possible environmental involvement in 15q11-q13 duplication autism spectrum disorder. Environ Mol Mutagen. 2012;53(8):589-98. [Crossref] [PubMed] [PMC] 
  45. Kimura-Kuroda J, Nagata I, Kuroda Y. Disrupting effects of hydroxy-polychlorinated biphenyl (PCB) congeners on neuronal development of cerebellar Purkinje cells: a possible causal factor for developmental brain disorders? Chemosphere. 2007;67(9):S412-20. [Crossref] [PubMed] 
  46. Jolous-Jamshidi B, Cromwell HC, McFarland AM, Meserve LA. Perinatal exposure to polychlorinated biphenyls alters social behaviors in rats. Toxicol Lett. 2010;199(2):136-43. [Crossref] [PubMed] [PMC] 
  47. Wayman GA, Bose DD, Yang D, Lesiak A, Bruun D, Impey S, et al. PCB-95 modulates the calcium-dependent signaling pathway responsible for activity-dependent dendritic growth. Environ Health Perspect. 2012;120(7):1003-9. [Crossref] [PubMed] [PMC] 
  48. Eriksson P, Fredriksson A. Developmental neurotoxicity of four ortho-substituted polychlorinated biphenyls in the neonatal mouse. Environ Toxicol Pharmacol. 1996;1(3):155-65. [Crossref] [PubMed] 
  49. Lyall K, Croen LA, Sjödin A, Yoshida CK, Zerbo O, Kharrazi M, et al. Polychlorinated biphenyl and organochlorine pesticide concentrations in maternal mid-pregnancy serum samples: association with autism spectrum disorder and intellectual disability. Environ Health Perspect. 2017;125(3):474-80. [Crossref]  [PubMed]  [PMC] 
  50. Lemaire G, Terouanne B, Mauvais P, Michel S, Rahmani R. Effect of organochlorine pesticides on human androgen receptor activation in vitro. Toxicol Appl Pharmacol. 2004;196(2):235-46. [Crossref] [PubMed] 
  51. Androutsopoulos VP, Hernandez AF, Liesivuori J, Tsatsakis AM. A mechanistic overview of health associated effects of low levels of organochlorine and organophosphorous pesticides. Toxicology. 2013;307:89-94. [Crossref] [PubMed] 
  52. Saeedi Saravi SS, Dehpour AR. Potential role of organochlorine pesticides in the pathogenesis of neurodevelopmental, neurodegenerative, and neurobehavioral disorders: a review. Life Sci. 2016;145:255-64. [Crossref] [PubMed] 
  53. Lee I, Eriksson P, Fredriksson A, Buratovic S, Viberg H. Developmental neurotoxic effects of two pesticides: Behavior and neuroprotein studies on endosulfan and cypermethrin. Toxicology. 2015;335:1-10. [Crossref] [PubMed] 
  54. Roberts EM, English PB, Grether JK, Windham GC, Somberg L, Wolff C. Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley. Environ Health Perspect. 2007;115(10):1482-9. [Crossref] [PubMed] [PMC] 
  55. Ribas-Fitó N, Torrent M, Carrizo D, Mu-oz-Ortiz L, Júlvez J, Grimalt JO, et al. In utero exposure to background concentrations of DDT and cognitive functioning among preschoolers. Am J Epidemiol. 2006;164(10):955-62. [Crossref] [PubMed] 
  56. Dallaire R, Muckle G, Rouget F, Kadhel P, Bataille H, Guldner L, et al. Cognitive, visual, and motor development of 7-month-old Guadeloupean infants exposed to chlordecone. Environ Res. 2012;118:79-85. [Crossref] [PubMed] 
  57. Martin S, Griswold W. Human health effects of heavy metals. Environmental Science and Technology Briefs for Citizens. 2009;15(1):1-6. [Link] 
  58. Mohod CV, Dhote J. Review of heavy metals in drinking water and their effect on human health. IJIRSET. 2013;2(7):2992-6. [Link] 
  59. Hill DS, Cabrera R, Wallis Schultz D, Zhu H, Lu W, Finnell RH, et al. Autism-like behavior and epigenetic changes associated with autism as consequences of ın utero exposure to environmental pollutants in a mouse model. Behav Neurol. 2015;2015:426263. [Crossref] [PubMed] [PMC] 
  60. Blaurock-Busch E, Amin OR, Rabah T. Heavy metals and trace elements in hair and urine of a sample of arab children with autistic spectrum disorder. Maedica (Bucur). 2011;6(4):247-57. [PubMed] [PMC] 
  61. Blaurock-Busch E, Amin OR, Dessoki HH, Rabah T. Toxic metals and essential elements in hair and severity of symptoms among children with autism. Maedica (Bucur). 2012;7(1):38-48. [PubMed] [PMC] 
  62. Yassa HA. Autism: a form of lead and mercury toxicity. Environ Toxicol Pharmacol. 2014;38(3):1016-24. [Crossref] [PubMed] 
  63. Mohamed Fel B, Zaky EA, El-Sayed AB, Elhossieny RM, Zahra SS, Salah Eldin W, et al. Assessment of hair aluminum, lead, and mercury in a sample of autistic Egyptian children: environmental risk factors of heavy metals in autism. Behav Neurol. 2015;2015:545674. [Crossref]  [PubMed]  [PMC] 
  64. Fiore M, Barone R, Copat C, Grasso A, Cristaldi A, Rizzo R, et al. Metal and essential element levels in hair and association with autism severity. J Trace Elem Med Biol. 2020;57:126409. [Crossref] [PubMed] 
  65. Hessabi M, Rahbar MH, Dobrescu I, Bach MA, Kobylinska L, Bressler J, et al. Concentrations of lead, mercury, arsenic, cadmium, manganese, and aluminum in blood of romanian children suspected of having autism spectrum disorder. Int J Environ Res Public Health. 2019;16(13):2303. [Crossref] [PubMed] [PMC] 
  66. Rahbar MH, Samms-Vaughan M, Ardjomand-Hessabi M, Loveland KA, Dickerson AS, Chen Z, et al. The role of drinking water sources, consumption of vegetables and seafood in relation to blood arsenic concentrations of Jamaican children with and without Autism Spectrum Disorders. Sci Total Environ. 2012;433:362-70. [Crossref] [PubMed] [PMC] 

.: Up To Date

.: Process List

Login

 Forgot your password?

 New Registration  

Contact

Ortadoğu Reklam Tanıtım Yayıncılık Turizm Eğitim İnşaat Sanayi ve Ticaret A.Ş.

.: Address

Turkocagi Caddesi No:30 06520 Balgat / ANKARA
Phone: +90 312 286 56 56
Fax: +90 312 220 04 70
E-mail: info@turkiyeklinikleri.com

.: Manuscript Editing Department

Phone: +90 312 286 56 56/ 2
E-mail: yaziisleri@turkiyeklinikleri.com

.: English Language Redaction

Phone: +90 312 286 56 56/ 145
E-mail: tkyayindestek@turkiyeklinikleri.com

.: Marketing Sales-Project Department

Phone: +90 312 286 56 56/ 142
E-mail: reklam@turkiyeklinikleri.com

.: Subscription and Public Relations Department

Phone: +90 312 286 56 56/ 118
E-mail: abone@turkiyeklinikleri.com

.: Customer Services

Phone: +90 312 286 56 56/ 118
E-mail: satisdestek@turkiyeklinikleri.com

1. TERMS OF USE

1.1. To use the web pages with http://www.turkiyeklinikleri.com domain name or the websites reached through the sub domain names attached to the domain name (They will be collectively referred as "SITE"), please read the conditions below. If you do not accept these terms, please cease to use the "SITE." "SITE" owner reserves the right to change the information on the website, forms, contents, the "SITE," "SITE" terms of use anytime they want.

1.2. The owner of the "SITE" is Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. (From now on it is going to be referred as "Turkiye Klinikleri", shortly) and it resides at Turkocagi cad. No:30, 06520 Balgat Ankara. The services in the "SITE" are provided by "Turkiye Klinikleri."

1.3. Anyone accessing the "SITE" with or without a fee whether they are a natural person or a legal identity is considered to agree these terms of use. In this contract hereby, "Turkiye Klinikleri" may change the stated terms anytime. These changes will be published in the "SITE" periodically and they will be valid when they are published. Any natural person or legal identity benefiting from and reaching to the "SITE" are considered to be agreed to any change on hereby contract terms done by "Turkiye Klinikleri."

1.4. The "Terms of Use" hereby is published in the website with the last change on March 30th 2014 and the "SITE" is activated by enabling the access to everyone. The "Terms of Use" hereby is also a part of the any "USER Contract" was and/or will be done with the users using "Turkiye Klinikleri" services with or without a fee an inseparable.

2. DEFINITIONS

2.1. "SITE": A website offering different kind of services and context with a certain frame determined by "Turkiye Klinikleri" and it is accessible on-line on http://www.turkiyeklinikleri.com domain name and/or subdomains connected to the domain name.

2.2. USER: A natural person or a legal identity accessing to the "SITE" through online settings.

2.3. LINK: A link enabling to access to another website through the "SITE", the files, the context or through another website to the "SITE", the files and the context.

2.4. CONTEXT: Any visual, literary and auditory images published in the "Turkiye Klinikleri", "SITE" and/or any website or any accessible information, file, picture, number/figures, price, etc.

2.5. "USER CONTRACT": An electronically signed contract between a natural or a legal identity benefiting from special services "Turkiye Klinikleri" will provide and "Turkiye Klinikleri".

3. SCOPE OF THE SERVICES

3.1. "Turkiye Klinikleri" is completely free to determine the scope and quality of the services via the "SITE".

3.2. To benefit the services of "Turkiye Klinikleri" "SITE", the "USER" must deliver the features that will be specified by "Turkiye Klinikleri". "Turkiye Klinikleri" may change this necessity any time single-sided.

3.3. Not for a limited number, the services "Turkiye Klinikleri" will provide through the "SITE" for a certain price or for free are;

- Providing scientific articles, books and informative publications for health industry.

- Providing structural, statistical and editorial support to article preparation stage for scientific journals.

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