Turkiye Klinikleri Journal of Health Sciences

.: REVIEW
Otizm Spektrum Bozukluğunda Endokrin Bozucuların Rolü
The Role of Endocrine Disruptors in Autism Spectrum Disorder
Gizem AYTEKİN ŞAHİNa
aBeslenme ve Diyetetik Bölümü, Erciyes Üniversitesi, Sağlık Bilimleri Fakültesi,Kayseri, TÜRKİYE
Turkiye Klinikleri J Health Sci. 2019;4(3):348-57
doi: 10.5336/healthsci.2018-61638
Article Language: TR
Full Text
ÖZET
 Otizm spektrum bozukluğu (OSB), günümüzde oldukça yaygın görülen nörogelişimsel bir hastalıktır. Genetik, biyolojik ve çevresel faktörlerin hastalık gelişiminde rolü olduğu düşünülmektedir. Yapılan çalışmalar, çevresel kirleticilere maruziyetin genetik duyarlılığı olan bireylerde nörogelişimsel bozukluk riskinin artmasında rol oynayabileceğini göstermiştir. Endokrin bozucu bileşikler, bu çevresel kirleticilerin önemli bir bölümünü oluşturmaktadır. Endokrin bozucular kısaca, 'Vücutta görev yapan hormonların metabolizmasını etkileyen kimyasal maddeler' olarak tanımlanmıştır. Özellikle cıva, kurşun, bisfenol A, fitalatlar gibi çevresel toksik maddelere maruz kalmanın OSB riskinin artışı ile ilişkili olabileceği ileri sürülmektedir. Özellikle prenatal ve perinatal dönemdeki maruziyetin ciddi risk oluşturduğu öne sürülmüştür. Bu çalışmada, literatürde OSB gelişim riski ile ilişkilendirilmiş endokrin bozuculardan bisfenol A, fitalatlar, dioksinler, poliklorlu bifeniller ve ağır metallerin OSB gelişimindeki potansiyel rollerinin tartışılması amaçlanmıştır.

Anahtar Kelimeler: Otizm spektrum bozukluğu; endokrin bozucular
ABSTRACT
 Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is common today. Genetic, biological and environmental factors are thought to play a role in ASD development. Studies have shown that exposure to environmental pollutants may play a role in increasing the risk of neurodevelopmental disorder in genetically susceptible individuals. Endocrine disrupting compounds are an important part of these environmental pollutants. Endocrine disruptors are briefly described as 'Chemical substances that affect the metabolism of hormones acting in the body'. In particular, exposure to environmental toxic substances such as mercury, lead, bisphenol A, phthalates may be associated with an increase in ASD risk. It has been suggested that exposure in the prenatal and perinatal period poses a serious risk. In this review, the potential roles of endocrine disruptors bisphenol A, phthalates, dioxins, polychlorinated biphenyls and heavy metals in the development of ASD have been discussed.

Keywords: Autism spectrum disorder; endocrine disruptors
REFERENCES:
  1. American Psychiatric Association. Ruhsal Bozukluklarin Tanisal ve Sayimsal El Kitabi-DSM-IV-TR. Koroglu E, Ceviri editoru. 2. baski. Ankara: Hekimler Yayin Birligi; 2005. p.344.
  2. World Health Organization (WHO). The ICD-10 Classification of Mental and Behavioural Disorders. Geneva: WHO; 1993. p.263. http://www.who.int/classifications/icd/en/GRNBOOK.pdf
  3. American Psychiatric Association. DSM-5 Ruhsal Bozukluklarin Tanisal ve Sayimsal El Kitabi. Koroglu E, Ceviri editoru. 5. baski. Ankara: Hekimler Yayin Birligi; 2013. p.396.
  4. Bryn V, Aass HC, Skjeldal OH, Isaksen J, Saugstad OD, Ormstad H. Cytokine profile in autism spectrum disorders in children. J Mol Neurosci. 2017;61(1):1-7. [Crossref]  [PubMed] 
  5. Ye BS, Leung AOW, Wong MH. The association of environmental toxicants and autism spectrum disorders in children. Environ Pollut. 2017;227:234-42. [Crossref]  [PubMed] 
  6. Hu VW. From genes to environment: using integrative genomics to build a "systems level" understanding of autism spectrum disorders. Child Dev. 2013;84(1):89-103. [Crossref]  [PubMed]  [PMC] 
  7. LaSalle JM. Epigenomic strategies at the interface of genetic and environmental risk factors for autism. J Hum Genet. 2013;58(7): 396-401. [Crossref]  [PMC] 
  8. Deth R, Muratore C, Benzecry J, Power-Charnitsky VA, Waly M. How environmental and genetic factors combine to cause autism: a redox/methylation hypothesis. Neurotoxicology. 2008;29(1):190-201. [Crossref]  [PubMed] 
  9. Braun JM. Endocrine disrupting compounds, gonadal hormones, and autism. Dev Med Child Neurol. 2012;54(11):1068. [Crossref]  [PubMed] 
  10. Rebuli ME, Patisaul HB. Assessment of sex specific endocrine disrupting effects in the prenatal and pre-pubertal rodent brain. J Steroid Biochem Mol Biol. 2016;160:148-59. [Crossref]  [PubMed]  [PMC] 
  11. Schug TT, Blawas AM, Gray K, Heindel JJ, Lawler CP. Elucidating the links between endocrine disruptors and neurodevelopment. Endocrinology. 2015;156(6):1941-51. [Crossref]  [PubMed]  [PMC] 
  12. Preciados M, Yoo C, Roy D. Estrogenic endocrine disrupting chemicals influencing NRF1 regulated gene networks in the development of complex human brain diseases. Int J Mol Sci. 2016;17(12):1-62. [Crossref]  [PMC] 
  13. Moosa A, Shu H, Sarachana T, Hu VW. Are endocrine disrupting compounds environmental risk factors for autism spectrum disorder? Horm Behav. 2018;101:13-21. [Crossref]  [PubMed]  [PMC] 
  14. Kavlock RJ, Daston GR, DeRosa C, Fenner-Crisp P, Gray LE, Kaattari S, et al. Research needs for the risk assessment of health and environmental effects of endocrine disruptors: a report of the U.S. EPA-sponsored workshop. Environ Health Perspect. 1996;104 Suppl 4:715-40. [Crossref]  [PubMed]  [PMC] 
  15. Kortenkamp A, Martin O, Faust M, Evans R, McKinlay R, Orton F, et al. State of the art assessment of endocrine disrupters. Final Report Project. European Commission, Directorate-General for the Environment (Project Contract No.070307/2009/550687/SER/D3); 2011. p.135. http://ec.europa.eu/environment/chemicals/endocrine/pdf/sota_edc_final_report.pdf Erisim Tarihi: 01.05.2018.
  16. Solecki R, Kortenkamp A, Bergman A, Chahoud I, Degen GH, Dietrich D, et al. Scientific principles for the identification of endocrine-disrupting chemicals: a consensus statement. Arch Toxicol. 2017;91(2):1001-6. [Crossref]  [PubMed]  [PMC] 
  17. Cetinkaya S. [Endocrine disruptors and their effects on puberty]. Dicle Tip Dergisi. 2009;36(1):59-66.
  18. Goldman LR. New approaches for assessing the etiology and risk sor developmental abnormalities from chemical exposure. Reprod Toxicol. 1997;11(2-3):443-51. [Crossref] 
  19. Grun F, Blumberg B. Endocrine disruptors as obesogens. Mol Cell Endocrinol. 2009;304(1-2):19-29. [Crossref]  [PubMed]  [PMC] 
  20. Grun F. Obesogens. Cur Opin Endocr Diabetes Obes. 2010;17(5):453-9. [Crossref]  [PubMed] 
  21. Caliman FA, Gavrilescu M. Pharmaceuticals, personal care products and endocrine disrupting agents in the environment-a review. Clean-Soil Air Water. 2009;37(4-5):277-303. [Crossref] 
  22. Casals-Casas C, Desvergne B. Endocrine disruptors: from endocrine to metabolic disruption. Annu Rev Physiol. 2011;73:135-62. [Crossref]  [PubMed] 
  23. U.S. Food and Drug Administration (FDA). Bisphenol A (BPA): use in food contact application. http://www.fda.gov/NewsEvents/PublicHealthFocus/ucm064437. Access Date: 01.01.2018.
  24. Cichna-Markl M. Sample clean-up by sol-gel immunoaffinity chromatography for the determination of bisphenol A in food and urine. Methods. 2012;56(2):186-91. [Crossref]  [PubMed] 
  25. Zoeller RT, Bansal R, Parris C. Bisphenol-A, an environmental contaminant that acts as a thyroid hormone receptor antagonist in vitro, increases serum thyroxine, and alters rc3/neurogranin expression in the developing rat brain. Endocrinology. 2005;146(2):607-12. [Crossref]  [PubMed] 
  26. Vandenberg LN, Chahoud I, Heindel JJ, Padmanabhan V, Paumgartten FJ, Schoenfelder G. Urinary, circulating, and tissue biomonitoring studies indicate widespread exposure to bisphenol A. Environ Health Perspect. 2010;118(8):1055-70. [Crossref]  [PubMed]  [PMC] 
  27. Stahlhut RW, Welshons WV, Swan SH. Bisphenol A data in NHANES suggest longer than expected half-life, substantial nonfood exposure, or both. Environ Health Perspect. 2009;117(5):784-9. [Crossref]  [PubMed]  [PMC] 
  28. Xu XH, Zhang J, Wang YM, Ye YP, Luo QQ. Perinatal exposure to bisphenol-A impairs learning-memory by concomitant down-regulation of N-methyl-D-aspartate receptors of hippocampus in male offspring mice. Horm Behav. 2010;58(2):326-33. [Crossref]  [PubMed] 
  29. Saili KS, Corvi MM, Weber DN, Patel AU, Das SR, Przybyla J, et al. Neurodevelopmental low-dose bisphenol A exposure leads to early life-stage hyperactivity and learning deficits in adult zebrafish. Toxicology. 2012;291(1-3):83-92. [Crossref]  [PubMed]  [PMC] 
  30. Wolstenholme JT, Goldsby JA, Rissman EF. Transgenerational effects of prenatal bisphenol A on social recognition. Horm Behav. 2013;64(5):833-9. [Crossref]  [PubMed]  [PMC] 
  31. Wolstenholme JT, Edwards M, Shetty SR, Gatewood JD, Taylor JA, Rissman EF, et al. Gestational exposure to bisphenol A produces transgenerational changes in behaviors and gene expression. Endocrinology. 2012;153(8): 3828-38. [Crossref]  [PubMed]  [PMC] 
  32. Miyagawa K, Narita M, Narita M, Akama H, Suzuki T. Memory impairment associated with a dysfunction of the hippocampal cholinergic system induced by prenatal and neonatal exposures to bisphenol-A. Neurosci Lett. 2007;418(3):236-41. [Crossref]  [PubMed] 
  33. Narita M, Miyagawa K, Mizuo K, Yoshida T, Suzuki T. Prenatal and neonatal exposure to low-dose of bisphenol-A enhance the morphine-induced hyperlocomotion and rewarding effect. Neurosci Lett. 2006;402(3):249-52. [Crossref]  [PubMed] 
  34. Wolstenholme JT, Rissman EF, Connelly JJ. The role of bisphenol A in shaping the brain, epigenome and behavior. Horm Behav. 2011;59(3):296-305. [Crossref]  [PubMed]  [PMC] 
  35. Harley KG, Gunier RB, Kogut K, Johnson C, Bradman A, Calafat AM, et al. Prenatal and early childhood bisphenol A concentrations and behavior in school-aged children. Environ Res. 2013;126:43-50. [Crossref]  [PubMed]  [PMC] 
  36. 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] 
  37. 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] 
  38. 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] 
  39. 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] 
  40. Technical Briefing. Phthalates and Their Alternatives: Health and Environmental Concerns. Massachusetts Lowell: The Lowell Center for Sustainable Production at the University of Massachusetts Lowell; 2011. p.21. http://ec.europa.eu/environment/aarhus/pdf/35/Annex_11_report_from_Lowell_Center.pdf. Access date: 02.05.2018.
  41. Wittassek M, Angerer J. Phthalates: metabolism and exposure. Int Androl. 2008;31(2):131-8. [Crossref]  [PubMed] 
  42. Zhang Y, Lin L, Cao Y, Chen B, Zheng L, Ge RS. Phthalate levels and low birth weight: a nested case-control study of Chinese newborns. J Pediatr. 2009;15(4):500-4. [Crossref]  [PubMed] 
  43. Albro PW, Corbett JT, Schroeder JL Jordan S, Matthews HB. Pharmacokinetics, interactions with macromolecules and species differences in metabolism of DEHP. Environ Health Perspect. 1982;45:19-25. [Crossref]  [PubMed]  [PMC] 
  44. Li L, Zhang T, Qin XS, Ge W, Ma HG, Sun LL, et al. Exposure to diethylhexyl phthalate (DEHP) results in a heritable modification of imprint genes DNA methylation in mouse oocytes. Mol Biol Rep. 2014;41(3):1227-35. [Crossref]  [PubMed] 
  45. Li Y, Zhuang M, Li T, Shi N. Neurobehavioral toxicity study of dibutyl phthalate on rats following in utero and lactational exposure. J Appl Toxicol. 2009;29(7):603-11. [Crossref]  [PubMed] 
  46. Tanaka T. Reproductive and neurobehavioural effects of bis (2-ethylhexyl) phthalate (DEHP) in a cross-mating toxicity study of mice. Food Chem Toxicol. 2005;43(4):581-9. [Crossref]  [PubMed] 
  47. Ishido M, Masuo Y, Sayato-Suzuki J, Oka S, Niki E, Morita M. Dicyclohexylphthalate causes hyperactivity in the rat concomitantly with impairment of tyrosine hydroxylase immunoreactivity. J Neurochem. 2004;91(1):69-76. [Crossref]  [PubMed] 
  48. Hoshi H, Ohtsuka T. Adult rats exposed to low-doses of di-n-butyl phthalate during gestation exhibit decreased grooming behavior. Bull Environ Contam Toxicol. 2009;83(1):62-6. [Crossref]  [PubMed] 
  49. Yolton K, Xu Y, Strauss D, Altaye M, Calafat AM, Khoury J. Prenatal exposure to bisphenol A and phthalates and infant neurobehavior. Neurotoxicol Teratol. 2011;33(5):558-66. [Crossref]  [PubMed]  [PMC] 
  50. Engel SM, Miodovnik A, Canfield RL, Zhu C, Silva MJ, Calafat AM, et al. Prenatal phthalate exposure is associated with childhood behavior and executive functioning. Environ Health Perspect. 2010;118(4):565-71. [Crossref]  [PubMed]  [PMC] 
  51. Cho SC, Bhang SY, Hong YC, Shin MS, Kim BN, Kim JW, et al. Relationship between environmental phthalate exposure and the intelligence of school-aged children. Environ Health Perspect. 2010;118(7):1027-32. [Crossref]  [PubMed]  [PMC] 
  52. Kim BN, Cho SC, Kim Y, Shin MS, Yoo HJ, Kim JW, et al. Phthalates exposure and attention-deficit/hyperactivity disorder in school-age children. Biol Psychiatry. 2009;66(10):958-63. [Crossref]  [PubMed] 
  53. 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] 
  54. 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] 
  55. Braun JM, Kalkbrenner AE, Just AC, Yolton K, Calafat AM, Sjodin A, et al. Gestational exposure to endocrine-disrupting chemicals and reciprocal social, repetitive, and stereotypic behaviors in 4- and 5-year-old children: the HOME study. Environ Health Perspect. 2014;122(5):513-20. [Crossref]  [PubMed]  [PMC] 
  56. de Cock M, Maas YG, van de Bor M. Does perinatal exposure to endocrine disruptors induce autism spectrum and attention deficit hyperactivity disorders? Review. Acta Paediatr. 2012;101(8):811-8. [Crossref]  [PubMed] 
  57. Pessah IN, Seegal RF, Lein PJ, LaSalle J, Yee BK, Van De Water J, et al. Immunologic and neurodevelopmental susceptibilities of autism. Neurotoxicology. 2008;29(3):532-45. [Crossref]  [PubMed]  [PMC] 
  58. Wells PG, Mackenzie PI, Chowdhury JR, Guillemette C, Gregory PA, Ishii Y, et al. Glucuronidation and the UDP-glucuronosyltransferases in health and disease. Drug Metab Dispos. 2004;32(3):281-90. [Crossref]  [PubMed] 
  59. Argikar UA, Iwuchukwu OF, Nagar S. Update on tools for evaluation of uridine diphosphoglucuronosyltransferase polymorphisms. Expert Opin Drug Metab Toxicol. 2008;4(7): 879-94. [Crossref]  [PubMed] 
  60. Stein TP, Schluter MD, Steer RA, Ming X. Autism and phthalate metabolite glucuronidation. Autism Dev Disord. 2013;43(11):2677-85. [Crossref]  [PubMed]  [PMC] 
  61. Baytok E, Bingol NT. [Dioxin: toxin entered in our table and life with our food]. YYU Vet Fak Derg. 2013;24(1):45-9.
  62. Yalcin H. [Dioxin and polychlorinated biphenyls]. Turkiye Klinikleri J Food Hyg Technol-Special Topics. 2015;1(1):38-47.
  63. Artik N, Sanlier N, Ceyhun Sezgin A. [Foodborne diseases and risks in food safety]. Gida Guvenligi ve Mevzuati. 1. Baski. Ankara: Detay Yayincilik; 2017. p.133-75.
  64. Mimura J, Yamashita K, Nakamura K, Morita M, Takagi TN, Nakao K, et al. Loss of teratogenic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin TCDD in mice lacking the Ah (dioxin) receptor. Genes Cells. 1997;2(10):645-54. [Crossref]  [PubMed] 
  65. Hossain A, Tsuchiya S, Minegishi M, Osada M, Ikawa S, Tezuka FA, et al. The Ah receptor is not involved in 2,3,7,8-tetrachlorodibenzo- p-dioxin-mediated apoptosis in human leukemic T cell lines. J Biol Chem. 1998;273(31):19853-8. [Crossref]  [PubMed] 
  66. Ciftci O. [The investigation of effect mechanism, chemical structure and toxicokinetics properties of dioxins compounds]. Inonu Universitesi Tip Fakultesi Dergisi. 2010;17(4): 413-22.
  67. Nishijo M, Kuriwaki J, Hori E, Tawara K, Nakagawa H, Nishijo H. Effects of maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin on fetal brain growth and motor and behavioral development in offspring rats. Toxicol Lett. 2007;173(1):41-7. [Crossref]  [PubMed] 
  68. Nguyen AT, Nishijo M, Hori E, Nguyen NM, Pham TT, Fukunaga K, et al. Effects of maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin on socioemotional behaviors in offspring rats. Environ Health Insights. 2013;7:1-14. [Crossref]  [PubMed]  [PMC] 
  69. Weiss B. Vulnerability of children and the developing brain to neurotoxic hazards. Environ Health Perspect. 2000;108 Suppl 3:375-81. [Crossref]  [PubMed]  [PMC] 
  70. Tai PT, Nishijo M, Anh NT, Maruzeni S, Nakagawa H, Van Luong H, et al. Dioxin exposure in breast milk and infant neurodevelopment in Vietnam. Occup Environ Med. 2013;70(9): 656-62. [Crossref]  [PubMed] 
  71. Nishijo M, Tai PT, Nakagawa H, Maruzeni S, Anh NTN, Luong HV, et al. Impact of perinatal dioxin exposure on infant growth: a cross-sectional and longitudinal studies in dioxin-contaminated areas in Vietnam. PLoS One. 2012;7(7):e40273. [Crossref]  [PubMed]  [PMC] 
  72. Pham TT, Nishijo M, Nguyen ATN, Tran NN, Hoang LV, Tran AH, et al. Perinatal dioxin exposure and the neurodevelopment of Vietnamese toddlers at 1 year of age. Sci Total Environ. 2015;536:575-81. [Crossref]  [PubMed] 
  73. Nishijo M, Pham TT, Nguyen AT, Tran NN, Nakagawa H, Hoang LV, et al. 2,3,7,8-tetrachlorodibenzo-p-dioxin in breast milk increases autistic traits of 3-year-old children in Vietnam. Mol Psychiatry. 2014;19(11):1220-6. [Crossref]  [PubMed] 
  74. Koopman-Esseboom C, Weisglas-Kuperus N, de Ridder MA, Van der Paauw CG, Tuinstra LG, Sauer PJ. Effects of polychlorinated biphenyl/dioxin exposure and feeding type on infants' mental and psychomotor development. Pediatrics. 1996;97(5):700-6.
  75. Nakajima S, Saijo Y, Kato S, Sasaki S, Uno A, Kanagami N, et al. Effects of prenatal exposure to polychlorinated biphenyls and dioxins on mental and motor development in Japanese children at 6 months of age. Environ Heath Perspect. 2006;114(5):773-8. [Crossref]  [PubMed]  [PMC] 
  76. Tran NN, Pham TT, Ozawa K, Nishijo M, Nguyen AT, Tran TQ, et al. Impacts of perinatal dioxin exposure on motor coordination and higher cognitive development in Vietnamese preschool children: a five-year follow-up. PLoS One. 2016;11(1):e0147655. [Crossref]  [PubMed]  [PMC] 
  77. Hays LE, Carpenter CD, Petersen SL. Evidence that GABAergic neurons in the preoptic area of the rat brain are targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin during development. Environ Health Perspect. 2002;110 Suppl 3:369-76. [Crossref]  [PubMed]  [PMC] 
  78. Shibamoto T, Bjeldanes L. Food contaminants from industrial wastes. In: Taylor SL, ed. Introduction to Food Toxicology. 2nd ed. Cambridge, Massachusetts: Academic Press; 2009. p.181-206.
  79. Balci A, Erkekoglu P, Kocer Gumusel B. [Evaluation of relationship between obesity and endocrine disrupting chemicals-II: polychlorinated biphenyls: review]. Turkiye Klinikleri J Pharm Sci. 2015;4(2):50-67. [Crossref] 
  80. Ahlborg UG, Beck H, Berg M, Birnbaum LS, Dybing E, Hagenmaier H, et al. Air Quality Guidelines-Polychlorinated biphenyls (PCBs). 2nd ed. Copenhagen, Denmark: WHO Regional Office for Europe; 2000. p.1-22. http://apps.who.int/iris/bitstream/handle/10665/107335/E71922.pdf;jsessionid=B64A61E17120428852A91FE9B8E97663?sequence=1. Access Date: 05.05.2018.
  81. Topfer K. Guidelines for the Indentification of PCBs and Materials Containing PCBs. UNEP Chemicals. Geneva, Switzerland: United Nations Environment Programme; 1999. p.40.
  82. Carpenter DO. Polychlorinated biphenyls and human health. Int J Occup Med Environ Health. 1998;11(4):291-303.
  83. 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] 
  84. Boix J, Cauli O. Alteration of serotonin system by polychlorinated biphenyls exposure. Neurochem Int. 2012;60(8):809-16. [Crossref]  [PubMed] 
  85. Plusquellec P, Muckle G, Dewailly E, Ayotte P, Begin G, Desrosiers C, et al. The relation of environmental contaminants exposure to behavioral indicators in Inuit preschoolers in Arctic Quebec. Neurotoxicology. 2010;31(1): 17-25. [Crossref] 
  86. DeSoto MC. Ockham's Razor and autism: the case for developmental neurotoxins contributing to a disease of neurodevelopment. Neurotoxicology. 2009;30(3):331-7. [Crossref]  [PubMed] 
  87. Jarup L. Hazards of heavy metal contamination. Br Med Bull. 2003;68:167-82. [Crossref]  [PubMed] 
  88. Jaishankar M, Mathew BB, Shah MS, Murthy K, Gowda KRS. Biosorption of few heavy metal ions using agricultural wastes. Journal of Environment Pollution and Human Health. 2014;2(1):1-6.
  89. Nagajyoti PC, Lee KD, Sreekanth TVM. Heavy metals, occurrence and toxicity for plants: a review. Environ Chem Lett. 2010;8(3):199-216. [Crossref] 
  90. Jaishankar M, Tseten T, Anbalagan N, Mathew BB, Beeregowda KN. Toxicity, mechanism and health effects of some heavy metals. Interdiscip Toxicol. 2014;7(2):60-72. [Crossref]  [PubMed]  [PMC] 
  91. Guha Mazumder DN. Chronic arsenic toxicity & human health. Indian J Med Res. 2008;128(4):436-47.
  92. Saha JC, Dikshit AK, Bandyopadhyay M, Saha KC. A review of arsenic poisoning and its eff ects on human health. Crit Rev Env Sci Technol. 1999;29(3):281-313. [Crossref] 
  93. Sharma P, Dubey RS. Lead toxicity in plants. Brazilian Journal of Plant Physiology. 2005;17(1):35-52. [Crossref] 
  94. Thurmer K, Williams E, Reutt-Robey J. Autocatalytic oxidation of lead crystallite surfaces. Science. 2002;297(5589):2033-5. [Crossref]  [PubMed] 
  95. Ayaz A. Yurttagul M. Cevresel kirleticiler. Besinlerdeki Toksik Ogeler II. 2. Baski. Ankara: Saglik Bakanligi Yayinlari; 2012. p.8-13.
  96. Chen CW, Chen CF, Dong CD. Distribution and accumulation of mercury in sediments of Kaohsiung River Mouth, Taiwan. APCBEE Procedia. 2012;1:153-8. [Crossref] 
  97. Turkozu D, Sanlier N. [Current overview: heavy metal contamination of food]. Selcuk Tarim ve Gida Bilimleri Dergisi. 2012;26(4):73-80.
  98. Sharma SK, Goloubinoff P, Christen P. Heavy metal ions are potent inhibitors of protein folding. Biochem Biophys Res Commun. 2008;372(2):341-5. [Crossref]  [PubMed] 
  99. Iavicoli I, Fontana L, Bergamaschi A. The effects of metals as endocrine disruptors. J Toxicol Environ Health B Crit Rev. 2009;12(3):206-23. [Crossref]  [PubMed] 
  100. Hu H, Tellez-Rojo MM, Bellinger D, Smith D, Ettinger AS, Lamadrid-Figueroa H, et al. Fetal lead exposure at each stage of pregnancy as a predictor of infant mental development. Environ Health Perspect. 2006;114(11):1730-5. [Crossref]  [PubMed]  [PMC] 
  101. 1.World Health Organization (WHO). State of the Science of Endocrine Disrupting Chemicals-2012. Geneva: WHO Press; p.296. http://www.who.int/ceh/publications/endocrine/en/. Access Date: 01.01.2018.
  102. James SJ, Melnyk S, Jernigan S, Cleves MA, Halsted CH, Wong DH, et al. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet. 2006;141B(8):947-56. [Crossref]  [PMC] 
  103. James SJ, Melnyk S, Fuchs G, Reid T, Jernigan S, Pavliv O, et al. Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism. Am J Clin Nutr. 2009;89(1):425-30. [Crossref]  [PubMed]  [PMC] 
  104. Adams JB, Romdalvik J, Levine KE, Hu LW. Mercury in first-cut baby hair of children with autism versus typically-developing children. Toxicol Environ Chem. 2008;90(4):739-53. [Crossref] 
  105. El Baz Mohamed F, Zaky EA, Bassuoni El-Sayed A, Elhossieny RE, Zahra SS, Eldin WS, 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;3:1-9. [Crossref]  [PubMed]  [PMC] 
  106. Dickerson AS, Rahbar MH, Bakian AV, Bilder DA, Harrington RA, Pettygrove S, et al. Autism spectrum disorder prevalence and associations with air concentrations of lead, mercury, and arsenic. Environ Monit Assess. 2016;188(7):407. [Crossref]  [PubMed] 
  107. Kim KN, Kwon HJ, Hong YC. Low-level lead exposure and autistic behaviors in school-age children. Neurotoxicology. 2016;53:193-200. [Crossref]  [PubMed] 
  108. Mostafa GA, Bjorklund G, Urbina MA, Al-Ayadhi LY. The positive association between elevated blood lead levels and brain-specific autoantibodies in autistic children from low lead-polluted areas. Metab Brain Dis. 2016;31(5):1047-54. [Crossref]  [PubMed] 

.: Up To Date

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