Journal of Literature Pharmacy Sciences

Ağır Metallerin Endokrin Bozucu Etkileri
The Endocrine Disrupting Effects of Heavy Metals
Selinay Başak ERDEMLİ KÖSEa,b, Aylin BALCIa, Pınar ERKEKOĞLUa
aFarmasötik Toksikoloji AD, Hacettepe Üniversitesi Eczacılık Fakültesi, Ankara, TÜRKİYE
bKimya Bölümü, Burdur Mehmet Akif Ersoy Üniversitesi Fen-Edebiyat Fakültesi, Burdur, TÜRKİYE
J Lit Pharm Sci. 2019;8(2):147-62
doi: 10.5336/pharmsci.2019-65353
Article Language: TR
Full Text
ÖZET
Kimyasal özellikleri ve biyolojik işlevleri açısından oldukça farklılık gösteren ağır metaller; toprak erozyonu, yer kabuğundaki doğal ayrışmalar, madencilik, endüstriyel ve kentsel atık sular, kanalizasyon deşarjı, bitkilere uygulanan pestisit veya insektisitler gibi pek çok kaynaktan çevreye yayılabilmektedirler. Doğada kalıcılıkları yüksektir; bu nedenle topraklarda ve bitkilerde birikmektedirler. Ağır metaller önemli çevresel kirleticilerdir ve bunların toksisitesi ekolojik, evrimsel, besinsel ve çevresel nedenlerden dolayı ciddi bir halk sağlığı problemi olarak kabul edilmektedir. Çalışmalar, ağır metallerin spesifik hücresel yolaklar üzerinden endokrin bozucu maddeler olarak hareket edebileceğine dair çok sayıda kanıt ortaya koymaktadır. Yapılan çalışmalarda, ağır metal maruziyetine bağlı olarak erkek üreme sisteminde bozukluklar (sperm parametrelerinde ve testis dokusunda hasar, spermatogenezin bozulması, plazma üreme hormon düzeylerinde değişiklikler), dişi üreme sisteminde bozukluklar (yumurtalık doku hasarı, üreme hormon düzey değişimleri, spontan düşük ve ölü doğum riski ve doğan yavrularda anomaliler), erken ya da geç ergenlik, tiroid hormon düzeylerinde değişim ve nöroendokrin sistemde ters etkiler gibi önemli toksik etkilerin görülebileceği sonucuna varılmıştır. Bu çalışmada, literatürdeki in vitro ve in vivo araştırmalar ışığında ağır metallerin endokrin bozucu etkileri sunulması amaçlanmıştır.

Anahtar Kelimeler: Ağır metaller; endokrin bozucular; kadmiyum; arsenik; kurşun; cıva
ABSTRACT
Heavy metals, which differ considerably in terms of their chemical properties and biological functions, can spread to the environment from many sources such as soil erosion, natural disintegration in the earth's crust, mining, industrial and urban wastewater, sewage discharge, pesticides applied to plants and insecticides. Their permanence in nature is high and they accumulate in soils and plants. Heavy metals are important environmental pollutants and their toxicity is considered to be a serious public health problem due to ecological, evolutionary, nutritional and environmental reasons. Studies have shown a great deal of evidence that heavy metals can act as endocrine disrupters through specific cellular pathways. According to the studies, it has been concluded that important toxic effects such as anomalies in male reproductive system (Damage in sperm parameters and testis tissue, changes in spermatogenesis, changes in plasma reproductive hormone levels), disorders in female reproductive system (Ovarian tissue damage, reproductive hormone level changes, spontaneous abortion, abnormalities in the offspring and stillbirth risk), early or late adolescence, changes in thyroid hormone levels and adverse effects in neuroendocrine system can be seen due to heavy metal exposures. In this review, it is aimed to present the endocrine disrupting effects of heavy metals in the light of in vitro and in vivo studies.

Keywords: Heavy metals; endocrine disruptors; cadmium; arsenic; lead; mercury
REFERENCES:
  1. Sharma RK, Agrawal M. Biological effects of heavy metals: an overview. J Environ Biol. 2005;26(2 Suppl):301-13.
  2. Dyer CA. Heavy metals as endocrine-disrupting chemicals. In: Gore AC, ed. EndocrineDisrupting Chemicals: From Basic Research to Clinical Practice. 1st ed. Totowa, New Jersey: Humana Press Inc; 2007. p.111-33. [Crossref]
  3. 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]
  4. Rana SV. Perspectives in endocrine toxicity of heavy metals--a review. Biol Trace Elem Res. 2014;160(1):1-14. [Crossref] [PubMed]
  5. Zoeller RT, Brown TR, Doan LL, Gore AC, Skakkebaek NE, Soto AM, et al. Endocrinedisrupting chemicals and public health protection: a statement of principles from The Endocrine Society. Endocrinology. 2012;153 (9):4097-110. [Crossref] [PubMed] [PMC]
  6. Georgescu B, Georgescu C, Dărăban S, Bouaru A, Paşcalău S. Heavy metals acting as endocrine disrupters. Animal Science and Biotechnologies. 2011;44(2):89-93.
  7. Alsberg CL, Schwartze EW. Pharmacological action of Cd. Pharmacology. 1919;13:504-9.
  8. Yang JM, Arnush M, Chen QY, Wu XD, Pang B, Jiang XZ. Cadmium-induced damage to primary cultures of rat Leydig cells. Reprod Toxicol. 2003;17(5):553-60. [Crossref]
  9. Laskey JW, Phelps PV. Effect of cadmium and other metal cations on in vitro Leydig cell testosterone production. Toxicol Appl Pharmacol. 1991;108(2):296-306. [Crossref]
  10. 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]
  11. Martínez-Campa C, Alonso-González CA, Mediavilla MD, Cos S, González A, Ramons S, et al. Melatonin inhibits both ER activation and breast cancer cell proliferation induced by a metalloestrogen, cadmium. J Pineal Res. 2006;40(4):291-6. [Crossref] [PubMed]
  12. Beyersmann D, Hechtenberg S. Cadmium, gene regulation, and cellular signaling in mammalian cells. Toxicol Appl Pharmacol. 1997;144(2):247-61. [Crossref] [PubMed]
  13. Wilson VS, Bobseine K, Gray LE Jr. Development and characterization of a cell line that stably expresses an estrogen-responsive luciferase reporter for the detection of estrogen receptor agonist and antagonists. Toxicol Sci. 2004;81(1):69-77. [Crossref]
  14. Garcia-Morales P, Saceda M, Kenney N, Kim N, Salomon DS, Gottardis MM, et al. Effect of cadmium on estrogen receptor levels and estrogen-induced responses in human breast cancer cells. J Biol Chem. 1994;269(24): 16896-901.
  15. Piasek M, Laskey JW. Effects of in vitro cadmium exposure on ovarian steroidogenesis in rats. J Appl Toxicol. 1999;19(3):211-7. [Crossref]
  16. Benoff S, Jacob A, Hurley IR. Male infertility and environmental exposure to lead and cadmium. Hum Reprod Update. 2000;6(2):107-21. [Crossref] [PubMed]
  17. Thompson J, Bannigan J. Cadmium: toxic effects on the reproductive system and the embryo. Reprod Toxicol. 2008;25(3):304-15. [Crossref] [PubMed]
  18. Hew KW, Ericson WA, Welsh MJ. A single low cadmium dose causes failure of spermiation in the rat. Toxicol Appl Pharmacol. 1993;121 (1):15-21. [Crossref] [PubMed]
  19. Xu LC, Wang SY, Yang XF, Wang XR. Effects of cadmium on rat sperm motility evaluated with computer assisted sperm analysis. Biomed Environ Sci. 2001;14(4):312-7.
  20. Laskey JW, Rehnberg GL, Laws SC, Hein JF. Reproductive effects of low acute doses of cadmium chloride in adult male rats. Toxicol Appl Pharmacol. 1984;73(2):250-5. [Crossref]
  21. Benoff S, Auborn K, Marmar JL, Hurley IR. Link between low-dose environmentally relevant cadmium exposures and asthenozoospermia in a rat model. Fertil Steril. 2008;89(2 Suppl):e73-9. [Crossref] [PubMed] [PMC]
  22. Wirth JJ, Mijal RS. Adverse effects of low level heavy metal exposure on male reproductive function. Syst Biol Reprod Med. 2010;56(2): 147-67. [Crossref] [PubMed]
  23. Phelps PV, Laskey JW. Comparison of agerelated changes in in vivo and in vitro measures of testicular steroidogenesis after acute cadmium exposure in the Sprague-Dawley rat. J Toxicol Environ Health. 1989;27(1):95-105. [Crossref] [PubMed]
  24. Lafuente A, Márquez N, Pérez-Lorenzo M, Pazo D, Esquifino AI. Cadmium effects on hypothalamic-pituitary-testicular axis in male rats. Exp Biol Med (Maywood). 2001;226(6): 605-11. [Crossref] [PubMed]
  25. Henson MC, Chedrese PJ. Endocrine disruption by cadmium, a common environmental toxicant with paradoxical effects on reproduction. Exp Biol Med (Maywood). 2004;229(5): 383-92. [Crossref] [PubMed]
  26. Saksena SK. Cadmium: its effects on ovulation, egg transport and pregnancy in the rabbit. Contraception. 1997;26(2):181-92. [Crossref]
  27. Barański B. Effect of cadmium on prenatal development and on tissue cadmium, copper, and zinc concentrations in rats. Environ Res. 1987;42(1):54-62. [Crossref]
  28. Zeng X, Jin T, Zhou Y, Nordberg GF. Changes of serum sex hormone levels and MT mRNA expression in rats orally exposed to cadmium. Toxicology. 2003;186(1-2):109-18. [Crossref]
  29. Lafuente A, Márquez N, Pérez-Lorenzo M, Pazo D, Esquifino AI. Pubertal and postpubertal cadmium exposure differentially affects the hypothalamic-pituitary-testicular axis function in the rat. Food Chem Toxicol. 2000; 38(10):913-23. [Crossref]
  30. Johnson MD, Kenney N, Stoica A, HilakiviClarke L, Singh B, Chepko G, et al. Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland. Nat Med. 2003;9(8):1081-4. [Crossref] [PubMed]
  31. Lafuente A, Cano P, Esquifino A. Are cadmium effects on plasma gonadotropins, prolactin, ACTH, GH and TSH levels, dosedependent? Biometals. 2003;16(2):243-50. [Crossref] [PubMed]
  32. Piasek M, Laskey JW. Acute cadmium exposure and ovarian steroidogenesis in cycling and pregnant rats. Reprod Toxicol. 1994;8(6):495-507. [Crossref]
  33. Paksy K, Rajczy K, Forgács Z, Lázár P, Bernard A, Gáti I, et al. Effect of cadmium on morphology and steroidogenesis of cultured human ovarian granulosa cells. J Appl Toxicol. 1997;17(5):321-7. [Crossref]
  34. ATSDR. Toxicological profile for Cadmium. US Department of Health and Human Services. Public Health Service, Atlanta, GA, USA, 2012. p487. (Erişim: 01.01.2019). [Link]
  35. Xu B, Chia SE, Tsakok M, Ong CN. Trace elements in blood and seminal plasma and their relationship to sperm quality. Reprod Toxicol. 1993;7(6):613-8. [Crossref]
  36. Chia SE, Ong CN, Lee ST, Tsakok FH. Blood concentrations of lead, cadmium, mercury, zinc, and copper and human semen parameters. Arch Androl. 1992;29(2):177-83. [Crossref] [PubMed]
  37. Akinloye O, Arowojolu AO, Shittu OB, Anetor JI. Cadmium toxicity: a possible cause of male infertility in Nigeria. Reprod Biol. 2006;6(1):1730.
  38. Pant N, Banerjee AK, Pandey S, Mathur N, Saxena DK, Srivastava SP. Correlation of lead and cadmium in human seminal plasma with seminal vesicle and prostatic markers. Hum Exp Toxicol. 2003;22(3):125-8. [Crossref] [PubMed]
  39. Jurasović J, Cvitković P, Pizent A, Colak B, Telisman S. Semen quality and reproductive endocrine function with regard to blood cadmium in Croation male subjects. Biometals. 2004;17(6):735-43. [Crossref] [PubMed]
  40. Meeker JD, Rossano MG, Protas B, Diamond MP, Puscheck E, Daly D, et al. Cadmium, lead, and other metals in relation to semen quality: human evidence for molybdenum as a male reproductive toxicant. Environ Health Perspect. 2008;116(11):1473-9. [Crossref] [PubMed] [PMC]
  41. Telisman S, Cvitković P, Jurasović J, Pizent A, Gavella M, Rocić B. Semen quality and reproductive endocrine function in relation to biomarkers of lead, cadmium, zinc, and copper in men. Environ Health Perspect. 2000; 108(1):45-53. [Crossref] [PubMed] [PMC]
  42. Zeng X, Jin T, Zhou Y, Kong Q. Alterations of serum hormone levels in male workers occupationally exposed to cadmium. J Toxicol Environ Health A. 2002;65(7):513-21. [Crossref] [PubMed]
  43. Nagata C, Nagao Y, Shibuya C, Kashiki Y, Shimizu H. Urinary cadmium and serum levels of estrogens and androgens in postmenopausal Japanese women. Cancer Epidemiol Biomarkers Prev. 2005;14(3):705-8. [Crossref] [PubMed]
  44. Davey JC, Bodwell JE, Gosse JA, Hamilton JW. Arsenic as an endocrine disruptor: effects of arsenic on estrogen receptor-mediated gene expression ın vivo and in cell culture. Toxicol Sci. 2007;98(1):75-86. [Crossref] [PubMed]
  45. Chow SK, Chan JY, Fung KP. Suppression of cell proliferation and regulation of estrogen receptor signal pathway by arsenic trioxide on human breast cancer MCF-7 cells. J Endocrinol. 2004;182(2):325-37. [Crossref] [PubMed]
  46. Lopez S, Miyashita Y, Simons SS Jr. Structurally based, selective interaction of arsenite with steroid receptors. J Biol Chem. 1990;265(27):16039-42.
  47. Kaltreider RC, Davis AM, Lariviere JP, Hamilton JW. Arsenic alters the function of the glucocorticoid receptor as a transcription factor. Environ Health Perspect. 2001;109(3):245-51. [Crossref] [PubMed] [PMC]
  48. Kitchin KT, Wallace K. Arsenite binding to synthetic peptides based on the Zn finger region and the estrogen binding region of the human estrogen receptorα. Toxicol Appl Pharmacol. 2005;206(1):66-72. [Crossref] [PubMed]
  49. Pant N, Kumar R, Murthy RC, Srivastava SP. Male reproductive effect of arsenic in mice. Biometals. 2001;14(2):113-7. [Crossref] [PubMed]
  50. Chiou TJ, Chu ST, Tzeng WF, Huang YC, Liao CJ. Arsenic trioxide impairs spermatogenesis via reducing gene expression levels in testosterone synthesis pathway. Chem Res Toxicol. 2008;21(8):1562-9. [Crossref] [PubMed]
  51. Chang SI, Jin B, Youn P, Park C, Park JD, Ryu DY. Arsenic-induced toxicity and the protective role of ascorbic acid in mouse testis. Toxicol Appl Pharmacol. 2007;218(2):196-203. [Crossref] [PubMed]
  52. Biswas S, Talukder G, Sharma A. Prevention of cytotoxic effects of arsenic by short-term dietary supplementation with selenium in mice in vivo. Mutat Res. 1999;441(1):155-60. [Crossref]
  53. Jana K, Jana S, Samanta PK. Effects of chronic exposure to sodium arsenite on hypothalamopituitary-testicular activities in adult rats: possible an estrogenic mode of action. Reprod Biol Endocrinol. 2006;4:9. [Crossref] [PubMed] [PMC]
  54. Sarkar M, Chaudhuri GR, Chattopadhyay A, Biswas NM. Effect of sodium arsenite on spermatogenesis, plasma gonadotrophins and testosterone in rats. Asian J Androl. 2003;5(1):27-31.
  55. Waalkes MP, Keefer LK, Diwan BA. Induction of proliferative lesions of the uterus, testes, and liver in swiss mice given repeated injections of sodium arsenate: possible estrogenic mode of action. Toxicol Appl Pharmacol. 2000;166(1):24-35. [Crossref] [PubMed]
  56. Waalkes MP, Ward JM, Liu J, Diwan BA. Transplacental carcinogenicity of inorganic arsenic in the drinking water: induction of hepatic, ovarian, pulmonary, and adrenal tumors in mice. Toxicol Appl Pharmacol. 2003;186(1): 7-17. [Crossref]
  57. Chattopadhyay S, Ghosh S, Chaki S, Debnath J, Ghosh D. Effect of sodium arsenite on plasma levels of gonadotrophins and ovarian steroidogenesis in mature albino rats: duration-dependent response. J Toxicol Sci. 1999;24(5):425-31. [Crossref] [PubMed]
  58. Meeker JD, Rossano MG, Protas B, Padmanahban V, Diamond MP, Puscheck E, et al. Environmental exposure to metal and male reproductive hormones: circulating testosterone is inversely associated with blood molybdenum. Fertil Steril. 2010;93(1):130-40. [Crossref] [PubMed] [PMC]
  59. Tabacova S, Baird DD, Balabaeva L, Lolova D, Petrov I. Placental arsenic and cadmium in relation to lipid peroxides and glutathione levels in maternal-infant pairs from a copper smelter area. Placenta. 1994;15(8):873-81. [Crossref]
  60. Aschengrau A, Zierler S, Cohen A. Quality of community drinking water and the occurrence of spontaneous abortion. Arch Environ Health. 1989;44(5):283-90. [Crossref] [PubMed]
  61. Ihrig MM, Shalat SL, Baynes C. A hospitalbased case-control study of stillbirths and environmental exposure to arsenic using an atmospheric dispersion model linked to a geographical information system. Epidemiology. 1998;9(3):290-4. [Crossref] [PubMed]
  62. Clarkson TW. The three modern faces of mercury. Environ Health Perspect. 2002;110 Suppl 1:11-23. [Crossref] [PubMed] [PMC]
  63. Clarkson TW, Magos L. The toxicology of mercury and its chemical compounds. Crit Rev Toxicol. 2006;36(8):609-62. [Crossref] [PubMed]
  64. Tan SW, Meiller JC, Mahaffey KR. The endocrine effects of mercury in humans and wildlife. Crit Rev Toxicol. 2009;39(3):228-69. [Crossref] [PubMed]
  65. Ernst E, Møller-Madsen B, Danscher G. Ultrastructural demonstration of mercury in Sertoli and Leydig cells of the rat following methyl mercuric chloride or mercuric chloride treatment. Reprod Toxicol. 1991;5(3):205-9. [Crossref]
  66. Lee IP, Dixon RL. Effects of mercury on spermatogenesis studied by velocity sedimentation cell separation and serial mating. J Pharmacol Exp Ther. 1975;194(1):171-81.
  67. Schuurs AH. Reproductive toxicity of occupational mercury. A review of the literature. J Dent. 1999;27(4):249-56. [Crossref]
  68. Monsees TK, Franz M, Gebhardt S, Winterstein U, Schill WB, Hayatpour J. Sertoli cells as a target for reproductive hazards. Andrologia. 2000;32(4-5):239-46. [Crossref] [PubMed]
  69. Rao MV, Gangadharan B. Antioxidative potential of melatonin against mercury induced intoxication in spermatozoa in vitro. Toxicol In Vitro. 2008;22(4):935-42. [Crossref] [PubMed]
  70. Arabi M, Heydarnejad MS. In vitro mercury ex posure on spermatozoa from normospermic individuals. Pak J Biol Sci. 2007;10(15):2448-53. [Crossref] [PubMed]
  71. Choe SY, Kim SJ, Kim HG, Lee JH, Choi Y, Lee H, et al. Evaluation of estrogenicity of major heavy metals. Sci Total Environ. 2003;312(1-3):15-21. [Crossref]
  72. Sukocheva OA, Yang Y, Gierthy JF, Seegal RF. Methyl mercury influences growth-related signaling in MCF-7 breast cancer cells. Environ Toxicol. 2005;20(1):32-44. [Crossref] [PubMed]
  73. Gierthy JF, Lincoln DW 2nd, Roth KE, Bowser SS, Bennett JA, Bradley L, et al. Estrogen stimulation of postconfluent cell accumulation and foci formation of human MCF-7 breast cancer cells. J Cell Biochem. 1991;45(2):177-87. [Crossref] [PubMed]
  74. Chowdhury AR, Vachhrajani KD, Chatterjee BB. Inhibition of 3 beta-hydroxy-delta 5-steroid dehydrogenase in rat testicular tissue by mercuric chloride. Toxicol Lett. 1985;27(1-3):45-9. [Crossref]
  75. Vachhrajani KD, Chowdhury AR. Distribution of mercury and evaluation of testicular steroidogenesis in mercuric chloride and methylmercury administered rats. Indian J Exp Biol. 1990;28(8):746-51.
  76. Ramalingam V, Vimaladevi V, Rajeswary S, Suryavathi V. Effect of mercuric chloride on circulating hormones in adult albino rats. J Environ Biol. 2003;24(4):401-4.
  77. Nagar RN, Bhattacharya L. Effect of mercuric chloride on testicular activities in mice, Musculus albinus. J Environ Biol. 2001;22(1):158.
  78. Rao MV, Sharma PS. Protective effect of vitamin E against mercuric chloride reproductive toxicity in male mice. Reprod Toxicol. 2001;15(6):705-12. [Crossref]
  79. Tong MH, Christenson LK, Song WC. Aberrant cholesterol transport and impaired steroidogenesis in Leydig cells lacking estrogen sulfotransferase. Endocrinology. 2004; 145(5):2487-97. [Crossref] [PubMed]
  80. Lamperti AA, Printz RH. Effects of mercuric chloride on the reproductive cycle of the female hamster. Biol Reprod. 1973;8(3):378-87. [Crossref] [PubMed]
  81. Davis BJ, Price HC, O?Connor RW, Fernando R, Rowland AS, Morgan DL. Mercury vapor and female reproductive toxicology. Toxicol Sci. 2001;59(2):291-6. [Crossref] [PubMed]
  82. Rignell-Hydbom A, Axmon A, Lundh T, Jönsson BA, Tiido T, Spano M. Dietary exposure to methyl mercury and PCB and the associations with semen parameters among Swedish fishermen. Environ Health. 2007;6:14. [Crossref] [PubMed] [PMC]
  83. Choy CM, Lam CW, Cheung LT, Briton-Jones CM, Cheung LP, Haines CJ. Infertility, blood mercury concentrations and dietary seafood consumption: a case-control study. BJOG. 2002;109(10):1121-5. [Crossref] [PubMed]
  84. Choy CM, Yeung QS, Briton-Jones CM, Cheung CK, Lam CW, Haines CJ. Relationship between semen parameters and mercury concentrations in blood and in seminal fluid from subfertile males in Hong Kong. Fertil Steril. 2002;78(2):426-8. [Crossref]
  85. Dickman MD, Leung CK, Leong MK. Hong Kong male subfertility links to mercury in human hair and fish. Sci Total Environ. 1998;214:165-74. [Crossref]
  86. Dickerson EH, Sathyapalan T, Knight R, Maguiness SM, Killick SR, Robinson J, et al. Endocrine disruptor & nutritional effects of heavy metals in ovarian hyperstimulation. J Assist Reprod Genet. 2011;28(12):1223-8. [Crossref] [PubMed] [PMC]
  87. Barregård L, Lindstedt G, Schütz A, Sällsten G. Endocrine function in mercury exposed chloralkali workers. Occup Environ Med. 1994;51(8):536-40. [Crossref] [PubMed] [PMC]
  88. Oken E, Radesky JS, Wright RO, Bellinger DC, Amarasiriwardena CJ, Kleinman KP, et al. Maternal fish intake during pregnancy, bloodmercury levels, and child cognition at age 3 years in a US cohort. Am J Epidemiol. 2008;167(10):1171-81. [Crossref] [PubMed] [PMC]
  89. Geier DA, Kern JK, Geier MR. A prospective study of prenatal mercury exposure from maternal dental amalgams and autism severity. Acta Neurobiol Exp (Wars). 2009;69(2):18997.
  90. Myers GJ, Thurston SW, Pearson AT, Davidson PW, Cox C, Shamlaye CF, et al. Postnatal exposure to methyl mercury from fish consumption: a review and new data from the Seychelles Child Development Study. Neurotoxicology. 2009;30(3):338-49. [Crossref] [PubMed] [PMC]
  91. Juberg DR, Kleiman CF, Kwon SC. Position paper of the American Council on Science and Health: lead and human health. Ecotoxicol Environ Saf. 1997;38(3):162-80. [Crossref] [PubMed]
  92. Pirkle JL, Kaufmann RB, Brody DJ, Hickman T, Gunter EW, Paschal DC. Exposure of the U.S. population to lead, 1991-1994. Environ Health Perspect. 1998;106(11):745-50. [Crossref] [PubMed] [PMC]
  93. Gittleman JL, Engelgau MM, Shaw J, Wille KK, Seligman PJ. Lead poisoning among battery reclamation workers in Alabama. J Occup Med. 1994;36(5):526-32.
  94. Taupeau C, Poupon J, Treton D, Brosse A, Richard Y, Machelon V. Lead reduces messenger RNA and protein levels of cytochrome P450 aromatase and estrogen receptor in human ovarian granulosa cells. Biol Reprod. 2003;68(6):1982-8. [Crossref] [PubMed]
  95. Srivastava V, Dearth RK, Hiney JK, Ramirez LM, Bratton GR, Dees WL. The effects of lowlevel Pb on steroidogenic acute regulatory protein (StAR) in the prepubertal rat ovary. Toxicol Lett. 2004;77(1):35-40. [Crossref] [PubMed]
  96. Sengupta P, Banerjee R, Nath S, Das S, Banerjee S. Metals and female reproductive toxicity. Hum Exp Toxicol. 2015;34(7):679-97. [Crossref] [PubMed]
  97. Wide M. Lead and development of the early embryo. In: Clarkson TW, Nordberg GF, Sager PR, eds. Reproductive and Developmental Toxicity of Metals. 1st ed. New York: Plenum Press; 1983. p.343-55. [Crossref]
  98. Wide M, Wide L. Estradiol receptor activity in uteri of pregnant mice given lead before implantation. Fertil Steril. 1980;34(5):503-8. [Crossref]
  99. Kimmel CA, Grant LD, Sloan CS, Gladen BC. Chronic low-level lead toxicity in the rat. I. Maternal toxicity and perinatal effects. Toxicol Appl Pharmacol. 1980;56(1):28-41. [Crossref]
  100. McGivern RF, Sokol RZ, Berman NG. Prenatal lead exposure in the rat during the third week of gestation: long-term behavioral, physiological, and anatomical effects associated with reproduction. Toxicol Appl Pharmacol. 1991;110(2):206-15. [Crossref]
  101. Sokol RZ, Madding CE, Swerdloff RS. Lead toxicity and the hypothalamic-pituitarytesticular axis. Biol Reprod. 1985;33(3):722-8. [Crossref] [PubMed]
  102. Thoreux-Manlay A, Vélez de la Calle JF, Olivier MF, Soufir JC, Masse R, Pinon-Lataillade G. Impairment of testicular endocrine function after lead intoxication in the adult rat. Toxicology. 1995;100(1-3):101-9. [Crossref]
  103. Marchlewicz M, Protasowicki M, Rózewicka L, Piasecka M, Laszczyńska M. Effect of longterm exposure to lead on testis and epididymis in rats. Folia Histochem Cytobiol. 1993;31(2): 55-62.
  104. Oldereid NB, Thomassen Y, Attramadal A, Olaisen B, Purvis K. Concentrations of lead, cadmium and zinc in the tissues of reproductive organs of men. J Reprod Fertil. 1993;99 (2):421-5. [Crossref] [PubMed]
  105. Nathan E, Huang HF, Pogach L, Giglio W, Bogden JD, Seebode J. Lead acetate does not impair secretion of Sertoli cell function marker proteins in the adult Sprague Dawley rat. Arch Environ Health. 1992;47(5): 370-5. [Crossref] [PubMed]
  106. Wiebe JP, Salhanick AI, Myer KI. On the mechanism of action of lead in the testis: in vitro suppression of FSH receptors, cyclic AMP and steroidogenesis. Life Sci. 1983;32 (17):1997-2005. [Crossref]
  107. Rodamilans M, Martinez-Osaba MJ, ToFigueras J, Rivera-Fillat F, Torra M, Pérez P, et al. Inhibition of intratesticular testosterone synthesis by inorganic lead. Toxicol Lett. 1988;42(3):285-90. [Crossref]
  108. Thoreux-Manlay A, Le Goascogne C, Segretain D, Jégou B, Pinon-Lataillade P. Lead affects steroidogenesis in rat Leydig cells in vivo and in vitro. Toxicology. 1995;103(1):53-62. [Crossref]
  109. Liu MY, Leu SF, Yang HY, Huang BM. Inhibitory mechanisms of lead on steroidogenesis in MA-10 mouse Leydig tumor cells. Arch Androl. 2003;49(1):29-38. [Crossref] [PubMed]
  110. Ronis MJ, Gandy J, Badger T. Endocrine mechanisms underlying reproductive toxicity in the developing rat chronically exposed to dietary lead. J Toxicol Environ Health A. 1998;54(2):77-99. [Crossref] [PubMed]
  111. Dearth RK, Hiney JK, Srivastava V, Burdick SB, Bratton GR, Dees WL. Effects of lead (Pb) exposure during gestation and lactation on female pubertal development in the rat. Reprod Toxicol. 2002;16(4):343-52. [Crossref]
  112. Iavicoli I, Carelli G, Stanek EJ, Castellino N, Li Z, Calabrese EJ. Low doses of dietary lead are associated with a profound reduction in the time to the onset of puberty in female mice. Reprod Toxicol. 2006;22(4):586-90. [Crossref] [PubMed]
  113. Foster WG. Reproductive toxicity of chronic lead exposure in the female cynomolgus monkey. Reprod Toxicol. 1992;6(2):123-31. [Crossref]
  114. Wiebe JP, Barr KJ, Buckingham KD. Effect of prenatal and neonatal exposure to lead on gonadotropin receptors and steroidogenesis in rat ovaries. J Toxicol Environ Health. 1988;24(4):461-76. [Crossref] [PubMed]
  115. Wide M. Lead exposure on critical days of fetal life affects fertility in the female mouse. Teratology. 1985;32(3):375-80. [Crossref] [PubMed]
  116. McMichael AJ, Vimpani GV, Robertson EF, Baghurst PA, Clark PD. The port pirie cohort study: maternal blood lead and pregnancy outcome. J Epidemiol Commun Health. 1986;40 (1):18-25. [Crossref] [PubMed] [PMC]
  117. Falcón M, Viñas P, Luna A. Placental lead and outcome of pregnancy. Toxicology. 2003;185(1-2):59-66. [Crossref]
  118. Hu H, Pepper L, Goldman R. Effect of repeated occupational exposure to lead, cessation of exposure, and chelation on levels of lead in bone. Am J Ind Med. 1991;20(6):723-35. [Crossref] [PubMed]
  119. Alexander BH, Checkoway H, van Netten C, Muller CH, Ewers TG, Kaufman JD, et al. Semen quality of men employed at a lead smelter. Occup Environ Med. 1996;53(6):411-6. [Crossref] [PubMed] [PMC]
  120. Alexander BH, Checkoway H, Faustman EM, van Netten C, Muller CH, Ewers TG. Contrasting associations of blood and semen lead concentrations with semen quality among lead smelter workers. Am J Ind Med. 1998;34(5): 464-9. [Crossref]
  121. Assennato G, Paci C, Baser ME, Molinini R, Candela RG, Altamura BM, et al. Sperm count suppression without endocrine dysfunction in lead-exposed men. Arch Environ Health. 1987;42(2):124-7. [Crossref] [PubMed]
  122. Eibensteiner L, Del Carpio Sanz A, Frumkin H, Gonzales C, Gonzales GF. Lead exposure and semen quality among traffic police in Arequipa, Peru. Int J Occup Environ Health. 2005;11(2):161-6. [Crossref] [PubMed]
  123. Gennart JP, Buchet JP, Roels H, Ghyselen P, Ceulemans E, Lauwerys R. Fertility of male workers exposed to cadmium, lead, or manganese. Am J Epidemiol. 1992;135(11):1208-19. [Crossref] [PubMed]
  124. Hu WY, Wu SH, Wang LL, Wang GI, Fan H, Liu ZM. A toxicological and epidemiological study on reproductive functions of male workers exposed to lead. J Hyg Epidemiol Microbiol Immunol. 1992;36(1):25-30.
  125. Lancranjan I, Popescu HI, Gavănescu O, Klepsch I, Serbănescu M. Reproductive ability of workmen occupationally exposed to lead. Arch Environ Health. 1975;30(8):396-401. [Crossref] [PubMed]
  126. Lerda D. Study of sperm characteristics in persons occupationally exposed to lead. Am J Ind Med. 1992;22(4):567-71. [Crossref] [PubMed]
  127. Plechaty MM, Noll B, Sunderman FW Jr. Lead concentrations in semen of healthy men without occupational exposure to lead. Ann Clin Lab Sci. 1977;7(6):515-8.
  128. Robins TG, Bornman MS, Ehrlich RI, Cantrell AC, Pienaar E, Vallabh J, et al. Semen quality and fertility of men employed in a South African lead acid battery plant. Am J Ind Med. 1997;32(4):369-76. [Crossref]
  129. Telisman S, Colak B, Pizent A, Jurasović J, Cvitković P. Reproductive toxicity of low-level lead exposure in men. Environ Res. 2007;105(2):256-66. [Crossref] [PubMed]
  130. Meeker JD, Rossano MG, Protas B, Diamond MP, Puscheck E, Daly D, et al. Multiple metals predict prolactin and thyrotropin (TSH) levels in men. Environ Res. 2009;109(7):869-73. [Crossref] [PubMed] [PMC]
  131. Selevan SG, Rice DC, Hogan KA, Euling SY, Pfahles-Hutchens A, Bethel J. Blood concentration and delayed puberty in girls. N Engl J Med. 2003;348(16):1527-36. [Crossref] [PubMed]
  132. Wu T, Buck GM, Mendola P. Blood lead levels and sexual maturation in U.S. girls: the Third Nation Health and Nutrition Examination Survey, 1988-1994. Environ Health Perspect. 2003;111(5):737-41. [Crossref] [PubMed] [PMC]
  133. Denham M, Schell LM, Deane G, Gallo MV, Ravenscroft J, DeCaprio AP, et al. Relationship of lead, mercury, mirex, dichlorodiphenyldichloroethylene, hexachlorobenzene, and polychlorinated biphenyls to timing of menarche among Akwesasne Mohawk girls. Pediatrics. 2005;115(2):e127-34. [Crossref] [PubMed]

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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