Journal of Literature Pharmacy Sciences

Bazı Çevresel Kirleticilerin Bağırsak Mikrobiyotası Üzerindeki Etkileri ve Toksikolojik Açıdan Değerlendirilmesi:Geleneksel Derleme
Toxicological Evaluation of Effects of Some Environmental Pollutants on Intestinal Microbiota: Traditional Review
Ekin ERDOĞMUŞa, Deniz ÖZKAN VARDARb , Gizem YILDIZTEKİNc, Belma KOÇER GÜMÜŞELa
aLokman Hekim Üniversitesi Eczacılık Fakültesi, Farmasötik Toksikoloji ABD, Ankara, Türkiye
bLokman Hekim Üniversitesi Sağlık Hizmetleri Meslek Yüksek Okulu, Eczane Hizmetleri, Ankara, Türkiye
cErzincan Binali Yıldırım Üniversitesi Eczacılık Fakültesi, Farmasötik Toksikoloji ABD, Erzincan, Türkiye
J Lit Pharm Sci. 2023;12(2):157-70
doi: 10.5336/pharmsci.2022-93493
Article Language: TR
Full Text
ÖZET
Bağırsak mikrobiyotası, insanların ve hayvanların sindirim kanallarında yaşayan çeşitli mikroorganizmaların bir araya gelmesi sonucu oluşan ve bakteri, virüs ile bazı ökaryotlar dâhil binlerce mikroorganizmayı içeren bir yapıdır. Bacteroidetes, Firmicutes, Proteobacteria ve Fusobacterianın baskın olarak bulunduğu bağırsak mikrobiyotası, konakçının genetiği ve beslenme şekline göre değişiklik göstermektedir. Bağırsak mikrobiyotasının insan metabolizması üzerinde birçok etkisinin olduğu; mikrobiyotanın bağırsak mukozal yüzeylerini kolonize ederek patojenlerden korunmayı desteklediği, bağışıklık sistemini güçlendirdiği, insülin direncini değiştirdiği ve insülinin salgılanmasını etkilediği bildirilmektedir. Metabolik ürünlerin birçoğu bağırsak mikrobiyomunda bulunan bakteriler tarafından üretildiği için mikrobiyomun değişmesi çeşitli hastalıklara sebep olabilmektedir. Endüstriyel ve tarımsal uygulamalar için kullanılan sentetik kimyasal maddeler çevrenin yaygın şekilde kirlenmesine yol açmaktadır. Bu çevresel kirleticilerin insan sağlığı üzerindeki etkilerinin araştırıldığı çok sayıda çalışma bulunmaktadır ve organizmada farklı hedef organların etkilendiği çalışmalar da rapor edilmiştir. Özellikle son yıllarda yapılan çalışmalarda, çevresel kirleticilerin bağırsak mikrobiyotası ile etkileşimine ve bu etkileşim sonucunda bağırsak mikrobiyomunun bileşiminin, enerji metabolizmasını, besin emilimi miktarını ve bağışıklık sistemi işlevlerini değiştirebileceğine, bununla birlikte toksik etkilerin oluşabileceğine işaret edilmektedir. Bu derleme kapsamında, sıklıkla maruz kalınabilen çevresel kirleticiler arasında yer alan pestisitler, ftalatlar ve bisfenol A'nın bağırsak mikrobiyotası üzerindeki etkilerini inceleyen in vivo ve in vitro çalışmalar araştırılmış; bu bileşiklerin mikrobiyotanın fonksiyonlarını ve yapısını ne şekilde etkilediği ile buna bağlı ortaya çıkabilecek istenmeyen etkileri değerlendirilmiştir.

Anahtar Kelimeler: Mikrobiyota; pestisit; bisfenol A; ftalat
ABSTRACT
The intestinal microbiota is a structure that is formed as a result of the combination of various microorganisms living in the digestive tracts of humans and animals and includes thousands of microorganisms, including bacteria, viruses, and some eukaryotes. Intestinal microbiota, in which Bacteroidetes, Firmicutes, Proteobacteria, and Fusobacteria are dominant, varies according to the genetics and diet of the host. The intestinal microbiota has many effects on human metabolism; It is reported that the microbiota supports protection from pathogens by colonizing intestinal mucosal surfaces, strengthens the immune system, changes insulin resistance, and affects insulin secretion. Since many of the metabolic products are produced by bacteria in the gut microbiome, changes in the microbiome can cause various diseases. Synthetic chemicals used for industrial and agricultural practices cause widespread environmental pollution. In many studies investigating the effects of environmental pollutants on human health, it has been reported in studies that different target organs in the organism are affected. Especially in recent studies, it has been pointed out that the interaction of environmental pollutants with the intestinal microbiota, and as a result of this interaction, the composition of the intestinal microbiome can change the energy metabolism, nutrient absorption amount and immune system functions, however toxic effects may occur. In this review, in vivo and in vitro studies examining the effects of pesticides, phthalates, and bisphenol A, which are among the environmental pollutants that can be frequently exposed to, on the intestinal microbiota were investigated. How the compounds affect the functions and structure of the microbiota and the undesirable effects that may arise due to this were evaluated.

Keywords: Microbiota; pesticide; bisphenol A; phthalates
REFERENCES:
  1. Passos MDCF, Moraes-Filho JP. Intestinal microbiota in digestive diseases. Arq Gastroenterol. 2017;54(3):255-62. [Crossref]  [PubMed] 
  2. Jethwani P, Grover K. Gut microbiota in health and diseases-A review. Int J Curr Microbiol Appl Sci. 2019;8(8):1586-99. [Crossref] 
  3. Nagpal R, Tsuji H, Takahashi T, Nomoto K, Kawashima K, Nagata S, et al. Ontogenesis of the gut microbiota composition in healthy, full-term, vaginally born and breast-fed infants over the first 3 years of life: a quantitative bird's-eye view. Front Microbiol. 2017;8:1388. [Crossref]  [PubMed]  [PMC] 
  4. Hasan N, Yang H. Factors affecting the composition of the gut microbiota, and its modulation. PeerJ. 2019;7:e7502. [Crossref]  [PubMed]  [PMC] 
  5. Thursby E, Juge N. Introduction to the human gut microbiota. Biochem J. 2017;474(11):1823-36. [Crossref]  [PubMed]  [PMC] 
  6. Louis P, Flint HJ. Formation of propionate and butyrate by the human colonic microbiota. Environ Microbiol. 2017;19(1):29-41. [Crossref]  [PubMed] 
  7. Perry RJ, Peng L, Barry NA, Cline GW, Zhang D, Cardone RL, et al. Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome. Nature. 2016;534(7606):213-7. [Crossref]  [PubMed]  [PMC] 
  8. Mills S, Stanton C, Lane JA, Smith GJ, Ross RP. Precision nutrition and the microbiome, part I: current state of the science. Nutrients. 2019;11(4):923. [Crossref]  [PubMed]  [PMC] 
  9. Rothschild D, Weissbrod O, Barkan E, Kurilshikov A, Korem T, Zeevi D, et al. Environment dominates over host genetics in shaping human gut microbiota. Nature. 2018;555(7695):210-5. [Crossref]  [PubMed] 
  10. Wiley NC, Dinan TG, Ross RP, Stanton C, Clarke G, Cryan JF. The microbiota-gut-brain axis as a key regulator of neural function and the stress response: Implications for human and animal health. J Anim Sci. 2017;95(7):3225-46. [Crossref]  [PubMed] 
  11. Kelly CJ, Zheng L, Campbell EL, Saeedi B, Scholz CC, Bayless AJ, et al. Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe. 2015;17(5):662-71. [Crossref]  [PubMed]  [PMC] 
  12. Wasi S, Tabrez S, Ahmad M. Toxicological effects of major environmental pollutants: an overview. Environ Monit Assess. 2013;185(3):2585-93. [Crossref]  [PubMed] 
  13. Jin C, Zeng Z, Fu Z, Jin Y. Oral imazalil exposure induces gut microbiota dysbiosis and colonic inflammation in mice. Chemosphere. 2016;160:349-58. [Crossref]  [PubMed] 
  14. Tu W, Xu C, Jin Y, Lu B, Lin C, Wu Y, et al. Permethrin is a potential thyroid-disrupting chemical: In vivo and in silico envidence. Aquat Toxicol. 2016;175:39-46. [Crossref]  [PubMed] 
  15. Jin Y, Zhu Z, Wang Y, Yang E, Feng X, Fu Z. The fungicide imazalil induces developmental abnormalities and alters locomotor activity during early developmental stages in zebrafish. Chemosphere. 2016;153:455-61. [Crossref]  [PubMed] 
  16. Jin Y, Zeng Z, Wu Y, Zhang S, Fu Z. Oral exposure of mice to carbendazim induces hepatic lipid metabolism disorder and gut microbiota dysbiosis. Toxicol Sci. 2015;147(1):116-26. [Crossref]  [PubMed] 
  17. Zhang S, Jin Y, Zeng Z, Liu Z, Fu Z. Subchronic exposure of mice to cadmium perturbs their hepatic energy metabolism and gut microbiome. Chem Res Toxicol. 2015;28(10):2000-9. [Crossref]  [PubMed] 
  18. Chiu K, Warner G, Nowak RA, Flaws JA, Mei W. The impact of environmental chemicals on the gut microbiome. Toxicol Sci. 2020;176(2):253-84. [Crossref]  [PubMed]  [PMC] 
  19. Giambò F, Teodoro M, Costa C, Fenga C. Toxicology and microbiota: how do pesticides influence gut microbiota? A review. Int J Environ Res Public Health. 2021;18(11):5510. [Crossref]  [PubMed]  [PMC] 
  20. Peshin R, Kranthi KR, Sharma R. Pesticide use and experiences with integrated pest management programs and Bt cotton in India. Integrated Pest Management Experiences with Implementation, Global Overview. Vol. 4. Dordrecht: Springer; 2014. p.269-306. [Crossref] 
  21. Claus SP, Guillou H, Ellero-Simatos S. Erratum: The gut microbiota: a major player in the toxicity of environmental pollutants? NPJ Biofilms Microbiomes. 2017;3:17001. Erratum for: NPJ Biofilms Microbiomes. 2016;2:16003. [Crossref]  [PubMed]  [PMC] 
  22. Rueda-Ruzafa L, Cruz F, Roman P, Cardona D. Gut microbiota and neurological effects of glyphosate. Neurotoxicology. 2019;75:1-8. [Crossref]  [PubMed] 
  23. Yuan X, Pan Z, Jin C, Ni Y, Fu Z, Jin Y. Gut microbiota: An underestimated and unintended recipient for pesticide-induced toxicity. Chemosphere. 2019;227:425-34. [Crossref]  [PubMed] 
  24. Gálvez-Ontiveros Y, Páez S, Monteagudo C, Rivas A. Endocrine disruptors in food: impact on gut microbiota and metabolic diseases. Nutrients. 2020;12(4):1158. [Crossref]  [PubMed]  [PMC] 
  25. Syromyatnikov MY, Isuwa MM, Savinkova OV, Derevshchikova MI, Popov VN. The effect of pesticides on the microbiome of animals. Agriculture. 2020;10(3):79. [Crossref] 
  26. Liu Q, Shao W, Zhang C, Xu C, Wang Q, Liu H, et al. Organochloride pesticides modulated gut microbiota and influenced bile acid metabolism in mice. Environ Pollut. 2017;226:268-76. [Crossref]  [PubMed] 
  27. Nasuti C, Coman MM, Olek RA, Fiorini D, Verdenelli MC, Cecchini C, et al. Changes on fecal microbiota in rats exposed to permethrin during postnatal development. Environ Sci Pollut Res Int. 2016;23(11):10930-7. [Crossref]  [PubMed] 
  28. Daisley BA, Trinder M, McDowell TW, Welle H, Dube JS, Ali SN, et al. Neonicotinoid-induced pathogen susceptibility is mitigated by Lactobacillus plantarum immune stimulation in a Drosophila melanogaster model. Sci Rep. 2017;7(1):2703. [Crossref]  [PubMed]  [PMC] 
  29. Scheperjans F, Aho V, Pereira PA, Koskinen K, Paulin L, Pekkonen E, et al. Gut microbiota are related to Parkinson's disease and clinical phenotype. Mov Disord. 2015;30(3):350-8. [Crossref]  [PubMed] 
  30. Yang G, Yuan X, Jin C, Wang D, Wang Y, Miao W, et al. Imidacloprid disturbed the gut barrier function and interfered with bile acids metabolism in mice. Environ Pollut. 2020;266(Pt 1):115290. [Crossref]  [PubMed] 
  31. Zhao Y, Zhang Y, Wang G, Han R, Xie X. Effects of chlorpyrifos on the gut microbiome and urine metabolome in mouse (Mus musculus). Chemosphere. 2016;153:287-93. [Crossref]  [PubMed] 
  32. Walker AW, Sanderson JD, Churcher C, Parkes GC, Hudspith BN, Rayment N, et al. High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease. BMC Microbiol. 2011;11:7. [Crossref]  [PubMed]  [PMC] 
  33. Gao B, Bian X, Mahbub R, Lu K. Sex-specific effects of organophosphate diazinon on the gut microbiome and its metabolic functions. Environ Health Perspect. 2017;125(2):198-206. [Crossref]  [PubMed]  [PMC] 
  34. Gao B, Chi L, Tu P, Gao N, Lu K. The carbamate aldicarb altered the gut microbiome, metabolome, and lipidome of C57BL/6J mice. Chem Res Toxicol. 2019;32(1):67-79. [Crossref]  [PubMed] 
  35. Jin C, Luo T, Zhu Z, Pan Z, Yang J, Wang W, et al. Imazalil exposure induces gut microbiota dysbiosis and hepatic metabolism disorder in zebrafish. Comp Biochem Physiol C Toxicol Pharmacol. 2017;202:85-93. [Crossref]  [PubMed] 
  36. Catenza CJ, Farooq A, Shubear NS, Donkor KK. A targeted review on fate, occurrence, risk and health implications of bisphenol analogues. Chemosphere. 2021;268:129273. [Crossref]  [PubMed] 
  37. Vom Saal FS, Nagel SC, Coe BL, Angle BM, Taylor JA. The estrogenic endocrine disrupting chemical bisphenol A (BPA) and obesity. Mol Cell Endocrinol. 2012;354(1-2):74-84. [Crossref]  [PubMed]  [PMC] 
  38. Javurek AB, Spollen WG, Johnson SA, Bivens NJ, Bromert KH, Givan SA, et al. Effects of exposure to bisphenol A and ethinyl estradiol on the gut microbiota of parents and their offspring in a rodent model. Gut Microbes. 2016;7(6):471-85. [Crossref]  [PubMed]  [PMC] 
  39. Ni Y, Hu L, Yang S, Ni L, Ma L, Zhao Y, et al. Bisphenol A impairs cognitive function and 5-HT metabolism in adult male mice by modulating the microbiota-gut-brain axis. Chemosphere. 2021;282:130952. [Crossref]  [PubMed] 
  40. Kaur S, Sarma SJ, Marshall BL, Liu Y, Kinkade JA, Bellamy MM, et al. Developmental exposure of California mice to endocrine disrupting chemicals and potential effects on the microbiome-gut-brain axis at adulthood. Sci Rep. 2020;10(1):10902. Erratum in: Sci Rep. 2020;10(1):12524. [Crossref]  [PubMed]  [PMC] 
  41. Koestel ZL, Backus RC, Tsuruta K, Spollen WG, Johnson SA, Javurek AB, et al. Bisphenol A (BPA) in the serum of pet dogs following short-term consumption of canned dog food and potential health consequences of exposure to BPA. Sci Total Environ. 2017;579:1804-14. [Crossref]  [PubMed] 
  42. Lai KP, Chung YT, Li R, Wan HT, Wong CK. Bisphenol A alters gut microbiome: Comparative metagenomics analysis. Environ Pollut. 2016;218:923-30. [Crossref]  [PubMed] 
  43. Reddivari L, Veeramachaneni DNR, Walters WA, Lozupone C, Palmer J, Hewage MKK, et al. Perinatal bisphenol a exposure induces chronic inflammation in rabbit offspring via modulation of gut bacteria and their metabolites. mSystems. 2017;2(5):e00093-17. [Crossref]  [PubMed]  [PMC] 
  44. Malaisé Y, Menard S, Cartier C, Gaultier E, Lasserre F, Lencina C, et al. Gut dysbiosis and impairment of immune system homeostasis in perinatally-exposed mice to Bisphenol A precede obese phenotype development. Sci Rep. 2017;7(1):14472. [Crossref]  [PubMed]  [PMC] 
  45. DeLuca JA, Allred KF, Menon R, Riordan R, Weeks BR, Jayaraman A, et al. Bisphenol-A alters microbiota metabolites derived from aromatic amino acids and worsens disease activity during colitis. Exp Biol Med (Maywood). 2018;243(10):864-75. [Crossref]  [PubMed]  [PMC] 
  46. Feng D, Zhang H, Jiang X, Zou J, Li Q, Mai H, et al. Bisphenol A exposure induces gut microbiota dysbiosis and consequent activation of gut-liver axis leading to hepatic steatosis in CD-1 mice. Environ Pollut. 2020;265(Pt A):114880. [Crossref]  [PubMed] 
  47. Chen L, Guo Y, Hu C, Lam PKS, Lam JCW, Zhou B. Dysbiosis of gut microbiota by chronic coexposure to titanium dioxide nanoparticles and bisphenol A: Implications for host health in zebrafish. Environ Pollut. 2018;234:307-17. [Crossref]  [PubMed] 
  48. Commission E. Commission regulation (EU) 2018/213. Official Journal of the European Communities. 2018:6-12. [Link] 
  49. Catron TR, Keely SP, Brinkman NE, Zurlinden TJ, Wood CE, Wright JR, et al. Host developmental toxicity of BPA and BPA alternatives is inversely related to microbiota disruption in zebrafish. Toxicol Sci. 2019;167(2):468-83. [Crossref]  [PubMed] 
  50. Krause JL, Engelmann B, Nunes da Rocha U, Pierzchalski A, Chang HD, Zenclussen AC, et al. MAIT cell activation is reduced by direct and microbiota-mediated exposure to bisphenols. Environ Int. 2022;158:106985. [Crossref]  [PubMed] 
  51. Wang Y, Wang B, Wang Q, Liu Y, Liu X, Wu B, et al. Intestinal toxicity and microbial community disorder induced by bisphenol F and bisphenol S in zebrafish. Chemosphere. 2021;280:130711. [Crossref]  [PubMed] 
  52. Shih MK, Tain YL, Cheng CM, Hsu CN, Chen YW, Huang HT, et al. Separation and identification of resveratrol butyrate ester complexes and their bioactivity in HepG2 cell models. Int J Mol Sci. 2021;22(24):13539. [Crossref]  [PubMed]  [PMC] 
  53. Liao JX, Chen YW, Shih MK, Tain YL, Yeh YT, Chiu MH, et al. Resveratrol butyrate esters inhibit BPA-induced liver damage in male offspring rats by modulating antioxidant capacity and gut microbiota. Int J Mol Sci. 2021;22(10):5273. [Crossref]  [PubMed]  [PMC] 
  54. Fendoğlu BY, Koçer-Gümüşel B, Erkekoğlu P. Endokrin bozucu kimyasal maddelere ve etki mekanizmalarına genel bir bakış [A general overview on endocrine disrupting chemicals and their mechanism of action]. Hacettepe University Journal of the Faculty of Pharmacy. 2019;39(1):30-43. [Link] 
  55. Erkekoglu P, Rachidi W, Yuzugullu OG, Giray B, Favier A, Ozturk M, et al. Evaluation of cytotoxicity and oxidative DNA damaging effects of di(2-ethylhexyl)-phthalate (DEHP) and mono(2-ethylhexyl)-phthalate (MEHP) on MA-10 Leydig cells and protection by selenium. Toxicol Appl Pharmacol. 2010;248(1):52-62. Erratum in: Toxicol Appl Pharmacol. 2013;273(2):425. [Crossref]  [PubMed] 
  56. Erkekoglu P, Zeybek ND, Giray B, Asan E, Arnaud J, Hincal F. Reproductive toxicity of di(2-ethylhexyl) phthalate in selenium-supplemented and selenium-deficient rats. Drug Chem Toxicol. 2011;34(4):379-89. [Crossref]  [PubMed] 
  57. Balci A, Ozkemahli G, Erkekoglu P, Zeybek ND, Yersal N, Kocer-Gumusel B. Histopathologic, apoptotic and autophagic, effects of prenatal bisphenol A and/or di(2-ethylhexyl) phthalate exposure on prepubertal rat testis. Environ Sci Pollut Res Int. 2020;27(16):20104-16. [Crossref]  [PubMed] 
  58. Ozkemahli G, Balci Ozyurt A, Erkekoglu P, Zeybek ND, Yersal N, Kocer-Gumusel B. The effects of prenatal and lactational bisphenol A and/or di(2-ethylhexyl) phthalate exposure on female reproductive system. Toxicol Mech Methods. 2022;32(8):597-605. [Crossref]  [PubMed] 
  59. Fu X, Han H, Li Y, Xu B, Dai W, Zhang Y, et al. Di-(2-ethylhexyl) phthalate exposure induces female reproductive toxicity and alters the intestinal microbiota community structure and fecal metabolite profile in mice. Environ Toxicol. 2021;36(6):1226-42. [Crossref]  [PubMed]  [PMC] 
  60. Balcı A, Özkemahlı G, Erkekoglu P, Zeybek D, Yersal N, Kocer-Gumusel B. Effects of prenatal and lactational bisphenol a and/or di(2-ethylhexyl) phthalate exposure on male reproductive system. Int J Environ Health Res. 2022;32(4):902-15. [Crossref]  [PubMed] 
  61. EUR-Lex [Internet]. Phthalates Directive 2005/84/EC. 2005. Cited: 20 Sep 2022. Available from: [Link] 
  62. EU CR. Official Journal of the European Union. 2018 [Available from: COMMISSION REGULATION (EU) 2018/ 213 - of 12 February 2018 - on the use of bisphenol A in varnishes and coatings intended to come into contact with food and amending Regulation (EU) No 10 / 2011 as regards the use of that substance in plastic food contact materials (europa.eu)]. Cited: 20 Sep 2022. Available from: [Link] 
  63. EPA, US. "Priority Pollutant List. 2014. Cited: 20 Sep 2022. Available from: [Link] 
  64. Zhao TX, Wei YX, Wang JK, Han LD, Sun M, Wu YH, et al. The gut-microbiota-testis axis mediated by the activation of the Nrf2 antioxidant pathway is related to prepuberal steroidogenesis disorders induced by di-(2-ethylhexyl) phthalate. Environmental Science and Pollution Research. 2020;27(28):35261-71. [Crossref]  [PubMed] 
  65. Wang C, Yue S, Hao Z, Ren G, Lu D, Zhang Q, et al. Pubertal exposure to the endocrine disruptor mono-2-ethylhexyl ester at body burden level caused cholesterol imbalance in mice. Environ Pollut. 2019;244:657-66. [Crossref]  [PubMed] 
  66. Hu J, Raikhel V, Gopalakrishnan K, Fernandez-Hernandez H, Lambertini L, Manservisi F, et al. Effect of postnatal low-dose exposure to environmental chemicals on the gut microbiome in a rodent model. Microbiome. 2016;4(1):26. [Crossref]  [PubMed]  [PMC] 
  67. Wang G, Chen Q, Tian P, Wang L, Li X, Lee YK, et al. Gut microbiota dysbiosis might be responsible to different toxicity caused by Di-(2-ethylhexyl) phthalate exposure in murine rodents. Environ Pollut. 2020;261:114164. [Crossref]  [PubMed] 
  68. Deng Y, Yan Z, Shen R, Wang M, Huang Y, Ren H, et al. Microplastics release phthalate esters and cause aggravated adverse effects in the mouse gut. Environ Int. 2020;143:105916. [Crossref]  [PubMed] 
  69. Yang YN, Yang YSH, Lin IH, Chen YY, Lin HY, Wu CY, et al. Phthalate exposure alters gut microbiota composition and IgM vaccine response in human newborns. Food Chem Toxicol. 2019;132:110700. [Crossref]  [PubMed] 
  70. Fan Y, Qin Y, Chen M, Li X, Wang R, Huang Z, et al. Prenatal low-dose DEHP exposure induces metabolic adaptation and obesity: Role of hepatic thiamine metabolism. J Hazard Mater. 2020;385:121534. [Crossref]  [PubMed]  [PMC] 
  71. Yu Z, Shi Z, Zheng Z, Han J, Yang W, Lu R, et al. DEHP induce cholesterol imbalance via disturbing bile acid metabolism by altering the composition of gut microbiota in rats. Chemosphere. 2021;263:127959. [Crossref]  [PubMed] 
  72. Xiong Z, Zeng Y, Zhou J, Shu R, Xie X, Fu Z. Exposure to dibutyl phthalate impairs lipid metabolism and causes inflammation via disturbing microbiota-related gut-liver axis. Acta Biochim Biophys Sin (Shanghai). 2020;52(12):1382-93. [Crossref]  [PubMed] 
  73. Su H, Yuan P, Lei H, Zhang L, Deng D, Zhang L, et al. Long-term chronic exposure to di-(2-ethylhexyl)-phthalate induces obesity via disruption of host lipid metabolism and gut microbiota in mice. Chemosphere. 2022;287(Pt 4):132414. [Crossref]  [PubMed] 
  74. Lei M, Menon R, Manteiga S, Alden N, Hunt C, Alaniz RC, et al. Environmental chemical diethylhexyl phthalate alters intestinal microbiota community structure and metabolite profile in mice. mSystems. 2019;4(6):e00724-19. [Crossref]  [PubMed]  [PMC] 
  75. Tian X, Yu Z, Feng P, Ye Z, Li R, Liu J, et al. Lactobacillus plantarum TW1-1 alleviates diethylhexylphthalate-induced testicular damage in mice by modulating gut microbiota and decreasing inflammation. Front Cell Infect Microbiol. 2019;9:221. [Crossref]  [PubMed]  [PMC] 

.: Up To Date

Login



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