Oxidative stress, DNA damage and apoptosis levels in those who use borderline high level fluoride content drinking water

Abstract

Aim: Fluoride is necessary for tooth and bone development, but when exposed to excessive levels can cause oxidative stress, DNA damage, apoptosis, fluorosis and cancer. The aim of this study is to reveal the underlying mechanism of fluoride toxicity and to clarify, in part, the uncertainty of the fluoride level in the reference value ranges of drinking water. Material and Methods: Two groups were included in the study as exposure and control groups. Serum Total Oxidant Status and Total Antioxidant Status were measured with colorimetric; Urine 8-OHdG (8-hydroxy-2-deoxyguanosine) (CUSABIO) levels as DNA damage biomarkers and serum M30 and M65 levels (PEVIVA) as apoptosis biomarkers were studied by ELISA method. In addition, all participants underwent a dental examination by the dentist. Results: Serum total antioxidant status (TAS) were lower in the exposure group compared to the control group (p <0.001); serum total oxidant status (TOS) (p <0.001), OSI (p <0.001), M30 (p <0.001) and M65 (p <0.001) levels and urine 8-OHdG (p = 0.011) levels were high. However, the M30 / M60 ratio was not statistically different between the two groups (p = 0.371). Dental fluorosis was detected in all participants in the exposure group. Conclusion: This study showed increased levels of oxidative stress, DNA damage and apoptosis biomarkers in drinking water users with borderline high level fluoride. Therefore, instead of the World Health Organization's reference value range (0.5-1.5 mg/L) for fluoride levels in drinking water, the US Public Health Service’s (0.7 mg/L) reference value range seems to be more appropriate to the precaution.

Keywords

• Fluoride,Oxidative stress,DNA damage,8-OHdG,Apoptosis,M30,M65,Fluorosis

Sınırda Yüksek Düzeyde Florid İçeren İçme Suyu Kullananlarda Oksidatif Stres, DNA Hasarı ve Apoptoz Düzeyleri

Abstract

Amaç: Florid, diş ve kemik gelişimi için gereklidir, ancak aşırı seviyelerde maruz kaldığında oksidatif stres, DNA hasarı, apoptoz, floroz ve kansere neden olabilmektedir. Bu çalışmanın amacı, florid toksisitesinin altta yatan mekanizmasını ortaya çıkarmak ve kısmen, içme suyu florid seviyesinin referans değer aralıkları arasındaki belirsizliğini açıklığa kavuşturmaktır. Gereç ve Yöntemler: Çalışmaya maruziyet ve control grupları olarak iki grup dahil edildi. Serum Toplam Oksidan Seviyesi ve Toplam Antioksidan Seviyeleri kolorimetrik; DNA hasarı biyobelirteci olarak idrar 8-OHdG (8-hidroksi-2-deoksiguanozin) (CUSABIO) seviyeleri ve apoptoz biyobelirteci olarak serum M30 ve M65 seviyeleri (PEVIVA) ELISA yöntemi ile çalışılmıştır. Ayrıca, tüm katılımcılara diş hekimi tarafından diş muayenesi yapıldı. Bulgular: Serum total antioksidan seviye (TAS) maruziyet grubunda kontrol grubuna kıyasla daha düşüktü (p <0.001); serum toplam oksidan seviye (TOS) (p <0.001), OSI (p <0.001), M30 (p <0.001) ve M65 (p <0.001) seviyeleri ve idrar 8-OHdG (p = 0.011) seviyeleri yüksekti. Ancak, M30 / M60 oranı iki grup arasında istatistiksel olarak farklı değildi (p = 0.371). Maruziyet grubundaki tüm katılımcılarda dental florozis saptandı. Sonuç: Bu çalışma, sınırda yüksek düzeyde florid içeren içme suyu kullananlarda oksidatif stres, DNA hasarı ve apoptoz biyobelirteçlerinin arttığını göstermiştir. Bu nedenle, Dünya Sağlık Örgütü'nün içme sularında florid seviyeleri için referans değer aralığı (0.5-1.5 mg/L) yerine ABD Halk Sağlığı Hizmetleri biriminin (0.7 mg/L) referans değer aralıkları ihtiyata daha uygun görünmektedir.

Keywords

• Florid,Oksidatif stres,DNA hasarı,8-OHdG,Apoptoz,M30,M65,Florozis

References

1. 1. Jha SK, Mishra VK, Sharma DK, Damodaran T. Fluoride in the environment and its metabolism in humans. Rev Environ Contam Toxicol. 2011;211:121-42.
2. 2. Yeşilnacar Mİ, Demir Yetiş A, Dülgergil ÇT, Kumral M, Atasoy AD, Rastgeldi Doğan T, et al. Geomedical assessment of an area having high-fluoride groundwater in southeastern Turkey. Environ Earth Sci. 2016;75(2):162.
3. 3. Wei Q, Luo Q, Liu H, Chen L, Cui H, Fang J, et al. The mitochondrial pathway is involved in sodium fluoride (NaF)-induced renal apoptosis in mice. Toxicol Res (Camb). 2018;7(5):792-808.
4. 4. Wang AG, Xia T, Chu QL, Zhang M, Liu F, Chen XM, et al. Effects of fluoride on lipid peroxidation, DNA damage and apoptosis in human embryo hepatocytes. Biomed Environ Sci. 2004;17(2):217-22.
5. 5. Bassin EB, Wypij D, Davis RB, Mittleman MA. Age-specific fluoride exposure in drinking water and osteosarcoma (United States). Cancer Causes Control. 2006;17(4):421-8.
6. 6. Singh R, Banerjee C, Ray A, Rajamani P, Mazumder S. Fluoride-induced headkidney macrophage cell apoptosis involves activation of the CaMKIIg-ERK 1/2-caspase-8 axis: the role of superoxide in initiating the apoptotic cascade. Toxicol Res (Camb). 2016;5(5):1477-89.
7. 7. Meenakshi, Maheshwari RC. Fluoride in drinking water and its removal. J Hazard Mater. 2006;137(1):456-63.
8. 8. Altundağ H, Dündar MŞ, Yüceel Ç, Albayrak S. Sakarya İli İçme Sularında Flor Düzeylerinin İyon Seçici Elektrot Ve İyon Kromotografisi İle Tayini. SAÜ Fen Bilimleri Dergisi. 2011;15(2):129-38.

9. 9. Chen T, Cui Y, Bai C, Gong T, Peng X, Cui H. Decreased percentages of the peripheral blood T-cell subsets and the serum IL-2 contents in chickens fed on diets excess in fluorine. Biol Trace Elem Res. 2009;132(1-3):122-8.
10. 10. Yujiao Lu, Qin Luo, Hengmin Cui, Huidan Deng, Ping Kuang, Huan Liu, et al. Sodium fluoride causes oxidative stress and apoptosis in the mouse liver. Aging (Albany NY). 2017;9(6):1623-39.
11. 11. Bai C, Chen T, Cui Y, Gong T, Peng X, Cui HM. Effect of high fluorine on the cell cycle and apoptosis of renal cells in chickens. Biol Trace Elem Res. 2010;138(1-3):173-80.
12. 12. Chen T, Cui H, Cui Y, Bai C, Gong T, Peng X. Cell-cycle blockage associated with increased apoptotic cells in the thymus of chickens fed on diets high in fluorine. Hum Exp Toxicol. 2011;30(7):685-92.
13. 13. Chen T, Cui H, Cui Y, Bai C, Gong T. Decreased antioxidase activities and oxidative stress in the spleen of chickens fed on high-fluorine diets. Hum Exp Toxicol. 2011;30(9):1282-6.
14. 14. Liu J, Cui H, Peng X, Fang J, Zuo Z, Wang H, et al. Dietary High Fluorine Induces Apoptosis and Alters Bcl-2, Bax, and Caspase-3 Protein Expression in the Cecal Tonsil Lymphocytes of Broilers. Biol Trace Elem Res. 2013;152(1):25-30.
15. 15. Luo Q, Cui H, Peng X, Fang J, Zuo Z, Deng J, et al. Suppressive effects of dietary high fluorine on the intestinal development in broilers. Biol Trace Elem Res. 2013;156(1-3):153-65.
16. 16. Kuang P, Deng H, Cui H, Chen L, Fang J, Zuo Z, et al. Sodium fluoride (NaF) causes toxic effects on splenic development in mice. Oncotarget. 2017;8(3):4703-17.
17. 17. Cabiscol E, Tamarit J, Ros J. Oxidative stress in bacteria and protein damage by reactive oxygen species. Int Microbiol. 2000;3(1):3-8.
18. 18. Mittler R. Oxidative stress, antioxidants and stress tolerance. Trends Plant Sci. 2002;7(9):405-10.
19. 19. Kale M, Rathore N, John S, Bhatnagar D. Lipid peroxidative damage on pyrethroid exposure and alterations in antioxidant status in rat erythrocytes: a possible involvement of reactive oxygen species. Toxicol Lett. 1999;105(3):197-205.
20. 20. Shivarajashankara YM, Shivashankara AR, Bhat PG, Rao SH. Lipid peroxidation and antioxidant systems in the blood of young rats subjected to chronic fluoride toxicity. Indian J Exp Biol. 2003;41(8):857-60.
21. 21. Ghosh D, Das Sarkar S, Maiti R, Jana D, Das UB. Testicular toxicity in sodium fluoride treated rats: association with oxidative stress. Reprod Toxicol. 2002;16(4):385-90.
22. 22. Bharti VK, Srivastava RS. Fluoride-induced oxidative stress in rat's brain and its amelioration by buffalo (Bubalus bubalis) pineal proteins and melatonin. Biol Trace Elem Res. 2009;130(2):131-40.
23. 23. Nabavi SF, Nabavi SM, Ebrahimzadeh MA, Eslami S, Jafari N, Moghaddam H. The protective effect of curcumin against sodium fluoride-induced oxidative stress in rat heart. Arch Biol Sci. 2011;63(3):563-9.
24. 24. Xiao-ying Guo, Gui-fan Sun, Sun Y-c. Oxidative Stress From Fluoride-Induced Hepatotoxicity in Rats. Fluoride. 2003;36(1):25-9.
25. 25. R Ranjan, D Swarup, RC Patra. Oxidative stress indices in erythrocytes, liver, and kidneys of fluoride-exposed rabbits. Fluoride. 2009;42(2):88-93.
26. 26. Mukhopadhyay D, Chattopadhyay A. Induction of oxidative stress and related transcriptional effects of sodium fluoride in female zebrafish liver. Bull Environ Contam Toxicol. 2014;93(1):64-70.
27. 27. Valavanidis A, Vlachogianni T, Fiotakis C. 8-hydroxy-2' -deoxyguanosine (8-OHdG): A critical biomarker of oxidative stress and carcinogenesis. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2009;27(2):120-39.
28. 28. Adams JM, Cory S. The BCL-2 arbiters of apoptosis and their growing role as cancer targets. Cell Death Differ. 2018;25(1):27-36.
29. 29. Olofsson MH, Ueno T, Pan Y, Xu R, Cai F, van der Kuip H, et al. Cytokeratin-18 is a useful serum biomarker for early determination of response of breast carcinomas to chemotherapy. Clin Cancer Res. 2007;13(11):3198-206.
30. 30. Cummings J, Hodgkinson C, Odedra R, Sini P, Heaton SP, Mundt KE, et al. Preclinical evaluation of M30 and M65 ELISAs as biomarkers of drug induced tumor cell death and antitumor activity. Mol Cancer Ther. 2008;7(3):455-63.
31. 31. Kumbicak U, Cavas T, Cinkilic N, Kumbicak Z, Vatan O, Yilmaz D. Evaluation of in vitro cytotoxicity and genotoxicity of copper-zinc alloy nanoparticles in human lung epithelial cells. Food Chem Toxicol. 2014;73:105-12.
32. 32. Dasarathy S, Yang Y, McCullough AJ, Marczewski S, Bennett C, Kalhan SC. Elevated hepatic fatty acid oxidation, high plasma fibroblast growth factor 21, and fasting bile acids in nonalcoholic steatohepatitis. Eur J Gastroenterol Hepatol. 2011;23(5):382-8.
33. 33. Abdellatif H, NasrEldin E, Galal S, Ibrahim M. Study of m65 hepatocyte death marker in multitransfused patients with β-thalassemia major in upper Egypt. Egypt J Haematol. 2019;44(2):124-7.
34. 34. Fawell J, Bailey K, Chilton J, Dahi E, Magara Y. Fluoride in Drinking-water: IWA publishing; 2006.
35. 35. U.S. Public Health Service Recommendation for Fluoride Concentration in Drinking Water for the Prevention of Dental Caries. Public health reports (Washington, DC : 1974). 2015;130(4):318-31.
36. 36. Review of the Fluoride Drinking Water Regulation [Internet]. Environmental Protection Agency. [cited 07.11.2019]. Available from: https://www.epa.gov/dwsixyearreview/review-fluoride-drinking-water-regulation.
37. 37. Rozier RG. Epidemiologic Indices for Measuring the Clinical Manifestations of Dental Fluorosis: Overview and Critique. Advances in Dental Research. 1994;8(1):39-55.
38. 38. Erel O. A novel automated method to measure total antioxidant response against potent free radical reactions. Clinical biochemistry. 2004;37(2):112-9.
39. 39. Halliwell B, Gutteridge JM. Oxygen free radicals and iron in relation to biology and medicine: some problems and concepts. Arch Biochem Biophys. 1986;246(2):501-14.
40. 40. Shivarajashankara YM, Arnadi Ramachandrayya S, Rao S, Bhat P. Oxidative stress in children with endemic skeletal fluorosis. Fluoride. 2001;34:103-7.
41. 41. YM Shivarajashankara, AR Shivashankara, P Gopalakrishna Bhat, S Hanumanth Rao. Effect of Fluoride Intoxication on Lipid Peroxidation and Antioxidant Systems in Rats. Fluoride. 2001;34(2):108-13.
42. 42. Chlubek D, Grucka-Mamczar E, Birkner E, Polaniak R, Stawiarska-Pieta B, Duliban H. Activity of pancreatic antioxidative enzymes and malondialdehyde concentrations in rats with hyperglycemia caused by fluoride intoxication. J Trace Elem Med Biol. 2003;17(1):57-60.
43. 43. Lee JH, Jung JY, Jeong YJ, Park JH, Yang KH, Choi NK, et al. Involvement of both mitochondrial- and death receptor-dependent apoptotic pathways regulated by Bcl-2 family in sodium fluoride-induced apoptosis of the human gingival fibroblasts. Toxicology. 2008;243(3):340-7.
44. 44. Jothiramajayam M, Sinha S, Ghosh M, Nag A, Jana A, Mukherjee A. Sodium fluoride promotes apoptosis by generation of reactive oxygen species in human lymphocytes. J Toxicol Environ Health A. 2014;77(21):1269-80.
45. 45. Qu WJ, Zhong DB, Wu PF, Wang JF, Han B. Sodium fluoride modulates caprine osteoblast proliferation and differentiation. J Bone Miner Metab. 2008;26(4):328-34.
46. 46. Xu H, Wang CH, Zhao ZT, Zhang WB, Li GS. Role of oxidative stress in osteoblasts exposed to sodium fluoride. Biol Trace Elem Res. 2008;123(1-3):109-15.
47. 47. Jundong Wang, Yaming Ge, Hongmei Ning, Shaolin Wang. Effects of High Fluoride and Low Iodine on Oxidative Stress And Antioxidant Defense of The Brain in Offspring Rats. Fluoride. 2004;37(4):264–70.
48. 48. Jianhai Zhang, Chen Liang, Junjie Ma, Bianhua Zhou, Wang J. Effects Of Sodium Fluoride and Sulfur Dioxide on Oxidative Stress and Antioxidant Defenses in Rat Testes. Fluoride. 2006;39(3):185–90.
49. 49. Atmaca N, Atmaca HT, Kanici A, Anteplioglu T. Protective effect of resveratrol on sodium fluoride-induced oxidative stress, hepatotoxicity and neurotoxicity in rats. Food Chem Toxicol. 2014;70:191-7.
50. 50. Ueno T, Toi M, Linder S. Detection of epithelial cell death in the body by cytokeratin 18 measurement. Biomed Pharmacother. 2005;59 Suppl 2:S359-62.