Skip to main content
SpringerLink
Log in

Acute fluoride exposure alters myocardial redox and inflammatory markers in rats

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Acute fluoride (F−) exposure adversely impairs cardiac functions. We previously reported that acute F− toxicity causes modulation in oxidant and antioxidant systems, heat shock proteins, cytoskeletal proteins and AMPK signaling proteins in the myocardium of rats. With these findings, we hypothesized that acute F− intoxication may trigger an acute myocardial inflammatory response through the activation of NF-κB signaling and reduction of redox signaling regulatory system. To test this hypothesis, we treated male Wistar rats with single oral doses of 45 and 90 mg/kg of F− for 24 h. The myocardium of F− treated rats showed increased expression of pNF-κB, pIκKα/β eventually leading to the increased expression of downstream target TNFα—a major proinflammatory cytokine secreted in the inflammatory process. F− intoxication decreased the mRNA expression of redox genes—Sirt1, Sirt3, Prdx2, Glrx1, Trx1, and Trx2. In addition, we observed decreased protein expression of Nrf2, GCLC, and NQO1 in the cardiac tissues of F− treated rats. This study reveals that F− toxicity triggers myocardial inflammatory response and depletes redox signaling molecules in the myocardium of rats. We conclude that NF-κB activation with decreased redox gene expression might be associated with the pathophysiology of F− induced cardiac dysfunction in rats. This finding provides new insights into the cardiovascular pathophysiology in acute F− toxicity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

AMPK :

5′ Adenosine monophosphate-activated protein kinase

DAB :

3,3′-Diaminobenzidine

F − :

Fluoride

GCLC :

Glutamate-cysteine ligase catalytic subunit

Glrx1 :

Glutaredoxin 1

IκKα/β :

Inhibitor of nuclear factor kappa-B kinase α/β

NF-κB :

Nuclear factor kappa light chain enhancer of activated B cells

NQO1 :

NAD(P)H dehydrogenase [quinone] 1

Nrf2 :

Nuclear factor-erythroid 2 (NF-E2)-related factor 2

Prdx2 :

Peroxiredoxin 2

ROS :

Reactive oxygen species

Sirt1 :

Silent mating type information regulation 2, homolog 1

Sirt3 :

Silent mating type information regulation 2, homolog 3

TMB :

3,3′,5,5′-Tetramethylbenzidine

TNFα :

Tumour necrosis factor alpha

Trx1 :

Cytosolic thioredoxin 1

Trx2 :

Mitochondrial thioredoxin 2

References

  1. Jagtap S, Yenkie MK, Labhsetwar N, Rayalu S (2012) Fluoride in drinking water and defluoridation of water. Chem Rev 112:2454–2466

    CAS  PubMed  Google Scholar 

  2. Strubelt O, Iven H, Younes M (1982) The pathophysiological profile of the acute cardiovascular toxicity of sodium fluoride. Toxicology 24:313–323

    CAS  PubMed  Google Scholar 

  3. McIvor ME, Cummings CE, Mower MM, Wenk RE, Lustgarten JA, Baltazar RF, Salomon J (1987) Sudden cardiac death from acute fluoride intoxication: the role of potassium. Ann Emerg Med 16:777–781

    CAS  PubMed  Google Scholar 

  4. Cummings CC, McIvor ME (1988) Fluoride-induced hyperkalemia: the role of Ca2+-dependent K+ channels. Am J Emerg Med 6:1–3

    CAS  PubMed  Google Scholar 

  5. Vohra R, Velez LI, Rivera W, Benitez FL, Delaney KA (2008) Recurrent life threatening ventricular dysrhythmias associated with acute hydrofluoric acid ingestion: observations in one case and implications for mechanism of toxicity. Clin Toxicol 46:79–84

    CAS  Google Scholar 

  6. Panneerselvam L, Govindarajan V, Ameeramja J, Nair HR, Perumal E (2015) Single oral acute fluoride exposure causes changes in cardiac expression of oxidant and antioxidant enzymes, apoptotic and necrotic markers in male rat. Biochimie 119:27–35

    CAS  PubMed  Google Scholar 

  7. Panneerselvam L, Raghunath A, Perumal E (2017) Acute fluoride poisoning alters myocardial cytoskeletal and AMPK signaling proteins in rats. Int J Cardiol 229:96–101

    PubMed  Google Scholar 

  8. Panneerselvam L, Raghunath A, Perumal E (2017) Differential expression of myocardial heat shock proteins in rats acutely exposed to fluoride. Cell Stress Chaperones 22:743–750

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Nishida K, Otsu K (2017) Inflammation and metabolic cardiomyopathy. Cardiovasc Res 113:389–398

    CAS  PubMed  Google Scholar 

  10. Oeckinghaus A, Ghosh S (2009) The NF-kappaB family of transcription factors and its regulation, Cold. Spring Harb Perspect Biol 1:a000034

    Google Scholar 

  11. Van der Heiden K, Cuhimann S, le Luong A, Zakkar M, Evans PC (2010) Role of nuclear factor kappaB in cardiovascular health and disease. Clin Sci (Lond) 118:593–605

    Google Scholar 

  12. Karin M (1999) The beginning of the end: I-kappa-B kinase (IKK) and NF-kappaB activation. J Biol Chem 274:27339–27342

    CAS  PubMed  Google Scholar 

  13. Oyagbemi AA, Omobowale TO, Asenuga ER, Adejumobi AO, Ajibade TO, Ige TM, Ogunpolu BS, Adedapo AA, Yakubu MA (2017) Sodium fluoride induces hypertension and cardiac complications through generation of reactive oxygen species and activation of nuclear factor kappa beta. Environ Toxicol 32:1089–1101

    CAS  PubMed  Google Scholar 

  14. Chen C, Chen H, Zhou HJ, Ji W, Min W (2017) Mechanistic role of thioredoxin 2 in heart failure. Adv Exp Med Biol 982:265–276

    CAS  PubMed  Google Scholar 

  15. Dutnall LP (2001) Deciphering NAD-dependent deacetylases. Cell 105:161–164

    CAS  PubMed  Google Scholar 

  16. Tanno M, Kuno A, Horio Y, Miura T (2012) Emerging beneficial roles of sirtuins in heart failure. Basic Res Cardiol 107:273–286

    PubMed  PubMed Central  Google Scholar 

  17. Shinmura K, Tamaki K, Sano M, Nakashima-Kamimura N, Wolf AM, Amo T, Ohta S, Katsumata Y, Fukuda K, Ishiwata K, Suematsu M, Adachi T (2011) Caloric restriction primes mitochondria for ischemic stress by deacetylating specific mitochondrial proteins of the electron transport chain. Circ Res 109:396–406

    CAS  PubMed  Google Scholar 

  18. Xie J, Zhang X, Zhang L (2013) Negative regulation of inflammation by SIR. Pharmacol Res 67:60–67

    CAS  PubMed  Google Scholar 

  19. Fina BL, Lombarte M, Rigalli JP, Rigalli A (2014) Fluoride increases superoxide production and impairs the respiratory chain in ROS 17/2.8, osteoblastic cells. PLoS ONE 9:e100768

    PubMed  PubMed Central  Google Scholar 

  20. Izquierdo-Vega JA, Sanchez-Gutierrez M, Del Razo LM (2008) Decreased in vitro fertility in male rats exposed to fluoride-induced oxidative stress damage and mitochondrial transmembrane potential loss. Toxicol Appl Pharmacol 230:352–357

    CAS  PubMed  Google Scholar 

  21. Zhao W, Fan GC, Zhang ZG, Bandyopadhyay A, Zhou X, Kranias EG (2009) Protection of peroxiredoxin II on oxidative stress-induces cardiomyocyte death and apoptosis. Basic Res Cardiol 104:377–389

    CAS  PubMed  Google Scholar 

  22. Lekli I, Mukherjee S, Ray D, Gurusamy N, Kim YH, Tosaki A, Engelman RM, Ho YS, Das DK (2010) Functional recovery of diabetic mouse hearts by glutaredoxin-1 gene therapy: role of Akt-FoxO-signaling network. Gene Ther 17:478–485

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Ago T, Sadoshima J (2007) Thioredoxin1 as a negative regulator of cardiac hypertrophy. Antioxid Redox Signal 9:679–687

    CAS  PubMed  Google Scholar 

  24. Whitford GM, Bridsong WNL, Findori C (1990) Acute oral toxicity of sodium fluoride and monofluorophsphate separately or in combination in rats. Caries Res 24:121–126

    CAS  PubMed  Google Scholar 

  25. Yu W, Zhou HF, Lin RB, Fu YC, Wang W (2014) Short-term calorie restriction activates SIRT1-4 and -7 in cardiomyocytes in vivo and in vitro. Mol Med Rep 9:1218–1224

    CAS  PubMed  Google Scholar 

  26. Sung J, Gim S, Koh P (2014) Ferulic acid attenuates the cerebral ischemic injury-induced decrease in peroxiredoxin-2 and thioredoxin expression. Neurosci Lett 566:88–92

    CAS  PubMed  Google Scholar 

  27. Wang S, Wang B, Feng Y, Mo M, Du F, Li H, Yu X (2015) 17b-estradiol ameliorates light-induced retinal damage in Sprague-Dawley rats by reducing oxidative stress. J Mol Neurosci 55:141–151

    CAS  PubMed  Google Scholar 

  28. Lappalainen Z, Lappalainen J, Oksala NK, Laaksonen DE, Khanna S, Sen CK, Atalay M (2009) Diabetes impairs exercise training-associated thioredoxin response and glutathione status in rat brain. J Appl Physiol 106:461–467

    CAS  PubMed  Google Scholar 

  29. Max D, Brandsch C, Schumann S, Kuhne H, Frommhagen M, Schutkowski A, Hirche F, Staege MS, Stangl GI (2014) Maternal vitamin D deficiency causes smaller muscle fibers and altered transcript levels of genes involved in protein degradation, myogenesis, and cytoskeleton organization in the newborn rat. Mol Nutr Food Res 58:343–352

    CAS  PubMed  Google Scholar 

  30. Lund K, Refsnes M, Ramis I, Dunster C, Boe J, Schwarze PE, Skovlund E, Kelly FJ, Kongerud J (2002) Human exposure to hydrogen fluoride induces acute neutrophilic, eicosanoid, and antioxidant changes in nasal lavage fluid. Inhal Toxicol 14:119–132

    CAS  PubMed  Google Scholar 

  31. Aydin G, Cicek E, Akdogan M, Gökalp O (2003) Histopathological and biochemical changes in lung tissues of rats following administration of fluoride over several generations. J Appl Toxicol 23:437–446

    CAS  PubMed  Google Scholar 

  32. Gutowska I, Baranowska-Bosiacka I, Goschorska M, Kolasa A, Lukomska A, Jakubczyk K, Dec K, Chlubek D (2015) Fluoride as a factor initiating and potentiating inflammation in THP1 differentiated monocytes/macrophages. Toxicol In Vitro 29:1661–1668

    CAS  PubMed  Google Scholar 

  33. Bradham WS, Bozkurt B, Gunasinghe H, Mann D, Spinale FG (2002) Tumor necrosis factor-alpha and myocardial remodeling in progression of heart failure: a current perspective. Cardiovasc Res 53:822–830

    CAS  PubMed  Google Scholar 

  34. Hamid T, Gu Y, Ortines RV, Bhattacharya C, Wang G, Xuan YT, Prebhu SD (2009) Divergent tumor necrosis factor receptor-related remodeling responses in heart failure: role of nuclear factor-kappaB and inflammatory activation. Circulation 119:1386–1397

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Gordon JW, Shaw JA, Kirshenbaum LA (2011) Multiple facets of NF-κB in the heart: to be or not to NF-κB. Circ Res 108:1122–1132

    CAS  PubMed  Google Scholar 

  36. Kratsios P, Huth M, Temmerman L, Salimova E, Al Banchaabouchi M, Sqoifo A, Manghi M, Suzuki K, Rosenthal N, Mourkioti F (2010) Antioxidant amelioration of dilated cardiomyopathy caused by conditional deletion of NEMO/IKKgamma in cardiomyocytes. Circ Res 106:133–144

    CAS  PubMed  Google Scholar 

  37. Maier HJ, Schips TG, Wietelmann A, Kruger M, Brunner C, Sauter M, Klingel K, Bottger T, Braun T, Wirth T (2012) Cardiomyocyte-specific IkB kinase (IKK)/NF-kB activation induces reversible inflammatory cardiomyopathy and heart failure. Proc Natl Acad Sci USA 109:11794–11799

    CAS  PubMed  Google Scholar 

  38. Chen R, Zhao LD, Liu H, Li HH, Ren C, Zhang P, Guo KT, Zhang HX, Geng DQ, Zhang CY (2017) Fluoride induces neuroinflammation and alters Wnt signaling pathway in BV2 microglial cells. Inflammation 40:1123–1130

    CAS  PubMed  Google Scholar 

  39. Kuroda J, Ago T, Matsushima S, Zhai P, Schneider MD, Sadoshima J (2010) NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart. Proc Natl Acad Sci USA 107:15565–15570

    CAS  PubMed  Google Scholar 

  40. Miltonprabu S, Thangapandiyan S (2015) Epigallocatechin gallate potentially attenuates fluoride induced oxidative stress mediated cardiotoxicity and dyslipidemia in rats. J Trace Elem Med Biol 29:321–335

    CAS  PubMed  Google Scholar 

  41. Raghunath A, Sundarraj K, Nagarajan R, Arfuso F, Bian J, Kumar AP, Sethi G, Perumal E (2018) Antioxidant response elements: discovery, classes, regulation and potential applications. Redox Biol 17:297–314

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Raghunath A, Nagarajan R, Sundarraj K, Panneerselvam L, Perumal E (2018) Genome-wide identification and analysis of Nrf2 binding sites—antioxidant response elements in zebrafish. Toxicol Appl Pharmacol 360:236–248

    CAS  PubMed  Google Scholar 

  43. Thangapandiyan S, Miltonprabu S (2014) Epigallocatechin gallate supplementation protects against renal injury induced by fluoride intoxication in rats: role of Nrf2/HO-1 signaling. Toxicol Rep 1:12–30

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Suzuki M, Bandoski C, Bartlett JD (2015) Fluoride induces oxidative damage and SIRT1/autophagy through ROS-mediated JNK signaling. Free Radic Biol Med 89:369–378

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Kauppinen A, Suuronen T, Ojala J, Kaarniranta K, Salminen A (2013) Antagonistic crosstalk between NF-kB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal 25:1939–1948

    CAS  PubMed  Google Scholar 

  46. Song C, Fu B, Zhang J, Zhao J, Yuan M, Peng W, Zhang Y, Wu H (2017) Sodium fluoride induces nephrotoxicity via oxidative stress-regulated mitochondrial SIRT3 signaling pathway. Sci Rep 7:672–692

    PubMed  PubMed Central  Google Scholar 

  47. Zeng Y, Yang K, Wang F, Zhou L, Hu Y, Tang M, Zhang S, Jin S, Zhang J, Wang J, Li W, Lu L, Xu GT (2016) The glucagon like peptide 1 analogue, exendin-4, attenuates oxidative stress-induced retinal cell death in early diabetic rats through promoting Sirt1 and Sirt3 expression. Exp Eye Res 151:203–211

    CAS  PubMed  Google Scholar 

  48. Sun Z, Niu R, Wang B, Jiao Z, Wang J, Zhang J, Wang S, Wang J (2011) Fluoride-induced apoptosis and gene expression profiling in mice sperm in vivo. Arch Toxicol 85:1441–1452

    CAS  PubMed  Google Scholar 

  49. Adluri RS, Thirunavukkarasu M, Zhan L, Dunna NR, Akita Y, Selvaraju V, Otani H, Sanchez JA, Ho YS, Maulik N (2012) Glutaredoxin-1 overexpression enhances neovascularization and diminishes ventricular remodeling in chronic myocardial infarction. PLoS ONE 7:e34790

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Masutani H, Yodoi J (2002) Thioredoxin. Overview. Methods Enzymol 347:7279–7286

    Google Scholar 

  51. Yamamoto M, Yang G, Hong C, Liu J, Holle E, Yu X, Wagner T, Vatner SF, Sadoshima J (2003) Inhibition of endogenous thioredoxin in the heart increases oxidative stress and cardiac hypertrophy. J Clin Invest 112:1395–1406

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhang R, Al-Lamki R, Bai L, Streb JW, Miano JM, Bradley J, Min W (2004) Thioredoxin-2 inhibits mitochondria-located ASK1-mediated apoptosis in a JNK-independent manner. Circ Res 94:1483–1491

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

LP extends his thanks to the Indian Council of Medical Research, New Delhi, for financial assistance in the form of a Senior Research Fellowship (No. 45/25/2013/BMS/TRM). AR acknowledges the UGC-BSR Senior Research Fellowship (UGC-BSR No. F7-25/2007) funded by UGC-BSR, New Delhi, India. This work was supported by the University Grants Commission—Special Assistance Programme (UGC-SAP-II:F-3-20/2013) and Department of Science and Technology, Fund for Improvement of Science and Technology infrastructure in universities and higher educational institutions (DST-FIST:SR/FST/LSI-618/2014), New Delhi, India.

Author information

Author notes

  1. Lakshmikanthan Panneerselvam, Azhwar Raghunath and Kiruthika Sundarraj have contributed equally to this work.

Authors and Affiliations

  1. Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore, Tamilnadu, 641 046, India

    Lakshmikanthan Panneerselvam, Azhwar Raghunath, Kiruthika Sundarraj & Ekambaram Perumal

Authors
  1. Lakshmikanthan Panneerselvam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Azhwar Raghunath
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kiruthika Sundarraj
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ekambaram Perumal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ekambaram Perumal.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interest regarding the publication of the paper.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Panneerselvam, L., Raghunath, A., Sundarraj, K. et al. Acute fluoride exposure alters myocardial redox and inflammatory markers in rats. Mol Biol Rep 46, 6155–6164 (2019). https://doi.org/10.1007/s11033-019-05050-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-019-05050-9

Keywords

Search

Navigation