Skip to main content

Advertisement

SpringerLink
Log in

Interactive effect of arsenic and fluoride on cardio-respiratory disorders in male rats: possible role of reactive oxygen species

  • Published:
BioMetals Aims and scope Submit manuscript

Abstract

Epidemiological evidence demonstrates positive correlation between environmental and occupational arsenic or fluoride exposure and risk to various cardio-respiratory disorders. Arsenic-exposure has been associated with atherosclerosis, hypertension, cerebrovascular diseases, ischemic heart disease, and peripheral vascular disorders, whereas Fluoride-exposure manifests cardiac irregularities and low blood pressure (BP). Present study aims to study the combined effects of these toxicants on various cardio-respiratory variables in male rats. Single intravenous (i.v.) dose of arsenic (1, 5, 10 mg/kg) or fluoride (5, 10, 20, 36.5 mg/kg) either alone or in combination were administered. Individual exposure to arsenic or fluoride led to a significant depletion of mean arterial pressure, heart rate (HR), respiration rate and neuromuscular (NM) transmission in a dose-dependent manner. These changes were accompanied by increased levels of blood reactive oxygen species (ROS) and decreased glutathione (GSH) concentrations. An increase in the blood acetyl cholinesterase (AChE) activity was observed in both arsenic or fluoride exposed rats. These changes were significantly more pronounced in arsenic-exposed animals than in fluoride. During combined exposure to arsenic (5 mg/kg) + fluoride (20 mg/kg) or arsenic (10 mg/kg) + fluoride (36.5 mg/kg) the toxic effects were more pronounced compared to individual toxicities of arsenic or fluoride alone. However, combined exposure to arsenic (5 mg/kg) + fluoride (36.5 mg/kg) resulted in antagonistic effects on variables suggestive of altered cardio-respiratory function and oxidative stress. The results from the present study suggest that arsenic or fluoride individually demonstrate cardio-respiratory failure at all doses whereas during combination exposure these toxins show variable toxicities; both synergistic and antagonistic effects depending upon the dose. Moreover, it may be concluded that arsenic and/or fluoride cardio-respiratory toxicity may be mediated via oxidative stress. However, these results are new in the discipline thus requires further exploration.

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
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

As:

Arsenic

F:

Fluoride

NM:

Neuromuscular

ROS:

Reactive oxygen species

GSH:

Reduced glutathione

AChE:

Acetyl cholinesterase

SBP:

Systolic BP

MAP:

Mean arterial pressure

References

  • Balakumar P, Kaur J (2009) Arsenic exposure and cardiovascular disorders: an overview. Cardiovasc Toxicol 9:169–176

    Article  PubMed  CAS  Google Scholar 

  • Barbey JT, Pezzullo JC, Soignet SL (2003) Effect of arsenic trioxide on QT interval in patients with advanced malignancies. J Clin Oncol 21:3609–3615

    Article  PubMed  CAS  Google Scholar 

  • Barbier O, Arreola-Mendoza L, Del Razo LM (2010) Molecular mechanisms of fluoride toxicity. Chem Biol Interact 188:319–333

    Article  PubMed  CAS  Google Scholar 

  • Chen CJ, Hsueh YM, Lai MS, Shyu MP, Chen SY, Wu MM, Kuo TL, Tai TY (1995) Increased prevalence of hypertension and long-term arsenic exposure. Hypertension 25:53–65

    PubMed  Google Scholar 

  • Chevrier PJ, Brownstein S (1980) Complex fluoroanions in solution-X complexes of phosphorus and arsenic fluorides with simple anions. J Inorg Nucl Chem 42:1397–1405

    Article  CAS  Google Scholar 

  • Chiang C, Luk H, Wang T, Ding PY (2002) Prolongation of cardiac repolarization by arsenic trioxide. Blood 100:2249–2252

    Article  PubMed  CAS  Google Scholar 

  • Chlubek D (2003) Fluoride and oxidative stress. Fluoride 36:217–228

    CAS  Google Scholar 

  • Chouhan S, Flora SJS (2008) Effects of fluoride on the tissue oxidative stress and apoptosis in rats: biochemical assays supported by IR spectroscopy data. Toxicology 254:61–67

    Article  PubMed  CAS  Google Scholar 

  • Chouhan S, Flora SJS (2010) Arsenic and fluoride: two major ground water pollutants. Indian J Exp Biol 48:666–678

    PubMed  CAS  Google Scholar 

  • Col M, Col C, Soran A, Sayli BS, Ozturk S (1999) Arsenic-related Bowen’s disease, palmar keratosis, and skin cancer. Environ Health Perspect 107:687–699

    Article  PubMed  CAS  Google Scholar 

  • Dhar V, Bhatnagar M (2009) Physiology and toxicity of fluoride. Indian J Dent Res 20:350–355

    Article  PubMed  Google Scholar 

  • Donmez N, Cinar A (2003) Effects of chronic fluorosis on electrocardiogram in sheep. Biol Trace Elem Res 92:115–122

    Article  PubMed  CAS  Google Scholar 

  • Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem 82:70–77

    Article  PubMed  CAS  Google Scholar 

  • Ellman GL, Courtney KD, Andres V, Featherstone RM (1961) A new and rapid colorimetric determination of acetyl cholinesterase activity. Biochem Pharmacol 7:88–95

    Article  PubMed  CAS  Google Scholar 

  • Farooqi A, Masuda H, Siddiqui R, Naseem M (2009) Sources of arsenic and fluoride in highly contaminated soils causing groundwater contamination in Punjab, Pakistan. Arch Environ Contam Toxicol 56:693–706

    Article  PubMed  CAS  Google Scholar 

  • Flora SJS, Mittal M, Mishra D (2009) Co-exposure to arsenic and fluoride on oxidative stress, glutathione linked enzymes, biogenic amines and DNA damage in mouse brain. J Neurol Sci 285:198–205

    Article  PubMed  CAS  Google Scholar 

  • Guha Mazumder DN (2003) Chronic arsenic toxicity: clinical features, epidemiology, and treatment: experience in West Bengal. J Environ Sci Health A Tox Hazard Subst Environ Eng 38:141–163

    PubMed  CAS  Google Scholar 

  • Imanishi M, Dote T, Tsuji H, Tanida E, Yamadori E, Kono K (2009) Time-dependent changes of blood parameters and fluoride kinetics in rats after acute exposure to subtoxic hydrofluoric acid. J Occup Health 51:287–293

    Article  PubMed  CAS  Google Scholar 

  • Jollow DJ, Mitchell JR, Zamppaglione Z, Gillette JR (1974) Bromobenzene induced liver necrosis. Protective role of glutathione and evidence for 3,4-bromobenzene oxide as the hepatotoxic metabolites. Pharmacology 11:151

    Article  PubMed  CAS  Google Scholar 

  • Kant V, Srivastava AK, Verma PK, Raina R, Pankaj NK (2010) Alterations in electrocardiographic parameters after sub-acute exposure of fluoride and ameliorative action of aluminum sulphate in goats. Biol Trace Elem Res 134:188–194

    Article  PubMed  CAS  Google Scholar 

  • Kolditz L (1967) Arsenic chemistry with halogens. In: Gutmann V (ed) Halogen chem, vol 2. Academic Press, London, p 142

  • Kolditz L, Nussbuk BZ (1965) Complexes of arsenic with hydroxides. Anorg Allg Chem 337:191

    Article  CAS  Google Scholar 

  • Lai MW, Boyer EW, Kleinman ME, Rodig NM, Ewald MB (2005) Acute arsenic poisoning in two siblings. Pediatrics 116:249–257

    Article  PubMed  Google Scholar 

  • Lee MY, Bae ON, Chung SM, Kang KT, Lee JY, Chung JH (2002) Enhancement of platelet aggregation and thrombus formation by arsenic in drinking water: a contributing factor to cardiovascular disease. Toxicol Appl Pharmacol 179:83–88

    Article  PubMed  CAS  Google Scholar 

  • Li XS, Zhi JL, Gao RO (1995) Effect of fluoride exposure on intelligence in children. Fluoride 28:189–192

    CAS  Google Scholar 

  • Luoma H, Aromaa A (1983) Risk of myocardial infarction in Finnish men in relation to fluoride, magnesium and calcium concentration in drinking water. Acta Medica Scandinavica 213:171–176

    Article  PubMed  CAS  Google Scholar 

  • Lynn S, Gurr JR, Lai HT, Jan KY (2000) NADH oxidase activation is involved in arsenite induced oxidative DNA damage in human vascular smooth muscle cells. Circulat Res 86:514–519

    PubMed  CAS  Google Scholar 

  • Martínez-Barbeito MB, Aceves BN, Teres NL, Martín RG, Verdúguez TQ, Méndez CP (2007) An unusual case of acute arsenic poisoning in which the patient made good progress. Emergencias 19:225–228

    Google Scholar 

  • Mazej Z, Zemva B (2005) Synthesis of arsenic pentafluoride by static fluorination of As2O3 in a closed system. J Fluorine Chem 126:1432–1434

    Article  CAS  Google Scholar 

  • Mclvor ME (1990) Acute fluoride toxicity. Pathophysiology and management. Drug Safety 5:79–85

    Article  Google Scholar 

  • Mclvor 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

    Article  Google Scholar 

  • Mittal M, Flora SJS (2006) Effects of individual and combined exposure to sodium arsenite and sodium fluoride on tissue oxidative stress, arsenic and fluoride levels in male mice. Chem Biol Interact 162:128–139

    Article  PubMed  CAS  Google Scholar 

  • Mittal M, Flora SJS (2007) Vitamin E protects oxidative stress and essential metal imbalance during concomitant exposure to arsenic and fluoride in male mice. Drug Chem Toxicol 30:263–281

    Article  PubMed  CAS  Google Scholar 

  • Mordukhovich I, Wright RO, Amarasiriwardena C, Baja E, Baccarelli A, Suh H, Sparrow D, Vokonas P, Schwartz J (2009) Association between low-level environmental arsenic exposure and QT interval duration in a general population study. Am J Epidemiol 170:739–746

    Article  PubMed  Google Scholar 

  • Munro NB, Watson AP, Ambrose KR, Griffin GD (1990) Treating exposure to chemical warfare agents: implications for health care providers and community emergency planning. Environ Health Perspect 89:205–215

    Article  PubMed  CAS  Google Scholar 

  • Navas-Acien A, Sharrett AR, Silbergeld EK, Schwartz BS, Nachman KE, Burke Guallar E (2005) Arsenic exposure and cardiovascular disease: a systematic review of the epidemiologic evidence. Am J Epidemiol 162:1037

    Article  PubMed  Google Scholar 

  • Ohnishi K, Yoshida H, Shigeno K (2000) Prolongation of the QT interval and ventricular tachycardia in patients treated with arsenic trioxide for acute promyelocytic leukemia. Ann Intern Med 133:881–885

    PubMed  CAS  Google Scholar 

  • Ohnishi K, Yoshida H, Shigeno K, Nakamura S, Fujisawa S, Naito K (2002) Arsenic trioxide therapy for relapsed or refractory Japanese patients with acute promyelocytic leukemia: need for careful electrocardiogram monitoring. Leukemia 16:617–622

    Article  PubMed  CAS  Google Scholar 

  • Okushi I (1954) Experimental studies on the effects of sodium fluoride upon the heart muscle of rabbits. Shikoku Acta Med 5:238–245

    CAS  Google Scholar 

  • Opie LH (2004) Cardiac output and exercise. In: Weinberg RW (ed) Heart physiology: from cell to circulation, 4th edn. Lippincott Williams and Wilkins, Philadelphia, PA, USA, p 461

    Google Scholar 

  • Pandey A (2010) Prevalence of fluorosis in an endemic village in central India. Trop Doct 40:217–221

    Article  PubMed  Google Scholar 

  • Raghu KG, Cherian OL (2009) Characterization of cytotoxicity induced by arsenic trioxide (a potent anti-APL drug) in rat cardiac myocytes. J Trace Elem Med Biol 23:61–68

    Article  PubMed  CAS  Google Scholar 

  • Rahman M, Tondel M, Ahmad SA, Chowdhary IA, Faruquee MH, Axelson O (1999) Hypertension and arsenic exposure in Bangladesh. Hypertension 33:74–78

    PubMed  CAS  Google Scholar 

  • Rao MV, Tiwari H (2006) Amelioration by melatonin of chromosomal anomalies induced by arsenic and/or fluoride in human blood lymphocyte cultures. Fluoride 39:255–260

    CAS  Google Scholar 

  • Rao JV, Begum G, Pallela R, Usman PK, Rao RN (2005) Changes in behavior and brain acetyl cholinesterase activity in mosquito fish, Gambusia affinis in response to the sub-lethal exposure to chlorpyrifos. Int J Environ Res Public Health 2:478–483

    Article  PubMed  CAS  Google Scholar 

  • Rocha-Amador D, Navarro ME, Carrizales L, Morales R, Calderon J (2007) Decreased intelligence in children and exposure to fluoride and arsenic in drinking water. Cad Saude Publica 23:S579–S587

    Article  PubMed  Google Scholar 

  • Saralakumari D, Ramakrishna Rao P (1991) Red cell membrane alterations in human chronic fluoride toxicity. Biochem Int 23:639–648

    Google Scholar 

  • Shan KR, Qi XL, Long YG, Nordberg A, Guan ZZ (2004) Decreased nicotinic receptors in PC12 cells and rat brains influenced by fluoride toxicity—a mechanism relating to a damage at the level in post-transcription of the receptor genes. Toxicology 200:169–177

    Article  PubMed  CAS  Google Scholar 

  • Shashi A, Thapar SP (2001) Histopathology of myocardial damage in experimental fluorosis in rabbits. Fluoride 34:43–50

    CAS  Google Scholar 

  • Shi Y, Wei Y, Qu S, Wang Y, Li Y, Li R (2010) Arsenic induces apoptosis of human umbilical vein endothelial cells through mitochondrial pathways. Cardiovasc Toxicol 10:153–160

    Article  PubMed  CAS  Google Scholar 

  • Shivarajashankara YM, Shivashankara AR, Gopalakrishna BP, Hanumanth RS (2001) Effect of fluoride intoxication on lipid peroxidation and antioxidant systems in rats. Fluoride 34:108–113

    CAS  Google Scholar 

  • Smith AH, Steinmaus CM (2000) Arsenic in urine and drinking water. Environ Health Perspect 108:494–505

    Article  Google Scholar 

  • Socci DJ, Bjugstad KB, Jones HC, Pattisapu JV, Arendash GW (1999) Evidence that oxidative stress is associated with the pathophysiology of inherited hydrocephalus in the H-Tx rat model. Exp Neurol 155:109–117

    Article  PubMed  CAS  Google Scholar 

  • Straub AC, Stolz DB, Vin H, Ross MA, Soucy NV, Klei LR, Barchowsky A (2007) Low level arsenic promotes progressive inflammatory angiogenesis and liver blood vessel remodeling in mice. Toxicol Appl Pharmacol 222:327–336

    Article  PubMed  CAS  Google Scholar 

  • Takamori T, Miyanaga S, Kawahara H, Okushi D, Hirao M, Wakatsuki H (1956) Electrocardiographic studies of the inhabitants in high fluoride districts. Tokushima J Exp Med 3:50–53

    Google Scholar 

  • Tortora GJ, Grabowski SR (1993) The cardiovascular system: blood vessels and hemodynamics. In: Principals of anatomy and physiology, 7th edn. Harper Collins College, pp 366–632

  • Tseng CH, Chong CK, Tseng CP, Hsueh YM, Chiou H, Tseng CC, Chen CJ (2003) Long-term arsenic exposure and ischemic heart disease in arseniasis-hyperendemic villages in Taiwan. Toxicol Lett 137:15–21

    Article  PubMed  CAS  Google Scholar 

  • Vani ML, Reddy KP (2000) Effects of fluoride accumulation on some enzymes of brain and gastrocnemius muscle of mice. Fluoride 33:17–26

    CAS  Google Scholar 

  • Wang CH, Jeng JS, Yip PK, Chen CL, Hsu LI, Hsueh YM (2002) Biological gradient between long-term arsenic exposure and carotid atherosclerosis. Circulation 105:1804–1809

    Article  PubMed  CAS  Google Scholar 

  • Wang CH, Hsiao CK, Chen CL, Hsu LI, Chiou HY, Chen SY, Hsueh YM, Wu MM, Chen CJ (2007) A review of the epidemiologic literature on the role of environmental arsenic exposure and cardiovascular diseases. Toxicol Appl Pharmacol 222:315–326

    Article  PubMed  Google Scholar 

  • Westervelt P, Brown RA, Adkins DR, Khoury H, Curtin P, Hurd D, Luger SM, Ma MK, Ley TJ, DiPersio JF (2001) Sudden death among patients with acute promyelocytic leukemia treated with arsenic trioxide. Blood 98:266–271

    Article  PubMed  CAS  Google Scholar 

  • Whetzel TP, Stevenson TR, Sharman RB, Carlsen RC (1997) The effect of ischemic preconditioning on the recovery of skeletal muscle following tourniquet ischemia. Plast Reconstr Surg 100:1767–1775

    Google Scholar 

  • Yanez L, Carrizales L, Zanatta MT, Mejia JJ, Batres L, Diaz-Barriga F (1991) Arsenic-cadmium interaction in rats: toxic effects in the heart and tissue metal shifts. Toxicology 67:227–234

    Article  PubMed  CAS  Google Scholar 

  • Yao H, Wang G (1988a) Acute and chronic experimental studies on joint effect of fluoride and arsenic. Chin J Prevent Med 22:284–286

    CAS  Google Scholar 

  • Yao H, Wang G (1988b) Recent situation of studies on the interactions between fluoride and other chemical substances. Chin J Endemic Dis 7:18

    Google Scholar 

  • Yolken R, Konecny P, McCarthy P (1976) Acute fluoride poisoning. Pediatrics 58:90–93

    PubMed  CAS  Google Scholar 

  • Zierold KM, Knobeloch L, Anderson H (2004) Prevalence of chronic diseases in adults exposed to arsenic-contaminated drinking water. Am J Pubic Health 94:1936–1947

    Article  Google Scholar 

Download references

Acknowledgment

Authors thank Dr. R. Vijayaraghavan, Director of the establishment for his support and encouragement.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior, 474 002, India

    S. J. S. Flora, Vidhu Pachauri, Megha Mittal & Deo Kumar

Authors
  1. S. J. S. Flora
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vidhu Pachauri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Megha Mittal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Deo Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. J. S. Flora.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Flora, S.J.S., Pachauri, V., Mittal, M. et al. Interactive effect of arsenic and fluoride on cardio-respiratory disorders in male rats: possible role of reactive oxygen species. Biometals 24, 615–628 (2011). https://doi.org/10.1007/s10534-011-9412-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10534-011-9412-y

Keywords

Search

Navigation