SpringerLink
Log in

Hematobiochemical Disturbances and Oxidative Stress After Subacute Manganese Chloride Exposure and Potential Protective Effects of Ebselen in Rats

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

The present study aimed to detect the possible disturbances induced by subacute exposure to manganese chloride (MnCl2) on some biomarkers of hematology, clinical chemistry and oxidative stress, serum iron homeostasis, and ferritin status beside the histopathological alterations in hepatic and renal tissues, and the potential protective effects of ebselen on the Mn toxicity were also evaluated. Forty-eight rats were divided into four groups: Group 1 was used as a control. Groups 2, 3, and 4 were administered of ebselen as a single protective dose (15 mg/kg BW) intraperitoneal, daily manganese chloride (50 mg/kg BW) orally, and ebselen plus manganese chloride, respectively. The administrations were conducted for 30 days. Blood and tissue samples were collected at the end of the treatment for various experimental tests. Results revealed that MnCl2 did not significantly change in erythrogram with leukocytosis and neutrophilia but significantly increased serum aminotransferases and alkaline phosphatase activities, bilirubin (total, direct, and indirect), globulins, triglycerides, total cholesterol, creatinine, urea, manganese, iron and ferritin concentrations and hepatic glutathione, renal malondialdehyde and nitric oxide levels and hepatic superoxide dismutase activity, while serum albumin, hepatic malondialdehyde, and nitric oxide concentrations were significantly decreased besides non-statistical change in serum total proteins concentration. Ebselen has reduced the disturbances in these analytes in combined treatment group. Collectively, subacute exposure to MnCl2 causes disturbance in the leukogram, and hepatic and renal functions with marked renal oxidative stress. It also disturbed serum iron homeostasis and ferritin status. Remarkably, ebselen appears to be highly effective in attenuating the various adverse effects of manganese.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. WHO (1999) Concise international chemical assessment document 12. Manganese and its compounds, http://whqlibdoc.who.int/publications.

  2. Markiewicz-Górka I, Januszewska L, Michalak A, Prokopowicz A, Januszewska E, Pawlas N, Pawlas K (2015) Effects of chronic exposure to lead, cadmium, and manganese mixtures on oxidative stress in rat liver and heart. Arh Hig Rada Toksikol 66:51–62. https://doi.org/10.1515/aiht-2015-66-2515

    Article  CAS  PubMed  Google Scholar 

  3. HSDB (1998) Hazardous substances data bank, Toxicology data network, Bethesda, MD, National Institutes of Health, National Library of Medicine, http://toxnet.nlm.nih.gov.

  4. Lebda MA, El-Neweshy MS, El-Sayed YS (2012) Neurohepatic toxicity of subacute manganese chloride exposure and potential chemoprotective effects of lycopene. Neurotoxicology 33:98–104 https://doi.org/10.1016/j.neuro.2011.12.008

  5. Takasago T, Peters EE, Graham DI, Masayasu H, Macrae IM (1997) Neuroprotective efficacy of ebselen, an anti-oxidant with anti-inflammatory actions, in a rodent model of permanent middle cerebral artery occlusion. Br J Pharmacol 122(6):1251–1256. https://doi.org/10.1038/sj.bjp.0701426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Azad GK, Tomar RS (2014) Ebselen, a promising antioxidant drug: mechanisms of action and targets of biological pathways. Mol Biol Rep 41:4865–4879. https://doi.org/10.1007/s11033-014-3417-x

    Article  CAS  PubMed  Google Scholar 

  7. Dos Santos AP, Lucas RL, Andrade V et al (2012) Protective effects of ebselen (Ebs) and para-aminosalicylic acid (PAS) against manganese (Mn)-induced neurotoxicity. Toxicol Appl Pharmacol 258(3):394–402. https://doi.org/10.1016/j.taap.2011.12.003

    Article  CAS  PubMed  Google Scholar 

  8. Xu JH, Hu HT, Liu Y et al (2006) Neuroprotective effects of ebselen are associated with the regulation of Bcl-2 and Bax proteins in cultured mouse cortical neurons. Neurosci Lett 399(3):210–214. https://doi.org/10.1016/j.neulet.2006.02.024

    Article  CAS  PubMed  Google Scholar 

  9. Koizumi H, Fujisawa H, Suehiro E, Shirao S, Suzuki M (2011) Neuroprotective effects of ebselen following forebrain ischemia: involvement of glutamate and nitric oxide. Neurol Med Chir 51(5):337–343. https://doi.org/10.2176/nmc.51.337

    Article  Google Scholar 

  10. Yin Z, Lee E, Ni M, Jiang H, Milatovic D, Rongzhu L, Farina M, Rocha JBT, Aschner M (2011) Methylmercury-induced alterations in astrocyte functions are attenuated by ebselen. Neurotoxicology 32(3):291–299. https://doi.org/10.1016/j.neuro.2011.01.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Usuki F, Yamashita A, Fujimura M (2011) Post-transcriptional defects of antioxidant selenoenzymes cause oxidative stress under methylmercury exposure. J Biol Chem 286(8):6641–6649. https://doi.org/10.1074/jbc.M110.168872

    Article  CAS  PubMed  Google Scholar 

  12. Ardais AP, Santos FW, Nogueira CW (2008) Ebselen attenuates cadmium-induced testicular damage in mice. J Appl Toxicol 28(3):322–328. https://doi.org/10.1002/jat.1282

    Article  CAS  PubMed  Google Scholar 

  13. Husain K, Morris C, Whitworth C, Trammell GL, Rybak LP, Somani SM (1998) Protection by ebselen against cisplatin induced nephrotoxicity: antioxidant system. Mol Cell Biochem 178(1–2):127–133. https://doi.org/10.1023/A:1006889427520

    Article  CAS  PubMed  Google Scholar 

  14. Ozyigit F, Kucuk A, Akcer S et al (2015) Different dose-dependent effects of ebselen in sciatic nerve ischemia-reperfusion injury in rats. Bosn J Basic Med Sci 15(4):36–43. https://doi.org/10.17305/bjbms.2015.521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mahmoud SM, Bahr HI (2015) Potential protective effects of Ginkgo biloba and rosemary on hepatoencephalopathy and chromosomal aberrations induced by manganese chloride in rats. Int J Adv Res 3(3):483–497

    CAS  Google Scholar 

  16. ATSDR (2012) Toxicological profile for manganese. United States Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA

    Google Scholar 

  17. Tsoumbaris P (1990) Heavy metals determination in food stuff, PhD Thesis, Thessalonica, Greece.

  18. Bancroft JD, Stevens A, Turner DR (1996) Theory and practice of histological technique, 4th edn. Churchill Livingstone, New York, USA

    Google Scholar 

  19. Snedecor GW, Cochran WG (1994) Statistical method, 8th edn. Iowa State University Press, Ames, Iowa

    Google Scholar 

  20. Jozsef L, Filep JG (2003) Selenium-containing compounds attenuates peroxynitrite-mediated NF-kappa B and AP-1 activation and interleukin-8 gene and protein expression in human leukocytes. Free Radic Biol Med 35:1018–1027. https://doi.org/10.1016/S0891-5849(03)00439-8

    Article  CAS  PubMed  Google Scholar 

  21. Dobson AW, Erikson KM, Aschner M (2004) Manganese neurotoxicity. Ann N Y Acad Sci 1012:115–128. https://doi.org/10.1196/annals.1306.009

    Article  CAS  PubMed  Google Scholar 

  22. Aschner M, Guilarte TR, Schneider JS, Zheng W (2007) Manganese: recent advances in understanding its transport and neurotoxicity. Toxicol Appl Pharmacol 221(2):131–147. https://doi.org/10.1016/j.taap.2007.03.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Avila DS, Benedetto A, Au C, Manarin F, Erikson K et al (2012) Organotellurium and organoselenium compounds attenuate Mn-induced toxicity in Caenorhabditis elegans by preventing oxidative stress. Free Radic Biol Med 52(9):1903–1910. https://doi.org/10.1016/j.freeradbiomed.2012.02.044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Indravathi G, Kumari KK, Devi BC (2014) Manganese induced hematological alterations in albino rats: reversal effect of alpha tocopherol. Int J Innov Res Sci Eng Tchnol 3:14988–14999 https://www.ijirset.com/upload/2014/july/100_Manganese

    Google Scholar 

  25. Sharma J, Langer S (2014) Effect of manganese on haematological parameters of fish, Garra gotyla gotyla. J Entomol Zool Stud 2(3):77–81 http://www.entomoljournal.com/vol2Issue3/pdf/39.1.pdf

    Google Scholar 

  26. Chandel M, Jain GC (2016) Manganese-induced hematological alteration in Wistar rats. J Environ Occup Sci 5(4):77–81. https://doi.org/10.5455/jeos.20161126061501

    Article  Google Scholar 

  27. Hayes AW (2008) Principles and methods of toxicology. 5th edn. CRC Press, Taylor and Francis group, New York, USA.

  28. Zhang S, Zhou Z, Fu J (2003) Effect of manganese chloride exposure on liver and brain mitochondria function in rats. Environ Res 93:149–157. https://doi.org/10.1016/S0013-9351(03)00109-9

    Article  CAS  PubMed  Google Scholar 

  29. Gupta RC (2014) Biomarkers in toxicology. Academic Press/Elsevier, Amsterdam

    Google Scholar 

  30. Thrall MA, Weiser G, Allison R, Campbell T (2012) Veterinary hematology and clinical chemistry, 2nd edn. Wiley-Blackwell, Ames, USA

    Google Scholar 

  31. Ballatori N (2000) Molecular mechanism of hepatic metal transport. In: Zalups RK, Koropatnick DJ (eds) Molecular biology and toxicology of metals. Taylor and Francis, London

    Google Scholar 

  32. Goering PL (2003) The road to elucidating the mechanism of manganese bilirubin induced cholestasis. Toxicol Sci 73(2):216–219. https://doi.org/10.1093/toxsci/kfg112

    Article  CAS  PubMed  Google Scholar 

  33. Fidelia O, Otitoloju AA, Igwo-Ezikpe MN (2014) Usefulness of liver and kidney function parameters as biomarkers of ‘heavy metals’ exposure in a mammalian model Mus musculus. Afr J Biochem Res 8(3):65–73. https://doi.org/10.5897/AJBR2013.0728

    Article  CAS  Google Scholar 

  34. Barger AM, MacNeill AL (2015) Clinical pathology and laboratory techniques for veterinary technicians, 1st edn. John Wiley and Sons Ltd, Wiley-Blackwell, Hoboken, USA

    Book  Google Scholar 

  35. Rusetskaya NY, Borodulin VB (2015) Biological activity of organoselenium compounds in heavy metal intoxication. Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry 9(1):45–57 https://springer.longhoe.net/article/10.1134/S1990750815010072

    Article  Google Scholar 

  36. Baly DL, Schneiderman JS, Garcia-Welsh AL (1990) Effect of manganese deficiency on insulin binding, glucose transport and metabolism in rat adipocytes. J Nutr 120(9):1075–1079. https://doi.org/10.1093/jn/120.9.1075

    Article  CAS  PubMed  Google Scholar 

  37. Athar M, Vohora SB (1995) Heavy metals and environment, 1st edn. New Age International Publisher, New Delhi, India

    Google Scholar 

  38. Talwar GP, Hasnain SE, Sarin SK (2015) Textbook of biochemistry, biotechnology, allied and molecular medicine, 4th edn. Prentice-Hall of India, New Delhi, India

    Google Scholar 

  39. Abou-Hozaifa BM (1997) Effect of selenium supplementation on plasma lipid and lipoprotein cholesterol levels in adult rats. Saudi Med J 18(3):294–298 http://www.smj.org.sa/index.php/smj/article/viewFile/17295/9013

    Google Scholar 

  40. Chtourou Y, Garoui E, Boudawara T, Zeghal N (2014) Protective role of silymarin against manganese-induced nephrotoxicity and oxidative stress in rat. Environ Toxicol 29(10):1147–1154. https://doi.org/10.1002/tox.21845

    Article  CAS  PubMed  Google Scholar 

  41. Noguchi N, Yoshida Y, Kaneda H, Yamamoto Y, Niki E (1992) Action of ebselen as an antioxidant against lipid peroxidation. Biochem Pharmacol 44(1):39–44. https://doi.org/10.1016/0006-2952(92)90035-H

    Article  CAS  PubMed  Google Scholar 

  42. Hamai D, Campbell A, Bondy SC (2001) Modulation of oxidative events by multivalent manganese complexes in brain tissue. Free Radic Biol Med 31(6):763–768. https://doi.org/10.1016/S0891-5849(01)00639-6

    Article  CAS  PubMed  Google Scholar 

  43. Eybl V, Kotyzová D (2010) Protective effect of manganese in cadmium-induced hepatic oxidative damage, changes in cadmium distribution and trace elements level in mice. Interdisc Toxicol 3(2):68–72. https://doi.org/10.2478/v10102-010-0013-3

    Article  CAS  Google Scholar 

  44. Coassin M, Ursini F, Bindoli A (1992) Antioxidant effect of manganese. Arch Biochem Biophys 299:330–333. https://doi.org/10.1016/0003-9861(92)90282-2

    Article  CAS  PubMed  Google Scholar 

  45. Gabriel D, Riffel AP, Finamor IA et al (2013) Effects of subchronic manganese chloride exposure on Tambaqui (Colossoma macropomum) tissues: oxidative stress and antioxidant defenses. Arch Environ Contam Toxicol 64:659–667. https://doi.org/10.1007/s00244-012-9854-4

    Article  CAS  PubMed  Google Scholar 

  46. Klaassen CD (1974) Biliary excretion of manganese in rats, rabbits, and dogs. Toxicol Appl Pharhacol 29:458–468. https://doi.org/10.1016/0041-008X(74)90115-X

    Article  CAS  Google Scholar 

  47. Ballatori N, Miles E, Clarkson TW (1987) Homeostatic control of manganese excretion in the neonatal rat. Am J Physiol 252:R842–R847. https://doi.org/10.1152/ajpregu.1987.252.5.R842

    Article  CAS  PubMed  Google Scholar 

  48. Aschner JL, Aschner M (2005) Nutritional aspects of manganese homeostasis. Mol Aspects Med 26:353–362. https://doi.org/10.1016/j.mam.2005.07.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ponka P (2000) Iron metabolism: physiology and pathophysiology. J Trace Elem Exp Med 13:73–83. https://doi.org/10.1002/(SICI)1520-670X(2000)13:1<73::AID-JTRA9>3.0.CO;2-X

    Article  CAS  Google Scholar 

  50. Thompson K, Molina R, Donaghey T, Brain JD, Wessling-Resnick M (2006) The influence of high iron diet on rat lung manganese absorption. Toxicol Appl Pharmacol 210:17–23. https://doi.org/10.1016/j.taap.2005.05.014

    Article  CAS  PubMed  Google Scholar 

  51. Lefkowitch JH (2015) Scheuer’s liver biopsy interpretation, 9th edn. Elsevier

  52. Lukacˇınova´ A, Ra´cz O, Lova´sova´ E, Niˇstiar F (2011) Effect of lifetime low dose exposure to heavy metals on selected serum proteins of Wistar rats during three subsequent generations. Ecotoxicol Environ Saf 74:1747–1755. https://doi.org/10.1016/j.ecoenv.2011.04.017

    Article  CAS  Google Scholar 

  53. Lee D, Zacharski LR, Jacobs DR (2006) Comparison of the serum ferritin and percentage of transferrin saturation as exposure markers of iron-driven oxidative stress–related disease outcomes. Am Heart J 151(6):1247.e1–1247.e7 http://www.ahjonline.com/article/S0002-8703(06)00266-3/abstract

    Article  Google Scholar 

Download references

Acknowledgements

The author wish to thank Vet/Naif A. Algabri, Department of Veterinary Medicine, Faculty of Agriculture and Veterinary Medicine, Thamar University, Yemen, Department of Pathology, Faculty of Veterinary Medicine, Zagazig University, Egypt, for his support in performing the histopathology.

Author information

Authors and Affiliations

  1. Department of Clinical Pathology, Faculty of Veterinary Medicine, Zagazig University, 1 Alzeraa Street, Zagazig, Sharkia Province, 44511, Egypt

    Hager Tarek H. Ismail

Authors
  1. Hager Tarek H. Ismail
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hager Tarek H. Ismail.

Ethics declarations

Conflict of Interest

The author declares that he has no conflicts of interest.

Ethical Approval

The protocol of this study was approved by the Committee of Animal Welfare and Research Ethics, Faculty of Veterinary Medicine, Zagazig University, Egypt. National and institutional guidelines for the animal welfare were followed during the experiment. Human care criteria identified in the ‘Guide for the Care and Use of Laboratory Animals’ in scientific research prepared by the National Institutes of Health (NIH) was followed.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ismail, H.T.H. Hematobiochemical Disturbances and Oxidative Stress After Subacute Manganese Chloride Exposure and Potential Protective Effects of Ebselen in Rats. Biol Trace Elem Res 187, 452–463 (2019). https://doi.org/10.1007/s12011-018-1395-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-018-1395-x

Keywords

Search

Navigation