Comparative assessment of the effects of meso-2,3-dimercaptosuccinic acid and salinomycin on spleen function of cadmium-exposed mice

  • Kalina Kamenova
  • Yordanka Gluhcheva
  • Petar Dorkov
  • Juliana IvanovaEmail author
Research Article


In this study, we present experimental data on the effects of meso-2,3-dimercaptosuccinic acid (DMSA) and tetraethylammonium salt of salinomycinic acid (Sal) on cadmium-induced spleen dysfunction and altered essential metal balance in mice. Sixty-day-old male mice (ICR line) were randomly divided into four groups: untreated control group (Ctrl)—obtained distilled water for 28 days, toxic control group (Cd)—exposed to cadmium acetate dihydrate at average daily dose of 20mg/kg body weight (BW) for 14 days, Cd + DMSA group—obtained cadmium acetate dihydrate as the toxic control group followed by treatment with 20mg/kg BW DMSA for 2 weeks, and Cd + Sal group—mice exposed to cadmium acetate dihydrate at average daily dose of 20mg/kg BW for 2 weeks followed by administration of Sal at an average daily dose of 20mg/kg BW for 2 weeks. The compounds were administered orally via the drinking water of the animals. We found that cadmium exposure caused splenomegaly and reduced the hemoglobin and hematocrit levels and total red blood cell count compared with untreated controls. Cadmium intoxication of mice induced accumulation of the toxic metal ion in the blood and spleen. Alterations in the endogenous levels of calcium (Ca) and iron (Fe) in the spleen of cadmium-exposed mice compared with those in untreated controls were observed. Treatment of cadmium-exposed mice with DMSA or Sal recovered the spleen weight and hematological parameters to normal control values, decreased cadmium concentration in the blood and spleen, and improved splenic architecture. The results prove that Sal is a potential antidote for treatment of Cd-induced spleen dysfunction.


Cadmium Splenomegaly Anemia DMSA Salinomycin 


Funding information

This work was supported by the Sofia University “St. Kliment Ohridski” Science Fund (grants no. 4/2015 and 5/2016, PI: Juliana Ivanova).

Compliance with ethical standards

The experimental protocol was approved by the Ethics Committee of the Institute of Experimental Morphology, Pathology and Anthropology with Museum of Bulgarian Academy of Sciences (approval number: 15/03/2016).


  1. Aaseth J, Grisponi G, Anderson O (2016) Chelation therapy in the treatment of metal intoxication, 1st edn. Elsevier Inc, AmsterdamGoogle Scholar
  2. Adon MA, Diaby V, Kipre GR, Konan KM, N’Guessan AAJ, Djama AJ, Dosso M (2018) Effect of acute cadmium exposure on body weight, spleen size and the relative number of spleen cells in mice. J Chem Biol Phys Sci 8(1):201–208Google Scholar
  3. Ashour TH (2014) Preventative effects of caffeic acid phenyl ester on cadmium intoxication induced hematological and blood coagulation disturbances and hepatorenal damage in rats. ISRN Hematol 2014:764754. CrossRefGoogle Scholar
  4. Blanusa M, Varnai VM, Piasek M, Kostial K (2005) Chelators as antidotes of metal toxicity: therapeutic and experimental aspects. Curr Med Chem 12(23):2771–2794CrossRefGoogle Scholar
  5. Chinopoulos C, Tretter L, Rozsa A, Adam-Vizi V (2000) Exacerbated responses to oxidative stress by an Na(+) load in isolated nerve terminals: the role of ATP depletion and rise of [Ca2+]i. J Neurosci 20(6):2094–2103CrossRefGoogle Scholar
  6. Demenesku J, Mirkov I, Ninkov M, Popov Aleksandrov A, Zolotarevski L, Kataranovski D, Kataranovski M (2014) Acute cadmium administration to rats exerts both immunosuppressive and proinflammatory effects in spleen. Toxicology 326:96–108CrossRefGoogle Scholar
  7. Flora SJ, Pachauri V (2010) Chelation in metal intoxication. Int J Environ Res Public Health 7(7):2745–2788CrossRefGoogle Scholar
  8. Gluhcheva Y, Ivanova J, Ganeva S, Mitewa M (2013) Effects of cadmium and monensin on spleen of mice, subjected to subacute cadmium intoxication. J Toxicol Environ Health A 76(4-5):328–332CrossRefGoogle Scholar
  9. Gluhcheva Y, Kamenova K, Dorkov P, Yu L, Skalnaya M, Ivanova J (2018) Effects of meso-2,3-dimercaptosuccinic acid, monensin and salinomycin on the concentrations of cadmium and some essential elements in skeletal muscles of Cd-exposed mice. J Trace Elem Med Biol 50:596–600CrossRefGoogle Scholar
  10. Hamada T, Tanimoto A, Arima N, Idel Y, Sasaguri T, Sh S, Yoshitaka M, Wang K-Y, Sasaguril Y (1998) Pathological study of cadmium-induced splenomegaly associated with anemia in rats. J UOEH 20(1):11–19CrossRefGoogle Scholar
  11. Horiguchi H, Teranishi H, Niiya K, Aoshima K, Katoh T, Sakuragawa N, Kasuaya M (1994) Hypoproduction of erythropoietin contributes to anemia in chronic cadmium intoxication: clinical study on Itai-itai disease in Japan. Arch Toxicol 68(10):632–636CrossRefGoogle Scholar
  12. Horiguchi H, Sato M, Konno N, Fukushima M (1996) Long-term cadmium exposure induces anemia in rats through hypoinduction of erythropoietin in the kidneys. Arch Toxicol 71:11–19CrossRefGoogle Scholar
  13. Horiguchi H, Oguma E, Kayama F (2011) Cadmium induces anemia through interdependent progress of hemolysis, body iron accumulation, and insufficient erythropoietin production in rats. Toxicol Sci 122(1):198–210CrossRefGoogle Scholar
  14. Inra CN, Zhou BO, Acar M, Murphy MM, Richardson J, Zhao Z, Morisson SJ (2015) A perisinusoidal niche for extramedullary haematopoiesis in the spleen. Nature 527(7579):466–471CrossRefGoogle Scholar
  15. Ivanova J, Petrova E, Kamenova K, Gluhcheva Y (2017) Comparative effects of meso-2,3-dimercaptosuccinic acid, monensin, and salinomycin on cadmium-induced brain dysfunction in cadmium-intoxicated mice. Interdiscip Toxicol 10(3):107–113CrossRefGoogle Scholar
  16. Kamenova K, Gluhcheva Y, Vladov I, Stoykova S, Ivanova J (2018) Ameliorative effect of the anticancer agent salinomycin on cadmium-induced hepatotoxicity and renal dysfunction in mice. Environ Sci Pollut Res Int 25(4):3616–3627CrossRefGoogle Scholar
  17. Khaleda SAA, Seifeldein GS (2016) Splenomegaly in patients with sideropenic anemias: clinical and hematologics. J Hematol 5(3):83–93CrossRefGoogle Scholar
  18. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoSBiol 8(6):e1000412. CrossRefGoogle Scholar
  19. Mebius RE, Kraal G (2005) Structure and function of the spleen. Nat Rev Immunol 5(8):606–616CrossRefGoogle Scholar
  20. Merra E, Calzaretti G, Bobba A, Storelli MM, Casalino E (2014) Antioxidant role of hydroxytyrosol on oxidative stress in cadmium-intoxicated rats: different effect in spleen and testes. Drug Chem Toxicol 37(4):420–426CrossRefGoogle Scholar
  21. Moqadam SMM, Salehi S, Mohammadkhani S, Saljooghi AS (2017) The effect of cadmium on iron metabolism in rats: a combined therapy by deferasirox and deferiprone. J Chem Pharm Res 9(4):310–314Google Scholar
  22. Moulis JM (2010) Cellular mechanisms of cadmium toxicity related to the homeostasis of essential metals. Biometals 23(5):877–896CrossRefGoogle Scholar
  23. Nordberg GF, Bernard A, Diamond GL, Duffus JH, Illing P, Nordberg M, Bergdahl IA, Jin T, Skerfving S (2018) Risk assessment of effects of cadmium on human health (IUPAC Technical Report). Pure Appl Chem 90(4):755–808CrossRefGoogle Scholar
  24. Park JD, Cherrington NJ, Klaassen CD (2002) Intestinal absorption of cadmium is associated with divalent metal transporter 1 in rats. Toxicol Sci 68(2):288–294CrossRefGoogle Scholar
  25. Pathak N, Khandelwal S (2007) Role of oxidative stress and apoptosis on cadmium induced thymic atrophy and splenomegaly in mice. Toxicol Lett 169:95–108CrossRefGoogle Scholar
  26. RafatiRahimzadeh M, RafatiRahimzadeh M, Kazemi S, Moghadamnia AA (2017) Cadmium toxicity and treatment: an update. Caspian J Intern Med 8(3):135–145Google Scholar
  27. Rikans LE, Yamano T (2000) Mechanisms of cadmium-mediated acute hepatotoxicity. J Biochem Mol Toxicol 14:110–117CrossRefGoogle Scholar
  28. Suzuki KT, Ohnuki R, Yaguchi K, Yamada YK (2009) Accumulation and chemical forms of cadmium and its effect on essential metals in rat spleen and pancreas. J Toxicol Environ Health 11:727–737CrossRefGoogle Scholar
  29. Yadav N, Khandelwal S (2006) Effect of Picroliv on cadmium-induced hepatic and renal damage in the rat. Hum Exp Toxicol 25(10):581–591CrossRefGoogle Scholar
  30. Yamano T, Shimizu M, Noda T (1998) Comparative effects of repeated administration of cadmium on kidney, spleen, thymus, and bone marrow in 2-, 4-, and 8-month-old male Wistar rats. Toxicol Sci 46:393–402CrossRefGoogle Scholar
  31. Yapo FA, Diaby V, N’Dah JK, Adon MA, Djyh NB, Dosso M, Djaman JA (2017) Assessment of biochemical parameters and histological study of spleen in the Wistar rats exposed to cadmium sulfate. IOSR J Biotechnol Biochem 3(2):21–30CrossRefGoogle Scholar
  32. Yiin SJ, Chern CL, Sheu JY, Lin TH (2000) Cadmium-induced liver, heart, and spleen lipid peroxidation in rats and protection by selenium. Biol Trace Elem Res 78(1-3):219–230CrossRefGoogle Scholar
  33. Zakeri S, Gorji N, Akhtari M, Moeini R (2018) Splenectomy may have more complications than currently proven. Med Hypothesis 112:43–46CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Faculty of Chemistry and PharmacySofia University “St. Kliment Ohridski”SofiaBulgaria
  2. 2.Institute of Experimental Morphology, Pathology and Anthropology with Museum – BASSofiaBulgaria
  3. 3.Chemistry Department, R&DBIOVET JSCPeshteraBulgaria
  4. 4.Faculty of MedicineSofia University “St. Kliment Ohridski”SofiaBulgaria

Personalised recommendations