Alterations in tissue content of iron and zinc in mice bearing hepatoma 22a and their correction by zinc sulphate supplementation

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It is known that many tumors induce iron and zinc deficiency in the organism. We studied the content of these metals, as well as the specific activity of two antioxidant metal-dependent enzymes – catalase and superoxide dismutase of three distal organs (thymus, liver and spleen) in animals bearing transplantable hepatoma 22a. These alterations were compared to weight changes of organs. On day 21 of tumor growth, as compared to control group, nonheme iron content in all three organs was decreased, and zinc content – only in the thymus. The specific activities of catalase and superoxide dismutase were both increased in the thymus, while in the liver activity of superoxide dismutase decreased. At the same time point thymic involution and splenomegaly were developed. In order to normalize metal content mice bearing hepatoma 22a were supplemented with 22 mkg of zinc sulphate per ml of drinking water during 3 weeks. Zinc sulphate supplementation partly compensated zinc deficiency in the thymus, increased zinc content in the liver and restored iron content in three organs. It also normalized superoxide dismutase activity in the liver and had no influence on enzymes in other organs. Zinc supplementation did not influence the weight of spleen and liver, but prevented the development of thymic involution. Moreover, metal deficiency in the thymus was restored while the activity of antioxidant enzymes remained unchanged. Based on this we can conclude that thymus involution in hepatoma 22a mice was associated with iron and zinc deficiency in this organ and was not linked with antioxidant enzyme activity, while splenomegaly had no relation to both types of parameters in the spleen. Thus, zinc sulphate positively influences metabolism of two vital trace elements – zinc and iron in animals bearing hepatoma 22a, what contributes to maintaining of the central immune organ – the thymus, and along with this it improves antioxidant system of the liver.

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Sobre autores

Е. Zelenskyi

Institute of Experimental Medicine

Autor responsável pela correspondência
Email: ekissele@yandex.ru
Rússia, Saint-Petersburg

K. Rutto

Institute of Experimental Medicine

Email: ekissele@yandex.ru
Rússia, Saint-Petersburg

A. Trulioff

Institute of Experimental Medicine

Email: ekissele@yandex.ru
Rússia, Saint-Petersburg

D. Magazenkova

Institute of Experimental Medicine

Email: ekissele@yandex.ru
Rússia, Saint-Petersburg

A. Sokolov

Institute of Experimental Medicine

Email: ekissele@yandex.ru
Rússia, Saint-Petersburg

Е. Kisseleva

Institute of Experimental Medicine; North-Western Medical University named after II Mechnikov

Email: ekissele@yandex.ru
Rússia, Saint-Petersburg; Saint-Petersburg

Bibliografia

  1. Bjørklund G, Aaseth J, Skalny AV, Suliburska J, Skalnaya MG, Nikonorov AA, Tinkov AA (2017) Interactions of iron with manganese, zinc, chromium, and selenium as related to prophylaxis and treatment of iron deficiency. J Trace Elem Med Biol 41: 41–53. https://doi.org/10.1016/j.jtemb.2017.02.005
  2. Cunzhi H, Jiexian J, Xianwen Z, Jingang G, Shumin Z, Lili D (2003) Serum and tissue levels of six trace elements and copper/zinc ratio in patients with cervical cancer and uterine myoma. Biol Trace Elem Res 94(2): 113–122. https://doi.org/10.1385/BTER:94:2:113
  3. Idriss ME, Modawe GA, Shrif NE (2015) Assessment of serum zinc and iron among Sudanese women with breast cancer in Khartoum State. Int J Appl Sci Res Rev 2(2): 074–078.
  4. Gulbahce-Mutlu E, Baltaci SB, Menevse E, Mogulkoc R, Baltaci AK (2021) The effect of zinc and melatonin administration on lipid peroxidation, IL-6 Levels, and element metabolism in DMBA-induced breast cancer in rats. Biol Trace Elem Res 199(3): 1044–1051. https://doi.org/10.1007/s12011–020–02238–0
  5. Aksan A, Farrag K, Aksan S, Schroeder O, Stein J (2021) Flipside of the coin: iron deficiency and colorectal cancer. Front Immunol 12: 635899. https://doi.org/10.3389/fimmu.2021.635899
  6. Hoang BX, Han B, Shaw DG, Nimni M (2016) Zinc as a possible preventive and therapeutic agent in pancreatic, prostate, and breast cancer. Eur J Cancer Prevent 25(5): 457–461. https://doi.org/10.1097/CEJ.0000000000000194
  7. Gelbard A (2022) Zinc in cancer therapy revisited. Isr Med Assoc J 24(4): 258–262.
  8. Zohora F, Bidad K, Pourpak Z, Moin M (2018). Biological and immunological aspects of iron deficiency anemia in cancer development: a narrative review. Nutr Cancer 70(4): 546–556. https://doi.org/10.1080/01635581.2018.1460685
  9. John E, Laskow TC, Buchser WJ, Pitt BR, Basse PH, Butterfield LH, Kalinski P, Lotze MT (2010) Zinc in innate and adaptive tumor immunity. J Transl Med 8: 118. https://doi.org/10.1186/1479–5876–8–118
  10. Haase H, Rink L (2014) Zinc signals and immune function. Bio-Factors 40: 27–40. https://doi.org/10.1002/biof.1114
  11. Carrio R, Lopez DM (2013) Insights into thymic involution in tumor-bearing mice. Immunol Res 57(1–3): 106–114. https://doi.org/ 10.1007/s12026–013–8446–3
  12. King LE, Frentzel JW, Mann JJ, Fraker PJ (2005) Chronic zinc deficiency in mice disrupted T cell lymphopoiesis and erythropoiesis while B cell lymphopoiesis and myelopoiesis were maintained. J Am College Nutr 24(6): 494–502. https://doi.org/10.1080/07315724.2005.10719495
  13. Kido T, Suka M, Yanagisawa H (2022) Effectiveness of interleukin-4 administration or zinc supplementation in improving zinc deficiency-associated thymic atrophy and fatty degeneration and in normalizing T cell maturation process. Immunology 165(4): 445–459. https://doi.org/10.1111/imm.13452
  14. Yokoi K, Kimura M, Itokawa Y (1991) Effect of dietary iron deficiency on mineral levels in tissues of rats. Biol Trace Elem Res 29(3): 257–265. https://doi.org/10.1007/BF03032682
  15. Kuvibidila SR, Porretta C, Baliga BS, Leiva LE (2001) Reduced thymocyte proliferation but not increased apoptosis as a possible cause of thymus atrophy in iron-deficient mice. Br J Nutr 86: 157–162. https://doi.org/10.1079/BJN2001366
  16. Kuvibidila SR, Velez M, Gardner R, Penugonda K, Chandra LC, Yu L (2012) Iron deficiency reduces serum and in vitro secretion of interleukin-4 in mice independent of altered spleen cell proliferation. Nutr Res 32(2): 107–115. https://doi.org/10.1016/j.nutres.2011.12.005
  17. Mocchegiani E, Romeo J, Malavolta M, Costarelli L, Giacconi R, Diaz LE, Marcos A (2013) Zinc: dietar y intake and impact of supplementation on immune function in elderly. Age (Dordr) 35(3): 839–860. https://doi.org/10.1007/s11357–011–9377–3
  18. Nakahara W, Fukuoka F (1958) The newer concept of cancer toxin. Adv Cancer Res 5: 157–177. https://doi.org/10.1016/s0065–230x(08)60411-x
  19. Rubin H (2003) Cancer cachexia: its correlations and causes. Proc Natl Acad Sci U S A 100(9): 5384–5389. https://doi.org/10.1073/pnas.0931260100
  20. Jarosz M, Olbert M, Wyszogrodzka G, Młyniec K, Librowski T (2017) Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent NF-κB signaling. Inflammopharmacology 25: 11–24. https://doi.org/10.1007/s10787–017–0309–4
  21. Katerji M, Filippova M, Duerksen-Hughes P (2019) Approaches and Methods to Measure Oxidative Stress in Clinical Samples: Research Applications in the Cancer Field. Oxid Med Cell Longev 2019: 1279250. https://doi.org/10.1155/2019/1279250
  22. Gagandeep, Rao AR., Kale RK (2005) Oxidative stress in tumour-bearing fore-stomach and distant normal organs of Swiss albino mice. Indian J Biochem Biophys 42(4): 216–221. PMID: 23923544
  23. Bhattacharyya A, Mandal D, Lahiry L, Bhattacharyya S, Chattopadhyay S, Ghosh UK, Sa G, Das T (2007) Black tea–induced amelioration of hepatic oxidative stress through antioxidative activity in EAC-bearing mice. J Environ Pathol Toxicol Oncol 26(4): 245–254. https://doi.org/10.1615/jenvironpatholtoxicoloncol.v26.i4.10
  24. Mandal D, Lahiry L, Bhattacharyya A, Chattopadhyay S, Siddiqi M, Sa G, Das T (2005) Black tea protects thymocytes in tumor-bearing animals by differential regulation of intracellular ROS in tumor cells and thymocytes. J Environ Pathol Toxicol Oncol 24(2): 91–104. https://doi.org/10.1615/jenvpathtoxoncol.v24.i2.30
  25. Barbouti A, Vasileiou PVS, Evangelou K, Vlasis KG, Papoudou-Bai A, Gorgoulis VG, Kanavaros P (2020) Implications of oxidative stress and cellular senescence in age-related thymus involution. Oxid Med Cell Longev 2020: 7986071. https://doi.org/10.1155/2020/7986071
  26. Zelenskyi EA, Rutto KV, Kudryavtsev IV, Sokolov AV, Kisseleva EP (2021) Iron content and cellular proliferation in thymus and spleen of hepatoma 22A bearing mice. Cell Tissue Biol 15(4): 393–401. https://doi.org/10.1134/S1990519X21040118
  27. Зеленский ЕА, Рутто КВ, Соколов АВ, Киселева ЕП (2021) Прием цинка тормозит развитие инволюции тимуса при опухолевом росте у мышей. Вопр онкол 67(3): 436–441. [Zelenskiy EA, Rutto KV, Sokolov AV, Kisseleva EP (2021) Zinc supplementation prevents the development of thymic involution induced by tumor growth in mice. Vopr onkol 67(3): 436–441. (In Russ)]. https://doi.org/10.37469/0507–3758–2021–67–3–436–441
  28. Mocchegiani E, Santarelli L, Muzzioli M, Fabris N (1995) Reversibility of the thymus involution and of age-related peripheral immune dysfunction by zinc supplementation in old mice. Int J Immunopharmacol 17(9): 703–718. https://doi.org/10.1016/0192–0561(95)00059-b
  29. Rebouche CJ, Wilcox CL, Widness JA (2004) Microanalysis of non-heme iron in animal tissues. J Biochem Biophys Methods 58(3): 239–251. https://doi.org/10.1016/j.jbbm.2003.11.003
  30. Hadwan MH, Ali SK (2018) New spectrophotometric assay for assessments of catalase activity in biological samples. Anal Biochem 542: 29–33. https://doi.org/10.1016/j.ab.2017.11.013
  31. Spitz DR, Oberley LW (1989) An assay for superoxide dismutase activity in mammalian tissue homogenates. Anal Biochem 179(1): 8–18. https://doi.org/10.1016/0003–2697(89)90192–9
  32. Samygina VR, Sokolov AV, Bourenkov G, Schneider TR, Anashkin VA, Kozlov SO, Kolmakov NN, Vasilyev VB (2017) Rat ceruloplasmin: new labile copper binding site and zinc/copper mosaic. Metallomics 9(12): 1828–1838. https://doi.org/10.1039/c7mt00157f
  33. Vigorita VJ, Hutchins GM (1978) The Thymus in hemochromatosis. Am J Pathol 93:661–666.
  34. Roberts RL, Sandra A (1994) Transport of transferrin across the blood-thymus barrier in young rats. Tissue and Cell 26 (5): 757–766.
  35. Kiseleva EP, Suvorov AN, Ogurtsov RP (1998) The role of apoptosis in the thymic involution during growth of the syngeneic transplanted tumor in mice. Biol Bull 25(2): 129–135.
  36. Skrajnowska D, Korczak BB, Tokarz A, Kazimierczuk A, Klepacz M, Makowska J, Gadzinski B (2015) The effect of zinc and phytoestrogen supplementation on the changes in mineral content of the femur of rats with chemically induced mammary carcinogenesis. J Trace Elem Med Biol 32: 79–85. https://doi.org/10.1016/j.jtemb.2015.06.004
  37. Kaiserlian D, Savino W, Dardenne M (1983) Studies of the thymus in mice bearing the Lewis lung carcinoma. II. Modulation of thymic natural killer activity by thymulin (FTS-Zn) and the antimetastatic effect of zinc. Clin Immunol Immunopathol 28: 192–204. https://doi.org/10.1016/0090–1229(83)90154-x
  38. Iovino L, Mazziotta F, Carulli G, Guerrini F, Morganti R, Mazzotti V, Maggi F, Macera L, Orciuolo E, Buda G, Benedetti E, Caracciolo F, Galimberti S, Pistello M, Petrini M (2018) High-dose zinc oral supplementation after stem cell transplantation causes an increase of TRECs and CD4+ naïve lymphocytes and prevents TTV reactivation. Leuk Res 70: 20–24. https://doi.org/10.1016/j.leukres.2018.04.016
  39. Cardinale A, De Luca CD, Locatelli F, Velardi E (2021) Thymic function and T-cell receptor repertoire diversity: implications for patient response to checkpoint blockade immunotherapy. Front Immunol 12: 752042. https://doi.org/10.3389/fimmu.2021.752042
  40. Zhou L, Zhao B, Zhang L, Wang S, Dong D, Lv H, Shang P (2018) Alterations in cellular iron metabolism provide more therapeutic opportunities for cancer. Int J Mol Sci 19(5): 1545. https://doi.org/10.3390/ijms19051545
  41. King LE, Fraker PJ (1991) Flow cytometric analysis of the phenotypic distribution of splenic lymphocytes in zinc-deficient adult mice. J Nutr 121(9): 1433–1438. https://doi.org/10.1093/jn/121.9.1433
  42. Beach RS, Gershwin ME, Hurley LS (1979) Altered thymic structure and mitogen responsiveness in postnatally zinc-deprived mice. Dev Comp Immunol 3(4): 725–738. https://doi.org/ 10.1016/s0145–305x(79)80065–8
  43. Cox DH, Schlicker SA, Chu RC (1969) Excess dietary zinc for the maternal rat, and zinc, iron, copper, calcium, and magnesium content and enzyme activity in maternal and fetal tissues. J Nutr 98(4): 459–466. https://doi.org/10.1093/jn/98.4.459
  44. Keen CL, Reinstein NH, Goudey-Lefevre J, Lefevre M, Lönnerdal B, Schneeman BO, Hurley LS (1985) Effect of dietary copper and zinc levels on tissue copper, zinc, and iron in male rats. Biol Trace Elem Res 8(2): 123–136. https://doi.org/10.1007/BF02917466
  45. Klecha AJ., Salgueiro J, Wald M, Boccio J, Zubillaga M, Leonardi NM, Gorelik G, Cremaschi GA (2005) In vivo iron and zinc deficiency diminished T- and B-selective mitogen stimulation of murine lymphoid cells through protein kinase C-mediated mechanism. Biol Trace Elem Res 104(2): 173–183. https://doi.org/10.1385/BTER:104:2:173
  46. Staniek H (2019) The сombined еffects of Cr(III) supplementation and iron deficiency on the сopper and zinc status in Wistar rats. Biol Trace Elem Res 190(2): 414–424. https://doi.org/10.1007/s12011–018–1568–7
  47. Campos MS, Barrionuevo M, Alférez MJ, Gómez-Ayala AE, Rodríguez-Matas MC, Lopez Aliaga I, Lisbona F (1998) Interactions among iron, calcium, phosphorus and magnesium in the nutritionally iron-deficient rat. Exp Physiol 83(6): 771–781. https://doi.org/10.1113/expphysiol.1998.sp004158
  48. Ranade SC, Nawaz S, Chakrabarti A, Gressens P, Mani S (2013) Spatial memory deficits in maternal iron deficiency paradigms are associated with altered glucocorticoid levels. Horm Behav 64(1): 26–36. https://doi.org/10.1016/j.yhbeh.2013.04.005
  49. Liao Z, Chua D, Tan NS (2019) Reactive oxygen species: a volatile driver of field cancerization and metastasis. Mol Cancer 18: 65. https://doi.org/10.1186/s12943–019–0961-y
  50. Rajendran J, Pachaiappan P, Subramaniyan S (2019) Dose-dependent chemopreventive effects of citronellol in DMBA-induced breast cancer among rats. Drug Dev Res 80(6): 867–876. https://doi.org/10.1002/ddr.21570
  51. Wallace J (2000) Humane endpoints and cancer research. ILAR J 41(2): 87–93. https://doi.org/10.1093/ilar.41.2.87

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2. Fig. 1. Effect of tumor growth on organ weight. Ordinate axis: organ weight, mg, (a) – thymus, (b) – spleen and (c) – liver (n = 15–20). Abscissa axis: days after tumor inoculation, days. Designations: C (Control) – control animals, Hep (Hepatoma 22a) – mice with hepatoma 22a. Here and below, data are presented as the mean value and error of the mean (M ± m), asterisks indicate significant differences between the tumor (Hep) and control (C) groups of animals: * – p < 0.05, ** – p < 0.01, *** – p < 0.001.

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3. Fig. 2. Effect of tumor growth and zinc sulfate intake for 21 days on endogenous zinc content in organs. Ordinate axis: (a) zinc content per unit mass, µg/g wet tissue, (b, c, d) zinc content per whole organ, µg/organ. Each group included 10 mice. Abscissa axis: animal groups. Designations: C (Control) – control animals, Hep (Hepatoma) – mice with hepatoma 22a, Hep+Zn22 – mice with hepatoma 22a that received zinc sulfate (22 µg/ml with drinking water). Asterisks indicate reliable differences between each experimental group and group (C) of control animals.

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4. Fig. 3. Effect of different concentrations of zinc sulfate in drinking water on the content of endogenous zinc in the thymus. Ordinate axis: content of endogenous zinc in the thymus per organ, µg/organ. Abscissa axis: animal groups C1 (Control1) – group of control animals; C2 (Control2) – group of control animals that received zinc sulfate at a concentration of 22 µg/ml for 21 days; Hep (Hepatoma) – animals with hepatoma 22a; Hep+Zn11, Hep+Zn22, Hep+Zn66 – animals with hepatoma 22a that received zinc sulfate at concentrations of 11, 22 and 66 µg/ml, respectively, for 21 days. Each group included 10 mice. Asterisks indicate reliable differences between each of the experimental groups in relation to the control (C1) group of animals.

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5. Fig. 4. Effect of tumor growth and zinc sulfate intake for 21 days on non-heme iron content in organs. Ordinate axis: (a) iron content per unit weight, µg/g wet tissue, (b, c, d) iron content per whole organ, µg/organ. Each group included 15–20 mice. Abscissa axis: animal groups. Designations: C (Control) – control animals, Hep (Hepatoma) – mice with hepatoma 22a, Hep+Zn22 – mice with hepatoma 22a that received zinc sulfate (22 µg/ml with drinking water). Asterisks indicate reliable differences between each experimental group and the control group of animals (C).

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6. Fig. 5. Effect of tumor growth on non-heme iron content in the thymus. Ordinate axis: (a) iron content in the thymus, µg/g wet tissue; (b) iron content in the thymus per organ, µg/organ, C – in control mice and Hep – in mice with hepatoma 22a. Each group included 15–20 mice. Abscissa axis: time after inoculation with hepatoma 22a, days.

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7. Fig. 6. Effect of tumor growth and zinc sulfate intake for 21 days on organ weight. Ordinate axis: (a) thymus weight, mg, (b) spleen weight, mg, (c) liver weight, mg. Each group had 10 mice. Designations: C (Control) – control animals, Hep (Hepatoma) – mice with hepatoma 22a, Hep+Zn22 – mice with hepatoma 22a that received zinc sulfate (22 μg/ml drinking water). Asterisks indicate reliable differences between each experimental group and group (C) of control animals.

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8. Fig. 7. Effect of tumor growth and zinc sulfate intake for 21 days on the specific activity of antioxidant enzymes in organs. Ordinate axis: (a) – catalase (CAT) activity, µmol (µmol) H2O2 absorbed in 1 min per 1 mg total protein (n = 10); (b) – superoxide dismutase (SOD) activity, c.u. per 1 mg total protein (n = 10). Abscissa axis: animal groups, C (Control) – control animals, Hep (Hepatoma) – mice with hepatoma 22a, Hep+Zn22 – mice with hepatoma 22a, receiving zinc sulfate (22 µg/ml with drinking water). Asterisks indicate reliable differences between each experimental group and the control group of animals (C).

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9. Fig. 8. Positive changes in the organism of animals with hepatoma 22a as a result of taking zinc sulfate at a concentration of 22 μg/ml in drinking water for 21 days. Systemic changes in mice with hepatoma 22a, starting from the 21st day of its growth, include a decrease in the content of non-heme iron in the thymus, liver and spleen, as well as a decrease in the zinc content in the thymus, which are accompanied by the development of thymus involution and splenomegaly. In addition, animals with hepatoma were noted to have disturbances in the activity of antioxidant enzymes: an increase in the activity of catalase and SOD in the thymus (not shown) and a decrease in SOD activity in the liver. Taking zinc sulfate with drinking water by animals with hepatoma 22a prevents a decrease in the content of non-heme iron in the thymus, liver and spleen and increases the zinc content in the thymus and liver. At the same time, SOD activity in the liver is also restored. Taking zinc sulfate slows down the development of thymus involution and does not affect the mass of other organs – the spleen and liver. Designations: ↑ increase, ↓ decrease.

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