Effect of chronic intake of cadmium chloride on the transcriptional activity of metallothionein and zinc transporter genes

Cover Page

Cite item

Full Text

Abstract

Introduction. Cadmium chloride is an inorganic compound containing cadmium, a heavy metal that is one of the active environmental pollutants today. Damage to organs in experimental animals due to cadmium poisoning is similar to that in humans. In this work, the activity of metallothionein and zinc transporters genes was studied in a chronic model of cadmium-induced poisoning in experimental animals.

Materials and methods. The experiment was carried out using seventy two individuals of white inbred rats of both sexes, the average weight of which was 215 g. Animals from four groups were injected with a solution of cadmium chloride in four different doses, respectively, individuals of the fifth group, the control group, received an equimolar volume of pure water. The objects of the study were the kidneys and livers of rats, removed after the animals were withdrawn from the experiment. Next, the activity of the Mt1A, Mt2A, Mt3A, Zip1 and Znt1 genes was analyzed in organ samples using real-time PCR.

Results. Significant increases in the expression multiplicity of Mt1A, Mt2A and Mt3A metallothionein genes in the kidneys at different doses of the toxicant were revealed. In liver samples, a decrease in the expression of the Mt2A gene was found in the experimental group exposed to cadmium chloride at a dose of 0.1 mg/kg (p<0.05). For the Znt1 gene in rat liver tissue, there was a statistically significant decrease in expression at a dose of 0.001 mg/kg (p<0.05) and, conversely, an increase at doses of 0.1 and 1 mg/kg (p<0.05) compared to the control group. Analysis of the level of transcripts of the Zip1 gene in the kidneys and liver after 6 months of inoculation with the toxicant in the presented doses did not reveal statistically significant differences between the groups.

Limitations. Laboratory animals of the only biological species were used for the experiment. Four doses of the cadmium salt alone were evaluated.

Conclusion. The results obtained allow concluding that the level of expression of the Mt1A, Mt2A and Mt3A genes in the kidneys can play the role of a diagnostic marker in chronic poisoning with the toxicant under study.

Compliance with ethical standards. Date of the meeting of the bioethical commission of the Federal Budgetary Institution “Ufa Research Institute of Occupational Medicine and Human Ecology” 12/11/2023 No. 01-12. Throughout the study, the animals were kept under standard conditions with 12 hours of artificial lighting during the day, a relatively constant level of humidity (30–70%) and an air temperature of 20–25 °C. Manipulations with all animals were carried out strictly in compliance with the rules prescribed in basic regulatory documents, including the European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes (Strasbourg, 1986) and the Declaration of Helsinki on the Humane Treatment of Animals.

Contribution:
Gizatullina A.A. — concept and design of the study, collection and processing of material, statistical processing, text writing;
Valova Y.V. — collection and processing of material, statistical processing;
Khusnutdinova N.Yu., Smolyankin D.O., Karimov D.D. — collection and processing of material;
Karimov D.O. — concept and design of the study, statistical processing;
Muhammadieva G.F. — editing;
Repina E.F. — concept and design of the study.
All authors are responsible for the integrity of all parts of the manuscript and approval of the manuscript final version.

Conflict of interest. The authors declare no conflict of interest.

Acknowledgement. Industry research program of the Federal Service for Supervision of Consumer Rights Protection and Human Welfare for 2021–2025. clause 6.1.9. "Experimental substantiation of highly sensitive markers of the effects of toxic metals on the body and development of preventive measures".

Received: December 26, 2023 / Revised: January 29, 2024 / Accepted: February 29, 2024 / Published: March 15, 2024

About the authors

Alina A. Gizatullina

Ufa Research Institute of Occupational Health and Human Ecology

Author for correspondence.
Email: alinagisa@yandex.ru
ORCID iD: 0000-0002-7321-0864

Junior researcher of the Dept. of toxicology and genetics with an experimental laboratory animal clinic of the Ufa Research Institute of Occupational Medicine and Human Ecology, Ufa, 450106, Russian Federation

e-mail: alinagisa@yandex.ru

Russian Federation

Yana V. Valova

Ufa Research Institute of Occupational Health and Human Ecology

Email: Q.juk@yandex.ru
ORCID iD: 0000-0001-6605-9994

Junior researcher of the Dept. of toxicology and genetics with an experimental laboratory animal clinic of the Ufa Research Institute of Occupational Medicine and Human Ecology, Ufa, 450106, Russian Federation

e-mail: Q.juk@yandex.ru

Russian Federation

Denis A. Smolyankin

Ufa Research Institute of Occupational Health and Human Ecology

Email: smolyankin.denis@yandex.ru
ORCID iD: 0000-0002-7957-2399

Junior researcher of the Dept. of toxicology and genetics with an experimental laboratory animal clinic of the Ufa Research Institute of Occupational Medicine and Human Ecology, Ufa, 450106, Russian Federation

e-mail: smolyankin.denis@yandex.ru

Russian Federation

Nadezhda Yu. Khusnutdinova

Ufa Research Institute of Occupational Health and Human Ecology

Email: h-n-yu@yandex.ru
ORCID iD: 0000-0001-5596-8180

Researcher of the Dept. of toxicology and genetics with an experimental laboratory animal clinic of the Ufa Research Institute of Occupational Medicine and Human Ecology, Ufa, 450106, Russian Federation

e-mail: h-n-yu@yandex.ru

Russian Federation

Denis O. Karimov

Ufa Research Institute of Occupational Health and Human Ecology

Email: karimovdo@gmail.com
ORCID iD: 0000-0003-0039-6757

MD, PhD, head of the Dept. of toxicology and genetics with an experimental laboratory animal clinic of the Ufa Research Institute of Occupational Medicine and Human Ecology, Ufa, 450106, Russian Federation

e-mail: karimovdo@gmail.com

Russian Federation

Denis D. Karimov

Ufa Research Institute of Occupational Health and Human Ecology

Email: lich-tsar@mail.ru
ORCID iD: 0000-0002-1962-2323

MD, PhD, senior researcher of the Dept. of toxicology and genetics with an experimental laboratory animal clinic of the Ufa Research Institute of Occupational Medicine and Human Ecology, Ufa, 450106, Russian Federation

e-mail: lich-tsar@mail.ru

Russian Federation

Guzel F. Mukhammadiyeva

Ufa Research Institute of Occupational Health and Human Ecology

Email: ufniimt@mail.ru
ORCID iD: 0000-0002-7456-4787

MD, PhD, senior researcher of the Dept. of toxicology and genetics with an experimental laboratory animal clinic of the Ufa Research Institute of Occupational Medicine and Human Ecology, Ufa, 450106, Russian Federation

e-mail: ufniimt@mail.ru

Russian Federation

Elvira F. Repina

Ufa Research Institute of Occupational Health and Human Ecology

Email: e.f.repina@bk.ru
ORCID iD: 0000-0001-8798-0846

MD, PhD, senior researcher of the Dept. of toxicology and genetics with an experimental laboratory animal clinic of the Ufa Research Institute of Occupational Medicine and Human Ecology, 450106, Ufa, Russian Federation

e-mail: e.f.repina@bk.ru

Russian Federation

References

  1. Kostyleva N.V., Racheva N.L. Characteristics of Pollutants [Kharakteristiki zagryaznyayushchikh veshchestv]. Perm’: Ekologiya; 2017. (in Russian)
  2. Kulentsan A.L., Marchuk N.A. Analysis of the impact of pollutants on humans and the environment. Izvestiya vysshikh uchebnykh zavedeniy «Khimiya i khimicheskaya tekhnologiya». 2022; 65(1): 116–21. https://doi.org/10.6060/ivkkt.20226501.6531 (in Russian)
  3. Yildirim S., Celikezen F.C., Oto G., Sengul E., Bulduk M., Tasdemir M., et al. An investigation of protective effects of litium borate on blood and histopathological parameters in acute cadmium-induced rats. Biol. Trace Elem. Res. 2018; 182(2): 287−94. https://doi.org/10.1007/s12011-017-1089-9
  4. Sanjeev S., Bidanchi R.M., Murthy M.K., Gurusubramanian G., Roy V.K. Influence of ferulic acid consumption in ameliorating the cadmium-induced liver and renal oxidative damage in rats. Environ. Sci. Pollut. Res. Int. 2019; 26(20): 20631−53. https://doi.org/10.1007/s11356-019-05420-7
  5. Arustamyan O.M., Tkachishin V.S., Alekseychuk A.Yu. Influence of сadmium compounds on the human body. Meditsina neotlozhnykh sostoyaniy. 2016; (7): 109–14. https://doi.org/10.22141/2224-0586.7.78.2016.86103 https://elibrary.ru/xeelvb (in Russian)
  6. Bazyl’chuk T.A., Braykova A.M., Shirkin A.A., Braykov N.D. Study of the hygienic properties and chemical toxicological safety of disposable medical masks. Endless light in science. 2023; (3–3): 66–73. https://doi.org/10.24412/2709-1201-2023-66-73 https://elibrary.ru/frergx (in Russian)
  7. Genchi G., Sinicropi M.S., Lauria G., Carocci A., Catalano A. The effects of cadmium toxicity. Int. J. Environ. Res. Public Health. 2020; 17(11): 3782. https://doi.org/10.3390/ijerph17113782
  8. Gulieva S.V., Garaev G.Sh., Khalilov V.G., Radzhabova F.O. The influence of cadmium on biochemical processes in the body under conditions of experimental hypothyroidism. Vestnik nauki i obrazovaniya. 2019; (5): 67–71. https://elibrary.ru/stdcsr (In Russian)
  9. Shagirtha K., Muthumani M., Prabu S.M. Melatonin abrogates cadmium induced oxidative stress related neurotoxicity in rats. Eur. Rev. Med. Pharmacol. Sci. 2011; 15(9): 1039–50.
  10. Marettová E., Maretta M., Legáth J. Toxic effects of cadmium on testis of birds and mammals: a review. Anim. Reprod. Sci. 2015; 155: 1–10. https://doi.org/10.1016/j.anireprosci.2015.01.007
  11. Kumar S., Sharma A. Cadmium toxicity: Effects on human reproduction and fertility. Rev. Environ. Health. 2019; 34(4): 327–38. https://doi.org/10.1515/reveh-2019-0016
  12. Wang M., Wang J., Sun H., Han S., Feng S., Shi L., et al. Time-dependent toxicity of cadmium telluride quantum dots on liver and kidneys in mice: histopathological changes with elevated free cadmium ions and hydroxyl radicals. Int. J. Nanomedicine. 2016; 11: 2319–28. https://doi.org/10.2147/ijn.s103489
  13. Martinez-Zamudio R., Ha H.C. Environmental epigenetics in metal exposure. Epigenetics. 2011; 6(7): 820–7. https://doi.org/10.4161/epi.6.7.16250
  14. Buha A., Wallace D., Matovic V., Schweitzer A., Oluic B., Micic D., et al. Cadmium exposure as a putative risk factor for the development of pancreatic cancer: three different lines of evidence. BioMed Res. Int. 2017; 2017: 1981839. https://doi.org/10.1155/2017/1981837
  15. Luevano J., Damodaran C. A review of molecular events of cadmium-induced carcinogenesis. J. Environ. Pathol. Toxicol. Oncol. 2014; 33(3): 183–94. https://doi.org/10.1615/jenvironpatholtoxicoloncol.2014011075
  16. Albrecht A.L., Singh R.K., Somji S., Sens M.A., Sens D.A., Garrett S.H. Basal and metal‐induced expression of metallothionein isoform 1 and 2 genes in the RWPE‐1 human prostate epithelial cell line. J. Appl. Toxicol. 2008; 28(3): 283–93. https://doi.org/10.1002/jat.1277
  17. Klaassen C.D., Liu J., Diwan B.A. Metallothionein protection of cadmium toxicity. Toxicol. Appl. Pharmacol. 2009; 238(3): 215–20. https://doi.org/10.1016/j.taap.2009.03.026
  18. Si M., Lang J. The roles of metallothioneins in carcinogenesis. J. Hematol. Oncol. 2018; 11(1): 107. https://doi.org/10.1186/s13045-018-0645-x
  19. Leung K.W., Liu M., Xu X., Seiler M.J., Barnstable C.J., Tombran-Tink J. Expression of ZnT and ZIP zinc transporters in the human RPE and their regulation by neurotrophic factors. Invest. Ophthalmol. Vis. Sci. 2008; 49(3): 1221–31. https://doi.org/10.1167/iovs.07-0781
  20. Kambe T., Tsuji T., Hashimoto A., Itsumura N. The physiological, biochemical, and molecular roles of zinc transporters in zinc homeostasis and metabolism. Physiol. Rev. 2015; 95(3): 749–84. https://doi.org/10.1152/physrev.00035.2014
  21. Zhu B., Huo R., Zhi Q., Zhan M., Chen X., Hua Z.C. Increased expression of zinc transporter ZIP4, ZIP11, ZnT1, and ZnT6 predicts poor prognosis in pancreatic cancer. J. Trace Elem. Med. Biol. 2021; 65: 126734. https://doi.org/10.1016/j.jtemb.2021.126734
  22. Nakamura Y., Ohba K., Ohta H. Participation of metal transporters in cadmium transport from mother rat to fetus. J. Toxicol. Sci. 2012; 37(5): 1035–44. https://doi.org/10.2131/jts.37.1035
  23. Nagamatsu S., Nishito Y., Yuasa H., Yamamoto N., Komori T., Suzuki T., et al. Sophisticated expression responses of ZNT1 and MT in response to changes in the expression of ZIPs. Sci. Rep. 2022; 12(1): 7334. https://doi.org/10.1038/s41598-022-10925-2
  24. Livak J., Schmittgen T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001; 25(4): 402–8. https://doi.org/10.1006/meth.2001.1262
  25. Aljazzar A., El-Ghareeb W.R., Darwish W.S., Abdel-Raheem S.M., Ibrahim A.M. Content of total aflatoxin, lead, and cadmium in the bovine meat and edible offal: study of their human dietary intake, health risk assessment, and molecular biomarkers. Environ. Sci. Pollut. Res. Int. 2021; 28(43): 61225–34. https://doi.org/10.1007/s11356-021-12641-2
  26. Sakulsak N. Metallothionein: An overview on its metal homeostatic regulation in mammals. Int. J. Morphol. 2020; 30(3): 1007–12. https://doi.org/10.4067/S0717-95022012000300039
  27. Wan M., Hunziker P.E., Kägi J.H. Induction of metallothionein synthesis by cadmium and zinc in cultured rabbit kidney cells (RK-13). Biochem. J. 1993; 292(2): 609–15. https://doi.org/10.1042/bj2920609
  28. Nordberg M., Nordberg G.F. Metallothionein and cadmium toxicology-historical review and commentary. Biomolecules. 2022; 12(3): 15. https://doi.org/10.3390/biom12030360
  29. Dai S., Yin Z., Yuan G., Lu H., Jia R., Xu J., et al. Quantification of metallothionein on the liver and kidney of rats by subchronic lead and cadmium in combination. Environ. Toxicol. Pharmacol. 2013; 36(3): 1207–16. https://doi.org/10.1016/j.etap.2013.10.003
  30. Kimura T., Kambe T. The functions of metallothionein and ZIP and ZnT transporters: an overview and perspective. Int. J. Mol. Sci. 2016; 17(3): 336. https://doi.org/10.3390/ijms17030336
  31. Yuan A.T., Stillman M.J. Arsenic binding to human metallothionein-3. Chem. Sci. 2023; 14(21): 5756–67. https://doi.org/10.1039/d3sc00400g
  32. Ziatdinova M.M., Valova Ya.V., Mukhammadieva G.F., Fazlyeva A.S., Karimov D.O., Khusnutdinova N.Yu. Estimation of the activity of the MT2A and MT3 genes in the liver and kidney of rats in response to the administration of different doses of cadmium chloride. Meditsina truda i ekologiya cheloveka. 2021; (1): 93–101. https://doi.org/10.24412/2411-3794-2021-10109 https://elibrary.ru/lcamjh (in Russian)
  33. Baba H., Tsuneyama K., Yazaki M., Nagata K., Minamisaka T., Tsuda T., et al. The liver in itai-itai disease (chronic cadmium poisoning): pathological features and metallothionein expression. Mod. Pathol. 2013; 26(9): 1228–34. https://doi.org/10.1038/modpathol.2013.62
  34. Ziatdinova M.M., Valova Ya.V., Mukhammadieva G.F., Usmanova E.N., Karimov D.O., Khusnutdinova N.Yu., et al. Transcriptional activity of metallothionein genes in acute poisoning caused by cadmium chloride. Gigiena i Sanitaria (Hygiene and Sanitation, Russian journal). 2020; 99(9): 990–5. https://doi.org/10.47470/0016-9900-2020-99-9-990-995 https://elibrary.ru/zlyech (in Russian)
  35. Fazlyeva A.S., Usmanova E.N., Daukaev R.A., Karimov D.O., Valova Ya.V., Smolyankin D.A., et al. Cadmium distribution and metallothionein expression in rat organs following acute intoxication. Gigiena i Sanitaria (Hygiene and Sanitation, Russian journal). 2020; 99(9): 1011–5. https://doi.org/10.47470/0016-9900-2020-99-9-1011-1015 https://elibrary.ru/thctsf (in Russian)
  36. Mikowska M., Dziublińska B., Świergosz-Kowalewska R. Variation of metallothionein I and II gene expression in the bank vole (Clethrionomys glareolus) under environmental zinc and cadmium exposure. Arch. Environ. Contam. Toxicol. 2018; 75(1): 66–74. https://doi.org/10.1007/s00244-017-0485-7
  37. Hirao-Suzuki M., Takeda S., Sakai G., Waalkes M.P., Sugihara N., Takiguchi M. Cadmium-stimulated invasion of rat liver cells during malignant transformation: Evidence of the involvement of oxidative stress/TET1-sensitive machinery. Toxicology. 2021; 447: 152631. https://doi.org/10.1016/j.tox.2020.152631
  38. Ziatdinova M.M., Valova Ya.V., Mukhammadieva G.F., Fazlyeva A.S., Karimov D.D., Kudoyarov E.R. Analysis of MT1 and ZIP1 gene expression in the liver of rats with chronic poisoning with cadmium chloride. Gigiena i Sanitaria (Hygiene and Sanitation, Russian journal). 2021; 100(11): 1298–302. https://doi.org/10.47470/0016-9900-2021-100-11-1298-1302 https://elibrary.ru/okjxoi (in Russian)
  39. Liuzzi J.P., Blanchard R.K., Cousins R.J. Differential regulation of zinc transporter 1, 2, and 4 mRNA expression by dietary zinc in rats. J. Nutr. 2001; 131(1): 46–52. https://doi.org/10.1093/jn/131.1.46
  40. Lin Y.F., Hassan Z., Talukdar S., Schat H., Aarts M.G. Expression of the Znt1 zinc transporter from the metal hyperaccumulator Noccaea caerulescens confers enhanced zinc and cadmium tolerance and accumulation to Arabidopsis thaliana. PLoS One. 2016; 11(3): e0149750. https://doi.org/10.1371/journal.pone.0149750
  41. Satarug S., Garrett S.H., Somji S., Sens M.A., Sens D.A. Zinc, zinc transporters, and cadmium cytotoxicity in a cell culture model of human urothelium. Toxics. 2021; 9(5): 94. https://doi.org/10.3390/toxics9050094

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Gizatullina A.A., Valova Y.V., Smolyankin D.A., Khusnutdinova N.Y., Karimov D.O., Karimov D.D., Mukhammadiyeva G.F., Repina E.F.


СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 37884 от 02.10.2009.