Transcriptional activity of metallothionein genes in acute poisoning caused by cadmium chloride

Introduction. Cadmium is one of the most toxic heavy metals widely distributed in the environment. It has a long half-life, leading to its accumulation in various organs, which in turn is the cause of many adverse effects on human health.

Material and methods. Acute toxic poisoning with cadmium chloride was simulated on white outbred male rats, divided into groups depending on the exposure time. Samples of liver and kidney tissues were used as study materials, in the homogenate of which the level of mRNA of metallothionein genes was determined.

Results. It was found that the maximum value of the multiplicity of MT1 gene expression in the liver was reached after 6 hours (16.36 ± 0.77; p <0.001), and in the kidneys one day after intoxication with cadmium chloride (6.12 ± 0.43; p <0.001). The activity of the MT2 gene in the liver was most pronounced in the range of 2-4 hours (14.35 ± 1.73; 14.78 ± 1.44; p <0.001), while in the renal tissues an increase in the amount of mRNA was recorded after 24 hours (7.32 ± 0.63; p <0.001). The level of MT3 gene transcripts in liver tissues was decreased throughout the experiment, however, the opposite picture was observed in the kidney tissue, where the maximum was reached one day after the administration of the toxicant (6.14 ± 0.31; p <0.001).

Conclusion. Thus, an increase in metallothionein expression in response to the presence of heavy metal ions in the body can be used as a genetic marker in case of poisoning with various compounds.

1. Nair A.R., Degheselle O., Smeets K., Van Kerkhove E., Cuypers A. Cadmium-Induced Pathologies: Where is the oxidative balance lost (or not)? Int. J. Mol. Sci. 2013; 14(3): 6116–43. https://doi.org/10.3390/ijms14036116

2. Agency for Toxic Substances and Disease Registry. ATSDR’s Substance Priority List; 2019. Available at: https://www.atsdr.cdc.gov/spl/index.html

3. Krivosheev A.B., Poteryaeva E.L., Krivosheev B.N., Kupriyanova L.Ya., Smirnova E.L. Toxic effects of cadmium on the human body (literature review). Meditsina truda i promyshlennaya ekologiya. 2012; (6): 35–42. (in Russian)

4. Buha A., Matovic V., Antonijevic B., Bulat Z., Curcic M., Renieri E.A., et al. Overview of cadmium thyroid disrupting effects and mechanisms. Int. J. Mol. Sci. 2018; 19(5): 1501. https://doi.org/10.3390/ijms19051501

5. Thirumoorthy N., Shyam Sunder A., Manisenthil Kumar K., Senthil Kumar M., Ganesh G., Chatterjee M. A review of metallothionein isoforms and their role in pathophysiology. World J. Surg. Oncol. 2011; 9: 54. https://doi.org/10.1186/1477-7819-9-54

6. International Agency for Research on Cancer. List of classifications, Volumes 1–122. Available at: https://monographs.iarc.fr/list-of-classifications-volumes/

7. Pal D., Suman S., Kolluru V., Sears S., Das T.P., Alatassi H., et al. Inhibition of autophagy prevents cadmium-induced prostate carcinogenesis. Br. J. Cancer. 2017; 117(1): 56–64. https://doi.org/10.1038/bjc.2017.143

8. Pykhteeva E.G. Metallotionein: biological functions 3. practical application of metallotionein and his diagnostic value. Aktual’nye problemy transportnoy meditsiny. 2010; (2): 58–63. (in Russian)

9. Hamer D.H. Metallothionein. Annu. Rev. Biochem. 1986; 55: 913–51. https://doi.org/10.1146/annurev.bi.55.070186.004405

10. Vašák M., Meloni G. Mammalian metallothionein-3: new functional and structural insights. Int. J. Mol. Sci. 2017; 18(6): 1117. https://doi.org/10.3390/ijms18061117

11. Ryspekova N.N., Nurmukhambetov A.N., Balabekova M.K., Akanov A.A. Metallothioneins and their role in adaptation to damaging factors. Vestnik Kazakhskogo Natsional’nogo meditsinskogo universiteta. 2014; (1): 298–303. (in Russian)

12. Bezruchko N.V., Rubtsov G.K., Grigor’eva O.M. Metallothionein: relationship with oxidative modification of proteins and lipids, monitoring methods. Vestnik Tomskogo gosudarstvennogo pedagogicheskogo universiteta. 2015; (11): 161–8. (in Russian)

13. Sharma S., Rais A., Sandhu R., Nel W., Ebadi M. Clinical significance of metallothioneins in cell therapy and nanomedicine. Int. J. Nanomedicine. 2013; 8: 1477–88. https://doi.org/10.2147/ijn.s42019

14. Ruttkay-Nedecky B., Nejdl L., Gumulec J., Zitka O., Masarik M., Eckschlager T., et al. The role of metallothionein in oxidative stress. Int. J. Mol. Sci. 2013; 14(3): 6044–66. https://doi.org/10.3390/ijms14036044

15. Takahashi S. Molecular functions of metallothionein and its role in hematological malignancies. J. Hematol. Oncol. 2012; 5: 41. https://doi.org/10.1186/1756-8722-5-41

16. 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

17. Klaassen C.D., Liu J. Metallothionein transgenic and knock-out mouse models in the study of cadmium toxicity. J. Toxicol. Sci. 1998; (23 Suppl. 2): 97–102. https://doi.org/10.2131/jts.23.supplementii_97

18. Liu Y.P., Liu J., Palmiter R.D., Klaassen C.D. Metallothionein-I-transgenic mice are not protected from acute cadmium–metallothionein-induced nephrotoxicity. Toxicol. Appl. Pharmacol. 1996; 137(2): 307–15. https://doi.org/10.1006/taap.1996.0085

19. Sandbichler A.M., Höckner M. Cadmium protection strategies—a hidden trade-off? Int. J. Mol. Sci. 2016; 17(1): 139. https://doi.org/10.3390/ijms17010139

20. Lu J., Jin T., Nordberg G., Nordberg M. Metallothionein gene expression in peripheral lymphocytes from cadmium-exposed workers. Cell Stress Chaperones. 2001; 6(2): 97–104. https://doi.org/10.1379/1466-1268(2001)006%3C0097:mgeipl%3E2.0.co;2

21. Andjelkovic M., Buha Djordjevic A., Antonijevic E., Antonijevic B., Stanic M., Kotur-Stevuljevic J., et al. Toxic effect of acute cadmium and lead exposure in rat blood, liver, and kidney. J. Environ. Res. Public Health. 2019; 16(2): 274. https://doi.org/10.3390/ijerph16020274

22. Ren X.Y., Zhou Y., Zhang J.P., Feng W.H., Jiao B.H. Expression of metallothionein gene at different time in testicular interstitial cells and liver of rats treated with cadmium. World J. Gastroenterol. 2003; 9(7): 1554–8. https://doi.org/10.3748/wjg.v9.i7.1554

23. Hozumi I., Suzuki J.S., Kanazawa H., Hara A., Saio M., Inuzuka T., et al. Metallothionein-3 is expressed in the brain and various peripheral organs of the rat. Neurosci. Lett. 2008; 438(1): 54–8. https://doi.org/10.1016/j.neulet.2008.04.047