Skip to main content

Advertisement

SpringerLink
Log in

Selenite Ameliorates Cadmium-induced Cytotoxicity Through Downregulation of ROS Levels and Upregulation of Selenoprotein Thioredoxin Reductase 1 in SH-SY5Y Cells

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

Abstract

Cadmium (Cd) as a ubiquitous toxic heavy metal in the environment, causes severe hazards to human health, such as cellular stress and organ injury. Selenium (Se) was reported to reduce Cd toxicity and the mechanisms have been intensively studied so far. However, it is not yet crystal clear whether the protective effect of Se against Cd-induced cytotoxicity is related to selenoproteins in nerve cells or not. In this study, we found that Cd inhibited selenoprotein thioredoxin reductase 1 (TrxR1; TXNRD1) and decreased the expression level of TrxR1, resulting in cellular oxidative stress, and Se supplements ameliorated Cd-induced cytotoxicity in SH-SY5Y cells. Mechanistically, the detoxification of Se against Cd is attributed to the increase of the cellular TrxR activity and upregulated TrxR1 protein level, culminating in strengthened antioxidant capacity. Results showed that Se supplements attenuated the ROS production and apoptosis in SH-SY5Y cells, and significantly mitigated Cd-induced SH-SY5Y cell death. This study may be a valuable reference for shedding light on the mechanism of Cd-induced cytotoxicity and the role of TrxR1 in Se-mitigated cytotoxicity of Cd in neuroblast cells, which may be helpful for understanding the therapeutic potential of Cd and Se in treating or preventing neurodegenerative diseases, like Alzheimer’s disease (AD) and Parkinson’s disease (PD).

Graphical abstract

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

DMEM:

Dulbecco’s Modified Eagle’s Medium

FBS:

Fetal bovine serum

Cd:

Cadmium

CdCl2 :

Cadmium chloride

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

PBS:

Phosphate-buffered saline

ROS:

Reactive oxygen species

Se:

Selenium

Na2SeO3 :

Sodium selenite

Trx1:

Cytosolic thioredoxin, thioredoxin, TXN1

TrxR1:

Cytosolic thioredoxin reductase, TXNRD1

Sec:

Selenocysteine

Cys:

Cysteine

DCFH-DA:

2,7-Dichlorofluorescein diacetate

References

  1. Kumar S, Sharma A (2019) Cadmium toxicity: effects on human reproduction and fertility. Rev Environ Health 34:327–338

    Article  CAS  Google Scholar 

  2. Bocca B, Pino A, Alimonti A, Forte G (2014) Toxic metals contained in cosmetics: a status report. Regulatory toxicology and pharmacology : RTP 68:447–467

    Article  CAS  Google Scholar 

  3. Graniel-Amador MA et al (2021) Cadmium exposure negatively affects the microarchitecture of trabecular bone and decreases the density of a subset of sympathetic nerve fibers innervating the developing rat femur. Biometals 34:87–96

    Article  CAS  Google Scholar 

  4. Erie JC et al (2005) Heavy metal concentrations in human eyes. Am J Ophthalmol 139:888–893

    Article  CAS  Google Scholar 

  5. Hudson KM, Belcher SM, Cowley M (2019) Maternal cadmium exposure in the mouse leads to increased heart weight at birth and programs susceptibility to hypertension in adulthood. Sci Rep 9:13553

    Article  Google Scholar 

  6. Wang B, Du Y (2013) Cadmium and its neurotoxic effects. Oxidative medicine and cellular longevity 2013:898034

    Article  Google Scholar 

  7. Cao X et al (2021) Cadmium induced BEAS-2B cells apoptosis and mitochondria damage via MAPK signaling pathway. Chemosphere 263:128346

    Article  CAS  Google Scholar 

  8. Chi Q et al (2021) Roles of selenoprotein S in reactive oxygen species-dependent neutrophil extracellular trap formation induced by selenium-deficient arteritis. Redox Biol 44:102003

    Article  CAS  Google Scholar 

  9. Hatfield DL, Tsuji PA, Carlson BA, Gladyshev VN (2014) Selenium and selenocysteine: roles in cancer, health, and development. Trends Biochem Sci 39:112–120

    Article  CAS  Google Scholar 

  10. Cheng Q et al (2021) Production and purification of homogenous recombinant human selenoproteins reveals a unique codon skipping event in E. coli and GPX4-specific affinity to bromosulfophthalein. Redox Biol 46:102070

    Article  CAS  Google Scholar 

  11. Mariotti M, Salinas G, Gabaldon T, Gladyshev VN (2019) Utilization of selenocysteine in early-branching fungal phyla. Nat Microbiol 4:759–765

    Article  CAS  Google Scholar 

  12. Chen M et al (2017) Selenium antagonizes cadmium-induced apoptosis in chicken spleen but not involving Nrf2-regulated antioxidant response. Ecotoxicol Environ Saf 145:503–510

    Article  CAS  Google Scholar 

  13. Zwolak I (2020) The role of selenium in arsenic and cadmium toxicity: an updated review of scientific literature. Biol Trace Elem Res 193:44–63

    Article  CAS  Google Scholar 

  14. Hossain KFB et al (2018) Inhibitory effects of selenium on cadmium-induced cytotoxicity in PC12 cells via regulating oxidative stress and apoptosis. Food Chem Toxicol 114:180–189

    Article  Google Scholar 

  15. Branca JJV et al (2018) Selenium and zinc: two key players against cadmium-induced neuronal toxicity. Toxicol In Vitro 48:159–169

    Article  CAS  Google Scholar 

  16. Ge J et al (2021) Comparative study on protective effect of different selenium sources against cadmium-induced nephrotoxicity via regulating the transcriptions of selenoproteome. Ecotoxicol Environ Saf 215:112135

    Article  CAS  Google Scholar 

  17. Zhang C et al (2020) Selenium prevent cadmium-induced hepatotoxicity through modulation of endoplasmic reticulum-resident selenoproteins and attenuation of endoplasmic reticulum stress. Environ Pollut 260:113873

    Article  CAS  Google Scholar 

  18. Dagnell M, Schmidt EE, Arnér ESJ (2018) The A to Z of modulated cell patterning by mammalian thioredoxin reductases. Free Radic Biol Med 115:484–496

    Article  CAS  Google Scholar 

  19. Arnér ESJ (2009) Focus on mammalian thioredoxin reductases–important selenoproteins with versatile functions. Biochim Biophys Acta 1790:495–526

    Article  Google Scholar 

  20. Xu J et al (2015) The conserved Trp114 residue of thioredoxin reductase 1 has a redox sensor-like function triggering oligomerization and crosslinking upon oxidative stress related to cell death. Cell Death Dis 6:e1616

    Article  CAS  Google Scholar 

  21. Xu J, Arner ES (2012) Pyrroloquinoline quinone modulates the kinetic parameters of the mammalian selenoprotein thioredoxin reductase 1 and is an inhibitor of glutathione reductase. Biochem Pharmacol 83:815–820

    Article  CAS  Google Scholar 

  22. Sun S et al (2021) Menadione inhibits thioredoxin reductase 1 via arylation at the Sec(498) residue and enhances both NADPH oxidation and superoxide production in Sec(498) to Cys(498) substitution. Free Radic Biol Med 172:482–489

    Article  CAS  Google Scholar 

  23. Zhang Y et al (2022) Thioredoxin reductase 1 inhibitor shikonin promotes cell necroptosis via SecTRAPs generation and oxygen-coupled redox cycling. Free Radic Biol Med 180:52–62

    Article  CAS  Google Scholar 

  24. Zhang B, Liu Y, Li X, Xu J, Fang J (2018) Small molecules to target the selenoprotein thioredoxin reductase. Chem Asian J 13:3593–3600

    Article  CAS  Google Scholar 

  25. Arodin L et al (2014) Alteration of thioredoxin and glutaredoxin in the progression of Alzheimer’s disease. Journal of Alzheimer’s disease : JAD 39:787–797

    Article  CAS  Google Scholar 

  26. Silva-Adaya D, Gonsebatt ME, Guevara J (2014) Thioredoxin system regulation in the central nervous system: experimental models and clinical evidence. Oxidative medicine and cellular longevity 2014

  27. Ren X et al (2017) Redox signaling mediated by thioredoxin and glutathione systems in the central nervous system. Antioxid Redox Signal 27:989–1010

    Article  CAS  Google Scholar 

  28. Kaplan N et al (2019) Does nimodipine, a selective calcium channel blocker, impair chondrocyte proliferation or damage extracellular matrix structures? Curr Pharm Biotechnol 20:517–524

    Article  CAS  Google Scholar 

  29. Wang H et al (2014) Hypoxia-inducible factor-1alpha mediates up-regulation of neprilysin by histone deacetylase-1 under hypoxia condition in neuroblastoma cells. J Neurochem 131:4–11

    Article  CAS  Google Scholar 

  30. Xu J, Croitoru V, Rutishauser D, Cheng Q, Arner ES (2013) Wobble decoding by the Escherichia coli selenocysteine insertion machinery. Nucleic Acids Res 41:9800–9811

    Article  CAS  Google Scholar 

  31. Arner ES, Holmgren A (2001) Measurement of thioredoxin and thioredoxin reductase. Curr Protoc Toxicol Chapter 7, Unit 7 4

  32. Branca JJV, Morucci G, Pacini A (2018) Cadmium-induced neurotoxicity: still much ado. Neural Regen Res 13:1879–1882

    Article  CAS  Google Scholar 

  33. Wang H, Abel GM, Storm DR, Xia Z (2019) Cadmium exposure impairs adult hippocampal neurogenesis. Toxicological sciences : an official journal of the Society of Toxicology https://doi.org/10.1093/toxsci/kfz152

  34. Wang H, Engstrom AK, Xia Z (2017) Cadmium impairs the survival and proliferation of cultured adult subventricular neural stem cells through activation of the JNK and p38 MAP kinases. Toxicology 380:30–37

    Article  CAS  Google Scholar 

  35. Sena LA, Chandel NS (2012) Physiological roles of mitochondrial reactive oxygen species. Mol Cell 48:158–167

    Article  CAS  Google Scholar 

  36. Halliwell B (2006) Oxidative stress and neurodegeneration: where are we now? J Neurochem 97:1634–1658

    Article  CAS  Google Scholar 

  37. Zhang J, Zheng S, Wang S, Liu Q, Xu S (2020) Cadmium-induced oxidative stress promotes apoptosis and necrosis through the regulation of the miR-216a-PI3K/AKT axis in common carp lymphocytes and antagonized by selenium. Chemosphere 258:127341

    Article  CAS  Google Scholar 

  38. Cheng P et al (2020) Inhibition of thioredoxin reductase 1 correlates with platinum-based chemotherapeutic induced tissue injury. Biochem Pharmacol 175:113873

    Article  CAS  Google Scholar 

  39. Smiri M, Jelali N, El Ghoul J (2013) Cadmium affects the NADP-thioredoxin reductase/thioredoxin system in germinating pea seeds. Journal of Plant Interactions 8:125–133

    Article  CAS  Google Scholar 

  40. Chrestensen CA, Starke DW, Mieyal JJ (2000) Acute cadmium exposure inactivates thioltransferase (Glutaredoxin), inhibits intracellular reduction of protein-glutathionyl-mixed disulfides, and initiates apoptosis. J Biol Chem 275:26556–26565

    Article  CAS  Google Scholar 

  41. Erkhembayar S, Mollbrink A, Eriksson M, Larsen EH, Eriksson LC (2011) Selenium homeostasis and induction of thioredoxin reductase during long term selenite supplementation in the rat. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements 25:254–259

    Article  CAS  Google Scholar 

  42. Sun S et al (2021) Chlorophyllin inhibits mammalian thioredoxin reductase 1 and triggers cancer cell death. Antioxidants 10:1733

    Article  CAS  Google Scholar 

  43. Xu J, Cheng Q, Arner ES (2016) Details in the catalytic mechanism of mammalian thioredoxin reductase 1 revealed using point mutations and juglone-coupled enzyme activities. Free Radic Biol Med 94:110–120

    Article  CAS  Google Scholar 

  44. Sun S et al (2022) Plumbagin reduction by thioredoxin reductase 1 possesses synergy effects with GLUT1 inhibitor on KEAP1-mutant NSCLC cells. Biomedicine & Pharmacotherapy 146:112546

    Article  CAS  Google Scholar 

  45. Li J et al (2019) The production of reactive oxygen species enhanced with the reduction of menadione by active thioredoxin reductase. Metallomics 11:1490–1497

    Article  CAS  Google Scholar 

  46. Zhang J, Li X, Han X, Liu R, Fang J (2017) Targeting the thioredoxin system for cancer therapy. Trends Pharmacol Sci 38:794–808

    Article  CAS  Google Scholar 

  47. Xu J, Fang J (2021) How can we improve the design of small molecules to target thioredoxin reductase for treating cancer? Expert Opin Drug Discov https://doi.org/10.1080/17460441.2021.1854220, 1–3

  48. Gencheva R, Arnér ESJ (2021) Thioredoxin reductase inhibition for cancer therapy. Annu Rev Pharmacol Toxicol https://doi.org/10.1146/annurev-pharmtox-052220-102509

  49. Bjorklund G, Zou L, Wang J, Chasapis CT, Peana M (2021) Thioredoxin reductase as a pharmacological target. Pharmacol Res https://doi.org/10.1016/j.phrs.2021.105854, 105854

  50. Sun S et al (2021) Efficient purification of selenoprotein thioredoxin reductase 1 by using chelating reagents to protect the affinity resins and rescue the enzyme activities. Process Biochem 101:256–265

    Article  CAS  Google Scholar 

  51. Lee CY et al (2018) Cadmium nitrate-induced neuronal apoptosis is protected by N-acetyl-l-cysteine via reducing reactive oxygen species generation and mitochondria dysfunction. Biomed Pharmacother 108:448–456

    Article  CAS  Google Scholar 

  52. Oboh G, Adebayo AA, Ademosun AO, Olowokere OG (2020) Rutin restores neurobehavioral deficits via alterations in cadmium bioavailability in the brain of rats exposed to cadmium. Neurotoxicology 77:12–19

    Article  CAS  Google Scholar 

  53. Su Y et al (2021) Rescue effects of Se-enriched rice on physiological and biochemical characteristics in cadmium poisoning mice. Environ Sci Pollut Res Int 28:20023–20033

    Article  CAS  Google Scholar 

  54. Jiayong Z, Shengchen W, Xiaofang H, Gang S, Shiwen X (2020) The antagonistic effect of selenium on lead-induced necroptosis via MAPK/NF-kappaB pathway and HSPs activation in the chicken spleen. Ecotoxicol Environ Saf 204:111049

    Article  Google Scholar 

  55. Ullah H et al (2019) A comprehensive review on environmental transformation of selenium: recent advances and research perspectives. Environ Geochem Health 41:1003–1035

    Article  CAS  Google Scholar 

  56. Carlisle AE et al (2020) Selenium detoxification is required for cancer-cell survival. Nat Metab 2:603–611

    Article  CAS  Google Scholar 

  57. Xing HJ et al (2019) Pharmacokinetics of selenium in healthy piglets after different routes of administration: application of pharmacokinetic data to the risk assessment of selenium. Biol Trace Elem Res 191:403–411

    Article  CAS  Google Scholar 

  58. Badiello R, Feroci G, Fini A (1996) Interaction between trace elements: selenium and cadmium ions. J Trace Elem Med Biol 10:156–162

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We want to thank Professor Yong Liu (Dalian University of Technology) for the experimental support and Professor Enyin Lai (Zhejiang University) for the scientific discussion.

Funding

This work was financially supported by the National Natural Science Foundation of China (31670767), the Fundamental Research Funds for the Central Universities (DUT20LK36, DUT21YG107, DUT21LK29, DUT17JC36), the Liaoning Provincial Natural Science Foundation Guidance Project (ZX20190531), the National Key R&D Program of China (2018AAA0100300), the Research and Development Program of Panjin Institute of Industrial Technology of DUT (PJYJY-002–862011), and the Liaoning Key Laboratory of Chemical Additive Synthesis and Separation (ZJKF2004).

Author information

Author notes

  1. Hecheng Wang, Shibo Sun and Yan Ren contributed equally to this work.

Authors and Affiliations

  1. School of Life and Pharmaceutical Sciences (LPS) & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin, 124221, China

    Hecheng Wang, Shibo Sun, Yan Ren, Rui Yang, Jianli Guo, Yu Zong, Qiuxian Zhang, Jing Zhao & Jianqiang Xu

  2. School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453000, China

    Wei Zhang

  3. School of Ocean Science and Technology (OST), Dalian University of Technology, Panjin, 124221, China

    Weiping Xu

  4. State Key Laboratory of Fine Chemicals, Dalian R&D Center for Stem Cell and Tissue Engineering, School of Chemical Engineering, Dalian University of Technology, Dalian, 116024, China

    Shui Guan

  5. Research & Educational Center for the Control Engineering of Translational Precision Medicine, School of Biomedical Engineering, Dalian University of Technology, Dalian, 116024, China

    Shui Guan

Authors
  1. Hecheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shibo Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rui Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jianli Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yu Zong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qiuxian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jing Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Weiping Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Shui Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jianqiang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Hecheng Wang and Jianqiang Xu conceived the project and designed experiments. Shibo Sun, Yan Ren, Yu Zong, and Qiuxian Zhang performed the experiments. Hecheng Wang, Shibo Sun, and Rui Yang analyzed the data. Jing Zhao, Wei Zhang, Weiping Xu, and Shui Guan contributed chemical, reagents, or analytical tools. Hecheng Wang, Shibo Sun, and Jianqiang Xu wrote the manuscript.

Corresponding author

Correspondence to Jianqiang Xu.

Ethics declarations

Competing Interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, H., Sun, S., Ren, Y. et al. Selenite Ameliorates Cadmium-induced Cytotoxicity Through Downregulation of ROS Levels and Upregulation of Selenoprotein Thioredoxin Reductase 1 in SH-SY5Y Cells. Biol Trace Elem Res 201, 139–148 (2023). https://doi.org/10.1007/s12011-022-03117-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-022-03117-6

Keywords

Search

Navigation