The Association Between Thyroid Injury and Apoptosis, and Alterations of Bax, Bcl-2, and Caspase-3 mRNA/Protein Expression Induced by Nickel Sulfate in Wistar Rats

A Correction to this article was published on 28 December 2019

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Abstract

To study the toxicity induced by Nickel sulfate (NiSO4) on thyroid tissue, and investigate the role of apoptosis as the possible mechanism, thirty-two male Wistar rats were randomly divided into control group (normal saline, ip), low dose group (2.5 mg/kg day NiSO4, ip), middle dose group (5 mg/kg day NiSO4, ip), high dose group (10 mg/kg day NiSO4, ip). After 40 consecutive days of treatment, there were obvious pathological changes in the thyroids of high dose group. Free T4 (FT4) and thyroid-stimulating hormone (TSH) were significantly lower in the NiSO4-treated groups than those in the control group (F = 4.992, p = 0.016; F = 4.524, p = 0.012). The mRNA expression of Caspase-3 was significantly higher (F = 10.259, p = 0.014) in all NiSO4-treated groups, and the mRNA expression of Bcl-2 was significantly lower (F = 9.225, p = 0.018) only in the high dose group. Both control group and the NiSO4-treated groups showed no changes in the mRNA expression of Bax gene. The ratio of Bcl-2/Bax decreased with the increase in exposure dose of NiSO4 (F = 13.382, p = 0.015). The mRNA expression of Fas went up in high dose group (F = 66.632, p < 0.001). The Caspase-3, Fas, and the Bax protein expressions measured by immunohistochemistry were consistent with the mRNA expression. The expression of Bcl-2 protein was significantly lower in the test groups than in the control group (F = 3.873, p = 0.025). NiSO4 as an Endocrine Disrupting Chemical may induce the thyroid injury through apoptosis and lead to hypothyroidism. Also, apoptosis in thyroid tissues was closely related to the alternations of Caspase-3, Bcl-2, and Fas mRNA and protein expression.

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  • 28 December 2019

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References

  1. 1.

    Haber L, Erdreicht L, Diamond MA, Ratney R, Zhao Q, Dourson M (2000) Hazard identification and dose response of inhaled nickel-soluble salts. Regul Toxicol Pharmacol 31:210–230

    CAS  Article  Google Scholar 

  2. 2.

    Diagomanolin V, Farhang M, Ghazi-Khansari M, Jafarzadeh N (2004) Heavy metals (Ni, Cr, Cu) in the Karoon waterway river, Iran. Toxicol Lett 151:63–67

    CAS  Article  Google Scholar 

  3. 3.

    Ma F, Feng YJ, Ren N (2003) Environmental biotechnology. Chemical Industry Press, Beijing, pp 124–126

    Google Scholar 

  4. 4.

    Gao J (2012) Study of ecological risk evaluation of heavy mental pollution at nickel-copper mining area in Jinchang City of Gansu Province. University of South China, Hengyang

    Google Scholar 

  5. 5.

    Von Burg DR (1999) Toxicology update. J Appl Toxicol 19:379–386

    Article  Google Scholar 

  6. 6.

    Qian C, Tang W (2006) Advances in research on the relationship between environmental endocrine disruptors and thyroid diseases. J Environmental Hygiene 33(2):106–109

  7. 7.

    Xu S, He M, Zhong M, Li L, Lu Y, Zhang Y, Zhang L, Yu Z, Zhou Z (2015) The neuroprotective effects of taurine against nickel by reducing oxidative stress and maintaining mitochondrial function in cortical neurons. Neurosci Lett 590:52–57

    CAS  Article  Google Scholar 

  8. 8.

    Gathwan KH, Al-Karkhi IHT, Al-Mulla EAJ (2012) Hepatic toxicity of nickel chloride in mice. Res Chem Intermed 39(6):2537–2542

    Article  Google Scholar 

  9. 9.

    Scutariu MD, Ciupilan C (2007) Nickel and magnesium effects in the rat kidney, treated with acid retinoic. Comparative study. Rev Med Chir Soc Med Nat Iasi 111(3):744–747

    CAS  PubMed  Google Scholar 

  10. 10.

    Chen CY, Lin TK, Chang YC, Wang YF, Shyu HW, Lin KH, Chou MC (2010) Nickel (II)-induced oxidative stress,apoptosis, G2/M arrest andgenotoxicity in normal rat kidney cells. J Toxicol Environ Health A 73(8):529–539

    CAS  Article  Google Scholar 

  11. 11.

    Goodman JE, Prueitt RL, Dodge DG, Thakali S (2009) Carcinogenicity assessment of water-soluble nickel compounds. Crit Rev Toxicol 39(5):365–417

    CAS  Article  Google Scholar 

  12. 12.

    Forgacs Z, Massanyi P, Lukac N, Somosy Z (2012) Reproductive toxicology of nickel-review. J Environ Sci Health A 47(9):1249–1260

    CAS  Article  Google Scholar 

  13. 13.

    Duman F, Ozturk F (2010) Nickel accumulation and its effect on biomass, protein content and antioxidative enzymes in roots and leaves of watercress (Nasturtium officinale R Br). J Environ Sci 22(4):526–532

    CAS  Article  Google Scholar 

  14. 14.

    Kasprzak KS, Sunderman FW Jr, Salnikow K (2003) Nickel carcinogenesis. Mutat Res 533(1–2):67–97

    CAS  Article  Google Scholar 

  15. 15.

    Sabir S, Akash MSH, Fiayyaz F, Saleem U, Mehmood MH, Rehman K (2019) Role of cadmium and arsenic as endocrine disruptors in the metabolism of carbohydrates: inserting the association into perspectives. Biomed Pharmacother 114:108802. https://doi.org/10.1016/j.biopha.2019.108802

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Wang Q, Yang H, Yang M, Yu Y, Yan M, Zhou L, Liu X, Xiao S, Yang Y, Wang Y, Zheng L, Zhao H, Li Y (2019) Toxic effects of bisphenol A on goldfish gonad development and the possible pathway of BPA disturbance in female and male fish reproduction. Chemosphere 221:235–245

    CAS  Article  Google Scholar 

  17. 17.

    Adedara IA, Awogbindin IO, Adesina AA, Oyebiyi OO, Lawal TA, Farombi EO (2015) Municipal landfill leachate-induced testicular oxidative damage is associated with biometal accumulation and endocrine disruption in rats. Arch Environ Contam Toxicol 68(1):74–82

    CAS  Article  Google Scholar 

  18. 18.

    Souza-Talarico JN, Suchecki D, Juster RP, Plusquellec P, Barbosa Junior F, Bunscheit V, Marcourakis T, de Matos TM, Lupien SJ (2017) Lead exposure is related to hypercortisolemic profiles and allostatic load in Brazilian older adults. Environ Res 154:261–268

    CAS  Article  Google Scholar 

  19. 19.

    Maqbool F, Bahadar H, Niaz K, Baeeri M, Rahimifard M, Navaei-Nigjeh M, Ghasemi-Niri SF (2016) Abdollahi M. Effects of methyl mercury on the activity and gene expression of mouse Langerhans islets and glucose metabolism. Food Chem Toxicol 93:119–128

    CAS  Article  Google Scholar 

  20. 20.

    Wang C, Liang G, Chai L, Wang H (2016) Effects of copper on growth, metamorphosis and endocrine disruption of Bufo gargarizans larvae. Aquat Toxicol 170:24–30

    CAS  Article  Google Scholar 

  21. 21.

    Cempel M, Nikel G (2006) Nickel: a review of its sources and environmental toxicology. Pol J Environ Stud 15:375–382

    CAS  Google Scholar 

  22. 22.

    Liu X, Xiang L, Shao J (2004) The molcular mechanisms of apoptosis induced by heavy metals. Chin J Cell Biol 26(3):235–240

    CAS  Google Scholar 

  23. 23.

    Guo H, Chen L, Cui H, Peng X, Fang J, Zuo Z, Deng J, Wang X, Wu B (2016) Research advances on pathways of nickel-induced apoptosis. Int J Mol Sci 17(1):10

    Article  Google Scholar 

  24. 24.

    Su L, Deng Y, Zhang Y, Li C, Zhang R, Sun Y, Zhang K, Li J, Yao S (2011) Protective effects of grape seed procyanidin extract against NiSO4-induced apoptosis and oxidative stress in rat testes. Toxicol Mech Methods 21(6):487–494

    CAS  Article  Google Scholar 

  25. 25.

    Zheng GH, Liu CM, Sun JM, Feng ZJ, Cheng C (2014) Nickel-induced oxidative stress and apoptosis in Carassius auratus liver by JNK pathway. Aquat Toxicol 147:105–111

    CAS  Article  Google Scholar 

  26. 26.

    Liu CM, Zheng GH, Ming QL, Chao C, Sun JM (2013) Sesamin protects mouse liver against nickel-induced oxidative DNA damage and apoptosis by the PI3K-Akt pathway. Agric Food Chem 61(5):1146–1154

    CAS  Article  Google Scholar 

  27. 27.

    Guo H, Cui H, Peng X, Fang J, Zuo Z, Deng J, Wang X et al (2014) Modulation of P13K/Akt pathway and Bcl-2 family proteins involved in chicken’s tubular apoptosis induced by nickel chloride (NiCl2). Int J Mol Sci 5(16):22989–23011

    Google Scholar 

  28. 28.

    Chung SM, Moon JS, Yoon JS, Won KC, Lee HW (2019) Sex-specific effects of blood cadmium on thyroid hormones and thyroid function status: Korean nationwide cross-sectional study. J Trace Elem Med Biol 5(53):55–61

    Article  Google Scholar 

  29. 29.

    Dolgova NV, Nehzati S, MacDonald TC, Summers KL, Crawford AM, Krone PH, George GN, Pickering IJ (2019) Disruption of selenium transport and function is a major contributor to mercury toxicity in zebrafish larvae. Metallomics 11(3):621–631

    CAS  Article  Google Scholar 

  30. 30.

    Zadjali SA, Nemmar A, Fahim MA, Azimullah S, Subramanian D, Yasin J, Amir N, Hasan MY, Adem A (2015) Lead exposure causes thyroid abnormalities in diabetic rats. Int J Clin Exp Med 8(5):7160–7167

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Jain RB, Choi YS (2016) Interacting effects of selected trace and toxic metals on thyroid function. Int J Environ Health Res 26(1):75–91

    CAS  Article  Google Scholar 

  32. 32.

    Andersen H, Larsen S, Spliid H, Christensen ND (1999) Multivariate statistical analysis of organ weights in toxicity studies. Toxicology 136:67–77

    CAS  Article  Google Scholar 

  33. 33.

    Cheng W, Yin C (1992) Effects of nickel chloride (NiCl2) and nickel sulfate (NiSO4) on serum T3, T4 and TSH levels in rats. Journal of Shijiazhuang Medical College (3):4–7

  34. 34.

    Guyot R, Chatonnet F, Gillet B et al (2014) Toxicogenomic analysis of the ability of brominated flame retardants TBBPA and BDE-209 to disrupt thyroid hormone signaling in neural cells. Toxicology 325:125–132

    CAS  Article  Google Scholar 

  35. 35.

    Parker K, Sunderman FW Jr (1974) Distribution of 63Ni in rabbit tissues following intravenous injection of 63NiCl2. Res Commun Chem Pathol Pharmacol 7(4):755–762

    CAS  PubMed  Google Scholar 

  36. 36.

    Xie Y, Jing SI, Wang YP et al (2018) E2Fisinvolvedinradioresistanceof carbon ion induced apoptosis via Bax/caspase3 signal pathwayinhuman hepatoma cell. J Cell Physiol 233(2):1312–1320

    CAS  Article  Google Scholar 

  37. 37.

    Chen M, Zhou B, Zhong P, Rajamanickam V, Dai X, Karvannan K, Zhou H, Zhang X, Liang G (2017) Increased intracellular reactive oxygen species mediates the anti-cancer effects of WZ35 via activating mitochondrial apoptosis pathway in prostate cancer cells. Prostate 77(5):489–504

    CAS  Article  Google Scholar 

Download references

Acknowledgments

The authors thank all those who participated in this study.

Funding

This study was supported by the Program for National Natural Science Foundation of China (31670518).

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Correspondence to Hui Chen.

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Our experiments involving the use of rats and all experimental procedures involving animals were approved by The Second Hospital of Lanzhou University Animal Care and Use Committee.

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Liu, Y., Chen, H., Zhang, L. et al. The Association Between Thyroid Injury and Apoptosis, and Alterations of Bax, Bcl-2, and Caspase-3 mRNA/Protein Expression Induced by Nickel Sulfate in Wistar Rats. Biol Trace Elem Res 195, 159–168 (2020). https://doi.org/10.1007/s12011-019-01825-0

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Keywords

  • Thyroid injury
  • Nickel sulfate
  • Thyroid hormone
  • mRNA expression
  • Apoptosis protein