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Copper Induces Spleen Damage Through Modulation of Oxidative Stress, Apoptosis, DNA Damage, and Inflammation

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Abstract

Copper (Cu) is an essential micronutrient for both humans and animals; however, excessive intake of Cu can be immunotoxic. There are limited studies on spleen toxicity induced by Cu. This study was conducted to investigate the effects of Cu on spleen oxidative stress, apoptosis, and inflammatory responses in mice orally administered with 0 mg/kg, 10 mg/kg, 20 mg/kg, and 40 mg/kg of CuSO4 for 42 days. As discovered in this work, copper sulfate (CuSO4) reduced the activities of antioxidant enzymes (SOD, CAT, and GSH-Px), decreased GSH contents, and increased MDA contents. Meanwhile, CuSO4 induced apoptosis by increasing TUNEL-positive cells in the spleen. Also, CuSO4 increased the expression of γ-H2AX, which is the marker of DNA damage. Concurrently, CuSO4 caused inflammation by increasing the mRNA levels of interleukin-1β (IL-1β), IL-2, IL-4, IL-6, IL-12, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). In conclusion, the abovementioned findings demonstrate that over 10 mg/kg CuSO4 can cause oxidative stress, apoptosis, DNA damage, and inflammatory responses, which contribute to spleen dysfunction in mice.

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Data Availability

All data generated or analyzed during this study are included in this published article.

References

  1. Rehman M, Liu L, Wang Q, Saleem MH, Bashir S, Ullah S, Peng D (2019) Copper environmental toxicology, recent advances, and future outlook: a review. Environ Sci Pollut Res Int 26(18):18003–18016. https://doi.org/10.1007/s11356-019-05073-6

    Article  CAS  PubMed  Google Scholar 

  2. Cadenas C (2015) Highlight report: toxicology of copper. Arch Toxicol 89(12):2471–2472. https://doi.org/10.1007/s00204-015-1648-9

    Article  CAS  PubMed  Google Scholar 

  3. Shabbir Z, Sardar A, Shabbir A, Abbas G, Shamshad S, Khalid S, Natasha MG, Dumat C, Shahid M (2020) Copper uptake, essentiality, toxicity, detoxification and risk assessment in soil-plant environment. Chemosphere 259:127436. https://doi.org/10.1016/j.chemosphere.2020.127436

    Article  CAS  PubMed  Google Scholar 

  4. Scheiber I, Dringen R, Mercer JF (2013) Copper: effects of deficiency and overload. Met Ions Life Sci 13:359–387. https://doi.org/10.1007/978-94-007-7500-8_11

    Article  PubMed  Google Scholar 

  5. Royer A, Sharman T (2020) Copper Toxicity. In: StatPearls. StatPearls Publishing Copyright © 2020, StatPearls Publishing LLC., Treasure Island (FL)

  6. Gaetke LM, Chow-Johnson HS, Chow CK (2014) Copper: toxicological relevance and mechanisms. Arch Toxicol 88(11):1929–1938. https://doi.org/10.1007/s00204-014-1355-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Liu H, Guo H, Jian Z, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L (2020) Copper Induces Oxidative Stress and Apoptosis in the Mouse Liver. Oxidative Med Cell Longev 2020:1359164–1359120. https://doi.org/10.1155/2020/1359164

    Article  CAS  Google Scholar 

  8. Jian Z, Guo H, Liu H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L (2020) Oxidative stress, apoptosis and inflammatory responses involved in copper-induced pulmonary toxicity in mice. Aging (Albany NY) 12(17):16867–16886. https://doi.org/10.18632/aging.103585

    Article  CAS  Google Scholar 

  9. Ozcelik D, Ozaras R, Gurel Z, Uzun H, Aydin S (2003) Copper-mediated oxidative stress in rat liver. Biol Trace Elem Res 96(1):209–215. https://doi.org/10.1385/BTER:96:1-3:209

    Article  CAS  PubMed  Google Scholar 

  10. Arafa MH, Amin DM, Samir GM, Atteia HH (2019) Protective effects of tribulus terrestris extract and angiotensin blockers on testis steroidogenesis in copper overloaded rats. Ecotoxicol Environ Saf 178:113–122. https://doi.org/10.1016/j.ecoenv.2019.04.012

    Article  CAS  PubMed  Google Scholar 

  11. Kawanishi S, Inoue S, Yamamoto K (1989) Hydroxyl radical and singlet oxygen production and DNA damage induced by carcinogenic metal compounds and hydrogen peroxide. Biol Trace Elem Res 21:367–372. https://doi.org/10.1007/BF02917277

    Article  CAS  PubMed  Google Scholar 

  12. Liu H, Guo H, Deng H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L (2020) Copper induces hepatic inflammatory responses by activation of MAPKs and NF-κB signalling pathways in the mouse. Ecotoxicol Environ Saf 201:110806. https://doi.org/10.1016/j.ecoenv.2020.110806

    Article  CAS  PubMed  Google Scholar 

  13. Strauch BM, Niemand RK, Winkelbeiner NL, Hartwig A (2017) Comparison between micro- and nanosized copper oxide and water soluble copper chloride: interrelationship between intracellular copper concentrations, oxidative stress and DNA damage response in human lung cells. Part Fibre Toxicol 14(1):28. https://doi.org/10.1186/s12989-017-0209-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25(4):402–408. https://doi.org/10.1006/meth.2001.1262

    Article  CAS  PubMed  Google Scholar 

  15. McElwee MK, Song MO, Freedman JH (2009) Copper activation of NF-kappaB signaling in HepG2 cells. J Mol Biol 393(5):1013–1021. https://doi.org/10.1016/j.jmb.2009.08.077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhao H, Wang Y, Shao Y, Liu J, Wang S, Xing M (2018) Oxidative stress-induced skeletal muscle injury involves in NF-κB/p53-activated immunosuppression and apoptosis response in copper (II) or/and arsenite-exposed chicken. Chemosphere 210:76–84. https://doi.org/10.1016/j.chemosphere.2018.06.165

    Article  CAS  PubMed  Google Scholar 

  17. Yang F, Liao J, Yu W, Pei R, Qiao N, Han Q, Hu L, Li Y, Guo J, Pan J, Tang Z (2020) Copper induces oxidative stress with triggered NF-κB pathway leading to inflammatory responses in immune organs of chicken. Ecotoxicol Environ Saf 200:110715. https://doi.org/10.1016/j.ecoenv.2020.110715

    Article  CAS  PubMed  Google Scholar 

  18. Taylor AA, Tsuji JS, Garry MR, McArdle ME, Goodfellow WL Jr, Adams WJ, Menzie CA (2020) Critical Review of Exposure and Effects: Implications for Setting Regulatory Health Criteria for Ingested Copper. Environ Manag 65(1):131–159. https://doi.org/10.1007/s00267-019-01234-y

    Article  Google Scholar 

  19. Babaei H, Roshangar L, Sakhaee E, Abshenas J, Kheirandish R, Dehghani R (2012) Ultrastructural and morphometrical changes of mice ovaries following experimentally induced copper poisoning. Iran Red Crescent Med J 14(9):558–568

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Hosseini MJ, Shaki F, Ghazi-Khansari M, Pourahmad J (2014) Toxicity of copper on isolated liver mitochondria: impairment at complexes I, II, and IV leads to increased ROS production. Cell Biochem Biophys 70(1):367–381. https://doi.org/10.1007/s12013-014-9922-7

    Article  CAS  PubMed  Google Scholar 

  21. Wang X, Wang H, Li J, Yang Z, Zhang J, Qin Z, Wang L, Kong X (2014) Evaluation of bioaccumulation and toxic effects of copper on hepatocellular structure in mice. Biol Trace Elem Res 159(1-3):312–319. https://doi.org/10.1007/s12011-014-9970-2

    Article  CAS  PubMed  Google Scholar 

  22. Kaleri NA, Sun K, Wang L, Li J, Zhang W, Chen X, Li X (2017) Dietary Copper Reduces the Hepatotoxicity of (-)-Epigallocatechin-3-Gallate in Mice. Molecules (Basel, Switzerland) 23(1). https://doi.org/10.3390/molecules23010038

  23. Zhou X, Zhao L, Luo J, Tang H, Xu M, Wang Y, Yang X, Chen H, Li Y, Ye G, Shi F, Lv C, Jing B (2019) The Toxic Effects and Mechanisms of Nano-Cu on the Spleen of Rats. Int J Mol Sci 20(6). https://doi.org/10.3390/ijms20061469

  24. Li W, Li H, Zhang J, Tian X (2015) Effect of melamine toxicity on Tetrahymena thermophila proliferation and metallothionein expression. Food Chem Toxicol 80:1–6. https://doi.org/10.1016/j.fct.2015.01.015

    Article  CAS  PubMed  Google Scholar 

  25. He H, Zou Z, Wang B, Xu G, Chen C, Qin X, Yu C, Zhang J (2020) Copper Oxide Nanoparticles Induce Oxidative DNA Damage and Cell Death via Copper Ion-Mediated P38 MAPK Activation in Vascular Endothelial Cells. Int J Nanomedicine 15:3291–3302. https://doi.org/10.2147/ijn.s241157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Durrani K, El Din SA, Sun Y, Rule AM, Bressler J (2021) Ethyl maltol enhances copper mediated cytotoxicity in lung epithelial cells. Toxicol Appl Pharmacol 410:115354. https://doi.org/10.1016/j.taap.2020.115354

    Article  CAS  PubMed  Google Scholar 

  27. Abdelazeim SA, Shehata NI, Aly HF, Shams SGE (2020) Amelioration of oxidative stress-mediated apoptosis in copper oxide nanoparticles-induced liver injury in rats by potent antioxidants. Sci Rep 10(1):10812. https://doi.org/10.1038/s41598-020-67784-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140(6):883–899. https://doi.org/10.1155/2017/6027305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kumar S, Chan CJ, Coussens LM (2016) Inflammation and Cancer. Encycl Immunobiol 420(6917):406–415

    Article  Google Scholar 

  30. He G, Karin M (2011) NF-κB and STAT3 – key players in liver inflammation and cancer. Cell Res 21(1):159–168. https://doi.org/10.1038/cr.2010.183

    Article  CAS  PubMed  Google Scholar 

  31. Leite CE, Maboni L, Cruz FF, Rosemberg DB, Zimmermann FF, Pereira TC, Bogo MR, Bonan CD, Campos MM, Morrone FB (2013) Involvement of purinergic system in inflammation and toxicity induced by copper in zebrafish larvae. Toxicol Appl Pharmacol 272(3):681–689. https://doi.org/10.1016/j.taap.2013.08.001

    Article  CAS  PubMed  Google Scholar 

  32. Pereira TC, Campos MM, Bogo MR (2016) Copper toxicology, oxidative stress and inflammation using zebrafish as experimental model. J Appl Toxicol 36(7):876–885. https://doi.org/10.1002/jat.3303

    Article  CAS  PubMed  Google Scholar 

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Funding

This research was supported by the program for Changjiang scholars and the university innovative research team (IRT 0848), the Shuangzhi project of Sichuan Agricultural University (03573050; 1921993267), and Sichuan Science and Technology Program (2020YJ0113).

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Author notes

  1. Hongrui Guo, Yuqin Wang and Hengmin Cui contributed equally to this work.

Authors and Affiliations

  1. College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu, 611130, China

    Hongrui Guo, Yuqin Wang, Hengmin Cui, Yujuan Ouyang, Tingyou Yang, Caiyun Liu, Xiaoyu Liu, Yanqiu Zhu & Huidan Deng

  2. Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu, 611130, China

    Hongrui Guo, Hengmin Cui, Yanqiu Zhu & Huidan Deng

  3. Key Laboratory of Agricultural information engineering of Sichuan Province, Sichuan Agriculture University, Yaan, 625014, Sichuan, China

    Hengmin Cui

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  1. Hongrui Guo
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Contributions

Hongrui Guo and Hengmin Cui designed research and wrote the paper; Huidan Deng performed research and wrote the paper; Yuqin Wang, Yujuan Ouyang, Tingyou Yang, Caiyun Liu, Xiaoyu Liu, and Yanqiu Zhu performed research analyzed data.

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Correspondence to Hengmin Cui or Huidan Deng.

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The protocol for animal experiments was ethically approved by the Animal Care and Use Committee, Sichuan Agricultural University.

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Guo, H., Wang, Y., Cui, H. et al. Copper Induces Spleen Damage Through Modulation of Oxidative Stress, Apoptosis, DNA Damage, and Inflammation. Biol Trace Elem Res 200, 669–677 (2022). https://doi.org/10.1007/s12011-021-02672-8

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