Skip to main content
SpringerLink
Log in

Low-Dose Hexavalent Chromium Exposure Induces Endoplasmic Reticulum Stress-Mediated Apoptosis in Rat Liver

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

Abstract

This study investigated the toxic effects of low-dose hexavalent chromium (Cr(VI)) on rat liver. Male specific pathogen-free (SPF) Sprague–Dawley (SD) rats (4–5 weeks of age) were randomly divided into groups: saline, 0.05 mg/kg Cr(VI), and 0.25 mg/kg Cr(VI). The rats were subjected to intratracheal instillation of K2Cr2O7 suspensions or saline once weekly, for a total of five times. The results showed that the accumulation of Cr(VI) in the blood of the 0.25 mg/kg K2Cr2O7 group was significantly higher than that in the saline group. Transmission electron microscopy (TEM) showed that exposure to hexavalent chromium caused endoplasmic reticulum (ER) oedema and a disordered arrangement. The levels of endoplasmic reticulum stress (ERS)-related proteins (ATF6, P-PERK, P-IRE1, Grp78, and CHOP) in the 0.25 mg/kg K2Cr2O7 group were significantly higher than those in the saline group. The expression of apoptosis-inhibitory protein Bcl-2 was significantly lower in the 0.25 mg/kg K2Cr2O7 group than that in the saline group, and the expression of apoptosis protein Bax was significantly higher in the 0.25 mg/kg K2Cr2O7 group than that in the saline group, indicating that Cr(VI) increased apoptosis. These findings revealed that Cr(VI) may be involved in rat liver injury by initiating ERS-mediated apoptosis. The expression of ATF6, P-PERK, P-IRE1, and Bax in the 0.05 mg/kg K2Cr2O7 group was not significantly different from that in the saline group, and the different effects produced by the two different dose groups provide a possible experimental basis for further study of occupational exposure limits.

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

Similar content being viewed by others

Data Availability

The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.

References

  1. Barceloux DG (1999) Chromium. J Toxicol Clin Toxicol 37(2):173–194. https://doi.org/10.1081/clt-100102418

    Article  CAS  PubMed  Google Scholar 

  2. Singh P, Itankar N, Patil Y (2021) Biomanagement of hexavalent chromium: current trends and promising perspectives. J Environ Manage 279:111547. https://doi.org/10.1016/j.jenvman.2020.111547

    Article  CAS  PubMed  Google Scholar 

  3. Deng Y, Wang M, Tian T, Lin S, Xu P, Zhou L, Dai C, Hao Q, Wu Y, Zhai Z, Zhu Y, Zhuang G, Dai Z (2019) The effect of hexavalent chromium on the incidence and mortality of human cancers: a meta-analysis based on published epidemiological cohort studies. Front Oncol 9:24. https://doi.org/10.3389/fonc.2019.00024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Loomis D, Guha N, Hall AL, Straif K (2018) Identifying occupational carcinogens: an update from the IARC Monographs. Occup Environ Med 75(8):593–603. https://doi.org/10.1136/oemed-2017-104944

    Article  PubMed  Google Scholar 

  5. Santonen T, Louro H, Bocca B, Bousoumah R, Duca RC, Fucic A, Galea KS, Godderis L, Göen T, Iavicoli I, Janasik B, Jones K, Leese E, Leso V, Ndaw S, Poels K, Porras SP, Ruggieri F, Silva MJ, Van Nieuwenhuyse A, Verdonck J, Wasowicz W, Tavares A, Sepai O, Scheepers PTJ, Viegas S (2023) The HBM4EU chromates study - outcomes and impacts on EU policies and occupational health practices. Int J Hyg Environ Health 248:114099. https://doi.org/10.1016/j.ijheh.2022.114099

    Article  CAS  PubMed  Google Scholar 

  6. Viegas S, Martins C, Bocca B, Bousoumah R, Duca RC, Galea KS, Godderis L, Iavicoli I, Janasik B, Jones K, Leese E, Leso V, Ndaw S, van Nieuwenhuyse A, Poels K, Porras SP, Ruggieri F, Silva MJ, Verdonck J, Wasowicz W, Scheepers PTJ, Santonen T, Hbm Eu Chromates Study Team (2022) HBM4EU Chromates Study: determinants of exposure to hexavalent chromium in plating, welding and other occupational settings. Int J Environ Res Public Health 19(6):3683. https://doi.org/10.3390/ijerph19063683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Renu K, Chakraborty R, Myakala H, Koti R, Famurewa AC, Madhyastha H, Vellingiri B, George A, Valsala Gopalakrishnan A (2021) Molecular mechanism of heavy metals (lead, chromium, arsenic, mercury, nickel and cadmium) - induced hepatotoxicity - a review. Chemosphere 271:129735. https://doi.org/10.1016/j.chemosphere.2021.129735

    Article  CAS  PubMed  Google Scholar 

  8. Yan J, Huang H, Liu Z, Shen J, Ni J, Han J, Wang R, Lin D, Hu B, Jin L (2020) Hedgehog signaling pathway regulates hexavalent chromium-induced liver fibrosis by activation of hepatic stellate cells. Toxicol Lett 320:1–8. https://doi.org/10.1016/j.toxlet.2019.11.017

    Article  CAS  PubMed  Google Scholar 

  9. Yang Q, Han B, Xue J, Lv Y, Li S, Liu Y, Wu P, Wang X, Zhang Z (2020) Hexavalent chromium induces mitochondrial dynamics disorder in rat liver by inhibiting AMPK/PGC-1α signaling pathway. Environ Pollut 265(Pt A):114855. https://doi.org/10.1016/j.envpol.2020.114855

    Article  CAS  PubMed  Google Scholar 

  10. Chakraborty R, Renu K, Eladl MA, El-Sherbiny M, Elsherbini DMA, Mirza AK, Vellingiri B, Iyer M, Dey A, Valsala Gopalakrishnan A (2022) Mechanism of chromium-induced toxicity in lungs, liver, and kidney and their ameliorative agents. Biomed Pharmacother 151:113119. https://doi.org/10.1016/j.biopha.2022.113119

    Article  CAS  PubMed  Google Scholar 

  11. Read A, Schröder M (2021) The unfolded protein response: an overview. Biology (Basel) 10(5):384. https://doi.org/10.3390/biology10050384

    Article  CAS  PubMed  Google Scholar 

  12. Oakes SA, Papa FR (2015) The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol 10:173–194. https://doi.org/10.1146/annurev-pathol-012513-104649

    Article  CAS  PubMed  Google Scholar 

  13. Rana SVS (2020) Endoplasmic reticulum stress induced by toxic elements-a review of recent developments. Biol Trace Elem Res 196(1):10–19. https://doi.org/10.1007/s12011-019-01903-3

    Article  CAS  PubMed  Google Scholar 

  14. Liang Q, Zhang Y, Huang M, Xiao Y, Xiao F (2019) Role of mitochondrial damage in Cr(VI)-induced endoplasmic reticulum stress in L-02 hepatocytes. Mol Med Rep 19(2):1256–1265. https://doi.org/10.3892/mmr.2018.9704

    Article  CAS  PubMed  Google Scholar 

  15. Zhang Y, Xiao F, Liu X, Liu K, Zhou X, Zhong C (2017) Cr(VI) induces cytotoxicity in vitro through activation of ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction via the PI3K/Akt signaling pathway. Toxicol In Vitro 41:232–244. https://doi.org/10.1016/j.tiv.2017.03.003

    Article  CAS  PubMed  Google Scholar 

  16. García-Niño WR, Zatarain-Barrón ZL, Hernández-Pando R, Vega-García CC, Tapia E, Pedraza-Chaverri J (2015) Oxidative stress markers and histological analysis in diverse organs from rats treated with a hepatotoxic dose of Cr(VI): effect of curcumin. Biol Trace Elem Res 167(1):130–145. https://doi.org/10.1007/s12011-015-0283-x

    Article  CAS  PubMed  Google Scholar 

  17. Ghosh P, Dey T, Majumder R, Datta M, Chattopadhyay A, Bandyopadhyay D (2023) Insights into the antioxidative mechanisms of melatonin in ameliorating chromium-induced oxidative stress-mediated hepatic and renal tissue injuries in male Wistar rats. Food Chem Toxicol 173:113630. https://doi.org/10.1016/j.fct.2023.113630

    Article  CAS  PubMed  Google Scholar 

  18. Karaulov AV, Renieri EA, Smolyagin AI, Mikhaylova IV, Stadnikov AA, Begun DN, Tsarouhas K, Buha Djordjevic A, Hartung T, Tsatsakis A (2019) Long-term effects of chromium on morphological and immunological parameters of Wistar rats. Food Chem Toxicol 133:110748. https://doi.org/10.1016/j.fct.2019.110748

    Article  CAS  PubMed  Google Scholar 

  19. Khalaf AA, Hassanen EI, Ibrahim MA, Tohamy AF, Aboseada MA, Hassan HM, Zaki AR (2020) Rosmarinic acid attenuates chromium-induced hepatic and renal oxidative damage and DNA damage in rats. J Biochem Mol Toxicol 34(11):e22579. https://doi.org/10.1002/jbt.22579

    Article  CAS  PubMed  Google Scholar 

  20. Song Y, Wang T, Pu J, Guo J, Chen Z, Wang Y, Jia G (2014) Multi-element distribution profile in Sprague-Dawley rats: effects of intratracheal instillation of Cr (VI) and Zn intervention. Toxicol Lett 226(2):198–205. https://doi.org/10.1016/j.toxlet.2014.02.008

    Article  CAS  PubMed  Google Scholar 

  21. Weber H (1983) Long-term study of the distribution of soluble chromate-51 in the rat after a single intratracheal administration. J Toxicol Environ Health 11(4–6):749–764. https://doi.org/10.1080/15287398309530382

    Article  CAS  PubMed  Google Scholar 

  22. Hong S, Zhang Y, Hu G, Jia G (2023) Exploration of whole blood chromium as biomarker of hexavalent chromium exposure: based on literature review and Monte Carlo simulation. Biol Trace Elem Res 201(5):2274–2283. https://doi.org/10.1007/s12011-022-03360-x

    Article  CAS  PubMed  Google Scholar 

  23. Chen X, Cubillos-Ruiz JR (2021) Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat Rev Cancer 21(2):71–88. https://doi.org/10.1038/s41568-020-00312-2

    Article  CAS  PubMed  Google Scholar 

  24. Chen P, Geng N, Zhou D, Zhu Y, Xu Y, Liu K, Liu Y, Liu J (2019) The regulatory role of COX-2 in the interaction between Cr(VI)-induced endoplasmic reticulum stress and autophagy in DF-1 cells. Ecotoxicol Environ Saf 170:112–119. https://doi.org/10.1016/j.ecoenv.2018.11.120

    Article  CAS  PubMed  Google Scholar 

  25. Liu K, Chen P, Lu J, Zhu Y, Xu Y, Liu Y, Liu J (2020) Protective effect of purple tomato anthocyanidin on chromium(VI)-induced autophagy in LMH cells by inhibiting endoplasmic reticulum stress. Biol Trace Elem Res 194(2):570–580. https://doi.org/10.1007/s12011-019-01795-3

    Article  CAS  PubMed  Google Scholar 

  26. Hetz C, Zhang K, Kaufman RJ (2020) Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol 21(8):421–438. https://doi.org/10.1038/s41580-020-0250-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wiseman RL, Mesgarzadeh JS, Hendershot LM (2022) Reshaping endoplasmic reticulum quality control through the unfolded protein response. Mol Cell 82(8):1477–1491. https://doi.org/10.1016/j.molcel.2022.03.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Guo C, Ma R, Liu X, Xia Y, Niu P, Ma J, Zhou X, Li Y, Sun Z (2018) Silica nanoparticles induced endothelial apoptosis via endoplasmic reticulum stress-mitochondrial apoptotic signaling pathway. Chemosphere 210:183–192. https://doi.org/10.1016/j.chemosphere.2018.06.170

    Article  CAS  PubMed  Google Scholar 

  29. Zhang J, Guo J, Yang N, Huang Y, Hu T, Rao C (2022) Endoplasmic reticulum stress-mediated cell death in liver injury. Cell Death Dis 13(12):1051. https://doi.org/10.1038/s41419-022-05444-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jackson KG, Way GW, Zeng J, Lipp MK, Zhou H (2023) The dynamic role of endoplasmic reticulum stress in chronic liver disease. Am J Pathol 193(10):1389–1399. https://doi.org/10.1016/j.ajpath.2023.03.009

    Article  CAS  PubMed  Google Scholar 

  31. Liu X, Green RM (2019) Endoplasmic reticulum stress and liver diseases. Liver Res 3(1):55–64. https://doi.org/10.1016/j.livres.2019.01.002

    Article  PubMed  PubMed Central  Google Scholar 

  32. Zheng Z, Shang Y, Tao J, Zhang J, Sha B (2019) Endoplasmic reticulum stress signaling pathways: activation and diseases. Curr Protein Pept Sci 20(9):935–943. https://doi.org/10.2174/1389203720666190621103145

    Article  CAS  PubMed  Google Scholar 

  33. Ajoolabady A, Kaplowitz N, Lebeaupin C, Kroemer G, Kaufman RJ, Malhi H, Ren J (2023) Endoplasmic reticulum stress in liver diseases. Hepatology 77(2):619–639. https://doi.org/10.1002/hep.32562

    Article  CAS  PubMed  Google Scholar 

  34. Patlolla AK, Barnes C, Yedjou C, Velma VR, Tchounwou PB (2009) Oxidative stress, DNA damage, and antioxidant enzyme activity induced by hexavalent chromium in Sprague-Dawley rats. Environ Toxicol 24(1):66–73. https://doi.org/10.1002/tox.20395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. El-Demerdash FM, El-Sayed RA, Abdel-Daim MM (2021) Hepatoprotective potential of Rosmarinus officinalis essential oil against hexavalent chromium-induced hematotoxicity, biochemical, histological, and immunohistochemical changes in male rats. Environ Sci Pollut Res Int 28(14):17445–17456. https://doi.org/10.1007/s11356-020-12126-8

    Article  CAS  PubMed  Google Scholar 

  36. Chen-Xu J, Jakobsen LS, Pires SM, Viegas S (2023) Burden of lung cancer and predicted costs of occupational exposure to hexavalent chromium in the EU - the impact of different occupational exposure limits. Environ Res 228:115797. https://doi.org/10.1016/j.envres.2023.115797

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (U2004202).

Author information

Author notes

  1. Xiaoying Li and Ningning Li contributed equally.

Authors and Affiliations

  1. Department of Pathology, Henan Medical College, Zhengzhou, Henan, China

    Xiaoying Li, Ningning Li & Xiuzhi Zhang

  2. Department of Occupational Health and Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, China

    Lixia Zhang

  3. Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing, China

    Guang Jia

  4. School of Public Health, Henan Medical College, Zhengzhou, Henan, China

    Shanfa Yu

Authors
  1. Xiaoying Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ningning Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiuzhi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lixia Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guang Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shanfa Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors Shanfa Yu, Guang Jia, Xiaoying Li, and Ningning Li designed the study. Xiaoying Li, Ningning Li, Xiuzhi Zhang, and Lixia Zhang performed the experiments. Xiaoying Li, Ningning Li, and Xiuzhi Zhang performed the statistical analysis of the data. All authors participated in the writing of the draft and final versions of the manuscript.

Corresponding author

Correspondence to Shanfa Yu.

Ethics declarations

Ethics Approval

The procedures of animal experiments were approved by the Ethics Committee of Zhengzhou University (Ethics Review Number: ZZUIRB: 2022–55).

Consent for Publication

All the authors have consented for publication of this research.

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.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 7.08 MB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, X., Li, N., Zhang, X. et al. Low-Dose Hexavalent Chromium Exposure Induces Endoplasmic Reticulum Stress-Mediated Apoptosis in Rat Liver. Biol Trace Elem Res (2023). https://doi.org/10.1007/s12011-023-03995-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12011-023-03995-4

Keywords

Search

Navigation