Cadmium Chloride-Induced Hepatotoxicity: Molecular Mechanisms, Oxidative Stress, and Histopathological Alterations—A Comprehensive Review

Cadmium chloride (CdCl) is a highly dangerous heavy metal commonly used in electroplating, pigment production, battery manufacturing, plastic stabilization, and other laboratory settings. Due to the speed of industrial growth and human activities, cadmium levels in air, water, and soil have gone up dramatically, This way the compound is a leading reason for environmental and occupational contamination of health. Essential trace elements are those the body relies on but with cadmium, the body does not. In fact, its biological half-life is up to forty years, making the chemical progressively accumulate in tissues. Although the kidney has long been known as the prime organ involved in chronic lead poisoning, cadmium absorption actually causes rapid damage to the liver due to this organ's primary role in metabolism and detoxification of foreign substances (xenobiotics). CdCl liver accumulation initiates many pathological responses including overproduction of reactive oxygen species (ROS), exhaustion of the cell's antioxidant systems, mitochondrial malfunctions, release of inflammatory cytokines, cell death, and fibrosis. At a larger level of tissues and functions, all these changes cause disturbances in liver structure and function leading to hepatocellular injury. Oxidative stress and disruption of calcium homeostasis are just two mechanisms of cadmium toxicity besides other effects like antioxidant enzyme inhibition, DNA and membrane (lipid) damage, and activation of several intracellular signaling pathways such as NF-B, MAPK, and Nrf2. From a histological standpoint, changes include liver cell (hepatocyte) alterations, widened blood sinuses, cells of the immune system coming into the tissue, blood vessels in a state of congestion, spots of necrosis (cell death), and fibrosis. From a clinical point of view, liver damage caused by CdCl is seen as an increase in the levels of some biomarkers, viz. alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and bilirubin, as indicators of disease state changes and alteration of enzyme activities for antioxidant defense (e.g. glutathione peroxidase).The article reviews the present state of knowledge on cadmium environmental exposure sources, toxicokinetic pattern of CdCl, mechanisms responsible for cadmium-induced liver damage, and the corresponding histopathological and biochemical manifestations. Comprehending the molecular events involved is a crucial step toward the designing of strategies aimed at preventing cadmium-induced liver injuries identification of biological indicators of exposure, and formulation of new ways of treatment that will lessen liver damage caused by cadmium exposure.

Apoptosis, Cadmium chloride, Hepatotoxicity, Oxidative stress, Liver injury, Reactive oxygen species, Toxicokinetics, Heavy metals, Histopathology, Inflammation

1. Park, J. H., Lee, B. M., & Kim, H. S. (2021). Potential protective roles of curcumin against cadmium-induced toxicity and oxidative stress. Journal of Toxicology and Environmental Health, Part B: Critical Reviews, 24(3), 95–118. https://doi.org/10.1080/10937404.2020.1860842 [Google Scholar] [Crossref]

2. Ali, H., Khan, E., & Ilahi, I. (2019). Environmental Chemistry and Ecotoxicology of Hazardous Heavy Metals: Environmental Persistence, Toxicity, and Bioaccumulation. Journal of Chemistry, 2019, Article 6730305. https://doi.org/10.1155/2019/6730305 [Google Scholar] [Crossref]

3. Cao, X., Wang, X., & Zhang, L. (2022). Cadmium-induced liver injury: Molecular mechanisms and therapeutic interventions. Ecotoxicology and Environmental Safety, 233, 113346,DOI: 10.1016/j.ecoenv.2022.113306 [Google Scholar] [Crossref]

4. Xu, Y., Zhang, J., Chen, H., et al. (2024). Oxidative stress and inflammatory responses in cadmium-induced hepatotoxicity. Antioxidants, 13(2), 214. [Google Scholar] [Crossref]

5. DOI: https://doi.org/10.3390/antiox13020214 [Google Scholar] [Crossref]

6. Renu, K., Chakraborty, R., Vellingiri, B., et al. (2021). Molecular mechanism of heavy metals (Lead, Chromium, Arsenic, Mercury, Nickel and Cadmium)-induced hepatotoxicity – A review. Chemosphere, 271, 129735. [Google Scholar] [Crossref]

7. DOI: https://doi.org/10.1016/j.chemosphere.2021.129735 [Google Scholar] [Crossref]

8. Aala, J., Beigi Harchegani, A., Akhlaghi Monsef, H., Mohsenifar, Z., Ebrahimi, P., & Parvizi, M. R. (2021). N-Acetyl cysteine mitigates histopathological changes and inflammatory genes expressions in the liver of cadmium exposed rats. Environmental Analysis, Health and Toxicology, 36(4), e2021024. [Google Scholar] [Crossref]

9. DOI: https://doi.org/10.5620/eaht.2021024 [Google Scholar] [Crossref]

10. Souza-Arroyo, V., Fabián, J. J., Bucio-Ortiz, L., Miranda-Labra, R. U., Gomez-Quiroz, L. E., & Gutiérrez-Ruiz, M. C. (2022). The mechanism of the cadmium-induced toxicity and cellular response in the liver. Toxicology, 480, 153339. [Google Scholar] [Crossref]

11. DOI: https://doi.org/10.1016/j.tox.2022.153339 [Google Scholar] [Crossref]

12. Liu, C., Zhu, Y., Lu, Z., et al. (2020). Cadmium induces acute liver injury by inhibiting Nrf2 and the role of NF-κB, NLRP3, and MAPKs signaling pathway. International Journal of Environmental Research and Public Health, 17(1), 138. [Google Scholar] [Crossref]

13. DOI: https://doi.org/10.3390/ijerph17010138 [Google Scholar] [Crossref]

14. Souza-Arroyo, V., Fabián, J. J., Bucio-Ortiz, L., Miranda-Labra, R. U., Gómez-Quiroz, L. E., & Gutiérrez-Ruiz, M. C. (2022). The mechanism of the cadmium-induced toxicity and cellular response in the liver. Toxicology, 480, 153339.DOI: https://doi.org/10.1016/j.tox.2022.153339 [Google Scholar] [Crossref]

15. Subramaniam, N. K., & Mann, K. K. (2024). Mechanisms of Metal-Induced Hepatic Inflammation. Current Environmental Health Reports, 11(4), 547–556.DOI: https://doi.org/10.1007/s40572-024-00463-6 [Google Scholar] [Crossref]

16. Gong, X., Guo, C., Liu, J., Li, Z., Ruan, J., Tang, M., Gu, J., & Shi, H. (2024). Unraveling cadmium-driven liver inflammation with a focus on arachidonic acid metabolites and TLR4/IκBα/NF-κB pathway. Ecotoxicology and Environmental Safety, 286, 117177. [Google Scholar] [Crossref]

17. DOI: https://doi.org/10.1016/j.ecoenv.2024.117177 [Google Scholar] [Crossref]

18. Pi, H., Xu, S., Zhang, L., Guo, P., Li, Y., Xie, J., Tian, L., He, M., & Lu, Y. (2013).Dynamin 1-like-dependent mitochondrial fission initiates overactive mitophagy in the hepatotoxicity of cadmium. Autophagy, 9(11), 1780–1800. [Google Scholar] [Crossref]

19. DOI: https://doi.org/10.4161/auto.25665 [Google Scholar] [Crossref]

20. Liu, X., Zhang, Y., et al. (2023). [Google Scholar] [Crossref]

21. MCU Upregulation Overactivates Mitophagy by Promoting VDAC1 Dimerization and Ubiquitination in the Hepatotoxicity of Cadmium. Advanced Science, 10(7), e2203869. [Google Scholar] [Crossref]

22. DOI: https://doi.org/10.1002/advs.202203869 [Google Scholar] [Crossref]

23. Yang, Y., Li, J., Zhang, Y., et al. (2023). Co-exposure to cadmium and microplastics promotes liver fibrosis through the hemichannels-ATP-P2X7 pathway. Chemosphere, 344, 140372. [Google Scholar] [Crossref]

24. DOI: https://doi.org/10.1016/j.chemosphere.2023.140372 [Google Scholar] [Crossref]

25. Liu, C., Zhu, Y., Lu, Z., et al. (2020). Cadmium induces acute liver injury by inhibiting Nrf2 and the role of NF-κB, NLRP3, and MAPKs signaling pathway. International Journal of Environmental Research and Public Health, 17(1), 138. [Google Scholar] [Crossref]

26. DOI: https://doi.org/10.3390/ijerph17010138 [Google Scholar] [Crossref]

27. Tao, L., Ren, X., Zhai, W., & Chen, Z. (2022). Progress and Prospects of Non-Canonical NF-κB Signaling Pathway in the Regulation of Liver Diseases. Molecules, 27(13), 4275. [Google Scholar] [Crossref]

28. DOI: https://doi.org/10.3390/molecules27134275 [Google Scholar] [Crossref]

29. Luo, M., Huang, S., Peng, W., et al. (2021). Cadmium exposure induces oxidative stress and hepatotoxicity by disrupting mitochondrial function and antioxidant defense mechanisms. Environmental Pollution, 290, 118126. [Google Scholar] [Crossref]

30. DOI: https://doi.org/10.1016/j.envpol.2021.118126 [Google Scholar] [Crossref]

31. Sheweita, S. A., Abd El Rafea, A., & Elbana, S. G. (2023). The deleterious effects of cadmium on oxidative stress markers, drug-metabolizing, and antioxidant enzyme activities: Role of silymarin and garlic as antioxidants. Environmental Science and Pollution Research, 30(52), 112490–112502. [Google Scholar] [Crossref]

32. DOI: https://doi.org/10.1007/s11356-023-30197-1 [Google Scholar] [Crossref]

33. Vahdati-Mashhadian, N., Rakhshandeh, H., & Omidi, A. (2018). Silymarin ameliorates oxidative stress and enhances antioxidant defense system capacity in cadmium-treated mice. Oxidative Medicine and Cellular Longevity, 2018, Article ID 2428707. [Google Scholar] [Crossref]

34. DOI: https://doi.org/10.1155/2018/2428707 [Google Scholar] [Crossref]

35. Liu, C., Zhu, Y., Lu, Z., et al. (2020). Cadmium induces acute liver injury by inhibiting Nrf2 and the role of NF-κB, NLRP3 and MAPKs signaling pathway. Int J Environ Res Public Health, 17(1), 138. DOI: https://doi.org/10.3390/ijerph17010138 [Google Scholar] [Crossref]

36. Renu, K., Chakraborty, R., Vellingiri, B., et al. (2021). Molecular mechanism of heavy metals (Lead, Chromium, Arsenic, Mercury, Nickel and Cadmium)-induced hepatotoxicity – A review. Chemosphere, 271, 129735. DOI: https://doi.org/10.1016/j.chemosphere.2021.129735 [Google Scholar] [Crossref]

37. Souza-Arroyo, V., et al. (2022). The mechanism of the cadmium-induced toxicity and cellular response in the liver. Toxicology, 480, 153339. DOI: https://doi.org/10.1016/j.tox.2022.153339 [Google Scholar] [Crossref]

38. Gong, X., Guo, C., Liu, J., et al. (2024). Unraveling cadmium-driven liver inflammation with a focus on arachidonic acid metabolites and TLR4/IκBα/NF-κB pathway. Ecotoxicology and Environmental Safety, 286, 117177. DOI: https://doi.org/10.1016/j.ecoenv.2024.117177 [Google Scholar] [Crossref]

39. Liu, C., Zhu, Y., Lu, Z., et al. (2020). Cadmium induces acute liver injury by inhibiting Nrf2 and the role of NF-κB, NLRP3 and MAPKs signaling pathway. DOI: https://doi.org/10.3390/ijerph17010138 [Google Scholar] [Crossref]

40. Wang, J., Wang, K., Ding, L., et al. (2022). Alleviating effect of quercetin on cadmium-induced oxidative damage and apoptosis by activating the Nrf2–Keap1 pathway. Frontiers in Pharmacology, 13, 969892. DOI: https://doi.org/10.3389/fphar.2022.969892 [Google Scholar] [Crossref]

41. Li, W., Tan, M., Wang, H., et al. (2023). METTL3-mediated m6A mRNA modification was involved in cadmium-induced liver injury. Environmental Pollution, 331, 121887. DOI: https://doi.org/10.1016/j.envpol.2023.121887 [Google Scholar] [Crossref]

42. World Health Organization. (2023). Cadmium in drinking-water: Background document for development of WHO Guidelines for Drinking-water Quality. Geneva: WHO. https://www.who.int/publications/i/item/9789241549950 [Google Scholar] [Crossref]

43. Liu, C., Zhu, Y., Lu, Z., et al. (2020). Cadmium induces acute liver injury by inhibiting Nrf2 and the role of NF-κB, NLRP3 and MAPKs signaling pathway. DOI: https://doi.org/10.3390/ijerph17010138 [Google Scholar] [Crossref]

44. Wang, J., Wang, K., Ding, L., et al. (2022). Alleviating effect of quercetin on cadmium-induced oxidative damage and apoptosis by activating the Nrf2–Keap1 pathway. Frontiers in Pharmacology, 13, 969892. DOI: https://doi.org/10.3389/fphar.2022.969892 [Google Scholar] [Crossref]

45. Souza-Arroyo, V., Fabián, J. J., Bucio-Ortiz, L., Miranda-Labra, R. U., Gómez-Quiroz, L. E., & Gutiérrez-Ruiz, M. C. (2022). The mechanism of the cadmium-induced toxicity and cellular response in the liver. Toxicology, 480, 153339. DOI: https://doi.org/10.1016/j.tox.2022.153339 [Google Scholar] [Crossref]

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