Clinical Pharmacist and Master’s student in Clinical Pharmacy with research interests in pharmacovigilance, behavioral interventions in mental health, and AI applications in clinical decision support. Experience includes digital health research with Bloomsbury Health (London) and pharmacovigilance practice in patient support programs. Published work covers drug awareness among healthcare providers, postpartum depression management, and patient safety reporting. What was reviewed?
This comprehensive review article examines the molecular mechanisms through which six heavy metals, lead, chromium, arsenic, mercury, nickel, and cadmium, induce liver damage. The analysis synthesizes evidence on how these metals trigger oxidative stress, disrupt cellular organelles, cause epigenetic alterations, and activate inflammatory and cell death pathways, ultimately leading to hepatotoxicity. The review consolidates findings from numerous experimental and epidemiological studies to provide a detailed understanding of the pathophysiological processes involved, making it a critical resource for understanding the multifaceted nature of heavy metal hepatotoxicity mechanisms.
Who was reviewed?
The review synthesizes data from a wide array of experimental models, including studies conducted on various rodent species (rats, mice), fish (zebrafish, catfish, trout), and human cell lines (HepG2, L-02 hepatocytes). It also incorporates findings from human epidemiological studies involving occupational exposures, such as automobile industry workers exposed to lead, and populations from regions like West Bengal and Bangladesh with chronic arsenic exposure through contaminated drinking water. This broad inclusion criterion ensures the reviewed heavy metal hepatotoxicity mechanisms are relevant across species and exposure scenarios.
Most important findings
| Critical Point | Details |
|---|---|
| Oxidative Stress as a Central Mechanism | All six metals induce reactive oxygen species (ROS) generation, leading to lipid peroxidation and depletion of antioxidant defenses (e.g., GSH, SOD, CAT). This oxidative imbalance is a primary event in cellular injury. |
| Mitochondrial Dysfunction | Heavy metals cause severe mitochondrial damage, including membrane depolarization, swelling, and disruption of the electron transport chain. This leads to impaired energy production and the release of pro-apoptotic factors. |
| Endoplasmic Reticulum Stress | Metals like Pb, As, and Cd activate the Unfolded Protein Response (UPR) via pathways like PERK and IRE1-JNK, impairing protein folding and promoting apoptosis through transcription factors like CHOP. |
| Epigenetic Alterations | Exposure leads to significant epigenetic changes, including DNA hypermethylation (Pb, Cd) and hypomethylation (As, Ni), which alter the expression of genes critical for metabolism, detoxification, and cell cycle control. |
| Inflammation and NF-κB Activation | A common outcome is the activation of the NF-κB pathway, leading to the overexpression of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6), which exacerbates tissue damage and promotes a pro-carcinogenic environment. |
| Activation of Cell Death Pathways | Metals induce both apoptosis and necrosis. Apoptosis is triggered via caspase activation (caspase-3, -8, -9), modulation of Bcl-2 family proteins, and p53 upregulation. Necrosis results from severe metabolic disruption and membrane damage. |
Key implications
The elucidation of these heavy metal hepatotoxicity mechanisms has direct primary regulatory impacts, necessitating lower permissible exposure limits and biomonitoring for oxidative stress markers. Certification requirements should mandate testing for early signs of mitochondrial dysfunction and epigenetic changes. Industry applications include developing safer industrial processes and personal protective equipment. Critical research gaps remain in understanding the long-term, low-dose synergistic effects of metal mixtures. Practical recommendations involve implementing robust environmental monitoring and advocating for nutritional interventions that boost antioxidant capacity in at-risk populations.
Citation
Renu K, Chakraborty R, Myakala H, et al. Molecular mechanism of heavy metals (Lead, Chromium, Arsenic, Mercury, Nickel and Cadmium) – induced hepatotoxicity — A review. Chemosphere. 2021;271:129735. doi:10.1016/j.chemosphere.2021.129735
Nickel is a widely used transition metal found in alloys, batteries, and consumer products that also contaminates food and water. High exposure is linked to allergic contact dermatitis, organ toxicity, and developmental effects, with children often exceeding EFSA’s tolerable daily intake of 3 μg/kg bw. Emerging evidence shows nickel crosses the placenta, elevating risks of preterm birth and congenital heart defects, underscoring HMTC’s stricter limits to safeguard vulnerable populations.
Cadmium is a persistent heavy metal that accumulates in kidneys and bones. Dietary sources include cereals, cocoa, shellfish and vegetables, while smokers and industrial workers receive higher exposures. Studies link cadmium to kidney dysfunction, bone fractures and cancer.
