Balali-Mood, Naseri, Tahergorabi, Khazdair, Sadeghi 2021 — Toxic mechanisms of five heavy metals: mercury, lead, chromium, cadmium, and arsenic
This Frontiers in Pharmacology review from the Birjand University of Medical Sciences Medical Toxicology and Drug Abuse Research Center is the canonical mechanistic-toxicology cross-cutting reference for the five regulated toxic heavy metals (Hg, Pb, Cr, Cd, As). The paper consolidates the shared toxicity pathways — ROS generation, weakening of antioxidant defense, enzyme inactivation, oxidative stress — and the metal-specific mechanisms (Pb binding to aminolevulinic acid dehydratase and ferrochelatase blocking heme biosynthesis; Cr(VI) ternary DNA adducts via ascorbate reduction; Cd glutathione depletion and metallothionein binding; iAs SAM-depleting methylation and BER/NER inhibition; Hg thiol affinity disrupting selenoenzymes). Carcinogenicity of Cr, Cd, and iAs is attributed to oxidative stress-induced DNA damage combined with repair-pathway inhibition. The review is the cross-metal anchor that wiki pages on these five metals should cite for mechanistic context, in parallel with the metal-specific primary references.
Key mechanistic findings
Shared toxicity pathways across the five metals
| Mechanism | Hg | Pb | Cr(VI) | Cd | iAs |
|---|---|---|---|---|---|
| ROS generation | ✓ | ✓ | ✓ (via ascorbate reduction) | ✓ (via ETC inhibition) | ✓ |
| Glutathione depletion | ✓ (thiol binding) | ✓ | ✓ (consumed in reduction) | ✓ (thiol binding) | ✓ (direct As-SG binding) |
| Enzyme inactivation | ✓ (SeCys) | ✓ (ALAD, FC) | ✓ (DNA repair enzymes) | ✓ (SOD, catalase) | ✓ (PDH, glutathione reductase) |
| DNA damage | indirect | indirect | direct (Cr-DNA adducts) | repair inhibition | repair inhibition |
| Carcinogenicity (IARC Group 1) | — | Group 2A | Group 1 (Cr(VI)) | Group 1 | Group 1 |
Metal-specific signatures
Mercury (Hg): Acts primarily through thiol affinity, binding cysteine residues in proteins. Targets selenoenzymes (selenoprotein P, glutathione peroxidase, thioredoxin reductase) through Hg-Se complex formation. Methylmercury (MeHg) crosses the blood-brain and placental barriers; inorganic mercury accumulates in kidneys. Acute and chronic neurotoxicity dominates clinical presentation.
Lead (Pb): Binds aminolevulinic acid dehydratase (ALAD) and ferrochelatase (FC) in the heme biosynthesis pathway, causing the classic anemia and porphyrin accumulation. Mimics calcium at voltage-gated channels, disrupting neurotransmission. No safe threshold for neurodevelopmental effects in children.
Chromium (Cr(VI)): Enters cells via sulfate/phosphate channels (mimicry). Intracellular reduction to Cr(III) by ascorbate (~90% in vivo) generates reactive intermediates (Cr(V), Cr(IV)) and ternary Cr-ascorbate-DNA adducts (50-75% of total adducts). Cr(VI) inhibits mismatch repair via hMLH1 suppression, microsatellite instability documented in chromate worker lung cancers. The ascorbate paradox: the same intracellular ascorbate that drives the DNA-damaging reduction pathway is also needed for DNA repair.
Cadmium (Cd): Inhibits mitochondrial ETC complexes II and III, generating ROS. Depletes glutathione via thiol binding. Inhibits SOD by displacing Zn/Mn cofactors. Binds metallothionein (Cd-MT complex half-life 25-30 years in renal cortex). Carcinogenicity via DNA repair inhibition (OGG1, XPA) rather than direct DNA damage. Itai-itai disease historical anchor.
Arsenic (iAs): Methylated by AS3MT to MMA then DMA, consuming SAM; SAM depletion has secondary effects on DNA/histone methylation (epigenetic disruption). Trivalent methylated intermediates (MMA(III), DMA(III)) may be more reactive than parent iAs. iAs inhibits NER and BER. Carcinogenicity primarily through cell proliferation and epigenetic disruption rather than direct DNA damage (distinguishing iAs from Cr(VI)).
Convergence on glutathione
The review identifies glutathione depletion as the single most common early event in metal toxicity. Each metal depletes GSH through a different mechanism: direct thiol binding (Hg, Cd, As), conjugate efflux as transport-out-of-cell strategy (As-SG, As(GS)3), consumption in the reduction pathway (Cr(VI) → Cr(III)), or inhibition of glutathione reductase (As). GSH depletion is the common upstream event that amplifies all downstream oxidative-stress effects across the five metals.
Methods (brief)
Comprehensive narrative review. Draws on approximately 250 primary references spanning the mechanistic toxicology of the five regulated heavy metals. Compartment-specific organ effects, biomarkers, and treatment options are covered. No primary data; this is a synthesis paper.
Implications
- Certification: HMTc threshold rationale for any of the five metals should cite this paper for the mechanistic-toxicology basis, separately from the per-metal occurrence-data references. The shared ROS/GSH-depletion framework supports a precautionary posture across the metal set; the metal-specific signatures (Pb-ALAD, Cr-DNA adducts, Cd-MT, As-methylation) support metal-specific threshold differentiation.
- Microbiome / clinical: GSH depletion is the cross-metal upstream event; this directly intersects with the bacterial GSH and thiol-handling pathways documented for each metal-microbiome interaction. The review does not cover microbiome content but establishes the host biochemistry that the microbiome literature builds on.
- Courses: Standard reference for the mechanistic comparison of the five regulated heavy metals. Foundational reading for any toxicology curriculum module on heavy metals.