A metalloid and potent carcinogen, primarily encountered through contaminated drinking water. Unlike nickel (epigenetic) and chromium (genotoxic), arsenic's carcinogenic mechanisms center on increased cellular proliferation and epigenetic disruption, while also acting as a powerful cocarcinogen through DNA repair inhibition.
Chemical Forms
- Exists as trivalent (As^III) and pentavalent (As^V) inorganic forms.
- Metabolized via methylation: As → MMA (monomethylarsonic acid) → DMA (dimethylarsinic acid).
- Methylation is paradoxical: it is the detoxification pathway (methylated forms are excreted faster), but methylated intermediates (especially DMA^III) are more reactive and potentially more carcinogenic than inorganic arsenic.
- Methylation consumes S-adenosylmethionine (SAM), depleting the universal methyl donor.
Human Exposure
- Drinking water contamination is the primary route — affects millions worldwide.
- Also found in food, soil, and ambient particulate matter.
- Cancers: skin, lung, bladder, kidney, liver.
- Very few animal models: DMA^V causes rat urinary bladder cancer; arsenic-induced bladder cancer in mice is possible but difficult.
Carcinogenic Mechanisms [[[salnikov-2008-metal-carcinogenesis]]]
Cellular Proliferation
- Activates signal transduction: EGFR, ERK activation.
- Upregulates Cyclin D1 even at low doses (12h exposure).
- Disrupts p53 function at low concentrations → downregulates p21.
- Induces growth factors in keratinocytes (GM-CSF, TGFα).
NF-κB and Apoptotic Signaling
- Low-dose arsenic activates NF-κB (unlike high doses, which inhibit it).
- This activation may be key to tumor promotion activity.
- Arsenic is used therapeutically (APL treatment with arsenic trioxide) — exploiting its apoptosis-inducing effects at pharmacological doses.
Epigenetic Changes
- Both hypo- and hypermethylation observed — depending on dose, duration, and tissue.
- Mechanism: arsenic methylation depletes SAM, reducing availability for DNA/histone methylation.
- Low dietary methionine or folate exacerbates effects.
- Since methylated arsenic is excreted faster than inorganic forms, methylation represents a detoxification-bioactivation trade-off.
Cocarcinogenesis
- Potent cocarcinogen with UV radiation: dramatically increases UV-induced skin tumors in mice.
- Mechanism: inhibition of DNA repair — specifically nucleotide excision repair (NER) and likely base excision repair.
- This may be more important for human cancer risk than direct carcinogenesis.
Comparison with Other Metals
| Feature | Arsenic | nickel | chromium |
|---------|---------|--------|----------|
| Direct DNA damage | No | No | Yes |
| Epigenetic effects | Strong | Strong | Moderate |
| Proliferative signaling | Primary mechanism | Not central | Not central |
| Repair inhibition | NER, BER | NER | MMR |
| Key metabolic feature | SAM depletion | Fe(II) mimicry | Ascorbate-driven reduction |
Open Questions
1. Which methylated form is the proximate carcinogen? DMA^III is highly reactive but transient.
2. Interaction with dietary factors: folate/methionine status may modulate cancer risk significantly.
3. Low-dose, long-term exposure effects in non-occupational populations.
Connections
- nickel, chromium — co-reviewed carcinogenic metals
- epigenetic modifications — shared mechanism with nickel
- oxidative stress — implicated but debated as primary mechanism
- metal carcinogenesis — overarching framework