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Immunotoxicology of metals

Evidence on how dietary and environmental metal exposures disrupt immune function: cytokine dysregulation, epigenetic programming, gut immune barrier disruption, autoimmunity induction, vascular inflammation, and systemic nickel allergy.

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Coverage

This page synthesizes evidence from nine indexed sources on how lead (Pb), cadmium (Cd), inorganic arsenic (As), mercury (Hg), and nickel (Ni) disrupt immune system function. Evidence ranges from mechanistic animal studies and human observational cohorts to case series and systematic reviews. The page covers six functional domains: epigenetic programming of immune genes, cytokine dysregulation and diet-metal interactions, gut immune barrier disruption and microbiota shifts, autoimmunity induction by mercury, vascular inflammatory marker elevation, and systemic nickel allergy syndrome triggered by dietary nickel. Human observational, experimental, and review evidence retain their source-specific designs and limitations; a combined causal synthesis has not been attempted here.

Immune-epigenetic programming by metals

Reddy et al. (2025) reviewed how Pb, Cd, As, and Hg alter immune gene expression through epigenetic mechanisms at three regulatory levels: DNA methylation, histone modification, and non-coding RNA expression 1. Metal-specific findings from cited primary studies included in that review: Pb activates TLR4-NF-kappaB signaling, increasing transcription of IL-1beta and IL-6; Cd triggers both TLR and NLRP3 inflammasome pathways, increasing TNF-alpha and IFNgamma; Hg and As suppress inflammasome activity, indicating metal-specific immunosuppressive profiles alongside the pro-inflammatory effects documented in other exposure contexts. At the epigenetic level, mercury exposure induces the repressive histone mark H3K27me3 at immune-regulatory gene loci, while cadmium disrupts global DNA methylation patterns.

The same review documented transgenerational persistence of metal-induced epigenetic marks. In a zebrafish cadmium model, DNA methylation changes induced by cadmium in the exposed generation persisted across the F1 through F4 generations without further cadmium exposure. MicroRNA biomarkers identified as dysregulated by metal exposures include miR-21 and miR-155, both of which regulate cytokine signaling cascades.

Cytokine dysregulation: human cohort evidence

Rodriguez-Carmona et al. (2026) examined associations between blood lead, urinary arsenic, and urinary cadmium with serum inflammatory biomarkers in 399 adolescents from the ELEMENT birth cohort, Mexico City 2. All blood lead concentrations were above the LOD (0.284 microg/dL); median blood lead was 2.3 microg/dL. All urinary arsenic concentrations were above the LOD (0.3 microg/L). Urinary cadmium was below the LOD (0.06 microg/L) in 42.1% of participants.

The principal statistically significant finding after Benjamini-Hochberg false discovery rate correction was an association between urinary cadmium and lower serum IL-6 (percent difference: -14.5%, 95% CI: -23.4 to -4.5; FDR P = 0.04), indicating an immunosuppressive direction for cadmium at this exposure level. Associations were expressed as percentage differences in inflammatory biomarkers per standard deviation increase in metal exposure.

A secondary finding was that the dietary inflammatory index (DII) modified the association between blood lead and cytokine profiles. In adolescents consuming the most anti-inflammatory diet (C-DII tertile 1), blood lead was associated with higher IL-4, IL-1beta, IL-6, and IL-8 (P-trend < 0.05 for diet-metal interactions). This interaction pattern suggests that dietary quality can amplify or attenuate lead-related cytokine changes, complicating predictions from metal exposure levels alone.

Gut immune barrier and microbiota

Li et al. (2026) synthesized evidence from Yunnan Province, China, a region with documented chronic metal contamination from mining and smelting, on how Pb, Cd, and As disrupt intestinal immune competence 3. In exposed Yunnan populations, mean blood lead was 82.87 microg/L and the lead poisoning rate (defined as blood Pb >=100 microg/L) was 24.7%. Crop cadmium concentrations in five cadmium-polluted Yunnan areas ranged from 0.29 to 0.83 mg/kg, substantially above typical agricultural background concentrations.

The mechanistic synthesis documented three converging pathways: (1) disruption of intestinal tight-junction proteins including Occludin, Claudin, and ZO-1; (2) gut microbiota dysbiosis characterized by a decreased Firmicutes/Bacteroidetes ratio, decreased Lactobacilaceae abundance, and increased Desulfovibrionaceae; and (3) Th17/Treg imbalance, with pro-inflammatory Th17 cells elevated relative to regulatory T cells in metal-exposed models.

Ma et al. (2026) reviewed the mechanistic links between environmental pollutants, gut microbiota, and systemic disease across four metals 4. Arsenic groundwater concentrations often exceed 10 microg/L in endemic regions such as Bangladesh and parts of western China. Four weeks of exposure to 10 ppm inorganic arsenic profoundly altered the gut microbial community structure in C57BL/6 mice (Lu et al. 2014, cited therein). Mice exposed to 3 mg/L cadmium in drinking water for 9 weeks exhibited cognitive impairment secondary to gut dysbiosis (Wang H. et al. 2025, cited therein). In a 696-participant human population study, urinary lead was positively associated with alpha- and beta-diversity shifts and with increased Proteobacteria and Burkholderia abundance.

Bonefeld-Jorgensen and Long (2024) summarized AMAP 2021 Human Health Assessment findings on Arctic Indigenous populations, in whom methylmercury, cadmium, and lead negatively impact both brain development and immune function at concentrations achievable through marine mammal dietary exposure 5. The AMAP assessment documented that PFAS exposure was associated with decreased vaccine antibody responses in Arctic children, and that persistent organic pollutants transferred prenatally were associated with reduced childhood vaccination antibody titers in offspring of exposed mothers.

Metal-induced autoimmunity

Mercury-induced autoimmunity: T-cell mechanisms

Salwen et al. (2026) used an adoptive T-cell transfer model in B10.S mice — a genetically susceptible inbred strain — to investigate how regulatory T cells (Tregs) and IFNgamma control mercury-induced autoimmunity (HgIA) 8. Donor mice were exposed to 4 mg HgCl2/L in drinking water for 4 weeks. CD4+CD25+Foxp3+ Tregs or CD4+CD25- non-Treg cells were isolated from water-primed or mercury-primed wild-type (WT) or IFNgamma-knockout (IFNgamma-/-) B10.S mice and transferred intravenously (approximately 1x10^6 cells per recipient) into WT B10.S recipients, which were then exposed to 4 mg HgCl2/L for 13 weeks.

Recipients of Treg cells from mercury-primed WT donors (group D) showed markedly suppressed antinucleolar antibody (ANoA) production: total IgG ANoA titer fell to 20 +/- 20 at week 13 (30% positive), compared with 2690 +/- 510 (100% positive) in recipients of non-Treg cells from mercury-primed donors (group C; p ⇐ 0.001). Glomerular immune-complex (C3c and IgG) deposits were likewise significantly reduced in Treg recipients (p <0.001). Anti-fibrillarin responses, which characterize the MHC class II-restricted autoantibody in HgIA, were absent in Treg-recipient mice.

IFNgamma was identified as a critical cofactor. Donor T cells from IFNgamma-/- mice (groups E-H) produced a uniformly muted autoimmune phenotype in recipients regardless of T-cell type (Treg or non-Treg), with ANoA essentially absent and glomerular deposits not significantly elevated. This demonstrates that the downstream pathways driving autoantibody production and B-cell activation in HgIA require IFNgamma signaling; Tregs lacking IFNgamma cannot exert their regulatory function.

Mercury-associated autoimmune encephalitis

Huang et al. (2026) described three patients with confirmed chronic mercury exposure who developed anti-LGI1 and/or anti-Caspr2 antibody-positive autoimmune encephalitis 6. All three patients developed acute neuropsychiatric deterioration within 1 to 3 days of initiating DMPS chelation therapy. This paradoxical worsening is documented as a consistent, temporally associated phenomenon in this small series, though causal inference from n=3 is not possible.

Pre-chelation blood and urine mercury concentrations at presentation (Table 1 of source, reference ranges in parentheses): Case 1 (female, 60s; mining area exposure for 8 years) blood mercury 24.2 microg/L (reference <7.8), urine mercury 113 micromol/mol creatinine (reference <2.25); Case 2 (female, 40s; suspected unregulated medication use) blood mercury 4.68 mg/L (reference 0-7.8), urine mercury 35.5 mmol/mol creatinine (reference 0-2.25); Case 3 (male, 50s; metallurgy for 2 years) blood mercury 14.7 microg/L, urine mercury 372 micromol/mol creatinine. All three patients responded to immunotherapy; antibody titers declined and long-term functional outcomes were favorable (mRS 0 to 2).

The authors propose that chelation may transiently mobilize mercury, triggering acute immune activation in susceptible individuals with pre-existing voltage-gated potassium channel complex (VGKC) antibodies, and that immunotherapy should be initiated promptly if neuropsychiatric deterioration occurs. These findings remain hypothesis-generating pending larger cohort data.

Vascular inflammation

Gokcen et al. (2026) compared serum pentraxin-3 (PTX-3) and whole-blood concentrations of Pb, As, Ni, Cd, Hg, tin (Sn), and aluminum (Al) between 50 angiographically confirmed ACS cases and 50 age- and sex-matched controls at a Turkish tertiary center (February to August 2024) 7. PTX-3 is synthesized locally by vascular endothelial cells and macrophages in response to inflammatory stimuli and is proposed as a marker of local vascular inflammation, rising earlier than CRP in acute myocardial infarction.

PTX-3, Pb, As, and Ni were markedly higher in ACS patients; all false discovery rate-adjusted q <0.001. Between-group discrimination by ROC analysis: lead AUC 0.962 (95% CI: 0.923-1.000; sensitivity 100%, specificity 92%); PTX-3 AUC 0.951 (95% CI: 0.907-0.995; sensitivity 94%, specificity 100%); arsenic AUC 0.859; nickel AUC 0.838 (sensitivity 80%, specificity 86%). Whole-blood nickel concentrations were approximately 4.4-fold higher in ACS patients (3.85 [IQR 2.69-6.90] vs 0.87 [0.54-1.44] ng/mL). Cadmium and mercury did not differ significantly between groups.

In Firth penalized logistic regression, PTX-3 (adjusted OR 38.0, 95% CI 6.6-1261.4; p <0.001) and lead (aOR 1.66 per 1 ng/mL, 95% CI 1.25-2.67; p <0.001) remained independently associated with ACS after adjustment for hypertension, hyperlipidemia, and smoking. The cross-sectional design precludes causal inference, and blood metal concentrations at presentation may reflect acute physiological responses to myocardial injury. PTX-3 was not significantly correlated with angiographic disease severity (Gensini score; rho = 0.12, p = 0.41).

Nickel: systemic allergy syndrome

Freeman et al. (2026) reviewed the epidemiology, pathophysiology, and management of systemic nickel allergy syndrome (SNAS), a type IV cell-mediated hypersensitivity condition in which ingestion of nickel-containing foods triggers both cutaneous and extracutaneous symptoms in individuals previously sensitized to nickel via skin contact 9. The prevalence of nickel contact allergy in the European general population is approximately 8% to 19% in adults and 8% to 10% in children and adolescents, with a strong female predominance. Contact allergy to nickel at a 5.0% patch concentration was elicited in 20.3% of tested individuals; at 2.5%, in 16.8% (Svedman et al., cited in source; P <0.0001).

Nickel-rich foods identified in the review include chocolate, leafy green vegetables, legumes, beans, soy, nuts, whole wheat, peas, oats, shellfish, and canned food. Drinking water is an additional nickel source; the European Union regulates the maximum amount of nickel in drinking water to 20 microg/L. SNAS clinical manifestations reported across case series cited in the review include gastrointestinal symptoms (nausea, heartburn, diarrhea, abdominal pain, constipation, bloating, irritable bowel syndrome-like disorder), dermatologic symptoms (vesicle/bullous hand dermatitis, systemic contact dermatitis), neurologic symptoms (headache, fatigue), and rheumatologic symptoms (arthralgia, fibromyalgia-like symptoms). The primary documented intervention is a low-nickel diet; symptom recurrence after dietary nickel reintroduction has been reported across studies.

Indexed source records

References

Works cited in this page’s text, in first-appearance order. Each title links to a source record with bibliographic details, reported findings, and document provenance.

  1. Immune-Epigenetic Effects of Environmental Pollutants: Mechanisms, Biomarkers, and Transgenerational ImpactReddy K and et al. · Current Issues in Molecular Biology · 2025 · doi.org/10.3390/cimb47090703Peer-reviewed
  2. Metal exposures and their interactions with the dietary inflammatory index on inflammatory biomarkers in Mexican adolescentsRodriguez-Carmona Y and et al. · Environmental Epidemiology · 2026 · doi.org/10.1097/ee9.0000000000000458Peer-reviewed
  3. Chronic heavy metal exposure in Yunnan Province disrupts intestinal defenses and increases susceptibility to pathogens: an integrative reviewLi X and et al. · Frontiers in Public Health · 2026 · doi.org/10.3389/fpubh.2026.1794373Peer-reviewed
  4. Environmental pollutants and the gut microbiota: mechanistic links from exposure to systemic diseaseMa W and et al. · Frontiers in Microbiology · 2026 · doi.org/10.3389/fmicb.2026.1737229Peer-reviewed
  5. Health effects associated with measured contaminants in the Arctic: short communicationBonefeld-Jorgensen EC and Long M · International Journal of Circumpolar Health · 2024 · doi.org/10.1080/22423982.2024.2425467Peer-reviewed
  6. Case Report: Mercury exposure and anti-LGI1/Caspr2 autoimmune encephalitis: a case series and literature review on the paradoxical worsening after chelation therapyHuang C, Chen T, Ge T, Li J, and Liu L · Frontiers in Immunology · 2026 · doi.org/10.3389/fimmu.2026.1855642Peer-reviewed
  7. Evaluation of Serum Pentraxin-3 and Heavy Metal Levels in Patients with Acute Coronary SyndromeGokcen E, Guclu HE, Turksoy VA, Ozsoy M, Kusdogan M, Demir V, et al. · Toxics · 2026 · doi.org/10.3390/toxics14100881Peer-reviewed
  8. Regulatory T Cells and IFNgamma in Mercury-Induced Autoimmunity: Insights from Adoptive Transfer in B10.S MiceSalwen R, Amirhosseini M, and Havarinasab S · Biology · 2026 · doi.org/10.3390/biology15040298Peer-reviewed
  9. Systemic Nickel Allergy SyndromeFreeman A, Letterman A, Boos J, and Jackson S · American Journal of Medicine Open · 2026 · doi.org/10.1016/j.ajmo.2026.100126Peer-reviewed

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