Cadmium

Biological Roles#

Cadmium has no essential biological function. Its toxicity operates through several interconnected mechanisms:

Oxidative Stress. Cadmium generates reactive oxygen species (ROS) by inhibiting electron transport chain complexes II and III in mitochondria, collapsing membrane potential and activating the caspase cascade.^{[2]The Effects of Cadmium ToxicityGiuseppe Genchi, Maria Stefania Sinicropi, Graziantonio Lauria et al. · 2020Open reference 2 ↓}

Simultaneously, cadmium (Cd) depletes the cellular antioxidant arsenal --- it binds Glutathione (GSH) via thiol groups, inhibits superoxide dismutase (SOD) by displacing zinc and manganese cofactors, and reduces catalase and glutathione peroxidase activity.^{[3]Toxic Mechanisms of Five Heavy Metals: Mercury, Lead, Chromium, Cadmium, and ArsenicBalali-Mood M, Naseri K, Tahergorabi Z et al. · 2021Open reference 3 ↓[6]Begg et al. 2015 — Dysregulation of Transition Metal Ion Homeostasis Is the Molecular Basis for Cadmium Toxicity in Streptococcus pneumoniaeStephanie L. Begg, Bart A. Eijkelkamp, Zhenyao Luo et al. · 2015Open reference 6 ↓}

The result is a synergistic toxicity: cadmium induces oxidative stress while simultaneously disabling the enzymes that would neutralize it.

Epigenetic modification. cadmium exposure alters DNA methylation patterns globally (hypomethylation with chronic exposure), modifies histone acetylation, and dysregulates microRNA expression. In MCF-7 breast cancer cells, cadmium treatment altered 997 genes by epigenetic modification, 400 of which are associated with breast cancer.^{[7]Cadmium and breast cancer - Current state and research gaps in the underlying mechanismsTarhonska K, Lesicka M, Janasik B et al. · 2022Open reference 7 ↓}

Defective DNA repair following cadmium-induced oxidative damage is considered a primary carcinogenic mechanism.^{[3]Toxic Mechanisms of Five Heavy Metals: Mercury, Lead, Chromium, Cadmium, and ArsenicBalali-Mood M, Naseri K, Tahergorabi Z et al. · 2021Open reference 3 ↓}

Metallothionein induction. The liver and kidneys synthesize metallothionein (MT) proteins (MW 7--8 kDa, containing 18--23 cysteine residues) that can complex 7 divalent cations.

cadmium binds MT with higher affinity than zinc, and the cadmium-MT complex has a half-life of 25--30 years, accounting for cadmium's extraordinary persistence in biological tissue.^{[2]The Effects of Cadmium ToxicityGiuseppe Genchi, Maria Stefania Sinicropi, Graziantonio Lauria et al. · 2020Open reference 2 ↓} MT overexpression predicts cancer progression and drug resistance.^{[7]Cadmium and breast cancer - Current state and research gaps in the underlying mechanismsTarhonska K, Lesicka M, Janasik B et al. · 2022Open reference 7 ↓}

Microbiome Interactions#

The relationship between cadmium and the gut microbiome is bidirectional: cadmium (Cd) reshapes microbial communities through selective pressure, while the microbiome modulates cadmium absorption, bioavailability, and toxicity.^{[14]Gut Microbiota: A Target for Heavy Metal Toxicity and a Probiotic Protective StrategyHui Duan, Leilei Yu, Fengwei Tian et al. · 2020Open reference 14 ↓[15]Toxic and Essential Metals: Metabolic Interactions with the Gut Microbiota and Health ImplicationsQinheng Zhu, Boyan Chen, Fu Zhang et al. · 2024Open reference 15 ↓}

This bidirectional axis makes the gut the critical interface in cadmium toxicology.

Metal-Specific Microbiome Effects Compared#

In a head-to-head comparison of five toxic metals given to rats by oral gavage, cadmium affected only 5 genera (compared to nickel's 37), but produced significant dose-dependent compositional shifts (PERMANOVA).^{[26]Exposure to toxic metals triggers unique responses from the rat gut microbiotaRichardson JB, Dancy BCR, Horton CL et al. · 2018Open reference 26 ↓}

This narrower but consistent taxonomic effect distinguishes cadmium (Cd) from the broader disruption caused by nickel and arsenic.

Gut Barrier Destruction --- The Vicious Cycle#

Cadmium destroys the intestinal barrier through direct reduction of tight junction proteins: ZO-1, ZO-2, JAM-A, occludin, and claudin-1.^{[21]Effects of Heavy Metals on Gut Barrier Integrity and Gut MicrobiotaSweta Ghosh, Syam P. Nukavarpu, Venkatakrishna Rao Jala · 2024Open reference 21 ↓[28]Oral Administration of Probiotics Inhibits Absorption of the Heavy Metal Cadmium by Protecting the Intestinal BarrierZhai Q, Wang G, Zhao J et al. · 2016Open reference 28 ↓}

In Caco-2 and T84 intestinal cell lines, cadmium (Cd) at 20 uM reduced transepithelial electrical resistance (TEER) dose-dependently; at 68 uM, resistance was abolished entirely.^{[29]Does oral exposure to cadmium and lead mediate susceptibility to colitis? The dark-and-bright sides of heavy metals in gut ecologyBreton J, Daniel C, Vignal C et al. · 2016Open reference 29 ↓}

Inflammatory cytokines TNF-alpha and IL-6 increase significantly in both intestine and blood following cadmium exposure.^{[19]Environmental cadmium exposure alters the internal microbiota and metabolome of Sprague-Dawley ratsSongqing Liu, Xin Deng, Zheng Li et al. · 2023Open reference 19 ↓}

This creates a self-amplifying loop: cadmium damages the barrier, increasing permeability, which increases cadmium absorption, which further damages the barrier.

The loop also enables bacterial translocation --- in cadmium-exposed rats, gut bacteria (Muribaculaceae) translocated into the blood, directly demonstrating how cadmium-induced barrier failure enables microbial invasion of the circulatory system.^{[19]Environmental cadmium exposure alters the internal microbiota and metabolome of Sprague-Dawley ratsSongqing Liu, Xin Deng, Zheng Li et al. · 2023Open reference 19 ↓}

Germ-free mice accumulate significantly more cadmium in organs than conventional mice, demonstrating that the intact microbiome is itself a defense against metal absorption.^{[21]Effects of Heavy Metals on Gut Barrier Integrity and Gut MicrobiotaSweta Ghosh, Syam P. Nukavarpu, Venkatakrishna Rao Jala · 2024Open reference 21 ↓}

Nutritional Immunity#

Cadmium's toxicity intersects with the host's nutritional immunity system in several ways:

cadmium (Cd) enters through essential metal transporters. DMT1 (the primary non-heme iron transporter) also imports cadmium.

Low iron availability and acidic pH increase DMT1 expression, paradoxically enhancing cadmium uptake --- making iron-deficient individuals more vulnerable to cadmium absorption.^{[4]Ghosh 2023 — Evaluation of Therapeutic Efficacy of Fecal Microbiota Transplantation on Cadmium-Induced Testicular Degeneration in RatsAditi Ghosh · 2023Open reference 4 ↓[33]Relationships Between Biological Heavy Metals and Breast Cancer: A Systematic Review and Meta-AnalysisLiu L, Chen J, Liu C et al. · 2022Open reference 33 ↓}

ZIP14, a zinc transporter in the small intestine and kidneys, is another route; cadmium downregulates ZIP14, reducing zinc bioavailability and creating functional zinc deficiency even with adequate dietary zinc.^{[24]Sun et al. 2024 — Zinc-Curcumin Complex Reverses Cadmium-Aggravated Diabetic Nephropathy via Microbiome MediationYujie Sun, Xiaoyu Zhang, Yingying Liu et al. · 2024Open reference 24 ↓}

Convergence with host zinc weaponization. In Streptococcus pneumoniae, cadmium competes with manganese for the PsaA permease --- the same transporter that host zinc targets during nutritional immunity. At 30 uM, cadmium reduces intracellular manganese (Mn) and zinc (Zn) by ~70%, causing widespread enzyme dysfunction.^{[6]Begg et al. 2015 — Dysregulation of Transition Metal Ion Homeostasis Is the Molecular Basis for Cadmium Toxicity in Streptococcus pneumoniaeStephanie L. Begg, Bart A. Eijkelkamp, Zhenyao Luo et al. · 2015Open reference 6 ↓}

This convergence of environmental cadmium toxicity and host zinc defense on the same transporter demonstrates that PsaA is a critical vulnerability node.

Glutathione as the cadmium buffer. Glutathione (GSH) serves as the primary intracellular cadmium chelator, binding free cadmium via thiol groups. When glutathione is depleted --- whether by genetic mutation, oxidative stress, or cadmium overload itself --- the cell loses its defense against cadmium-mediated mis-metallation.

Strains of S. pneumoniae with impaired glutathione synthesis show dramatically increased cadmium sensitivity.^{[6]Begg et al. 2015 — Dysregulation of Transition Metal Ion Homeostasis Is the Molecular Basis for Cadmium Toxicity in Streptococcus pneumoniaeStephanie L. Begg, Bart A. Eijkelkamp, Zhenyao Luo et al. · 2015Open reference 6 ↓}

Cd-Zn Competition and Mis-metallation#

Cadmium and Zinc share similar ionic radius and coordination chemistry, enabling cadmium (Cd) to substitute for zinc (Zn) in metalloenzymes, transcription factors, and structural proteins. This competition is the molecular engine of much of cadmium's pathology.

Proteome-wide mis-metallation. The most comprehensive demonstration comes from S. pneumoniae, where cadmium was shown to mis-metallate at least 16 metalloproteins, including glycolytic enzymes (enolase, phosphofructokinase) and superoxide dismutase (SOD). This forced metabolic rerouting from glycolysis to the pentose phosphate pathway --- a systems-level metabolic rewiring from a single toxic metal.

The downstream consequence was altered membrane fatty acid composition and reduced capsule production (the primary virulence factor), potentially attenuating pathogenicity.^{[34]Neville et al. 2020 — Cadmium Stress Dictates Central Carbon Flux and Alters Membrane Composition in Streptococcus pneumoniaeStephanie L. Neville, Jacqueline R. Morey, Erin B. Gillen et al. · 2020Open reference 34 ↓}

Functional zinc deficiency. Across cancer types, cadmium elevation co-occurs with zinc depletion. A meta-analysis of 36 case-control studies (n=4,151) confirmed that cadmium is significantly elevated in breast cancer patients (SMD 2.55 in Asia) while zinc is significantly depleted (SMD -2.09).^{[33]Relationships Between Biological Heavy Metals and Breast Cancer: A Systematic Review and Meta-AnalysisLiu L, Chen J, Liu C et al. · 2022Open reference 33 ↓}

The copper (Cu)/zinc ratio is proposed as a pan-cancer biomarker.^{[35]Recent advances in the application of metallomics in diagnosis and prognosis of human cancerYan Zhang, Jie He, Jiao Jin et al. · 2022Open reference 35 ↓[36]Zinc Deficiency as a General Feature of Cancer: A Review of the LiteratureRie Sugimoto, Lingaku Lee, Yuki Tanaka et al. · 2024Open reference 36 ↓}

In ASD, the same pattern recurs: toxic metals (lead (Pb), mercury (Hg), cadmium) elevated alongside consistent zinc depletion, with ~10% of the human genome encoding zinc-binding proteins that become vulnerable targets.^{[37]Metal Profiles in Autism Spectrum Disorders: A Crosstalk between Toxic and Essential MetalsBlazewicz A, Grabrucker AM · 2023Open reference 37 ↓}

The zinc/cadmium ratio as biomarker. In diabetic nephropathy, the zinc-to-cadmium ratio functions as a critical injury biomarker. A zinc-curcumin complex reversed cadmium-induced dysbiosis and nephropathy in mice, with FMT from treated mice reproducing the effect --- confirming microbiome mediation of the zinc/cadmium antagonism.^{[24]Sun et al. 2024 — Zinc-Curcumin Complex Reverses Cadmium-Aggravated Diabetic Nephropathy via Microbiome MediationYujie Sun, Xiaoyu Zhang, Yingying Liu et al. · 2024Open reference 24 ↓}

Bidirectionality. The competition is bidirectional: zinc deficiency exacerbates cadmium toxicity (more cadmium enters through vacant zinc binding sites), and cadmium exposure induces functional zinc deficiency (cadmium occupies zinc sites, rendering them nonfunctional).

Prenatal zinc deficiency causes ASD-like behavior in mice, and prenatal zinc therapy prevents VPA-induced ASD-like behaviors --- connecting the cadmium-zinc axis to neurodevelopmental outcomes.^{[37]Metal Profiles in Autism Spectrum Disorders: A Crosstalk between Toxic and Essential MetalsBlazewicz A, Grabrucker AM · 2023Open reference 37 ↓}

Conditions Associated#

Chronic Kidney Disease#

The kidney is cadmium's primary chronic target organ. The cadmium (Cd)-metallothionein (cadmium-MT) complex is filtered at the glomerulus and reabsorbed in proximal tubules, where lysosomal degradation at pH 4.5--5.5 releases free cadmium, causing tubular damage.^{[1]Exposure to Cadmium and Its Impacts on Human Health: A Short ReviewPuthiyavalappil Rasin, Ashwathi A V, Sabeel M Basheer et al. · 2025Open reference 1 ↓}

Beta-2 microglobulin in urine serves as a biomarker for cadmium-induced tubular toxicity (detectable at urinary cadmium as low as 360 ug/L).^{[3]Toxic Mechanisms of Five Heavy Metals: Mercury, Lead, Chromium, Cadmium, and ArsenicBalali-Mood M, Naseri K, Tahergorabi Z et al. · 2021Open reference 3 ↓}

The vicious cycle: cadmium accumulates in renal cortex proportional to lifetime exposure; cadmium impairs electron transport chain complexes II/III, inducing mitochondrial dysfunction and oxidative stress; tubular damage reduces GFR, impairing cadmium elimination; declining renal function increases cadmium retention, accelerating further damage.^{[40]Molecular Mechanisms of Cellular Injury and Role of Toxic Heavy Metals in Chronic Kidney DiseaseManish Mishra, Larry Nichols, Aditi A. Dave et al. · 2022Open reference 40 ↓}

Epidemiological evidence: Blood cadmium >=0.4 ug/L independently associated with CKD risk (OR 1.23); combined elevated lead (Pb) + cadmium shows highest risk (OR 1.65). Elevated cadmium associated with 42% increased mortality in CKD patients (HR 1.42).^{[41]Association of low-level heavy metal exposure with risk of chronic kidney disease and long-term mortalityKuo PF, Huang YT, Chuang MH et al. · 2024Open reference 41 ↓}

A longitudinal study (n=384, 4 repeated measurements) found synergistic effects of cadmium-chromium (Cr) on renal biomarkers (NAG, UACR), and a triple synergistic effect of lead-cadmium-chromium on UACR. Females and smokers showed greater kidney damage at equivalent exposure levels.^{[42]Complex interplay of heavy metals and renal injury: New perspectives from longitudinal epidemiological evidenceYin G, Zhao S, Zhao M et al. · 2024Open reference 42 ↓}

Cardiovascular Disease#

An overview of 8 systematic reviews (153 studies, ~160,000+ participants) confirmed that cadmium (Cd) exposure independently increases risk of atherosclerosis, coronary artery disease, hypertension, myocardial infarction, and stroke.^{[43]Nucera 2024 — Non-essential heavy metal effects in cardiovascular diseases: overview of systematic reviewsNucera S, Serra M, Caminiti R et al. · 2024Open reference 43 ↓} cadmium correlates with hypertension even at low concentrations (<1 ug/L plasma).

The mechanism involves ROS generation, TNF-alpha and NF-kB p65 activation, NLRP3 inflammasome engagement, endothelial damage via reduced NO and increased endothelin-1 (EDN-1).^{[43]Nucera 2024 — Non-essential heavy metal effects in cardiovascular diseases: overview of systematic reviewsNucera S, Serra M, Caminiti R et al. · 2024Open reference 43 ↓}

cadmium also drives cardiovascular risk indirectly through the microbiome: cadmium-induced dysbiosis upregulates indoxyl sulfate production (a pro-atherogenic uremic toxin) and depletes Clostridium and Lactobacillus species that produce protective tryptophan metabolites (IPA, IAld).^{[1]Exposure to Cadmium and Its Impacts on Human Health: A Short ReviewPuthiyavalappil Rasin, Ashwathi A V, Sabeel M Basheer et al. · 2025Open reference 1 ↓[19]Environmental cadmium exposure alters the internal microbiota and metabolome of Sprague-Dawley ratsSongqing Liu, Xin Deng, Zheng Li et al. · 2023Open reference 19 ↓}

Type 2 Diabetes#

A burden-of-disease analysis across 46 studies (n=56,191) estimated that eliminating cadmium exposure would reduce T2D incidence by approximately 65% (population attributable fraction). The dose-response relationship is linear: RR of 1.47 at 1.5--2.0 ug/L blood cadmium (Cd), 2.43 at 2.0--2.5 ug/L, and 4.00 at >2.5 ug/L.^{[8]Li 2023 — Burden of diabetes attributable to dietary cadmium exposure in adolescents and adults in ChinaShan Li, Muhadasi Tuerxunyiming, Zhe Sun et al. · 2023Open reference 8 ↓}

cadmium disrupts pancreatic beta-cell lipid metabolism, induces pancreatic Metal-Driven Inflammation, and alters glucose homeostasis. cadmium aggravated diabetic nephropathy alongside TLR4/NF-kB activation in an animal model.^{[24]Sun et al. 2024 — Zinc-Curcumin Complex Reverses Cadmium-Aggravated Diabetic Nephropathy via Microbiome MediationYujie Sun, Xiaoyu Zhang, Yingying Liu et al. · 2024Open reference 24 ↓}

Neurodegenerative Disease#

cadmium (Cd) enters neurons via voltage-gated calcium channels and diminishes glutathione peroxidase, catalase, and SOD activity.

In humanized ApoE4-KI mice (an Alzheimer's model), cadmium exposure caused gut microbiota changes --- increasing Prevotella (an AD microbial biomarker) and decreasing SCFA-producing Clostridiaceae and Lactobacillaceae --- and activated NF-kB/IL-1beta in the liver, disrupting the gut-liver axis.^{[20]Cadmium exposure modulates the gut-liver axis in an Alzheimer's disease mouse modelAngela Zhang, Megumi Matsushita, Liang Zhang et al. · 2021Open reference 20 ↓}

cadmium has been linked to Alzheimer's disease, Parkinson's disease, and multiple sclerosis through calcium signaling disruption and protein misfolding.^{[44]Heavy Metals Exposure and Alzheimer's Disease and Related DementiasBakulski KM, Seo YA, Hickman RC et al. · 2020Open reference 44 ↓[1]Exposure to Cadmium and Its Impacts on Human Health: A Short ReviewPuthiyavalappil Rasin, Ashwathi A V, Sabeel M Basheer et al. · 2025Open reference 1 ↓}

In the Parkinson's context, cadmium-driven enrichment of Proteobacteria (including iron-scavenging Enterobacteriaceae) mirrors the PD microbiome signature. cadmium competes with iron for DMT1 and ZIP transporter uptake, dysregulating iron homeostasis in a pattern consistent with PD pathology.^{[18]Zhang 2021 -- Cadmium Exposure and Gut Microbiome Disruption in NeurodegenerationPengya Zhang, Huizhen Zheng, Guangbo Qu · 2021Open reference 18 ↓}

Polycystic Ovary Syndrome (PCOS)#

A systematic review of 15 controlled studies found consistently elevated cadmium (Cd) in women with PCOS (1.2 vs 0.7 ppb; 1.75 vs 0.59 ppb in two studies). cadmium levels positively correlated with oxidative stress markers (MDA, TNF-alpha) and insulin resistance (HOMA-IR).

The metalloestrogen activity of cadmium disrupts the hypothalamic-pituitary-gonadal axis, contributing to the hormonal dysregulation characteristic of PCOS.^{[45]Heavy Metals and Essential Elements in Association with Oxidative Stress in Women with Polycystic Ovary Syndrome -- A Systematic ReviewSmovrsnik T, Virant-Klun I, Pinter B · 2023Open reference 45 ↓}

Autism Spectrum Disorder#

A comprehensive narrative review of 25+ studies across multiple biomatrices found cadmium (Cd) elevated in hair and urine of individuals with ASD.

The proposed mechanism centers on cadmium competing with zinc for binding sites across the ~10% of human genome that encodes zinc-binding proteins, creating functional zinc deficiency during critical neurodevelopmental windows.

Key synaptic ASD-associated pathways (NLGN-NRXN-SHANK, mTOR/PI3K) are modified by zinc and calcium and are vulnerable to toxic metal displacement.^{[37]Metal Profiles in Autism Spectrum Disorders: A Crosstalk between Toxic and Essential MetalsBlazewicz A, Grabrucker AM · 2023Open reference 37 ↓}

Female Infertility#

In a population-based analysis (NHANES 2013--2016), a two-fold increase in blood cadmium (Cd) was associated with 1.84-fold increased odds of infertility (95% CI 1.07--3.15) after full adjustment. Effects were observed even at low blood metal levels (geometric mean cadmium = 0.26 ug/L).^{[39]Female Infertility Associated with Blood Lead and Cadmium LevelsLee S, Min JY, Min KB · 2020Open reference 39 ↓}

cadmium affects ovulation, steroidogenesis, and pituitary function through both metalloestrogen activity and direct gonadotoxicity.

Inflammatory Bowel Disease#

Short-term cadmium (Cd) exposure (1 week) exacerbated acute colitis in mice, but paradoxically, subchronic (6-week) exposure showed protective effects through metallothionein induction and immunomodulation --- reducing IL-6, IL-1beta, and Nos2 transcription while upregulating TGF-beta.

This hormesis-like dose-duration response challenges simple dose-response assumptions in cadmium toxicology.^{[29]Does oral exposure to cadmium and lead mediate susceptibility to colitis? The dark-and-bright sides of heavy metals in gut ecologyBreton J, Daniel C, Vignal C et al. · 2016Open reference 29 ↓}

Male Reproductive Toxicity#

FMT from probiotic-enriched donors reversed cadmium (Cd)-induced testicular degeneration in rats, restoring sperm motility from 23% to 53%, concentration from 1.98 x 10^7 to 1.14 x 10^8/mL, and serum testosterone from 2.053 to 4.54 ng/mL.

cadmium enters testes via ZIP8 and CatSper channels (mimicking calcium(II) (Ca2+)), disrupting the blood-testis barrier and Leydig cell function.^{[4]Ghosh 2023 — Evaluation of Therapeutic Efficacy of Fecal Microbiota Transplantation on Cadmium-Induced Testicular Degeneration in RatsAditi Ghosh · 2023Open reference 4 ↓}

Itai-Itai Disease#

The historical epidemic of cadmium poisoning in Toyama Prefecture, Japan (1910s--1960s) produced itai-itai ("it hurts-it hurts") disease --- severe osteomalacia with renal tubular dysfunction. cadmium (Cd) interferes with calcium metabolism and bone mineralization, causing pathological fractures.

This remains the most dramatic example of chronic dietary cadmium poisoning.^{[1]Exposure to Cadmium and Its Impacts on Human Health: A Short ReviewPuthiyavalappil Rasin, Ashwathi A V, Sabeel M Basheer et al. · 2025Open reference 1 ↓}

Metal-Antibiotic Co-resistance#

Enterococcus species carry metal tolerance (MeT) genes for mercury, arsenic, and copper that co-occur with antibiotic resistance (ABR) genes on mobile genetic elements. MeT genes have been present since at least the 1900s, but co-occurrence with ABR genes has increased since the 1990s.

These resistance cassettes transfer horizontally across genera.^{[46]Diversity of metal and antibiotic resistance genes in Enterococcus spp. from the last century reflects multiple pollution and genetic exchange among phyla from overlapping ecosystemsRebelo A, Mourao J, Freitas AR et al. · 2021Open reference 46 ↓}

Three molecular mechanisms drive co-selection: (1) co-resistance --- physical linkage on the same plasmid or transposon; (2) cross-resistance --- the same gene conferring resistance to both (e.g., CzcCBA system expelling cobalt (Co), zinc (Zn), cadmium (Cd) and certain antibiotics); and (3) co-regulatory mechanisms --- shared transcriptional responses.^{[47]Baker-Austin 2006 — Co-selection of Antibiotic and Metal ResistanceBaker-Austin C, Wright MS, Stepanauskas R et al. · 2006Open reference 47 ↓} Heavy Metals, unlike antibiotics, are non-degradable and represent a permanent selective pressure in contaminated environments.