Cadmium-induced ATP6V0A1 destabilization impairs lysosomal function to disrupt hepatic lipid homeostasis.

Urinary cadmium and growth faltering in children aged 3-6 years: A nationwide cross-sectional study from China.

Mechanistic links between cadmium and MAPK pathways leading to neurodegeneration.

Integrative epidemiology and multi-omics reveal a frailty-associated ACKR1 redox axis linking cadmium exposure to atherosclerosis.

Cadmium (Cd) exposure is an emerging risk factor for neurodegeneration, yet the contribution of necroptosis to Cd-induced neuronal loss and its tractability for pharmacologic intervention remain unclear. Here, we identify an AMP-activated protein kinase (AMPK)-mitochondrial reactive oxygen species (mtROS)-RIPK1/RIPK3-MLKL axis as a central driver of Cd neurotoxicity and a critical target of metformin. In a chronic Cd-exposed mouse model and in primary hippocampal neurons, Cd provoked prominent neuronal injury characterized by the activation of necroptotic signaling (elevated p-RIPK1, p-RIPK3, and p-MLKL), excessive mtROS production, and mitochondrial injury. Oral metformin preserved hippocampal neuronal integrity and suppressed necroptotic markers invivo, while in cultured neurons and SH-SY5Y cells, it reduced mtROS, maintained mitochondrial morphology and membrane potential, and prevented necrosome assembly. Pharmacologic inhibition of RIPK1 (necrostatin-1) or RIPK3 (GSK-872), as well as CRISPR/Cas9-mediated deletion of RIPK1, RIPK3, or MLKL, attenuated Cd-induced necrosis and phenocopied or enhanced the anti-necroptotic effects of metformin. Mechanistically, metformin restored Cd-suppressed AMPK activity, whereas blockade of AMPK with compound C or expression of a dominant-negative AMPKα1 mutant abolished metformin-mediated suppression of mtROS, RIPK1/RIPK3-MLKL signaling, and necroptosis. Scavenging mtROS with Mito-TEMPO or MitoQ reduced necroptosis and synergized with metformin to disrupt RIPK3-MLKL complex formation. Collectively, these findings demonstrate that Cd triggers neuronal necroptosis via mtROS-driven activation of RIPK1/RIPK3-MLKL, and that metformin confers neuroprotection by activating AMPK to restore mitochondrial homeostasis and restrain necroptotic signaling. This work positions the AMPK-mtROS-necroptosis axis as a therapeutically actionable pathway in heavy-metal neurotoxicity and supports repurposing metformin for necroptosis-associated neurodegenerative conditions.

Cadmium (Cd) is a toxic heavy metal that disrupts plant nutrition and reduces biomass production. This study evaluated the effects of Cd contamination on biomass yield, nutrient status, nutrient use efficiency, and the phytoextraction potential of two tropical forage grasses. A greenhouse experiment was conducted in a randomized block design with a 3 × 2 factorial arrangement, including three Cd levels (0, 2, and 12 mg kg−1) and two forage species (Megathyrsus maximus cv. Mombaça and Urochloa brizantha cv. Marandu). Plants were grown in two soils with contrasting physicochemical properties (Typic Hapludox and Typic Quartzipsamment), both limed and fertilized. Cadmium exposure altered nutrient concentrations in plant tissues. Concentrations of N, P, K, S, Cu, and Zn increased with Cd contamination, while nutrient use efficiency declined, particularly at higher Cd levels. These effects were mainly attributed to a concentration effect caused by reduced biomass. U. brizantha showed greater tolerance to Cd stress, with higher biomass production, improved nutrient use efficiency, and greater removal of bioavailable Cd from the soil compared with M. maximus. The results highlight the importance of species selection and proper soil and nutrient management for phytoremediation of Cd-contaminated soils.

Cadmium (Cd) is a metallic pollutant which has been classified as a possible pancreatic carcinogen. Cd uses similar ion channels than divalent cations to accumulate into the cells. These include the Transient Receptor Potential Cation Channel Subfamily M Member 7 (TRPM7) which has been also shown as a biomarker of pancreatic cancer. Pancreatic carcinogenesis is associated with the establishment of a fibrous stroma induced by pancreatic stellate cell (PSC) activation. Although several stress factors have been identified as activators of PSCs, the impact of pollutants, particularly Cd, is still unknown. Here, we chronically exposed human PSCs to Cd and we observed that Cd-exposed cells acquired a myofibroblast-like phenotype. Moreover, TRPM7 expression and activity were upregulated following Cd exposure. Both TRPM7 inhibition by silencing or NS8593 treatment prevented the Cd-induced PSC cell migration indicating that TRPM7 regulated PSC activation. We used a model of indirect co-culture to study the impact of PSC on MIA PaCa-2 cancer cell migration. Interestingly, we showed that Cd-exposed PSCs stimulated MIA PaCa-2 cancer cell migration to a greater extent than non-exposed PSCs. TRPM7 inhibition in PSCs abolished the migration of cancer cells. Finally, in a mouse model with the KRASG12D mutation inducing spontaneous pancreatic intraepithelial neoplasia, Cd exposure aggravates collagen deposition in fibrotic areas showing high α-SMA and TRPM7 expressions. In summary, our study showed that Cd exposure upregulates TRPM7 leading to PSC activation and aggravation of precancerous pancreatic fibrosis in vivo.

IntroductionSkin aging is a complex, multifactorial biological process that can be significantly accelerated by environmental toxicants such as cadmium (Cd), a highly toxic and ubiquitous heavy metal. Although the broad cytotoxic impacts of Cd have been extensively reported, a comprehensive understanding of the precise molecular pathways underlying Cd-induced skin senescence is still lacking. In this study, we investigated the protective role of Sirtuin 1 (SIRT1), a highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that functions as a master regulator of mitochondrial homeostasis and cellular defense mechanisms.MethodsTo delineate the influence of SIRT1 on dermal aging, we established an in vitro model using primary rat dermal fibroblasts and C3H/10 T1/2 cells, where SIRT1 levels were modulated via lentiviral-mediated overexpression. Concurrently, an in vivo model was developed using Sprague–Dawley rats subjected to chronic Cd exposure via drinking water (50 mg/L) for 6 months, complemented by skin-targeted SIRT1 upregulation through the local injection of AAV-r-SIRT1.ResultsOur results demonstrate that Cd exposure elevates reactive oxygen species (ROS), disrupts mitochondrial integrity, and activates DNA damage responses, collectively driving cellular senescence. SIRT1 was shown to exert protective effects through the deacetylation of key substrates such as P53 and SOD2, thereby restoring redox balance and promoting DNA repair. The elevation of SIRT1 expression markedly mitigated mitochondrial impairments, senescent phenotypes, and apoptotic features triggered by Cd exposure.ConclusionOur findings position SIRT1 as a crucial regulator of Cd-induced skin aging and suggest that targeting this deacetylase may provide a viable strategy to counteract skin degeneration caused by environmental insults.

The association between cadmium, lead, and mercury exposure and lower urinary tract symptoms (LUTS) in middle-aged and elderly men remains underexplored. This study aimed to investigate the associations and dose-response relationships between blood levels of these heavy metals and the risk of LUTS, and to further examine potential causal links using Mendelian randomization (MR) analysis. We conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES 2005-2008). Weighted multivariable logistic regression models were used to assess associations between serum heavy metals and LUTS. Restricted cubic spline (RCS) analysis evaluated dose-response patterns, and MR analysis was performed to infer causality. Serum lead levels in Q2-Q4 were significantly associated with increased LUTS risk (OR = 1.54, 95% CI: 1.00-2.36, P = 0.047; OR = 1.67, 95% CI: 1.10-2.54, P = 0.016; OR = 1.58, 95% CI: 1.02-2.44, P = 0.039). Serum mercury in Q4 was also associated with higher LUTS risk (OR = 1.64, P = 0.009), while no significant association was observed for cadmium. RCS analysis suggested linear associations for cadmium, lead, and mercury, and a significant nonlinear U-shaped association for mixed metal exposure. MR analysis supported a potential causal effect of mercury on benign prostatic hyperplasia (OR = 1.54, P = 0.040). Elevated blood levels of lead and mercury are associated with increased risk of LUTS in men, with mercury possibly exerting a causal influence.

There is a great deal of evidence that cadmium toxicity can have a significant impact on nutritional deficiencies, particularly iron deficiency. Therefore, in this study, we aimed to investigate the effect of cadmium toxicity on iron deficiency by meta-analysis method in order to clarify the previously obtained results. Web of Science, Scopus, and Pubmed databases were used for systematic search until December 17th, 2024. RevMan 5.4 software was used to perform meta-analysis. Six studies were suitable for evaluating environmental/occupational cadmium exposure. In this analysis, serum cadmium levels were meaningfully higher in the cadmium-exposed groups (p=0.0005), while serum iron levels were meaningfully lower (p=0.0004). Forty-five studies were evaluated to include all diseases in which serum cadmium and serum iron levels were measured and included. According to this analysis, serum cadmium levels were meaningfully higher in case groups than in healthy controls (p<0.00001), while serum iron levels were meaningfully lower (p<0.00001). We also performed subgroup analysis exclusively for cancer patients and observed that serum cadmium levels were significantly elevated in cancer patients (p<0.00001), whereas serum iron levels were significantly decreased (p<0.00001). This is the first meta-analysis assessing the association between cadmium toxicity and iron deficiency. Our findings demonstrate that cadmium may be effective in triggering iron deficiency anemia and inflammation-induced anemia by impairing iron metabolism. However, it should be noted that more detailed studies are needed to clarify these effects of cadmium.

With increasing understanding of cadmium (Cd) exposure levels and toxicity mechanisms, the adequacy of current Cd limit standards for protecting public health requires comprehensive evaluation. Here, we found that 39.04% of rice Cd content surpassed the fifth percentile of benchmark dose lower limit (BMDL5; 17.100 micrograms per day) threshold for dietary Cd associated with chronic kidney disease in Jiangsu Province. Moreover, more than 90% of rice Cd levels posed potential health hazards, with some samples presenting lifetime carcinogenic risks. Blood and urinary Cd levels demonstrated age-dependent increases, with 48.40 and 20.61% of participants exceeding BMDL5 levels for blood Cd (0.640micrograms per liter) and urinary Cd (0.120micrograms per liter), respectively. The derived reference values for dietary Cd were 0.149 and 0.018 micrograms per kilogram of body weight per day for adults and children, respectively. The lowest concentrations of Cd in rice consumed by adults and children were also observed, which indicated that current Cd limit standards appear insufficient to protect public health, indicating a need for more stringent safety thresholds.

Introduction Fibrosis in the gossamer alveolar capillary membranes of the lung can lead to abnormalities in gas exchange, hypoxemia and death of the individual. These interstitial lung diseases (ILDs) of known or yet undefined etiologies (such as Idiopathic pulmonary fibrosis) highlight the need for predictive, physiologically relevant models for toxicity studies. Three-dimensional (3D) lung organoids derived from animal cells provide an advanced platform that replicates the structural and cellular complexity of lung tissue while reducing whole-animal use. Methods Mouse lung organoids (MiLO) were used to evaluate pulmonary toxicity caused by environmental toxicants and pharmacologic agents. MiLO were generated from perfused, minced mouse lungs that were digested with collagenase, filtered, depleted of red blood cells, and embedded in Matrigel. Organoids were stained for lineage markers to characterize cellular diversity, including SPC, α-SMA, CD31, F4/80 and ECM proteins collagen I and fibronectin. Gene expression in MiLO and native lung tissue was compared for fibrosis- and viability-related markers. A well-characterized mouse model of cadmium induced lung fibrosis was used as an in vivo benchmark to assess α-SMA expression, airway resistance to methacholine, hydroxyproline content, malondialdehyde levels (MDA), and superoxide dismutase (SOD) activity. For drug-induced fibrosis modeling, cell viability assays defined 20% inhibitory concentrations of nitrofurantoin (NF, 5 μM) and amiodarone (AD, 20 μM), which were then used to treat MiLO for assessment of MDA, invasion area on collagen-coated plates, and expression of fibrotic and signaling markers. Results MiLOs faithfully recapitulated native lung architecture, extracellular matrix composition, and fibrosis-related gene expression profiles. In vivo cadmium exposure increased α-SMA expression, airway resistance, collagen content, and malondialdehyde (MDA) levels, while reducing superoxide dismutase (SOD) activity. Consistently, Cd- treated MiLOs exhibited increases in COL1A1 deposition, cellular invasion, hydroxyproline content, and oxidative stress. Exposure to nitrofurantoin (NF) or amiodarone (AD) elevated MDA, enhanced invasion, and upregulated fibrogenic and signaling genes including Tgfb1, Col1a1, Acta2, Akt1, Nfkb1, and Mmp9. Environmental toxicant (Cd) and drug (AD or NF) treatments drove the development of hallmark fibrotic features in lung organoids, characterized by increased collagen deposition, oxidative stress, and profibrotic gene activation. Conclusions These findings demonstrate that mouse lung organoids effectively recapitulate key molecular and pathological aspects of drug- and toxin-induced pulmonary fibrosis and represent a powerful model for mechanistic investigation and preclinical screening of compounds with potential pro-fibrotic effects.

Background: The carcinogenic potential of cadmium has been suggested, but its association with endometrial cancer risk remains uncertain. This meta-analysis aimed to evaluate whether cadmium exposure is associated with the risk of endometrial cancer. Methods: A thorough search of seven databases was conducted to identify observational studies published up to September 2025. The Newcastle-Ottawa Scale (NOS) and the Agency for Healthcare Research and Quality (AHRQ) tool were utilized to evaluate the quality of observational studies. The I2 statistic was calculated to assess heterogeneity among studies. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using a random-effects model. Furthermore, sensitivity analysis, subgroup analysis, and an assessment of publication bias were performed. Results: Eight studies involving 196,456 participants were included. Study quality assessment indicated that all included studies were of moderate or high quality. Overall, cadmium exposure was associated with an increased risk of endometrial cancer (OR = 1.27, 95% CI: 1.07-1.50, I2 = 64.1%). Stronger associations were observed in case-control studies, European populations, and studies using blood or urinary cadmium biomarkers. The association remained significant in high-quality and adjusted analyses. Conclusions: The findings of this meta-analysis suggest a possible association between cadmium exposure and endometrial cancer risk. However, given the observational nature of the included studies, causality cannot be established. Further large-scale, well-designed prospective studies with standardized exposure assessment are needed to clarify this relationship.

To date, no effective chelation therapy exists to remove cadmium (Cd) from the kidneys, a condition that increases the risk of cadmium-induced chronic kidney disease among humans. consequently, it is vital to prevent kidney damage due to cadmium exposure. However, it has been challenging to identify an early diagnostic marker of cadmium-induced kidney damage through mechanism studies. Interestingly, our previous study revealed that the expression of the microRNA miR-363-3p was upregulated in workers who had been diagnosed with chronic occupational cadmium toxicity. Thus, we aimed to investigate the role of miR-363-3p and its potential signaling pathway in cadmium-induced kidney damage. In this study, we identified a novel signaling pathway, hsa_circ_0075684/miR-363-3p/Krüppel-Like Factor 4 (KLF4), through a comprehensive bioinformatics analysis involving six databases. Next, we validated the role of the hsa_circ_0075684/miR-363-3p/KLF4 pathway in human renal tubular epithelial cell line (HK-2) treated with 0, 5, 10 and 15 µM cadmium chloride (CdCl2). Reverse transcription quantitative PCR (RT-qPCR) and western blot analyses showed that cadmium exposure induced renal fibrosis by regulating the expression of classic renal fibrosis biomarkers, including Fibronectin (Fn), E-cadherin (E-cad) and α-smooth muscle actin (α-SMA) through hsa_circ_0075684/miR-363-3p/KLF4 pathway inhibition. In a mice subchronic model (treated with 0, 5, 10 and 20mg/kg CdCl2), Masson's staining revealed obvious renal fibrosis in mice treated with 5, 10 and 20mg/kg CdCl2 compared to the control group. The altered expression of hsa_circ_0075684/miR-363-3p/KLF4 pathway components and classic renal fibrosis biomarkers in model mice exposed to cadmium was consistent with that observed in HK-2 cells. In summary, we first report hsa_circ_0075684/miR-363-3p/KLF4 axis in cadmium nephrotoxicity, positioning it as a potential early diagnostic marker for cadmium-induced renal fibrosis.

Smoked-dried fish is an important source of affordable animal protein in Nigeria, but it may also represent a route of human exposure to toxic heavy metals. This study assessed the concentrations of arsenic (As), cadmium (Cd), copper (Cu), lead (Pb), and zinc (Zn) in commonly consumed smoked-dried fish sold at Afor-Ugbolu Market, Delta State, Southern Nigeria, and evaluated the associated health risks for both adult and child consumers. Fish samples were digested using standard wet-acid procedures and analysed using Atomic Absorption Spectrophotometry (AAS). Human health risks were evaluated using Estimated Daily Intake (EDI), Target Hazard Quotient (THQ), Hazard Index (HI), and Lifetime Cancer Risk (LCR) models based on USEPA guidelines. Zinc was the most abundant metal detected across all fish species, whereas cadmium and arsenic, though present at lower concentrations, contributed more substantially to health risk indices due to their higher toxicity. Recalculated THQ values for all metals were below unity for both adults and children. Similarly, cumulative Hazard Index values remained below the acceptable threshold (HI &lt; 1), indicating no significant non-carcinogenic health risk under the assumed consumption scenario, although children exhibited consistently higher risk indices than adults. However, lifetime cancer risk assessment revealed that cadmium exposure exceeded the USEPA acceptable risk range, suggesting a potential long-term carcinogenic concern. Overall, smoked-dried fish sold at Afor-Ugbolu Market is generally safe with respect to non-carcinogenic health effects, but continuous monitoring is recommended to minimise long-term carcinogenic risks associated with cadmium exposure.

ABSTRACT Using recycled water for agriculture offers a sustainable approach by adding inherent nutrients and moisture to the soil. However, it contains unwanted contaminants such as heavy metals like cadmium at lower concentrations. This study assessed the comparative response of three leafy crops ‐ lettuce, Indian spinach and methi, against cadmium exposure under hydroponic and soil‐based cultivation. Crops were irrigated with cadmium‐spiked water (0, 0.03, 0.06, and 0.09 mg L −1 ), using a nutrient film technique for hydroponics and fertilized soil pots for soil cultivation. All crops exhibited a biphasic hormetic response, with growth stimulation up to 0.06 mg L −1 and decreased response at 0.09 mg L −1 . Cadmium accumulation increased linearly in crops with rising concentrations in irrigation water, and higher accumulation was recorded in roots than shoots. The crops' response varied significantly between the two cultivation systems, with greater cadmium accumulation under the hydroponic (0.092, 0.109 and 0.088 mg Cd kg −1 of dry weight of lettuce, Indian spinach and methi, respectively) than soil based cultivation (0.025, 0.022 and 0.021 mg Cd kg −1 of dry weight of lettuce, Indian spinach and methi, respectively). Under soil‐based cultivation, Indian spinach and methi exhibited more root cadmium, limited translocation and higher growth response to cadmium than lettuce, which recorded higher shoot cadmium and lower response. On the other hand, under hydroponic cultivation, lettuce had lower accumulation and moderate response, while methi and Indian spinach showed higher uptake in respective root and shoot, and better response, indicating a stimulation effect at low cadmium doses. Despite cadmium accumulation, the human health risk index remained below one, indicating that it is safe to consume these leafy crops. However, under higher Cd concentrations, there could be an increased risk. This study indicates that crops grown hydroponically are more susceptible to cadmium accumulation than those grown in soil. These results indicate that, for using recycled water for growing food crops in hydroponics, it should be of desired quality, which can be achieved through appropriate treatment.

Cadmium exposure accelerates ovarian aging in broiler breeders through oxidative stress and inflammation.

Cadmium (Cd) is a toxic heavy metal that poses serious risks to human health and the ecological environment. Perilla frutescens (L.) Britt. has important medicinal and culinary value, yet its seedlings are highly sensitive to cadmium exposure. Carbohydrates, which mediate key aspects of plant-microbe interactions, play an essential role in recruiting rhizosphere microbiota. In this study, we examined how inoculation with Oceanobacillus picturae alleviates cadmium toxicity by secreting carbohydrate metabolites that reshape the rhizosphere microbial community of perilla. Inoculation markedly reduced cadmium-induced root damage, increasing fresh and dry plant weights by 2.3-fold and 1.1-fold, and enhancing root length by 14% compared with the control. In addition, root exudate profiles showed clear changes following inoculation. Metabolomic analyses revealed that stachyose was a key exudate enriched under stress conditions and acted synergistically with Azospirillum brasilense and Acinetobacter pittii to enhance perilla growth and cadmium tolerance. These findings demonstrate that perilla recruits specific plant growth-promoting rhizobacteria through stachyose-mediated chemical signaling in response to cadmium stress. This work advances our understanding of plant-microbe interactions under heavy metal stress and provides a foundation for microbiome-based phytoremediation technologies. It also offers practical value for developing sustainable agricultural practices and supporting ecological conservation.

Cadmium exposure is a known disruptor of ovarian redox homeostasis and steroidogenesis, with clinically relevant implications for fertility and pregnancy outcomes. We hypothesized that date seed extract (DS), rich in antioxidant constituents, and low-dose gamma radiation (LDR) could synergistically counteract Cd-induced ovarian toxicity. (1) To assess whether DS and/or low-dose γ-radiation mitigate Cd-induced oxidative stress, inflammatory signaling, and impairment of steroidogenesis; (2) to determine whether the combination of DS + LDR offers superior protection relative to single treatments; and (3) to evaluate whether biochemical improvements translate to preservation of ovarian histology. The present study highlights the combinatorial approach (DS + LDR) as a potential, novel intervention for reducing Cd-associated gonadotoxicity. Forty-eight female Swiss albino rats were allocated to eight groups (n = 6): Control; DS; R; DS + R; Cd; Cd + DS; Cd + R; Cd + DS + R. Treatments were administered for 21 days (DS) and 2 weeks (Cd exposure) with ongoing γ-radiation where indicated. Outcomes included: (i) oxidative stress markers (SOD, GSH); (ii) steroidogenic axis components (StAR, CYP11A1, 3β-HSD, 17β-HSD) at the ovarian level; (iii) hormonal profiles (e.g., estrogen, progesterone, and relevant gonadotropins); (iv) inflammatory signaling (NF-κβ); and (v) histopathology of ovarian sections. Cd exposure caused a significant decline in ovarian antioxidants (SOD, GSH) and a reduction in steroidogenic enzyme expression, accompanied by hormonal disturbances and prominent NF-κβ-driven inflammatory changes. Histologically, Cd induced cortical and follicular disruption with increased degenerative changes. DS and LDR mitigated these effects, with the combination DS + LDR showing the most robust rescue: antioxidant defenses and steroidogenic enzyme expression nearly normalized, hormonal levels stabilized, NF-κβ signaling reduced, and ovarian architecture preserved. Statistical significance was achieved for most endpoints (p < 0.05) and trends supported additive or synergistic benefits for DS + LDR. The combination of DS and low-dose γ-radiation offers superior protection against Cd-induced ovarian toxicity by restoring redox balance, downregulating inflammatory pathways, normalizing steroidogenesis, and preserving ovarian histology. These findings support further exploration of DS + R as a potential therapeutic strategy to mitigate heavy metal-related reproductive damage.

Multi-omics biomarkers in cadmium-related lung toxicity and carcinogenesis.