Nickel Exposure Research Articles

Association between nickel exposure and diabetes risk: an updated meta-analysis of observational studies

ObjectiveThe results of epidemiological studies on the association between nickel exposure and diabetes remain controversial. Therefore, an update meta-analysis was conducted to examine the association between urinary nickel levels and diabetes risk, and to focus on whether there is an association between blood nickel levels and diabetes risk.MethodsRelevant studies were comprehensively searched from PubMed, Web of Science, and Wanfang databases from their inception to July 2024. The random-effects model was utilized to determine pooled Standard Mean Difference (SMD) and 95% confidence intervals (CIs), with stratified and sensitivity analyses also performed. Heterogeneity between studies was assessed using I2 statistic, while publication bias was evaluated using Egger's and Begg's tests. The quality of the included studies was assessed using the Newcastle-Ottawa Scale.ResultsA total of 19 studies involving 46,071 participants were included in this meta-analysis. The random-effects model indicated that the pooled SMD for nickel exposure levels in diabetic patients and non-diabetic controls were 0.16 (95% CI 0.07–0.2) for urine and 0.03 (95% CI −0.20 to 0.27) for blood, respectively.ConclusionIt was discovered that diabetes risk was positively correlated with urinary nickel levels, whereas there was no significant correlation with blood nickel levels. Furthermore, it appeared that the association between nickel exposure and diabetes risk differ in individuals with diabetes compared to those with pre-diabetes, and that the direction of the correlation may even be reversed. In conclusion, more high-quality prospective studies are needed in order to validate these findings in future research endeavors.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO, registration number: CRD42024534139.

Role of the ROS/NLRP3/caspase-1 pathway in NiSO4-induced cellular pyroptosis and apoptosis in H9c2 cells

According to comprehensive research, the cardiovascular system is damaged by nickel exposure. The present study selected rat cardiomyocytes (H9c2 cells) and subjected them to varying doses of sodium nickel sulfate (NiSO4) for 24hours to better understand the mechanism of cardiovascular damage caused by NiSO4 exposure. The relevant indicators were detected employing biochemical analysis, real-time quantitative polymerase chain reaction (RT-qPCR), and western blot, and flow cytometry was used to detect the cell apoptosis rate. The study revealed that the survival rate of H9c2 cells fell significantly when the concentration of NiSO4 exposure rose. Moreover, it caused oxidative stress in H9c2 cells by raising the expression of reactive oxygen species and the concentration of LDH in the cell supernatants. After NiSO4 exposure, the levels of ASC, NLRP3, gasdermin D, and caspase-1 in H9c2 cells increased, suggesting that H9c2 cells underwent pyroptosis induced by NiSO4. In addition, NiSO4 exposure also led to inflammation, with increased levels of interleukin [IL]-18, IL-1β. After adding the antioxidant N-Acetyl-L-cysteine (NAC), the level of ROS indicated that the oxidative stress level in H9c2 cells was reduced, western blot inhibited inflammation, the level of pyroptosis was reduced, and the activity of the NLRP3/caspase1 signaling pathway was reduced. To examine the connection between pyroptosis and apoptosis, the cells were treated with the caspase1 inhibitor Z-YVAD-Fluoromethyl Ketone (Z-YVAD-FMK, YVAD), which resulted in a significant decrease in the rate of cell apoptosis as well as a reduction in the activity of the related protein in the signaling pathway, which in turn decreased the level of pyroptosis. NiSO4 could induce pyroptosis in H9c2 cells through the ROS/NLRP3/caspase-1 axis. Furthermore, NiSO4-induced apoptosis and pyroptosis were found to be reduced by the addition of the caspase-1 inhibitor.

Metabolipidomic changes induced by dermal nickel penetration determined in an ex vivo porcine ear skin model.

Nickel is one of humans' most prevalent triggers of allergic contact dermatitis. However, the underlying mechanisms of this allergy still need to be fully understood. One aspect that has yet to be explored is the direct impact of common metal allergens on the skin's metabolites and lipids composition. Our study employed matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) to analyze spatially resolved metabolic alterations induced by nickel exposure. Cross-sections of ex vivo porcine ear skin exposed to increasing nickel (II) ion concentrations (17-167 μg/cm2) were measured with an AP-SMALDI5 AF ion source coupled to Q Exactive HF Orbitrap mass spectrometer. Additionally, the penetration of nickel ions into the skin was observed through its pink complexation with dimethylglyoxime under light microscopy. For nickel ion concentrations up to 84 μg/cm2, most nickel ions were stopped within the stratum corneum, while only a very small proportion of nickel ions penetrated the viable epidermis and dermis. Stratum corneum locations with high nickel ion concentrations showed a decrease in arginine and ceramides. Furthermore, several phosphatidylcholine and sphingomyelin species were found to be downregulated in the viable epidermis and dermis due to the nickel exposure. Nickel penetrates at a trace level into the viable skin and induces severe metabolomic and lipidomic changes in the stratum corneum, epidermis, and dermis, indicating a change in the skin (barrier) function. These findings contribute to a deeper understanding of nickel-induced skin allergies and provide a solid foundation for further research.

Association Between Nickel Exposure and Metabolic Syndrome: Data from NHANES 2017-2018.

Previous studies have found a possible association between nickel and metabolic syndrome (MetS), but with conflicting results. No studies have determined whether nickel exposure increases the prevalence of MetS in the general U.S. population. Therefore, we used data from the National Health and Nutrition Examination Survey (NHANES) to assess the association between urinary nickel and MetS. Since urinary nickel levels were presented as a skewed distribution, they were normalized using a logarithmic transformation. Weighted multivariate logistic models, restricted cubic spline, threshold effect analysis, and subgroup analyses were used to examine the association between urinary nickel concentration and the risk of MetS and its components. Based on data from 1577 participants, individuals in the second, third, and fourth quartiles of urinary nickel had an adjusted OR for MetS of 1.42 (95% CI: 0.88, 2.28), 2.00 (95% CI: 1.22, 3.28), and 1.68 (95% CI: 1.05, 2.70), respectively, representing an inverted "L"-shaped nonlinear dose-response relationship with an inflection point at 0.2141ng/L. Patients over the age of 40, males, less educated, and smokers are more susceptible to nickel exposure. In addition, there were significant associations between nickel and most components of the MetS, with the strongest to weakest correlations being high fasting glucose, reduced high-density lipoprotein, abdominal obesity, and elevated blood pressure; however, there was no significant correlation between nickel and hyperlipidemia. In conclusion, environmental nickel exposure increases the prevalence of MetS in U.S. adults, particularly in males over 40years of age, those with less education, and smokers.

The mediating role of abnormal ZEB1 methylation in the association between nickel exposure and non-syndromic orofacial cleft

Our previous study found a positive relationship between fetal nickel exposure and the risk of OFCs. The teratogenic mechanism of nickel is not clear. In this study, we aim to examine the mediating effect of DNA methylation on the association of nickel(Ni) exposure with NSOFC in fetuses. 10 cases and 10 controls was used for screening target gene by Illumina Infinium Methylation EPIC(850k) BeadChip. 36 cases and 78 controls was conducted to determine DNA methylation level of selected gene in umbilical cord blood by Mass spectrometry assay. Mediation analysis was used to evaluate the potential mediating effect of selected gene methylation on the relation between concentrations of Ni and the risk for NSOFC. In the discovery stage, ZEB1 gene was identified to be hypermethylated in both nickel exposure and NSOFC group for validation. In the verification stage, the overall average methylation level of ZEB1 was significant higher in NSOFC cases(median = 8.70, interquartile range(IQR): 5.75–11.53) as compared to controls (median = 5.35, IQR: 4.30–7.78). The risk for NSOFC was increased by 1.43-fold with hypermethylation of ZEB1. Significant correlation was observed between concentrations of Ni in umbilical cord and methylation level of ZEB1. The hypermethylation of ZEB1 had a mediating effect by 20.47 % of total effect of Ni on NSOFC risk. Hypermethylation of ZEB1 is associated with the risk for NSOFC and may partially explain the association between Ni exposure and NSOFC risk. Our findings provide new insights into the epigenetic mechanisms underlying NSOFC and suggesting potential targets for future therapeutic interventions.

Associations between blood nickel and lung function in young Chinese: An observational study combining epidemiology and metabolomics

Prior research has explored the relationship between occupational exposure to nickel and lung function. Nonetheless, there is limited research examining the correlation between blood nickel levels and lung function among young adults in the general population. The metabolomic changes associated with nickel exposure have not been well elucidated. On August 23, 2019, we enrolled 257 undergraduate participants from the Chinese Undergraduates Cohort to undergo measurements of blood nickel levels and lung function. The follow-up study was conducted in May 2021. A linear mixed-effects model was employed to assess the relationship between blood nickel levels and lung function. We also conducted stratified analyses by home address. In addition, in order to explore the biological mechanism of lung function damage caused by nickel exposure, we performed metabolomic analyses of baseline serum samples (N = 251). Both analysis of variance and mixed linear effect models were utilized to assess the impact of blood nickel exposure on metabolism. Our findings from cross-sectional and cohort analyses revealed a significant association between blood nickel levels and decreased forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) among young adults in the general population. Furthermore, we found stronger associations in urban areas. In metabolomics analysis, a total of nine metabolites were significantly changed under blood nickel exposure. The changed metabolites were mainly enriched in six pathways including carbohydrate, amino acid, and cofactor vitamin metabolism. These metabolic pathways involve inflammation and oxidative stress, indicating that high concentrations of nickel exposure can cause inflammation and oxidative stress by disrupting the above metabolism of the body.

Sensitivity of Alabama Freshwater Gastropod Species to Nickel Exposure.

Snails are effective bioindicators due to their prolific distribution, high level of endemism, and capacity to accumulate contaminants. Freshwater snails have unique ecological niches which are imperiled by land-use change and the introduction of hazardous chemicals. To assess how environmental alterations affect gastropods, lab-based studies are needed to characterize the toxicity of specific stressors. This can help guide policy decisions and remediation efforts. The aim of this research was to characterize acute toxicity of nickel (Ni) on endemic snails (Somatogyrus georgianus [Walker, 1904], Elimia cahawbensis [Lea, 1861], and Elimia spp.) and measure the accumulation of Ni and mineral elements including calcium (Ca), magnesium, potassium, and sodium (Na). Snails were exposed to six concentrations (25-800 µg/L) of Ni for 96 h. Among the studied snail species, E. cahawbensis was the most sensitive to Ni, with the lowest lethal concentration where 50% of the organisms died (LC50) at 88.88 µg/L Ni after 96 h. The LC50 at 96 h for S. georgianus was 167.78 µg/L Ni, and 393.13 μg/L Ni for Elimia spp. Except for Elimia spp., mortality of the other two snail species corresponded to the whole-body uptake of Ni. Nickel exposure also influenced Ca and Na uptake for Elimia spp. All three endemic species are potential candidate species for evaluating localized effects of human activities, and the present study provides a first step in characterizing how snails would be affected by environmental alterations. More research could further characterize potential effects of other human stressors on these endemic snail species. Future research into subindividual responses and routes of exposure can further elucidate variations in species sensitivity. Environ Toxicol Chem 2024;00:1-11. © 2024 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Transcriptome Analysis of the Effect of Nickel on Lipid Metabolism in Mouse Kidney.

Although the human body needs nickel as a trace element, too much nickel exposure can be hazardous. The effects of nickel on cells include inducing oxidative stress, interfering with DNA damage repair, and altering epigenetic modifications. Glucose metabolism and lipid metabolism are closely related to oxidative stress; however, their role in nickel-induced damage needs further study. In Institute of Cancer Research (ICR) mice, our findings indicated that nickel stress increased the levels of blood lipid indicators (triglycerides, high-density lipoprotein, and cholesterol) by about 50%, blood glucose by more than two-fold, and glycated serum protein by nearly 20%. At the same time, nickel stress increased oxidative stress (malondialdehyde) and inflammation (Interleukin 6) by about 30% in the kidney. Based on next-generation sequencing technology, we detected and analyzed differentially expressed genes in the kidney caused by nickel stress. Bioinformatics analysis and experimental verification showed that nickel inhibited the expression of genes related to lipid metabolism and the AMPK and PPAR signaling pathways. The finding that nickel induces kidney injury and inhibits key genes involved in lipid metabolism and the AMPK and PPAR signaling pathways provides a theoretical basis for a deeper understanding of the mechanism of nickel-induced kidney injury.

Mechanism of Mitochondrial Kinetic Imbalance and Nrf2 Signaling Pathway-Mediated Oxidative Stress in Nickel and/or Chromium-Induced Kidney Injury in Mice.

Nickel and chromium are both common heavy metals that pose serious environmental and health hazards. However, the exact mechanism by which nickel and/or chromium cause renal injury is unclear. Therefore, we explored the molecular mechanisms of renal injury caused by nickel and/or chromium poisoning from the perspective of mitochondrial dynamics and the Nrf2 antioxidant pathway. In this study, eighty 6-week-old C57BL/6J mice were randomly divided into four groups: control (Con, untreated), nickel (Ni, 110 mg/L Ni2+), chromium (Cr, 50 mg/L Cr6+), and combined nickel-chromium (Ni + Cr, 110 mg/L Ni2+, 50 mg/L Cr6+). The results showed that chronic nickel and/or chromium exposure inhibited body weight gain and impaired kidney function and structure in mice. Chronic nickel and/or chromium exposure led to the disruption of mitochondrial dynamics and thus induced oxidative stress. On the other hand, the Nrf2 antioxidant pathway may play an important regulatory role in mitigating oxidative stress-induced oxidative damage in kidney. The present study partially elucidated the molecular mechanism of renal injury induced by nickel and/or chromium exposure in mice and the regulatory role of the Nrf2 pathway in inducing oxidative injury from the perspective of mitochondrial dynamics. This provides a theoretical basis for the development of prevention and control strategies, and environmental protection measures.

The toxicological analysis of problematic and sophisticated elements (Ni, Cr, and Se) in Food for Special Medical Purposes (FSMP) using in pharmacotherapy and clinical nutrition for oncological patients available in Polish pharmacies

This study focuses on FSMPs for oncologic patients, specifically analyzing the toxicological profiles of nickel (Ni), chromium (Cr), and selenium (Se) within these products available in Polish pharmacies. The presence of these elements was quantified using inductively coupled plasma mass spectrometry (ICP-MS). Results indicated variations in the concentrations of Ni, Cr, and Se across different FSMP samples, with some products exceeding the acceptable limits set by regulatory guidelines. The study highlights the potential health risks associated with nickel exposure, including dermatitis and carcinogenesis, and the complex roles of chromium and selenium, which can be both beneficial and harmful depending on their levels. Our findings reveal significant variability in the elemental content across different FSMP products, i.e.: Ni: 0.155–25.488 μg/portion, Cr: 0.076–28.726 μg/portion and Se: 0.083–20.304 μg/portion). Notably, selenium levels in FSMPs showed considerable discrepancies compared to manufacturers' declarations, averaging only about 20% of the stated values. Regulatory assessments based on the Acceptable Daily Intake (ADI) and Permitted Daily Exposure (PDE) descriptors indicated that the estimated weekly intake of Ni, Cr, and Se from these FSMPs did not exceed the provisional tolerable weekly intake (PTWI) values. However, the highest Ni content was 30.58% of the PTWI, raising concerns about potential health risks, including dermatitis and carcinogenesis. The results for Cr underscored the necessity for careful monitoring due to its potential toxic effects. Selenium, despite its essential role, showed levels inadequate to meet the Recommended Dietary Allowance (RDA), potentially impacting its intended health benefits.

Особливості діагностики та лікування жінок з синдромом полікістозних яєчників в умовах підвищеного рівня експонування нікелем

Abstract. Polycystic ovary syndrome (PCOS) refers to endocrinopathies that women of reproductive age could have. These disorders can be caused by both endogenous (endocrine disorders, chronic infections, stress, etc.) and exogenous factors (environmental, smoking, etc.). Aim. Determination of serum nickel values in women with polycystic ovary syndrome and investigation of the mechanisms underlying the toxic effects of nickel on the reproductive system. Explore potential sources of nickel exposure and develop recommendations for the prevention and treatment of PCOS caused by increased levels of nickel exposure. Materials and Methods. The research was conducted on the bases of State Institution “O.M. Lukianova Institute of Pediatrics, Obstetrics and Gynecology of NAMS of Ukraine” 52 women who were diagnosed with PCOS were selected for the study. The control group consisted of 38 women of reproductive age without reproductive system pathology. Determination of serum nickel values in women with PCOS was performed using a Bruker MS 820 inductively coupled plasma mass spectrometer (Australia) using special ICP-MS Expert software. The study of indicators of environmental pollution with nickel was carried out by processing data published in open sources of information. Results. Women with PCOS showed elevated serum nickel values (median ‒ 0.036 mg/l, 95-percentile ‒ 0.194 mg/l), which significantly exceeded the control group (median ‒ 0.001 mg/l, 95-percentile ‒ 0.097 mg/l, p=0.0012). The study of exposure possible sources showed that elevated levels of nickel were found in drinking water from surface water sources. Contamination of surface waters and soils used in agriculture was also detected. The authors propose a set of measures for the prevention and treatment of complications caused by nickel exposure. Conclusions. Nickel exposure occurs mainly by alimentary and inhalation. When exposed to nickel, there is a violation of the function of the endocrine system, activation of inflammatory processes and oxidative stress. In women with PCOS with an increased level of nickel exposure, it is necessary to carry out a set of measures aimed at reducing the level of exposure, accelerating nickel excretion and treating complications that have occurred. Keywords: polycystic ovary syndrome, nickel, exposure, principles of prevention and treatment.

Physiological responses of the nickel hyperaccumulator Bornmuellera emarginata under varying nickel dose levels and pH in hydroponics

Abstract Background and aims The nickel hyperaccumulator Bornmuellera emarginata (Brassicaceae) is a species adapted to thrive on naturally nickel-enriched ultramafic soils in the Balkans and a promising candidate for use in nickel agromining. The main aim of this study was to provide insight into the physiological mechanisms of nickel hyperaccumulation in B. emarginata. Methods Bornmuellera emarginata was cultivated under various nickel exposure concentrations (control, 1, 10, and 100 µM nickel in solution), and different pH levels of the hydroponic solution for four weeks. During this period, the plants underwent assessment for various physiological parameters, including photosynthetic pigments, leaf relative water content, tolerance index, and metal accumulation in plant tissues. Results The results show that the translocation factors and bioconcentration factors were > 1 even at 1 µM nickel in solution. This confirms the ability of B. emarginata to hyperaccumulate nickel (up to 6600 mg kg−1) over a wide range of nickel concentrations in hydroponics. Nickel at 100 µM (a concentration that is an order of magnitude higher than the highest soil solution nickel concentration found in ultramafic soils) induced only mild physiological stress symptoms (e.g. a minor proline response). Alterations in the solution pH did not cause any significant effect on nickel accumulation in the plants. Conclusions Bornmuellera emarginata is a highly adapted nickel-tolerant and nickel hyperaccumulating species that shows very little stress responses even to extreme nickel exposure concentrations in hydroponics. This species shows interesting trade-off responses between nickel and other metals, including non-competitive uptake of zinc. The potential for this species to accumulate zinc should therefore be further explored.

Effects of Cadmium and Nickel Mixtures on Multiple Endpoints of the Microalga Raphidocelis subcapitata.

It is crucial to investigate the effects of mixtures of contaminants on aquatic organisms, because they reflect what occurs in the environment. Cadmium (Cd) and nickel (Ni) are metals that co-occur in aquatic ecosystems, and information is scarce on their joint toxicity to Chlorophyceae using multiple endpoints. We evaluated the effects of isolated and combined Cd and Ni metals on multiple endpoints of the chlorophycean Raphidocelis subcapitata. The results showed that Cd inhibited cell density, increased reactive oxygen species (ROS) production (up to 308% at 0.075 mg L-1 of Cd), chlorophyll a (Chl a) fluorescence (0.050-0.100 mg L-1 of Cd), cell size (0.025-0.100 mg L-1 of Cd), and cell complexity in all concentrations evaluated. Nickel exposure decreased ROS production by up to 25% at 0.25 mg L-1 of Ni and Chl a fluorescence in all concentrations assessed. Cell density and oxygen-evolving complex (initial fluorescence/variable fluorescence [F0/Fv]) were only affected at 0.5 mg L-1 of Ni. In terms of algal growth, mixture toxicity showed antagonism at low doses and synergism at high doses, with a dose level change greater than the median inhibitory concentration. The independent action model and dose-level-dependent deviation best fit our data. Cadmium and Ni mixtures resulted in a significant increase in cell size and cell complexity, as well as changes in ROS production and Chl a fluorescence, and they did not affect the photosynthetic parameters. Environ Toxicol Chem 2024;43:1855-1869. © 2024 SETAC.

Correlation between environmental nickel exposure and the development of arthritis: A large-sample cross-sectional investigation

BackgroundNickel is a common metallic element in orthopedic implanted devices and living environment exposures. It is associated with varieties of diseases. The purpose of this investigation was to explore the correlation between nickel exposure and the prevalence of arthritis. MethodsData were obtained from the National Health and Nutrition Examination Survey (NHANES) database from 2017 to 2018. Multivariate logistic regression was utilized to analyze the relationship between urinary nickel levels and arthritis. In addition, hierarchical modeling further explored the interactions and trends between urinary nickel levels and arthritis. Propensity score matching (PSM) method was used to reduce the effect of confounders. Additionally, restricted cubic spline curve (RCS) was used to assess the possible nonlinear association between urinary nickel and arthritis. ResultsThe investigation was comprised of 139 arthritis patients and 547 healthy participants. After correction by PSM, there was a positive correlation between arthritis and Nickel exposure levels. The risk of developing arthritis was significantly increased when nickel exposure levels were in the Q4 interval (OR=2.25, 95 % CI=1.03–5.02). When stratified by age and sex, nickel exposure was significantly and positively associated with arthritis in the subgroup aged over 65 years. (OR=2.78,95 %CI=1.20–6.46). Also, the difference between nickel exposure and arthritis was significant in the different gender subgroups (interaction P<0.05). Restricted cubic spline (RCS) results showed a significant linear association between nickel exposure levels and arthritis. In addition, there was a non-linear association between nickel exposure and arthritis across gender and age subgroups. ConclusionA significant positive association between nickel exposure levels and arthritis was showed by the experimental data. Controlling the use of nickel-containing medical prostheses and reducing exposure to nickel-containing daily necessity could help to slow the onset of arthritis.

Exploring the Impact of Nickel Exposure on Female Fertility.

Introduction Infertility affects an estimated 186 million individuals globally and is associated with numerous mental health issues. Trace elements are essential for reproductive health, yet the role of nickel in female fertility is not well understood. Previous research has shown conflicting evidence regarding nickel's impact on ovarian function and its potential to disrupt reproductive processes. Methods We utilized data from the National Health and Nutrition Examination Survey (NHANES) focusing on a cohort of 7,839 women, with an emphasis on 1,404 women aged 18 to 35. Logistic regression was employed to investigate the relationship between urinary nickel levels and fertility status, controlling for age, BMI, and race/ethnicity. Results The fertility analysis included 880 fertile and 106 infertile women, identifying age as a significant predictor of fertility status. Nickel exposure did not demonstrate a statistically significant association with fertility. The racial distribution within the groups showed a higher proportion of non-Hispanic White women in the fertile category and Mexican American women in the infertile group, although race was not a significant predictor in the regression model. Conclusions We found no significant relationship between nickel exposure and fertility status when adjusted for race, BMI, and age. Age was the only significant factor associated with fertility. These results highlight the complexity of the interplay between environmental exposures and reproductive health, suggesting that further research is necessary to elucidate the role of nickel and other trace elements in fertility.

Subclinical immune responses to nickel in sensitized individuals-a dose-response study.

Nickel is the leading cause of contact allergy in Europe, with 14.5% of the adult population being sensitized. Despite regulations limiting nickel release from consumer items, the incidence and prevalence of nickel allergy remain high. To investigate the clinical and subclinical immune response to low-dose nickel exposure on nickel pre-exposed skin to assess the adequacy of current regulatory limits. Nickel-allergic and healthy controls were patch tested with nickel twice with a 3-4 weeks interval. The first exposure used the diagnostic concentration of 2000 μg/cm2 nickel sulphate, and the same skin areas were then re-exposed to 0.2, 0.5, 12.8 and 370 μg/cm2 nickel sulphate. After 48 h, the patch reactions were examined for clinical signs of eczema, and skin biopsies were collected. The transcriptomic immune profile was analysed with Nanostring nCounter and quantitative polymerase chain reaction. Two nickel-allergic participants (15%) had clinical reactions to the regulatory limiting doses for nickel (0.2/0.5 μg/cm2) following re-exposure. There was immune activation in all skin areas following re-exposure to nickel, predominantly mediated by up-regulation of cytokines and chemokines. In all nickel re-exposed skin areas, 81 genes were up-regulated independent from the clinical response. In skin areas exposed to 0.2 μg/cm2, 101 immune-related genes were differentially expressed, even when no clinical response was observed. Healthy controls showed up-regulation of three genes in response to nickel re-exposures without any clinical reactions. Immune activation can be induced in skin with local memory to nickel upon challenge with nickel doses within the regulatory limits. Our findings suggest that the regulatory limits in the European nickel regulation may not provide sufficient protection for consumers against low-dose exposures.

Urinary cadmium concentration is associated with the severity and clinical outcomes of COVID-19: a bicenter observational cohort study

BackgroundCadmium and nickel exposure can cause oxidative stress, induce inflammation, inhibit immune function, and therefore has significant impacts on the pathogenesis and severity of many diseases. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can also provoke oxidative stress and the dysregulation of inflammatory and immune responses. This study aimed to assess the potential associations of cadmium and nickel exposure with the severity and clinical outcomes of patients with coronavirus disease 2019 (COVID-19).MethodsWe performed a retrospective, observational, bicenter cohort analysis of patients with SARS-CoV-2 infection in Taiwan between June 2022 and July 2023. Cadmium and nickel concentrations in blood and urine were measured within 3 days of the diagnosis of acute SARS-CoV-2 infection, and the severity and clinical outcomes of patients with COVID-19 were analyzed.ResultsA total of 574 patients were analyzed and divided into a severe COVID-19 group (hospitalized patients) (n = 252; 43.9%), and non-severe COVID-19 group (n = 322; 56.1%). The overall in-hospital mortality rate was 11.8% (n = 68). The severe COVID-19 patients were older, had significantly more comorbidities, and significantly higher neutrophil/lymphocyte ratio, C-reactive protein, and interleukin-6 than the non-severe COVID-19 patients (all p < 0.05). Blood and urine cadmium and urine nickel concentrations were significantly higher in the severe COVID-19 patients than in the non-severe COVID-19 patients. Among the severe COVID-19 patients, those in higher urine cadmium/creatinine quartiles had a significantly higher risk of organ failure (i.e., higher APACHE II and SOFA scores), higher neutrophil/lymphocyte ratio, lower PaO2/FiO2 requiring higher invasive mechanical ventilation support, higher risk of acute respiratory distress syndrome, and higher 60-, 90-day, and all-cause hospital mortality (all p < 0.05). Multivariable logistic regression models revealed that urine cadmium/creatinine was independently associated with severe COVID-19 (adjusted OR 1.643 [95% CI 1.060–2.547], p = 0.026), and that a urine cadmium/creatinine value > 2.05 μg/g had the highest predictive value (adjusted OR 5.349, [95% CI 1.118–25.580], p = 0.036).ConclusionsUrine cadmium concentration in the early course of COVID-19 could predict the severity and clinical outcomes of patients and was independently associated with the risk of severe COVID-19.

Nickel Accumulation in Saliva and Urine Post Orthodontic Fixed Appliance Treatment in Malay Population

Objective: Prolonged nickel exposure, even in low amounts, is cytotoxic, genotoxic and carcinogenic. The study aims to evaluate the salivary and urinary nickel levels post-orthodontic fixed appliance treatment. Materials and Methods: Saliva and urine samples of fourteen orthodontic patients were taken at debonding (T0), after one month (T1), and three months post-debonding (T2), and compared with the control group. Samples were analysed using Inductively Coupled Plasma Optical Mass Spectrometry (ICP-MS) and IBM SPSS Version 27 was used for statistical analyses. Results: The mean (SD) of orthodontic treatment duration was 33.6 (9.6) months. In comparison to the control group, the mean (SD) nickel levels in saliva and urine were highest at debonding (T0) with 12.71 ppb (9.64) and 9.71 ppb (8.27), respectively. In the test group, there was a significant difference in nickel level in saliva between T0 and T1 (MD = 9.75, 95% CI: 3.71, 15.71; p &lt; 0.05) and in urine between T0 and T1 (MD = 6.46, 95% CI: 1.38, 11.55; p = 0.012). Conclusion: Our results clearly demonstrated that the nickel level in saliva and urine remained higher at the end of orthodontic treatment compared to the control group. Further studies with a longer duration of observation and larger samples are suggested. Furthermore, our study indicates it is essential to confirm the effects of long-duration of orthodontic treatment and its post-treatment nickel level. This study raised attention about the biocompatibility of mechanical orthodontic treatment vs sustainable general health.

RhoGDIβ inhibition via miR-200c/AUF1/SOX2/miR-137 axis contributed to lncRNA MEG3 downregulation-mediated malignant transformation of human bronchial epithelial cells.

Nickel pollution is a recognized factor contributing to lung cancer. Understanding the molecular mechanisms of its carcinogenic effects is crucial for lung cancer prevention and treatment. Our previous research identified the downregulation of a long noncoding RNA, maternally expressed gene 3 (MEG3), as a key factor in transforming human bronchial epithelial cells (HBECs) into malignant cells following nickel exposure. In our study, we found that deletion of MEG3 also reduced the expression of RhoGDIβ. Notably, artificially increasing RhoGDIβ levels counteracted the malignant transformation caused by MEG3 deletion in HBECs. This indicates that the reduction in RhoGDIβ contributes to the transformation of HBECs due to MEG3 deletion. Further exploration revealed that MEG3 downregulation led to enhanced c-Jun activity, which in turn promoted miR-200c transcription. High levels of miR-200c subsequently increased the translation of AUF1 protein, stabilizing SOX2 messenger RNA (mRNA). This stabilization affected the regulation of miR-137, SP-1 protein translation, and the suppression of RhoGDIβ mRNA transcription and protein expression, leading to cell transformation. Our study underscores the co-regulation of RhoGDIβ expression by long noncoding RNAMEG3, multiple microRNAs (miR-200c and miR-137), and RNA-regulated transcription factors (c-Jun, SOX2, and SP1). This intricate network of molecular events sheds light on the nature of lung tumorigenesis. These novel findings pave the way for developing targeted strategies for the prevention and treatment of human lung cancer based on the MEG3/RhoGDIβ pathway.

DNMT3a-mediated upregulation of the stress inducible protein sestrin-2 contributes to malignant transformation of human bronchial epithelial cells following nickel exposure

BackgroundNickel is a confirmed human lung carcinogen. Nonetheless, the molecular mechanisms driving its carcinogenic impact on lung tissue remain poorly defined. In this study, we assessed SESN2 expression and the signaling pathways responsible for cellular transformation in human bronchial epithelial cells (HBECs) as a result of nickel exposure. MethodsWe employed the Western blotting to determine the induction of SESN2 by nickel. To clarify the signaling pathways leading to cellular transformation following nickel exposure, we applied techniques such as gene knockdown, methylation-specific PCR, and chromatin immunoprecipitation. ResultExposure to nickel results in the upregulation of SESN2 and the initiation of autophagy in human bronchial epithelial cells (HBECs). This leads to degradation of HUR protein and consequently downregulation of USP28 mRNA, PP2AC protein, β-catenin protein, and diminished VHL transcription, culminating in the accumulation of hypoxia-inducible factor-1α (HIF-1α) and the malignant transformation of these cells. Mechanistic studies revealed that the increased expression of SESN2 is attributed to the demethylation of the SESN2 promoter induced by nickel, a process facilitated by decreased DNA methyl-transferase 3 A (DNMT3a) expression, while The downregulation of VHL transcription is linked to the suppression of the PP2A-C/GSK3β/β-Catenin/C-Myc pathway. Additionally, we discovered that SESN2-mediated autophagy triggers the degradation of HUR protein, which subsequently reduces the stability of USP28 mRNA and inhibits the PP2A-C/GSK3β/β-Catenin pathway and c-Myc transcription in HBECs post nickel exposure. ConclusionOur results reveal that nickel exposure leads to the downregulation of DNMT3a, resulting in the hypomethylation of the SESN2 promoter and its protein induction. This triggers autophagy-dependent suppression of the HUR/USP28/PP2A/β-Catenin/c-Myc pathway, subsequently leading to reduced VHL transcription, accumulation of HIF-1α protein, and the malignant transformation of human bronchial epithelial cells (HBECs). Our research offers novel insights into the molecular mechanisms that underlie the lung carcinogenic effects of nickel exposure. Specifically, nickel induces aberrant DNA methylation in the SESN2 promoter region through the decrease of DNMT3a levels, which ultimately leads to HIF-1α protein accumulation and the malignant transformation of HBECs. Specifically, nickel initiates DNA-methylation of the SESN2 promoter region by decreasing DNMT3a, ultimately resulting in HIF-1α protein accumulation and malignant transformation of HBECs. This study highlights DNMT3a as a potential prognostic biomarker or therapeutic target to improve clinical outcomes in lung cancer patients.