Low Doses Of Cadmium Research Articles

Chronic cadmium exposure in Japanese quails perturbs serum biochemical parameters and enzyme activity

Cadmium is a heavy metal, toxic even in trace amounts and its biological function in the human body has not been described to date. It is assumed that cadmium manifests in dose-dependent genotoxic and cytotoxic effects on many organs and tissue types. In this study, we have analyzed the biochemical parameters in the serum of Japanese quails (Coturnix japonica) after chronic in vivo exposure to cadmium. Adult animals were exposed to cadmium in the form of CdCl2 dissolved in water (0.20 mg/L) for 20 days. Significant differences between controls and exposed animals were found in 12 out of 13 analyzed biochemical parameters. Total bilirubin concentrations did not show any significant differences between the two groups. Exposure to cadmium has resulted in a significant increase in lactate dehydrogenase activity, sodium and chloride concentration, as well as significant reductions in total proteins, albumins, globulins, glucose, triglycerides, cholesterol, calcium concentration, and alkaline phosphatase activity. In this sense, chronic in vivo exposure to low doses of cadmium has induced severe changes in the levels of observed biochemical parameters and enzyme activity. Additionally, evident cytogenetic changes in the liver were also noted, where hepatocyte damage and even lack of organized nuclei, including nuclear fragmentation, clearly indicated ongoing apoptotic processes.

Low-dose cadmium potentiates lung inflammatory response to 2009 pandemic H1N1 influenza virus in mice

Cadmium (Cd) is a toxic, pro-inflammatory metal ubiquitous in the diet that accumulates in body organs due to inefficient elimination. Responses to influenza virus infection are variable, particularly severity of pneumonia. We used a murine model of chronic low-dose oral exposure to Cd to test if increased lung tissue Cd worsened inflammation in response to sub-lethal H1N1 infection. The results show that Cd-treated mice had increased lung tissue inflammatory cells, including neutrophils, monocytes, T lymphocytes and dendritic cells, following H1N1 infection. Lung genetic responses to infection (increasing TNF-α, interferon and complement, and decreasing myogenesis) were also exacerbated. To reveal the organization of a network structure, pinpointing molecules critical to Cd-altered lung function, global correlations were made for immune cell counts, leading edge gene transcripts and metabolites. This revealed that Cd increased correlation of myeloid immune cells with pro-inflammatory genes, particularly interferon-γ and metabolites. Together, the results show that Cd burden in mice increased inflammation in response to sub-lethal H1N1 challenge, which was coordinated by genetic and metabolic responses, and could provide new targets for intervention against lethal inflammatory pathology of clinical H1N1 infection.

Effects of Combined Exposure to Cadmium and High-Fat Diet on Bone Quality in Male Mice.

This study investigated the effects of combined exposure to low-dose cadmium and high-fat diet on femoral bone quality in male mice. Eight-week-old male SPF C57BL/6J mice were randomly divided into four groups: normal control group (Con), low-cadmium group (Cd), high-fat diet group (HFD), and high-fat diet plus low-dose cadmium group (HFD + Cd); the second and fourth groups were treated intraperitoneally with CdCl2 (1.0mg/kg body weight) twice weekly for 20weeks. Assays related to bone quality were performed. Body weight of HFD plus Cd mice was significantly lower than HFD mice. Femoral length was not different among groups, but femoral weight was decreased in the HFD plus Cd group compared with other three groups. Level of Cd in bone was significantly increased in HFD plus Cd group. There was no difference in cortical BMD among groups; however, cortical bone quality parameters were decreased in HFD plus Cd group. Cd and HFD each reduced trabecular bone quality and together had further detrimental effects on these bone parameters. Based on biomechanical analysis, femoral bone strength was decreased, being more brittle and less resistant to biomechanical forces in the HFD plus Cd mice. HFD plus Cd mice had lower OPG mRNA expression and higher RANKL mRNA expression than others. HFD or Cd can cause adverse effects on bone and together had further detrimental effects associated with RANKL/OPG signaling.

Effects of sub-chronic, low-dose cadmium exposure on kidney damage and potential mechanisms.

The present study was to investigate the potential mechanisms underlying the sub-chronic low-dose cadmium (Cd) exposure induced renal injury in rats. Totally 40 male adult SD rats were randomly divided into four groups: control group, low-dose Cd group (1 mg/kg CdCl2), moderate-dose Cd group (2.5 mg/kg) and high-dose Cd group (5 mg/kg). From the 3rd week, the body weight of rats in moderate-dose and high-dose declined significantly as compared to the control group (P<0.05); the liver to body weight ratio increased, the volumes of 24-hour urine and drinking-water decreased markedly (P<0.05), the BUN, SCr and β2-MG increased significantly, but the Fe2+ concentration decreased markedly as compared to the control group (P<0.05); the serum MDA and SOD1 content contents increased, but the serum SOD2 and CAT contents decreased significantly in Cd-treated groups (P<0.05); Renal injury deteriorated with the increase in Cd dose; swelling glomeruli showed stenotic renal-tubules, and epithelial-cell-necrosis, shedding and accumulation in the lumen, massive infiltrated inflammatory cells and interstitial hyperaemia were observed; The mitochondria in renal-tubular-epithelial-cells displayed swelling, deformation and vacuolation; the renal ROS content increased in Cd-exposure-groups; the renal SOD1 expression increased but the expression of SOD2 and CAT decreased (P<0.05). The Bcl-2 expression decreased, but Bax expression and Bax/Bcl-2 ratio increased significantly in a Cd-dose dependent manner. Cd may cause renal injury in a dose dependent manner, which may be ascribed to the disordered Fe2+ absorption, redox imbalance and apoptosis in the kidney.

Gender Differences in Cardiac Remodeling Induced by a High-Fat Diet and Lifelong, Low-Dose Cadmium Exposure.

Childhood obesity, which is prevalent in developed countries, is a metabolic risk factor for cardiovascular disease. Cadmium (Cd), a ubiquitous environmental toxic metal, also has deleterious effects on the cardiovascular system. However, the combined effects of a high-fat diet (HFD) and lifelong, low-dose Cd exposure on cardiac remodeling remain unclear. This study aims to determine the effects of combined HFD and Cd exposure on cardiac remodeling, as well as gender-specific differences in the response. C57BL/6J mice were exposed to Cd at a low dose (L-Cd, 0.5 ppm) or high dose (H-Cd, 5 ppm) via drinking water from conception to sacrifice. After being weaned, the offspring mice were fed with a HFD (42% kcal from fat) for an additional 10 weeks. H-Cd exposure significantly increased Cd accumulation in the hearts of both parents and their offspring; a HFD showed no added effects on cardiac Cd content. H-Cd exposure increased cardiac metallothionein protein levels only in female mice, regardless of dietary intake. Histological analysis revealed that H-Cd exposure combined with a HFD induced cardiac hypertrophy and fibrosis only in female mice. This was further supported by elevated expression of ANP and COL1A1 protein levels along with COL1A1, COL1A2, and COL3A1 mRNA levels. Profibrotic markers PAI-1, CTGF, and FN were also elevated in HFD/H-Cd-exposed female mice. Levels of the oxidative stress marker 3-NT significantly increased in the hearts of HFD-fed female mice, whereas Cd exposure showed no additional effects. Of all the antioxidant markers examined, levels of CAT significantly increased in mice fed a HFD, regardless of gender and Cd exposure. In summary, a HFD combined with lifelong, low-dose Cd exposure induces cardiac hypertrophy and fibrosis in female but not male mice, a response that is independent of oxidative stress.

Green olive leaf extract (OLE) provides cytoprotection in renal cells exposed to low doses of cadmium.

Cadmium (Cd) is a heavy and highly toxic metal that contaminates air, food and water. Cadmium accumulates in several organs altering normal functions. The kidney is the major organ at risk of damage from chronic exposure to cadmium as a contaminant in food and water. This study aims to investigate the beneficial effects of OLE in renal collecting duct MCD4 cells exposed to a low dose cadmium (1 μM). In MCD4 cells cadmium caused an increase in ROS production, as well as generation of lipid droplets and reduced cell viability. Moreover, cadmium exposure led to a remarkable increase in the frequency of micronuclei and DNA double-strand breaks, assessed using the alkaline comet assay. In addition, cadmium dramatically altered cell cytoskeleton architecture and caused S-glutathionylation of actin. Notably, all cadmium-induced cellular deregulations were prevented by co-treatment with OLE, possibly due to its antioxidant action and to the presence of bioactive phytocompounds. Indeed, OLE treatment attenuated Cd-induced actin S-glutathionylation, thereby stabilizing actin filaments. Taken together, these observations provide a novel insight into the biological action of OLE in renal cells and support the notion that OLE may serve as a potential adjuvant against cadmium-induced nephrotoxicity.

Low-dose cadmium exposure acts on rat mesenchymal stem cells via RANKL/OPG and downregulate osteogenic differentiation genes

Chronic cadmium (Cd) toxicity is a significant health concern, and the mechanism of long-term low-dose Cd exposure on bone has not been fully elucidated till date. This study aimed to assess the association between rat mesenchymal stem cells (MSCs) and long-term Cd exposure through 38-week intake of CdCl2 at 1 and 2 mg/kg body weight (bw). Increased gene expression of receptor activator of NF-κB ligand (RANKL) and decreased gene expression of osteoprotegerin (OPG) were observed. Fold change of RANKL gene expression (fold change = 1.97) and OPG gene expression (fold change = 1.72) showed statistically significant differences at dose 2 mg/kg bw. Decreased expression of key genes was observed during the early osteogenic differentiation of MSCs. The gene expression of Osterix in 1 mg/kg bw group was decreased by 3.70-fold, and the gene expressions of Osterix, Osteopontin, collagen type I alpha 2 chain (COL1a2) and runt-related transcription factor 2 (RUNX2) in 2 mg/kg bw group were decreased by 1.79, 1.67, 1.45 and 1.35-folds, respectively. Exposure to CdCl2 induced an increase in the renal Cd load, but only an adaptive response was observed, including increased expression of autophagy-related proteins LC3B and Beclin-1, autophagy receptor p62, and heme oxygenase 1 (HO-1), which is an inducible isoform that releases in response to stress. There were no significant changes in the urinary low molecular weight proteins including N-acetyl-b-D-glucosaminidase (NAG), β2-microglobulin and albumin (U-Alb). Urinary calcium (Ca) excretion showed no increase, and no obvious renal histological changes. Taken together, these results indicated that the chronic CdCl2 exposure directly act on MSCs through RANKL/OPG pathway and downregulate the key genes involved in osteogenic differentiation of MSCs. The toxic effect of Cd on bone may occur in parallel to nephrotoxicity.

Chronic low-level cadmium exposure in rats affects cytokine production by activated T cells.

Cadmium is a toxic metal and common environmental contaminant. Chronic cadmium exposure results in kidney, bone, reproductive, and immune toxicity as well as cancer. Cadmium induces splenomegaly and affects the adaptive immune system, but specific effects vary depending on the dose, model, and endpoint. This study investigates the effects of subchronic, oral, and low-dose cadmium exposure (32 ppm cadmium chloride in drinking water for 10 weeks) on the rat immune system, focusing on T cell function. Cadmium-exposed animals demonstrated slight increases in the spleen-to-body weight ratios, and decreases in overall splenic cell numbers and markers of oxidative stress. The relative ratios of splenic cell populations remained similar, except for modest increases in regulatory T cells in the cadmium-exposed animals. Cadmium exposure also significantly increased the production of IFNγ, a pro-inflammatory cytokine, and IL-10, a cytokine produced by multiple T cell subsets that typically inhibits IFNγ expression, by activated T cells. The increase in IFNγ and IL-10 suggests that cadmium exposure may affect multiple T cell subsets. Collectively, this study suggests that subchronic, low-dose cadmium exposure impacts both immune cell function and cellularity, and may enhance inflammatory responses.

Low-dose cadmium disrupts mitochondrial citric acid cycle and lipid metabolism in mouse lung

Cadmium (Cd) causes acute and chronic lung toxicities at occupational exposure levels, yet the impacts of Cd exposure at low levels through dietary intake remain largely uncharacterized. Health concerns arise because humans do not have an effective Cd elimination mechanism, resulting in a long (10- to 35-y) biological half-life. Previous studies showed increased mitochondrial oxidative stress and cell death by Cd yet the details of mitochondrial alterations by low levels of Cd remain unexplored. In the current study, we examined the impacts of Cd burden at a low environmental level on lung metabolome, redox proteome, and inflammation in mice given Cd at low levels by drinking water (0, 0.2, 0.6 and 2.0 mg Cd/L) for 16 weeks. The results showed that mice accumulated lung Cd comparable to non-smoking humans and showed inflammation in lung by histopathology at 2 mg Cd/L. The results of high resolution metabolomics combined with bioinformatics showed that mice treated with 2 mg Cd/L increased levels of lipids in the lung, accompanied by disruption in mitochondrial energy metabolism. In addition, targeted metabolomic analysis showed that these mice had increased accumulation of mitochondrial carnitine and citric acid cycle intermediates. The results of redox proteomics showed that Cd at 2 mg/L stimulated oxidation of isocitrate dehydrogenase, malate dehydrogenase and ATP synthase. Taken together, the results showed impaired mitochondrial function and accumulation of lipids in the lung with a Cd dose response relevant to non-smokers without occupational exposures. These findings suggest that dietary Cd intake could be an important variable contributing to human pulmonary disorders.

Disruption of Kidney Metabolism in Rats after Subchronic Combined Exposure to Low-Dose Cadmium and Chlorpyrifos.

Cadmium (Cd) and chlorpyrifos (CPF) often coexist in the environment and induce combined toxicity to organisms. Here we studied the combined nephrotoxicity of environmentally relevant low doses of Cd and CPF. We treated the mice for 90 days with different doses of Cd and CPF and their mixtures via oral gavage. Then histopathological evaluation and biochemical analysis for kidney tissues were carried out. The change of metabolites in kidney was detected by using a metabolomics approach using GC-MS. We found that Cd, CPF, and their mixtures caused oxidative damage as well as disturbance of renal amino acid metabolism. We identified potential metabolite biomarkers in kidney, which included acetic acid for CPF treatment, glycerol and carboxylic acid for Cd treatment, and l-ornithine for the mixture of CPF and Cd treatment, respectively. In addition, we found that Cd promoted the metabolism of CPF in kidney. This may contribute to the result that the toxicity of the mixtures was lower than the sum of the toxicities of Cd and CPF alone. In conclusion, our results indicated that CPF and Cd could disrupt the kidney metabolism in rats even when they were exposed to a very low dose of CPF and Cd.

191 - Low-dose cadmium disrupts mitochondrial citric acid cycle and lipid metabolism in mouse lung

191 - Low-dose cadmium disrupts mitochondrial citric acid cycle and lipid metabolism in mouse lung

Short-term effects of very low dose cadmium feeding on copper, manganese and iron homeostasis: A gastropod perspective

The available information on the interplay between low-dose cadmium intake and copper, manganese, and iron homeostasis in invertebrates is limited. We have currently studied the accumulation of these trace metals in the hepatopancreas of adult snails, Cantareus aspersus, following 14 and 28 days of exposure to low doses of dietary cadmium, up to 1 mg/kg dw (dry weight). The cadmium dose, but not the duration of exposure, had a significant effect on hepatopancreas copper deposition, the values being significantly elevated compared to controls. A significant peak in manganese levels at 14 days was found in snails administered the lowest cadmium dose. These increases occurred even in the absence of cadmium increase in the hepatopancreas. Our data suggest that low dose cadmium feeding can produce a transient disturbance in hepatopancreas copper and manganese homeostasis. Such responses may serve as early biomarkers of physiological changes occurring during the initial stages of cadmium intoxication.

Metabonomics analysis of kidneys in rats administered with chronic low-dose cadmium by ultra-performance liquid chromatography-mass spectrometry.

This study aimed to investigate the nephrotoxicity in rats administered with chronic low-dose cadmium (Cd) by ultra-performance liquid chromatography-mass spectrometry. A total of 40 male Sprague-Dawley rats were randomly assigned to four groups, namely: control; low-dose (0.13mg/kg·body weight [bw]); middle-dose (0.80mg/kg·bw); and high-dose (4.89mg/kg·bw). The rats received CdCl2 daily via drinking water for 24weeks. Rat kidneys were collected for metabonomics analysis. Principal components analysis and partial least-squares discriminant analysis were used to investigate the metabonomics profile changes in the kidney samples and to screen the potential biomarkers. Ten metabolites were identified in the positive and negative ion modes. Compared with the control group, the intensities of tetranor 12-HETE, uric acid, hypoxanthine, phenylacetylglycine, guanidinosuccinic acid and xanthosine significantly increased (P<0.01), and those of imidazolelactic acid, lactose 6-phosphate, l-urobilinogen and arachidonic acid significantly decreased (P<0.01) in the high-dose group. Results showed that exposure to Cd in rats induced oxidative stress to the kidneys and disrupted amino acid metabolism, fatty acid metabolism and energy metabolism.

Low-dose cadmium exposure exacerbates polyhexamethylene guanidine-induced lung fibrosis in mice

ABSTRACTCadmium (Cd) is a toxic metal present in tobacco smoke, air, food, and water. Inhalation is an important route of Cd exposure, and lungs are one of the main target organs for metal-induced toxicity. Cd inhalation is associated with an increased risk of pulmonary diseases. The present study aimed to assess the effects of repeated exposure to low-dose Cd in a mouse model of polyhexamethylene guanidine (PHMG)-induced lung fibrosis. Mice were grouped into the following groups: vehicle control (VC), PHMG, cadmium chloride (CdCl2), and PHMG + CdCl2. Animals in the PHMG group exhibited increased numbers of total cells and inflammatory cells in the bronchoalveolar lavage fluid (BALF) accompanied by inflammation and fibrosis in lung tissues. These parameters were exacerbated in mice in the PHMG + CdCl2 group. In contrast, mice in the CdCl2 group alone displayed only minimal inflammation in pulmonary tissue. Expression of inflammatory cytokines and fibrogenic mediators was significantly elevated in lungs of mice in the PHMG group compared with that VC. Further, expression of these cytokines and mediators was enhanced in pulmonary tissue in mice administered PHMG + CdCl2. Data demonstrate that repeated exposure to low-dose Cd may enhance the development of PHMG-induced pulmonary fibrosis.

Low-dose cadmium activates the JNK signaling pathway in human renal podocytes.

Cadmium (Cd) is an environmental toxin. Our previous study demonstrated that low‑dose Cd damages the integrity of the glomerular filtration barrier (GFB); however, the underlying mechanisms are poorly understood. Podocytes are a major component of the GFB, which regulate the passage of proteins. The present study aimed to investigate the effects of low‑dose Cd on human renal podocytes (HRPs). HRPs were treated with Cd and activation of the c-Jun N-terminal kinase (JNK) pathway was examined by western blot analysis. Proliferation, viability and apoptosis of HRPs were evaluated by MTT assay, trypan blue exclusion assay and flow cytometry, respectively. The properties of HRPs were validated by immunofluorescence staining and Phalloidin‑labeling. The results indicated that 4µM Cd may activate the JNK pathway, and increase the protein expression levels of c‑Jun and c‑Fos. However, proliferation, viability, apoptosis and alignment of the F‑actin cytoskeleton in HRPs were not significantly affected by Cd treatment, with or without SP600125 pretreatment. In addition, the expression levels of CD2‑associated protein and synaptopodin, which are differentiation markers of HRPs, remained unchanged following Cd treatment. These results indicated that low‑dose Cd activates the JNK pathway but does not significantly affect HRP function.

Progesterone attenuates hypertension and autoantibody levels to the angiotensin II type 1 receptor in response to elevated cadmium during pregnancy

IntroductionPreeclampsia is associated with the presence of pathogenic angiotensin-receptor-activating autoantibodies. Cadmium is an increasingly prevalent environmental pollutant that can mimic oestrogens, which may enhance immunoglobulin production. Progesterone exerts opposite effects to oestrogen. MethodsWe measured the levels of cadmium and progesterone in preeclamptic patients and controls. Pregnant rats exposed to cadmium (0.125 mg/kg body weight) from gestational day 9–12 were treated with/without progesterone (3 mg/kg) beginning from gestational day 9 to delivery. We analysed the main features of preeclampsia and circulating level of the angiotensin II type 1 receptor agonistic autoantibody. We also measured the expression of activation-induced cytosine deaminase in B cells. ResultsThere were higher cadmium levels and lower progesterone levels in the blood of preeclamptic women than in the blood of those with a healthy pregnancy. Based on this finding, a rat model of preeclampsia was established by intraperitoneally administrating low-dose cadmium on gestational days 9–12. Rats were then treated with/without progesterone. Key features of preeclampsia, including hypertension, proteinuria and placental abnormalities, appeared in pregnant rats after cadmium injection and improved after treatment with progesterone. Cadmium increased immunoglobulin production, mainly angiotensin II type 1-receptor-agonistic autoantibodies, by increasing the expression of activation-induced cytosine deaminase in B cells; progesterone exerted an opposite effect. ConclusionCadmium induced immune abnormalities that may be a key pathogenic contributor to preeclampsia. Progesterone supplementation to correct hormonal imbalance may be a viable strategy for preeclampsia management.

Metabolomic analysis of the toxic effect of chronic exposure of cadmium on rat urine

This study aimed to assess the toxic effect of chronic exposure to cadmium through a metabolomic approach based on ultra-performance liquid chromatography/mass spectrometry (UPLC-MS). Forty male Sprague-Dawley rats were randomly assigned to the following groups: control, low-dose cadmium chloride (CdCl2) (0.13mg/kg body weight (bw)), middle-dose CdCl2 (0.8/kgbw), and high-dose CdCl2 (4.9mg/kgbw). The rats continuously received CdCl2 via drinking water for 24weeks. Rat urine samples were then collected at different time points to establish the metabolomic profiles. Multiple statistical analyses with principal component analysis and partial least squares-discriminant analysis were used to investigate the metabolomic profile changes in the urine samples and screen for potential biomarkers. Thirteen metabolites were identified from the metabolomic profiles of rat urine after treatment. Compared with the control group, the treated groups showed significantly increased intensities of phenylacetylglycine, guanidinosuccinic acid, 4-pyridoxic acid, 4-aminohippuric acid, 4-guanidinobutanoic acid, allantoic acid, dopamine, LysoPC(18:2(9Z,12Z)), and L-urobilinogen. By contrast, the intensities of creatinine, L-carnitine, taurine, and pantothenic acid in the treated groups were significantly decreased. These results indicated that Cd disrupts energy and lipid metabolism. Meanwhile, Cd causes liver and kidney damage via induction of oxidative stress; serum biochemical indices (e.g., creatinine and urea nitrogen) also support the aforementioned results.

Chronic Low-Dose Cadmium Exposure Impairs Cutaneous Wound Healing With Defective Early Inflammatory Responses After Skin Injury.

Impairment of the immune system is a developing concern in evaluating the toxicity of cadmium (Cd). In the present study, we investigated if Cd could impair cutaneous wound healing through interfering with inflammation after injury. We found that exposure of mice to CdCl2 through drinking water at doses of 10, 30, and 50 mg/l for 8 weeks significantly impaired cutaneous wound healing. Chronic 30 mg/l CdCl2 treatment elevated murine blood Cd level comparable to that of low dose Cd-exposed humans, had no effect on blood total and differential leukocyte counts, but reduced neutrophil infiltration, chemokines (CXCL1 and CXCL2), and proinflammatory cytokines (TNFα, IL-1β, and IL-6) expression in wounded tissue at early stage after injury. Wounded tissue homogenates from CdCl2-treated mice had lower chemotactic activity for neutrophils than those from untreated mice. Mechanistic studies showed that chronic Cd treatment suppressed ERK1/2 and NF-κB p65 phosphorylation in wounded tissue at early stage after injury. Compared with neutrophils isolated from untreated mice, neutrophils from CdCl2 treated mice and normal neutrophils treated with CdCl2 invitro both had lower chemotactic response, calcium mobilization and ERK1/2 phosphorylation upon chemoattractant stimulation. Collectively, our study indicate that chronic low-dose Cd exposure impaired cutaneous wound healing by reducing neutrophil infiltration through inhibiting chemokine expression and neutrophil chemotactic response, and suppressing proinflammatory cytokine expression. Cd may suppress chemokine and proinflammatory expression through inactivating ERK1/2 and NF-κB, and inhibit neutrophil chemotaxis by attenuating calcium mobilization and ERK1/2 phosphorylation in response to chemoattractants.

P 253 - Integrative omics-defined redox, metabolic and functional responses to environmental metal exposure

Our previous studies showed that low dose cadmium (Cd) altered protein redox states resulting in inflammatory signaling, actin cytoskeleton disruption, and fibrosis. However, little is known about low-level Cd effects on the redox proteomic and metabolic regulation in pulmonary fibroblasts and potential impact on pulmonary health. To address this issue, we investigated low dose Cd effects using an integrative omics approach with biochemical and functional analyses. Redox proteomics was performed on lung fibroblasts and lung tissues of C57BL/6 male mice exposed to Cd (3.3 mg/L, 16 weeks). Lung tissues were also analyzed for metabolomics. Both redox proteomics and metabolomics identified a large number of mitochondrial proteins and metabolites altered by Cd, suggesting that mitochondria are sensitive to Cd-induced oxidation. Cd also increased nuclear translocation of thioredoxin-1 and stimulated myofibroblast differentiation and fibrosis as shown by smad transcription factor activity and subsequent differentiation marker proteins. Pathway analysis showed that PIP2 metabolism, carbohydrate metabolism with pyruvate and TCA metabolism, are significantly affected by Cd. The integrative redox proteomics and metabolomics with mechanistic and functional pathways provide a powerful approach to understand complex mechanisms of low environmental Cd in lung disease.

Protective effect of low dose intra-articular cadmium on inflammation and joint destruction in arthritis

Synovium hyperplasia characterizes joint diseases, such as rheumatoid arthritis (RA). The cytotoxic effect of low-dose Cadmium (Cd) was tested in vitro and ex vivo on synoviocytes, the mesenchymal key effector cells of inflammation and proliferation in arthritis. The anti-inflammatory and anti-proliferative effects of Cd were tested in vivo by intra-articular injection in the adjuvant induced arthritis rat joints, where the clinical scores and the consequences of arthritis were evaluated. Cell death through apoptosis was highly induced by Cd in inflammatory synoviocytes (80% reduction of cell viability, p < 0.01). TNF plus IL-17 cytokine combination induced a two-fold increase of Cd cell content by enhancing the ZIP-8 importer and the MT-1 homeostasis regulator expression. Addition of Cd reduced IL-6 production in TNF plus IL-17-activated synoviocytes (up to 83%, p < 0.05) and in ex-vivo synovium biopsies (up to 94%, p < 0.01). Cd-injection in rat joints improved arthritis, reducing clinical scores (arthritic score reduced from 4 to 2, p < 0.01), inflammatory cell recruitment (up to 50%, p < 0.01) and protecting from bone/cartilage destruction. This proof of concept study is supported by the limited Cd spread in body reservoirs, with low-dose Cd providing a safe risk/benefit ratio, without toxic effects on other cell types and organs.