Chronic Cadmium Exposure Research Articles

Chronic Cadmium Exposure can Alter Energy Allocation to Physiological Functions in the Shrimp Penaeus vannamei.

Environmental stressors in aquatic organisms can be assessed using a bioenergetic approach based on the evaluation of changes in their physiological parameters. We evaluated the chronic effects of cadmium (Cd2+) on the energy balance as well as the survival, growth, metabolism, nitrogen excretion, hepatosomatic index, oxidized energy substrate, and osmoregulation of the shrimp Penaeus vannamei with the hypothesis that the high energy demand related to the homeostatic regulation of Cd2+could disrupt the energy balance and as a consequence, their physiological functions. The shrimp exposed to Cd2+ had higher mortality (30%), directed more energy into growth (33% of energy intake), ingested 10% more energy, and defecated less than control animals. Cd2+ exposure caused a tendency to decrease metabolism and ammonia excretion but did not alter the hepatosomatic index, type of energy substrate oxidized, and the hyperosmorregulatory pattern of the species. The Cd+2 exposure may have induced a trade-off response because there was a growth rate increase accompanied by increased mortality.

Toxic effects and mechanisms of chronic cadmium exposure on Litopenaeus vannamei growth performance based on combined microbiome and metabolome analysis

Cadmium (Cd) pollution seriously affects marine organisms' health and poses a threat to food safety. Although Cd pollution has attracted widespread attention in aquaculture, little is known about the toxic mechanisms of chronic Cd exposure on shrimp growth performance. The study investigated the combined effects of chronic exposure to Cd of different concentrations including 0, 75, 150, and 300 μg/L for 30 days on the growth performance, tissue bioaccumulation, intestinal microbiology, and metabolic responses of Litopenaeus vannamei. The results revealed that the growth was significantly inhibited under exposure to 150 and 300 μg/L Cd2+. The bioaccumulation in gills and intestines respectively showed an increasing and inverted "U" shaped trend with increasing Cd2+ concentration. Chronic Cd altered the intestinal microflora with a significant decrease in microbial richness and increasing trends in the abundances of the potentially pathogenic bacteria Vibrio and Maribacter at exposure to 75 and 150 μg/L Cd2+, and Maribacter at 300 μg/L. In addition, chronic Cd interfered with intestinal metabolic processes. The expressions of certain metabolites associated with growth promotion and enhanced antioxidant power, including N-methyl-D-aspartic acid, L-malic acid, guanidoacetic acid, betaine, and gluconic acid were significantly down-regulated, especially at exposure to 150 and 300 μg/L Cd2+, and were negatively correlated with Vibrio and Maribacter abundance levels. In summary, chronic Cd exposure resulted in severe growth inhibition and increased Cd accumulation in shrimp tissues. Increased levels of intestinal pathogenic bacteria and decreased levels of growth-promoting metabolites may be the key causes of growth inhibition. Harmful bacteria Vibrio and Maribacter may be associated with the inhibition of growth-promoting metabolite expression and may be involved in disrupting intestinal metabolic functions, ultimately impairing shrimp growth potential. This study sheds light on the potential toxicological mechanisms of chronic Cd inhibition on shrimp growth performance, offering new insights into Cd toxicity studies in aquaculture.

Abstract 1474: Interleukin-8 and NF-κB mediated signaling axis: A potential driver for cadmium-induced prostate carcinogenesis

Abstract Cadmium (Cd) is a toxic heavy metal, ubiquitous in nature, and an industrial pollutant. Cadmium exposure can cause irreversible damage to lungs, liver and kidney including cancers. Alarmingly, abnormally high levels of cadmium are found in human prostate tissues. Studies on rodents have shown cadmium exposure causes liver, lung, and prostate cancers. The mechanism of carcinogenesis caused by Cd is multifactorial and specific organ carcinogenesis remains unclear. We and others have reported that the CXC-chemokine IL-8 drives cancer progression in prostate cancer (PCa). We tested a hypothesis that chronic cadmium-exposure induces upregulation of proinflammatory cytokines, such as IL-1β, IL-6, and IL-8, which individually or combined promote carcinogenesis and progression. The study used two non-transformed prostate epithelial cell lines (RWPE-1 and NHPrE1) to test whether continuous exposure to Cadmium chloride (CdCl2) perturbs cytokine expression pattern and selective silencing of elevated cytokines delays carcinogenesis and invasive potential. The CdCl2 exposed cells and culture conditioned media were analyzed regularly for changes in inflammatory milieu and for hallmarks of carcinogenesis. These studies measured changes in cell proliferation, production of cytokines (IL-8, IL-1β, IL-6, IFN-γ, TGF-β, and others), activation of Nuclear Factor-kB (NF-κB), and pro-tumorigenic factors, e.g., vascular endothelial growth factors (VEGF-A and B), cellular motility, and invasive potential, etc. Cells exposed to CdCl2 showed increased cell proliferation and clonogenic potential and specifically, increased expression of IL-8, it’s receptors (CXCR1 and CXCR2), IL-1β, and other cytokines & related genes. While un-exposed RWPE-1 cells did not express IL-8, it was the first cytokine to increase when exposed to CdCl2, followed by activation of NF-κB (p65-rel), VEGF-A, & B, CXCR1 and other markers. Gene silencing of IL-8 suppressed motility, invasion, and survival activity. These data supported that immediate-early IL-8 expression probably upregulates NF-κB mediated inflammatory signaling axis which is critical for Cd-induced carcinogenesis and may expose targets for countermeasures to prevent metal-induced toxicity & carcinogenesis. Citation Format: Kunj Bihari Gupta, Rajendra K. Singh, Juliette R. Seremak, Vinata B. Lokeshwar, Bal L. Lokeshwar. Interleukin-8 and NF-κB mediated signaling axis: A potential driver for cadmium-induced prostate carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1474.

Chronic cadmium exposure impairs flight behavior by dampening flight muscle carbon metabolism in bumblebees

Cadmium pollution affects the global ecosystem because cadmium can be transferred up the food chain. The bumblebee, Bombus terrestris, is an important insect pollinator. Their foraging activity on flowers exposes them to harmful heavy metals, which damages their health and leads to massive population declines. However, the effects of chronic exposure to heavy metals on the flight performance of bumblebees have not yet been characterized. Here, we studied variation in the flight capacity of bumblebees induced by chronic cadmium exposure at field-realistic concentrations using behavioral, physiological, and molecular approaches. Chronic cadmium exposure caused a significant reduction in the duration, distance, and mean velocity of bumblebee flight. Transcriptome analysis showed that the impairment of carbon metabolism and mitochondrial dysfunction in the flight muscle were the primary causes. Physiological, biochemical, and metabolomic analyses validated disruptions in energy metabolism, and impairments in mitochondrial respiratory chain complexes activities. Histological analysis revealed muscle fiber damage and mitochondrial loss. Exogenous decanoic acid or citric acid partially restored sustained flight ability of bumblebees by mitigating muscle fiber damage and increasing energy generation. These findings provide insights into how long-term cadmium stress affects the flight ability of insects and will aid human muscle or exercise-related disease research.

Cadmium exposure-induced rat testicular dysfunction and its mechanism of chronic stress

Cadmium is a common environmental pollutant in daily life, the toxic mechanisms of chronic cadmium exposure on the testes have not been fully elucidated. This study aimed to explore the effects of cadmium exposure on male reproductive health and its mechanism. The results showed that cadmium exposure led widened interstitial spaces, abnormal seminiferous tubule morphology, and decreased Leydig cell numbers. Moreover, sperm quality was significantly reduced, along with a decrease in fertility rate. And cadmium exposure could activate the hypothalamic-pituitary-adrenal (HPA) axis, elevate blood glucocorticoid levels, subsequently increase glucocorticoid receptor (GR) expression and activation in testicular Leydig cells.Then GR act on the glucocorticoid receptor element (GRE) in the DNA methyltransferase 3 A (DNMT3A) promoter region and upregulate DNMT3A expression. Consequently, this led to an increase in DNA methylation levels in the angiotensin II receptor 2 (AT2R) promoter region, resulting in reduced AT2R expression and inhibiting testicular steroidogenesis. This study systematically elucidated that cadmium exposure could lead to testicular steroidogenesis suppression and decreased fertility through the GR/DNMT3A/AT2R signaling pathway. This research further provides theoretical and experimental evidence for confirming the threat of cadmium exposure to human reproduction, and contributes to the guidance and protection of male reproductive health.

Alleviative effect of melatonin against the nephrotoxicity induced by cadmium exposure through regulating renal oxidative stress, inflammatory reaction, and fibrosis in a mouse model

Chronic cadmium (Cd) exposure causes severe adverse health effects on the human body, especially the kidney tissue. Studies have demonstrated oxidative stress to be involved in renal pathological variations after exposure to Cd, but few effective treatments are available for the disease yet. Therefore, the present study was carried out to investigate the potential therapeutic intervention and its underlying molecular mechanisms of melatonin (MT), a natural antioxidant with multiple biological activities, against renal injury caused by Cd exposure in mice. C57BL/6 male mice (eight-week-old) were intragastrically administered with CdCl2, MT, or both for 30 days. Biochemical analysis showed that MT intervention significantly improved the SOD, GSH, and CAT activities while markedly decreasing the kidney MDA content of the mice exposed to Cd. Histological examination indicated that Cd exposure resulted in the atrophy of the renal glomerular, the degeneration and dilation of tubules, and the accumulation of fibrocytes. By contrast, MT administration effectively ameliorated the histological outcome of the injured kidney tissue. Moreover, administrating MT significantly inhibited proinflammatory cytokines TNF-α and iNOS expression in Cd-treated mice. Further, MT treatment markedly suppressed the expressions of renal fibrosis-related factors TGF-β1, α-SMA, and collagen Ⅰ in the injured renal tissue and the accumulation and development of renal fibrosis. In addition, the administration of MT significantly reduced the expression of caspase-3 and cell apoptotic death in the kidney tissue of Cd-exposed mice. In all, the data showed that MT has a compelling therapeutic potential in alleviating the pathological variations of renal injury caused by Cd exposure.

Chronic cadmium exposure induces Parkinson-like syndrome by eliciting sphingolipid disturbance and neuroinflammation in the midbrain of C57BL/6J mice

Cadmium (Cd) is known as a widespread environmental neurotoxic pollutant. Cd exposure is recently recognized as an etiological factor of Parkinson's disease (PD) in humans. However, the mechanism underlying Cd neurotoxicity in relation to Parkinsonism pathogenesis is unclear. In our present study, C57BL/6 J mice were exposed to 100 mg/L CdCl2 in drinking water for 8 weeks. It was found Cd exposure caused motor deficits, decreased DA neurons and induced neuropathological changes in the midbrain. Non-targeted lipidomic analysis uncovered that Cd exposure altered lipid profile, increased the content of proinflammatory sphingolipid ceramides (Cer), sphingomyelin (SM) and ganglioside (GM3) in the midbrain. In consistency with increased proinflammatory lipids, the mRNA levels of genes encoding sphingolipids biosynthesis in the midbrain were dysregulated by Cd exposure. Neuroinflammation in the midbrain was evinced by the up-regulation of proinflammatory cytokines at mRNA and protein levels. Blood Cd contents and lipid metabolites in Parkinsonism patients by ICP-MS and LC-MS/MS analyses demonstrated that elevated blood Cd concentration and proinflammatory lipid metabolites were positively associated with the score of Unified Parkinson's Disease Rating Scale (UPDRS). 3 ceramide metabolites in the blood showed good specificity as the candidate biomarkers to predict and monitor Parkinsonism and Cd neurotoxicity (AUC>0.7, p < 0.01). In summary, our present study uncovered that perturbed sphingomyelin lipid metabolism is related to the Parkinsonism pathogenesis and Cd neurotoxicity, partially compensated for the deficiency in particular metabolic biomarkers for Parkinsonism in relation to Cd exposure, and emphasized the necessity of reducing Cd exposure at population level.

Chronic cadmium exposure triggered ferroptosis by perturbing the STEAP3-mediated glutathione redox balance linked to altered metabolomic signatures in humans

Cadmium (Cd), a predominant environmental pollutant, is a canonical toxicant that acts on the kidneys. However, the nephrotoxic effect and underlying mechanism activated by chronic exposure to Cd remain unclear. In the present study, male mice (C57BL/6J, 8 weeks) were treated with 0.6 mg/L cadmium chloride (CdCl2) administered orally for 6 months, and tubular epithelial cells (TCMK-1 cells) were treated with low-dose (1, 2, and 3 μM) CdCl2 for 72 h (h). Our study results revealed that environmental Cd exposure triggered ferroptosis and renal dysfunction. Spatially resolved metabolomics enabled delineation of metabolic profiles and visualization of the disruption to glutathione homeostasis related to ferroptosis in mouse kidneys. Multiomics analysis revealed that chronic Cd exposure induced glutathione redox imbalance that depended on STEAP3-driven lysosomal iron overload. In particular, glutathione metabolic reprogramming linked to ferroptosis emerged as a metabolic hallmark in the blood of Cd-exposed workers. In conclusion, this study provides the first evidence indicating that chronic Cd exposure triggers ferroptosis and renal dysfunction that depend on STEAP3-mediated glutathione redox imbalance, greatly increasing our understanding of the metabolic reprogramming induced by Cd exposure in the kidneys and providing novel clues linking chronic Cd exposure to nephrotoxicity.

Short-term Effects of Cadmium Exposure on Blood Pressure and Vascular Function in Wistar Rats.

Chronic cadmium exposure is known to be associated with vascular changes and increased blood pressure, but its short-term effects on the cardiovascular system remain poorly understood. This study aimed to investigate the pressoric and vascular effects of a 7-day exposure to CdCl2 in Wistar rats. The rats were divided in control group (Ct), which received tap water, and the Cd group, which received a 100mg/L CdCl2 solution via drinking water for 7days. We analyzed body weight, plasma Cadmium concentration, systolic blood pressure (SBP), and vascular responses. Despite relatively low plasma Cadmium concentration, the Cd group exhibited elevated SBP and increased contractile response to phenylephrine. Endothelium removal and NOS inhibition increased contractions in both groups. In the Cd group's aorta, we observed enhanced levels of phospho-eNOS (Ser1177) and basal NO release. Cd group showed reduced Catalase expression and increased basal release of H2O2, with catalase reducing the contractile response. In arteries pre-contracted with phenylephrine, Cd group showed impaired endothelium-dependent (Acetylcholine) and independent (sodium nitroprussiate-SNP) relaxation responses. However, responses to SNP were similar after pre-contraction with KCl in both groups. These data suggest early effects of Cadmium on blood pressure and aortic function, indicating impaired H2O2-scavenging by catalase. Increased H2O2 due to Cadmium exposure might explain heightened responses to phenylephrine and weakened relaxation responses mediated by the NO-K+-channels pathway. Our findings shed light on Cadmium's short-term impact on the cardiovascular system, providing insights into potential mechanisms underlying its effects on blood pressure regulation and vascular function.

Nrf2 protects against renal fibrosis induced by chronic cadmium exposure in mice.

Environmental cadmium (Cd) exposure is a serious public health concern, as the kidney is the primary target for Cd exposure. The present study aimed to investigate the role and underlying mechanisms of nuclear factor erythroid-derived 2-like 2 (Nrf2) in renal fibrosis induced by chronic Cd exposure. Nrf2 knockout (Nrf2-KO) mice and their wild-type littermates (Nrf2-WT) were exposed to 100 or 200ppm Cd in drinking water for up to 16 or 24 weeks. Following the Cd exposures, Nrf2-KO mice showed elevated urinary neutrophil gelatinase-associated lipocalin (NGAL) and BUN levels compared to Nrf2-WT mice. Masson's trichrome staining and expression of fibrosis-associated proteins revealed that more severe renal fibrosis occurred in Nrf2-KO than that in Nrf2-WT mice. Renal Cd content in the Nrf2-KO mice exposed to 200ppm Cd was lower than that in Nrf2-WT mice, which might be a consequence of the severe renal fibrosis in the Nrf2-KO mice. Mechanistic studies showed that Nrf2-KO mice exhibited higher levels of oxidative damage, lower antioxidant levels, and more regulated cell death, apoptosis in particular, than those in Nrf2-WT mice caused by Cd exposure. In conclusion, Nrf2-KO mice were more prone to develop renal fibrosis induced by chronic Cd exposure, partially due to a weakened antioxidant, detoxification capacity and increased oxidative damage.

Effects of zinc supplementation in mitigating the harmful effects of chronic cadmium exposure in a zebrafish model

Cadmium (Cd) is a heavy metal that is highly toxic to living organisms, including humans. But the dietary zinc (Zn) supplements play critical role in minimizing or preventing Cd poisoning, without any side effects. The underlying mechanisms, however, have not been thoroughly investigated. Therefore, in this study, we investigated the use of Zn as a protection against Cd toxicity in zebrafish models. The obtained results confirmed the levels of antioxidant enzymes and supported the synergistic effects of Zn in reducing Cd toxicity. The lipid, carbohydrate, and protein concentrations in the liver tissue have also been negatively impacted by Cd; however, treatment with Zn has lessened these adverse effects. Furthermore, the level of 8-hydroxy-2′ –deoxyguanosine (8-OHdG), caspase-3 also confirms the protective effects of Zn in reducing DNA damage caused by Cd. The results of this study demonstrate that a Zn supplement can lessen the harmful effects of Cd in zebrafish model.

Chronic Kidney Disease Induced by Cadmium and Diabetes: A Quantitative Case-Control Study.

Kidney disease associated with chronic cadmium (Cd) exposure is primarily due to proximal tubule cell damage. This results in a sustained decline in glomerular filtration rate (GFR) and tubular proteinuria. Similarly, diabetic kidney disease (DKD) is marked by albuminuria and a declining GFR and both may eventually lead to kidney failure. The progression to kidney disease in diabetics exposed to Cd has rarely been reported. Herein, we assessed Cd exposure and the severity of tubular proteinuria and albuminuria in 88 diabetics and 88 controls, matched by age, gender and locality. The overall mean blood and Cd excretion normalized to creatinine clearance (Ccr) as ECd/Ccr were 0.59 µg/L and 0.0084 µg/L filtrate (0.96 µg/g creatinine), respectively. Tubular dysfunction, assessed by β2-microglobulin excretion rate normalized to Ccr(Eβ2M/Ccr) was associated with both diabetes and Cd exposure. Doubling of Cd body burden, hypertension and a reduced estimated GFR (eGFR) increased the risks for a severe tubular dysfunction by 1.3-fold, 2.6-fold, and 84-fold, respectively. Albuminuria did not show a significant association with ECd/Ccr, but hypertension and eGFR did. Hypertension and a reduced eGFR were associated with a 3-fold and 4-fold increases in risk of albuminuria. These findings suggest that even low levels of Cd exposure exacerbate progression of kidney disease in diabetics.

Cadmium exposure induces histological damage and cytotoxicity in the cardiovascular system of mice.

Epidemiological studies have reported an association between chronic cadmium (Cd) exposure and increased cardiovascular risk; however, their causal relationship remains unclear. The aim of this study is to explore the effects of Cd exposure on the cardiac and arterial systems in mice. According to the concentration of cadmium chloride in drinking water, male mice were randomly divided into control and low-dose and high-dose Cd exposure groups. The intervention duration was 12 weeks. In cardiac tissues, Cd exposure led to focal necrosis, myofibril disarray, perivascular and interstitial fibrosis, and disorganized sarcomere structures. Cd also induced the apoptosis of cardiomyocytes and increased the expression levels of matrix metalloproteinase (MMP)-2 and MMP-14 in cardiac tissues. In the arterial tissues, Cd exposure damaged the intimal and medial layers of the aorta. Cd further reduced the viability of aortic smooth muscle cells in vitro. This study provides evidence for the Cd-induced damage of the cardiovascular system, which may contribute to various cardiovascular diseases.

Cadmium exposure induces a sex-dependent decline in left ventricular cardiac function

AimsCadmium exposure is a worldwide problem that has been linked to the development of cardiovascular disease. This study aimed to elucidate mechanistic details of chronic cadmium exposure on the structure and function of the heart. Main methodsMale and female mice were exposed to cadmium chloride (CdCl2) via drinking water for eight weeks. Serial echocardiography and blood pressure measurements were performed. Markers of hypertrophy and fibrosis were assessed, along with molecular targets of Ca2+-handling. Key findingsMales exhibited a significant reduction in left ventricular ejection fraction and fractional shortening with CdCl2 exposure, along with increased ventricular volume at end-systole, and decreased interventricular septal thickness at end-systole. Interestingly, no changes were detected in females. Experiments in isolated cardiomyocytes revealed that CdCl2-induced contractile dysfunction was also present at the cellular level, showing decreased Ca2+ transient and sarcomere shortening amplitude with CdCl2 exposure. Further mechanistic investigation uncovered a decrease in sarco/endoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) protein expression and phosphorylated phospholamban levels in male hearts with CdCl2 exposure. SignificanceThe findings of our novel study provide important insight into how cadmium exposure may act as a sex-specific driver of cardiovascular disease, and further underscore the importance of reducing human exposure to cadmium.

10 Chronic cadmium exposure is associated with Alzheimer’s Disease-related mortality in adults over age 60 in a representative US sample

OBJECTIVES/GOALS: Cadmium is a widespread neurotoxic metal pollutant; however prior study results of Cd and later-life cognition are mixed. We investigated association of urinary cadmium on Alzheimer’s Disease (AD) mortality risk, accounting for key co-pollutants smoking and lead, in the presence of competing risks. METHODS/STUDY POPULATION: We included 5692 persons, 60 years old from the 1998-2018 National Health and Nutrition Examination Survey. Underlying cause of death was determined via linked 1999-2019 National Death Index data. Urinary cadmium (UCD) reflects prolonged exposure and was adjusted for creatinine. We used multiple imputation (5 iterations) to recapture substantial model observation drop-out (N=782). We used three Cox proportional hazard models to estimate hazard ratios (HR) and 95% confidence interval (CI) per unit increase in UCD and time to AD mortality: a competing risks model, a survey-weighted model, and a baseline model including neither, all adjusted for demographic characteristics, lead, and smoking. RESULTS/ANTICIPATED RESULTS: Follow-up ranged from 0 to 20.8 years (mean 8.2 years), with a total of 1,987 individuals deceased (14,232 person-years at-risk), including 88 individuals dying from AD. Mean UCD was 0.50 μg/g creatinine (standard error=0.01). In baseline and survey-weighted models fully adjusted for NHANES cycle, poverty income ratio, age, race/ethnicity, sex, marital status, education, smoking status, and blood lead levels, a per unit increase in UCD was associated with approximately twice the rate of AD mortality (baseline model HR: 1.92, 95% CI: 1.28, 2.89; survey-weighted model HR: 2.08, 95% CI: 1.42, 3.06). In the competing risks model, this association was attenuated (HR: 1.58, 95% CI 1.06 2.36). DISCUSSION/SIGNIFICANCE: Our study finds chronic cadmium exposure associated with AD mortality even after accounting for competing risks of AD mortality and confounding effects of cigarette smoking and lead exposure, strengthening the evidence that long-term cadmium exposure adversely affects later-life cognitive health.

Molecular interplay between NOX1 and autophagy in cadmium-induced prostate carcinogenesis.

Chronic exposure to cadmium (Cd), a class I carcinogen, leads to malignant transformation of normal prostate epithelial cells (RWPE-1). The constant generation of Cd-induced ROS and resulting ER stress induces cellular responses that are needed for cell survival, and autophagy has an important role in this process. However, the mechanisms that regulate Cd-induced ROS and how these differ in terms of acute and chronic cadmium exposure remain unexplained. Here, we show that acute or chronic Cd exposure facilitates NOX1 assembly by activating its cytosolic regulators p47phox and p67phox in RWPE-1cells. Upregulation of NOX1 complex proteins and generation of ROS activates unfolded protein response (UPR) via phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor 2 alpha (eIF2α), and selective translation of activating transcription factor 4 (ATF4). Chronic Cd exposure constantly activates NOX1 complex and generates consistent ROS and ER stress that led to defective autophagy, wherein ATG5 expression is downregulated in contrast to acute Cd exposure. As a result, selective/defective autophagy creates depletion of autophagosome-lysosome fusion that gives a survival advantage to transforming cells, which is not available to RWPE-1cells acutely exposed to Cd. Knockdown of key molecules in a lockstep manner directly affects the most downstream autophagy pathways in transforming cells. Overall, this study demonstrates that assembly of NOX1 complex proteins is indispensable for Cd-induced persistent ROS and controls ER stress-induced defective autophagy in mice and humans.

Ascorbic acid attenuates cadmium-induced myocardial hypertrophy and cardiomyocyte injury through Nrf2 signaling pathways comparable to resveratrol.

Chronic cadmium (Cd) exposure severely affects the structural integrity of the heart, leading to cardiovascular disease. This study investigates the protective role of ascorbic acid (AA) and resveratrol (Res) in cellular defense against Cd-induced cardiomyocyte damage and myocardial hypertrophy in H9c2 cardiomyocytes. Experimental results showed that AA and Res treatment significantly increased cell viability, reduced ROS production, attenuated lipid peroxidation, and increased antioxidant enzyme activity in Cd-induced H9c2 cells. AA and Res decreased the mitochondrial membrane permeability and protected the cells from Cd induced cardiomyocyte damage. This also suppressed the pathological hypertrophic response triggered by Cd, which increased the cell size of cardiomyocytes. Gene expression studies revealed that cells treated with AA and Res decreased the expression of hypertrophic genes ANP (two-fold), BNP (one-fold) and β- MHC (two-fold) compared to Cd exposed cells. AA and Res promoted the nuclear translocation of Nrf2 and increased the expression of antioxidant genes (HO-1, NQO1, SOD and CAT) during Cd mediated myocardial hypertrophy. This study proves that AA and Res play a significant role in improving Nrf2 signaling, thereby reversing stress-induced injury, and facilitating the regression of myocardial hypertrophy.

Cadmium contributes to atherosclerosis by affecting macrophage polarization.

Chronic cadmium (Cd) exposure contributes to the progression of atherosclerosis, but the direct role of Cd and its mechanisms in atherosclerosis remains incompletely understood. Atherosclerosisis a chronic inflammatory disease promoting macrophage polarization to M1 phenotype and producing pro-inflammations that are vital in regulating the inflammatory response. Herein, through a case-control study, we found that Cd exposure may promote the occurrence of carotid plaque via inflammation, where interleukin-6 (IL-6) may play an important role. We also combined in vivo and in vitro experiments to explore the underlying mechanism of Cd promoted plaque formation and the production of IL-6. With or without cadmium chloride (CdCl2) fed ApoE-/- mouse and treated RAW264.7 cells, we found Cd accumulated in the aortas which significantly increased the plaque area in atherosclerotic mice, macrophage accumulation, and lipid accumulation, and Cd promoted M1 phenotype macrophage polarization reflected by the increased expression of CD86 which produced tumor necrosis factor-α (TNF-α) and IL-6. However, the influences on M2 phenotype and anti-inflammatory cytokines IL-4 and IFN-γ were non-significant. Moreover, we found that JAK2/STAT3 pathway was greatly activated in the plaques and CdCl2-treated macrophages. The inhibition of JAK2/STAT3 substantially reversed the Cd-stimulated macrophage M1 phenotype macrophage polarization and the expression of pro-inflammatory cytokines including TNF-α and IL-6. Altogether, Cd intensifies atherosclerosis by modulating macrophage polarization via JAK2/STAT3 to up-regulated the exression of IL-6.

Chronic Cadmium Exposure and Genetic Polymorphisms of MMP-2 and MMP-9 in a Population Exposed to Steel Slag in the State of Rio de Janeiro, Brazil: A Cross-Sectional Study.

Genetic polymorphisms in the matrix metalloproteinases (MMPs) family genes may be associated with cadmium (Cd) levels and its adverse effects. This study investigated the impact of MMP-2 and MMP-9 polymorphisms on Cd levels in 238 residents of a condominium in Rio de Janeiro, Brazil, built over an industrial steel slag waste. Polymorphisms were genotyped using TaqMan validated assays, and the Cd levels were measured in blood (BCd) and urine (UCd) samples by atomic absorption spectrometry. Associations were evaluated by linear correlation coefficients and multiple logistic regression, using odds ratios (OR) and 95% confidence intervals (CI). Mean age was 50 ± 15 years; 58% were female, 69% non-smokers. Mean concentrations for BCd and UCd were 0.70 ± 0.2 μg L-1 and 0.56 ± 0.55 μg L-1, respectively. Smoking status was associated with BCd ≥ 0.70 μg L-1 (OR = 2.9; 95% CI = 1.6-5.9). MMP-9 rs17576 A &gt; G was associated with BCd ≥ 0.70 μg L-1 (OR = 2.11; 95% CI = 1.10-4.05) and UCd ≥ 0.56 μg L-1 (OR = 3.38; 95% CI = 1.82-7.65). Knowing possible individual predisposing factors is essential to understand Cd toxicity, and to improve the monitoring of high-risk populations.

Chronic Cadmium Exposure Induces Impaired Olfactory Learning and Altered Brain Gene Expression in Honey Bees (Apis mellifera).

The honey bee (Apis mellifera) plays vital ecological roles in the pollination of crops and the maintenance of ecological balance, and adult honey bees may be exposed to exogenous chemicals including heavy metals during their foraging activities. Cadmium (Cd) is regarded as a nonessential toxic metal and is readily accumulated in plants; honey bees can therefore acquire Cd through the collection of contaminated nectar. In the present study, honey bees were chronically exposed to Cd to investigate the effects of sublethal cadmium doses on the olfactory learning and brain gene expression profiles of honey bees. The results showed that Cd-treated bees exhibited significantly impaired olfactory learning performances in comparison with control bees. Moreover, the head weight was significantly lower in Cd-treated bees than in control bees after chronic exposure to Cd. Gene expression profiles between the Cd treatment and the control revealed that 79 genes were significantly differentially expressed. Genes encoding chemoreceptors and olfactory proteins were downregulated, whereas genes involved in response to oxidative stress were upregulated in Cd-treated bees. The results suggest that Cd exposure exerts oxidative stress in the brain of honey bees, and the dysregulated expression of genes encoding chemoreceptors, olfactory proteins, and cytochrome P450 enzymes is probably associated with impaired olfactory learning in honey bees.