Cadmium-mediated pancreatic islet transcriptome changes in mice and cultured mouse islets.

Type II diabetes mellitus (T2DM) is a multifactorial disease process that is characterized by insulin resistance and impairment of insulin-producing pancreatic islets. There is evidence that environmental exposure to cadmium contributes to the development of T2DM. The presence of cadmium in human islets from the general population and the uptake of cadmium in ß-cells have been reported. To identify cadmium-mediated changes in gene expression and molecular regulatory networks in pancreatic islets, we performed next-generation RNA-Sequencing (RNA-Seq) in islets following either in vivo (1 mM CdCl2 in drinking water) or ex-vivo (0.5 µM CdCl2) exposure. Both exposure regiments resulted in islet cadmium concentrations that are comparable to those found in human islets from the general population. 6-week in vivo cadmium exposure upregulates the expression of five genes: Synj2, Gjb1, Rbpjl, Try5 and 5430419D17Rik. Rbpjl is a known regulator of ctrb, a gene associated with diabetes susceptibility. With 18-week in vivo cadmium exposure, we found more comprehensive changes in gene expression profile. Pathway enrichment analysis showed that these secondary changes were clustered to molecular mechanisms related to intracellular protein trafficking to the plasma membrane. In islet culture, cadmium ex vivo significantly induces the expression of Mt1, Sphk1, Nrcam, L3mbtl2, Rnf216 and Itpr1. Mt1 and Itpr1 are known to be involved in glucose homeostasis. Collectively, findings reported here revealed a complex cadmium-mediated effect on pancreatic islet gene expression at environmentally relevant cadmium exposure conditions, providing the basis for further studies into the pathophysiological processes arising from cadmium accumulation in pancreatic islets.

Bioaccessibility as a determining factor in the bioavailability and toxicokinetics of cadmium compounds.

Cadmium toxicity occurs where there is absorption and accumulation of cadmium ions (Cd2+) in tissues beyond tolerable levels. Significant differences in the release of Cd2+ from cadmium compounds in biological fluids, like gastric fluid, may indicate differences in bioavailability and absorption. This means that direct read-across from high solubility cadmium compounds to lower solubility compounds may not accurately reflect potential hazards. Here, the relative bioaccessibility in gastric fluid of cadmium telluride and cadmium chloride was evaluated using in vitro bioelution tests whilst the toxicokinetic behavior of these two compounds were compared after dietary administration for 90 days in male and female Wistar Han rats following OECD TG 408. Cadmium chloride was highly bioaccessible, whilst cadmium telluride showed low solubility in simulated gastric fluid (90 % and 1.5 % bioaccessibility, respectively). This difference in bioaccessibility was also reflected by a difference in bioavailability as shown by the difference in the liver and kidney concentrations of cadmium after repeat oral exposure. Feeding at doses of 750 and 1500 ppm of cadmium telluride did not result in tissue cadmium levels above the lower limit of quantification (LLOQ). In contrast, feeding with a lower test substance concentration yet higher concentration of bioaccessible cadmium (30 ppm cadmium chloride) resulted in tissue accumulation of cadmium. Only slight, non-adverse changes in hematology and clinical chemistry parameters were seen at these doses, indicating an absence of significant cadmium mediated toxicity towards target organs (kidney and liver), reflected in minimal cadmium accumulation in these organs. This study demonstrates that bioelution tests can help determine the bioaccessibility of cadmium, which can be used to estimate the potential for target tissue toxicity based on known toxicokinetic profiles and threshold levels for cadmium toxicity, while reducing and refining animal testing.

Subacute cadmium exposure promotes M1 macrophage polarization through oxidative stress-evoked inflammatory response and induces porcine adrenal fibrosis.

Cadmium (Cd) is a widely distributed environmental pollutant with immunotoxicity and endocrine toxicity. M1/M2 macrophages participate in the immune response and exert an essential influence on fibrosis. Nevertheless, whether Cd can induce porcineadrenal fibrosis by affecting the polarization of M1/M2 macrophages and its potential regulatory mechanism have not been explored. We added 20 mg/kg CdCl2 to the pig diet for 40 days to investigate the fibrogenic effect of subacute Cd exposure on the adrenal gland. The results indicated that the ACTH and CORT in serum were decreased by 15.26 % and 21.99 %, respectively. The contents of adrenal mineral elements Cd, Cr, Mn were increased up to 34, 1.93, 1.42 folds and Co, Zn, Sn were reduced by 21.57 %, 20.52 %, 15.75 %. Concurrently, the pro-oxidative indicators (LPO, MDA and H2O2) were increased by 1.85, 2.20, 2.77 folds and 3.60, 11.15, 4.11 folds upregulated mRNA levels of TLR4, NF-κB, NLRP3 were observed. Subsequently, the expression of M1 macrophages polarization markers (IL-6, iNOS, TNF-α, CCL2 and CXCL9) were raised by 2.03, 2.30, 2.35, 1.58, 1.56 folds, while M2 macrophages (IL-4, CCL24, Arg1, IL-10, MRC1) showed a 62.34 %, 31.88 %, 50.26 %, 74.00 %, 69.34 % downregulation. The expression levels of AMPK subunits and genes related to glycolysis, oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) were also markedly increased. Additionally, the expression level of TGF-ß1, Smad2/3 and downstream pro-fibrotic markers was obviously upregulated. Taken together, we conclude that Cd activates the oxidative stress-mediated TLR4/NF-κB/NLRP3 inflammatory signal transduction, leading to porcine adrenal fibrosis by promoting macrophage polarization toward M1.

Nrf2 deficiency aggravates the kidney injury induced by subacute cadmium exposure in mice.

Cadmium (Cd) is a heavy metal pollutant that adversely effects the kidney. Oxidative stress and inflammation are likely major mechanisms of Cd-induced kidney injury. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is crucial in regulating antioxidant and inflammatory responses. To investigate the role of Nrf2 in the development of subacute Cd-induced renal injury, we utilized Nrf2 knockout (Nrf2-KO) and control mice (Nrf2-WT) which were given cadmium chloride (CdCl2, 1 or 2 mg/kg i.p.) once daily for 7 days. While subacute CdCl2 exposure induced kidney injury in a dose-dependent manner, after the higher Cd dosage exposure, Nrf2-KO mice showed elevated blood urea nitrogen (BUN) and urinary neutrophil gelatinase-associated lipocalin (NGAL) levels compared to control. In line with the findings, the renal tubule injury caused by 2 mg Cd/kg, but not lower dosage, in Nrf2-KO mice determined by Periodic acid-Schiff staining was more serious than that in control mice. Further mechanistic studies showed that Nrf2-KO mice had more apoptotic cells and severe oxidative stress and inflammation in the renal tubules in response to Cd exposures. Although there were no significant differences in Cd contents of tissues between Cd-exposed Nrf2-WT and Nrf2-KO mice, the mRNA expression of Nrf2 downstream genes, including heme oxygenase 1 and metallothionein 1, were significantly less induced by Cd exposures in the kidney of Nrf2-KO compared with Nrf2-WT mice. In conclusion, Nrf2-deficient mice are more sensitive to kidney injury induced by subacute Cd exposure due to a muted antioxidant response, as well as a likely diminished production of specific Cd detoxification metallothioneins.

Cadmium exposure reduces invasion of the human trophoblast-derived HTR-8/SVneo cells by inhibiting cell adhesion and matrix metalloproteinase-9 secretion.

Preeclampsia and intrauterine growth restriction, multisystemic disorders characterized by a shallow trophoblast invasion, have been associated with maternal cadmium (Cd) exposure. The molecular mechanisms of this association remain unknown. Cell adhesion and matrix metalloproteinase production are essential for an adequate trophoblast invasion. Thus, the aim of this study was to determine the effect of Cd exposure on invasion, adhesion, and matrix metalloproteinase-9 (MMP-9) production in the trophoblast-derived HTR-8/SVneo cell line. Cultured HTR-8/SVneo trophoblast cells were incubated with different concentrations of CdCl2 for 6 h. Cell invasion was determined by the transwell assay, while cell adhesion was examined on collagen type I. MMP-9 release and activity were measured by ELISA and zymography, respectively. MMP-9 mRNA expression was detected by reverse-transcription polymerase chain reaction, while intracellular MMP-9 protein was assessed by Western blotting. Cd exposure significantly decreased the invasion and adhesion of HTR-8/SVneo cells. Also, MMP-9 levels and activity in the culture medium were significantly reduced after Cd incubation. In contrast, MMP-9 mRNA expression and intracellular protein levels were significantly increased. These data indicate that Cd reduces trophoblast cells invasiveness by inhibiting cell adhesion and MMP-9 secretion.

Chronic oral exposure to cadmium causes liver inflammation by NLRP3 inflammasome activation in pubertal mice.

Cadmium (Cd) is a potentially toxic trace element frequently existed in foods, water, and air, threatening liver function from its continuous bioaccumulation and induction of oxidative stress and inflammation. However, the hepatotoxicity of Cd during puberty remains unclear. In this study, pubertal mice were given cadmium chloride at a dose of 5.0 mg/kg·bw by gavage, and the liver damage was investigated at different treatment points of 10, 20, and 30 days. After Cd exposure, there is an obvious inflammatory hepatocyte infiltration accompanied by more apoptotic cells at 20 days and an increase in alanine aminotransferases and aspartate aminotransferases in circulation at 30 days. Additionally, the soaring TNF-α and MCP-1 were found in liver, and the mRNA expression of pro-inflammatory cytokines (IL-1α, IL-1ß, and IL-18) and anti-inflammatory cytokines (TGF-ß, IL-10, and IL-13) were both significantly upregulated. Moreover, the activated M1 and M2 macrophages were confirmed in charge of these cytokines release. Most importantly, the data validated a pivotal role of NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome in Cd-induced inflammation in liver at puberty. Collectively, our results suggested that low-dose Cd oral exposure can cause liver inflammation via activation of NLRP3 inflammasome and give rise to severe liver injury at puberty.

Evaluation of Blood Oxidant/Antioxidant Changes and Testicular Toxicity after Subacute Exposure to Cadmium in Albino Rats: Therapeutic Effect of Nigella sativa Seed Extracts.

AIM AND OBJECTIVE: Cells and tissues of the body are prone to oxidative damage as a result of an increased level of reactive oxygen species and nitrogen radical beyond the detoxifying ability of the endogenous antioxidant system. This study aimed to evaluate the ameliorative effect of methanolic extracts of Nigella sativa (MENS) against cadmium-induced blood oxidative stress and testicular toxicity in albino rats. MATERIALS AND METHODS: Twenty-five (25) male albino rats, weighing (200 ± 20g), were randomly grouped into five groups (A-E). Group B (Negative Control) received intraperitoneal administration of cadmium chloride (CdCl2, 5 mg/kg) only, group C received CdCl2 and low dose MENS (300 mg/kg, oral), group D received CdCl2 and high dose MENS (600 mg/kg, oral), group E (Positive control) received CdCl2 and Vitamin C (200 mg/kg, oral), for 14 days. No treatment was administered to group A (Normal control). The oxidative state of the blood was assessed by measuring the blood levels or activities of MDA, CAT, GSH and SOD; while testicular injury was assessed by measuring serum testosterone level using ELISA. The testes were harvested for histopathological examination. RESULTS: The results showed that cadmium induced a marked elevation in the level of MDA, and a decrease in SOD, CAT and GSH levels or activities (p<0.05 or p<0.01); but no significant alteration in the serum testosterone level was found (p>0.05); Histopathological studies on the testes showed that cadmium significantly induced testicular injury, which was however ameliorated by the seed extract of N. sativa. CONCLUSION: We conclude that N. sativa seed extract is potentially testiculoprotective and attenuates oxidative stress against harmful chemical toxins such as cadmium.

Protective Effect of Grape and Apple Juices against Cadmium Intoxication in the Kidney of Rats.

BACKGROUND: The objective of this study was to evaluate protective effect of grape and apple juices against toxicity induced by cadmium in the kidney of rats. METHODS: A total of 20 male-Wistar rats were distributed into four groups (n=5): Control group: animals received an intraperitoneal (i.p.) injection of 0.9% saline solution and after 15 days, 1 mL of water was administered for 15 days, via gavage; Cadmium group: animals received an intraperitoneal injection of cadmium chloride (1.2 mg/kg) and after 15 days, 1 mL of water was administered for 15 days via gavage; Cadmium+Grape Juice: animals received an i.p. injection of cadmium chloride (1.2 mg/kg), and after 15 days, 0.8 mL of grape juice was administered for 15 days, via gavage; Cadmium+Apple Juice: animals received i.p. injection of cadmium chloride (1.2 mg/kg) and after 15 days, 1.0 mL of apple juice was administered for 15 days, via gavage. RESULTS: Histopathological analysis revealed severe tubular lesion and necrosis in the group exposed to cadmium, while animals exposed to grape or apple juices showed a significant reduction of tissue injury. 8-OHdG immunoexpression, DNA damage, cytochrome C and catalase gene expressions and Toll like signaling pathway (TLR2, and pIKKα/ß) decreased in animals treated with grape juice when compared to cadmium group. CONCLUSION: Taken together, we conclude that grape and apple juices had a protective effect by means of antioxidant, antigenotoxic actions and for promoting tissue regeneration in the kidney of rats following cadmium intoxication.

Engineering of Nanospheres Dispersed Microneedle System for Antihypertensive Action.

BACKGROUND: A combinational therapy is mostly preferred in hypertension treatment because of low-dose and less side effects like pretibial edema, and gastrointestinal bleeding. OBJECTIVE: So the objective of the present work was to formulate an advanced drug delivery system in the form of bio-responsive microneedles by incorporating nifedipine, a cardiodepressant and diltiazem, a vasodilator for effective synergism in the treatment of hypertension. METHODS: The pH-responsive PLGA nanospheres of diltiazem were formulated using Water-in-Oil-in- Water (W/O/W) double emulsion and solvent-diffusion-evaporation technique. These nanospheres were added to nifedipine-PVP mixture and then incorporated into mold to develop microneedles. RESULTS: The microneedles showed the release of nifedipine almost 96.93± 2.31% for 24 h due to high PVP solubilization. The nanospheres of diltiazem on contact with acidic pH of skin managed to form of CO2 bubbles and increase the internal pressure to burst PLGA shell due to pore formation. The mean blood pressure observed for the normal group was 89.58 ± 3.603 mmHg, whereas the treatment with the new formulation significantly reduced the mean blood pressure up to 84.11 ± 2.98 mmHg in comparison to the disease control group (109.9 ± 1.825 mm Hg). CONCLUSION: This system co-delivers the drugs nifedipine and diltiazem in hypertension and shows an advance alternative approach over conventional drug delivery system.

Dietary cadmium chloride impairs shell biomineralization by disrupting the metabolism of the eggshell gland in laying hens.

In this study, we identified cadmium (Cd) as a potential endocrine disruptor that impairs laying performance, egg quality, and eggshell deposition and induces oxidative stress and inflammation in the eggshell glands of laying hens. A total of 480 38-wk-old laying hens were randomly assigned into 5 groups that were fed a basal diet (control) or a basal diet supplemented with Cd (provided as CdCl2·2.5 H2O) at 7.5, 15, 30, and 60 mg Cd per kg feed for 9 wk. The results showed that, when compared with the control group, a low dose of dietary Cd (7.5 mg/kg) had positive effects on egg quality by improving albumen height, Haugh unit, yolk color, and shell thickness at the third or ninth week. However, with the increase in the dose and duration of Cd exposure, the laying performance, egg quality, and activities of eggshell gland antioxidant enzymes (catalase [CAT], glutathione peroxide [GSH-Px]), and ATPase (Na+/K+-ATPase, Ca2+-ATPase, and Mg2+-ATPase) deteriorated, and the activity of total nitric oxide synthase (T-NOS) and the level of malondialdehyde (MDA) increased significantly (P < 0.05). The histopathology and real-time quantitative PCR results showed that Cd induced endometrial epithelial cell proliferation accompanied by upregulation of the mRNA levels of progesterone receptor (PgR) and epidermal growth factor receptor (EGFR), downregulation of the mRNA levels of estrogen receptor α (ERα) and interleukin 6 (IL6), and inflammation of the eggshell gland accompanied by significantly increased expression of complement C3 and pro-inflammatory cytokine tumor necrosis factor α (TNFα) (P < 0.05). In addition, the ultrastructure of the eggshell showed that dietary supplementation with 7.5 mg/kg Cd increased the palisade layer and total thickness of the shell, but with the increase in dietary Cd supplementation (30 and 60 mg/kg) the thickness of the palisade layer and mammillary layer decreased significantly (P < 0.05), and the outer surface of the eggshell became rougher. Correspondingly, the expression of calbindin 1 (CALB1), ovocalyxin-32 (OCX-32), ovocalyxin-36 (OCX-36), osteopontin (SPP1), and ovocledidin-17 (OC-17) decreased significantly (P < 0.05) with increasing dietary Cd supplementation. Conclusively, the present study demonstrates that dietary supplementation with Cd negatively affects laying performance, egg quality, and eggshell deposition by disturbing the metabolism of eggshell glands in laying hens but has a positive effect on egg quality at low doses.

Oral Co-Exposures to zinc oxide nanoparticles and CdCl2 induced maternal-fetal pollutant transfer and embryotoxicity by damaging placental barriers.

Synergistic toxicity from multiple environmental pollutants poses greater threat to humans, especially to susceptible pregnant population. Here we evaluated combined toxicity from environment pollutants zinc oxide nanoparticles (ZnO NPs) and cadmium chloride (CdCl2) using two pregnant mice models established by oral administration during peri-implantation or organogenesis period. We found that exposures to combined pollutants only at organogenesis stage induced higher fetal deformity rate compared to co-exposures at peri-implantation stage. We further discovered that surface charge of ZnO NPs were modified after Cd2+ adsorption and the resulting nanoadducts caused more severe damages in placental barriers by causing shed endothelial cells and decreased expressions of tight junction proteins ZO1, occludin, claudin-4 and claudin-8. These cellular and molecular events enhanced maternal-fetal transfer of both pollutants and aggravated embryotoxicity. Our findings help elucidate synergistic embryotoxicity by nanoparticle/pollutant adducts and establish proper safety criteria for pregnant population in an era that nanotechnology-based products are widely used.

Further verification of some postulates of the combined toxicity theory: New animal experimental data on separate and joint adverse effects of lead and cadmium.

Outbred male rats were repeatedly injected intraperitoneally two-level sub-lethal doses of lead acetate and/or cadmium chloride solutions 3 times a week during 6 weeks. The animals developed explicit, even if moderate, subchronic intoxication characterized by a large number of indices, both common to both metals (including increased DNA fragmentation coefficient) and lead-specific. Special attention was paid to hemodynamic and electrocardiographic effects. The combined action of lead and cadmium was modeled with the help of the Response Surface Methodology to obtain additional support for the previously substantiated postulates of combined toxicity's typological ambiguity. This is dependent on which particular effect comes under consideration, on its level, and on the acting dose ratio. For one and the same toxic combination, the type of combined toxic action can vary from synergistic to contra-directional. In particular, the actions of lead and cadmium on blood pressure were found to be opposite in direction. Furthermore, it is shown once again that the systemic toxic effects of a metal combination, its in vivo genotoxicity included, can be more or less attenuated by background administration of a theoretically justified composition of biologically active agents.

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.

Diacerein Downregulates NLRP3/Caspase-1/IL-1ß and IL-6/STAT3 Pathways of Inflammation and Apoptosis in a Rat Model of Cadmium Testicular Toxicity.

The potential gonadal protective effect of diacerein (DCN) and its underlying mechanisms were studied in a rat model of cadmium-induced testicular toxicity. The rats received DCN (50 mg/kg/day, p.o.) for 10 days and one injection of CdCl2 (2 mg/kg, i.p.) on day 9. Cadmium significantly declined serum testosterone and significantly raised interleukin-1ß, interleukin-6, interleukin-18, tumor necrosis factor-α, caspase-1, phosphorylated signal transducer and activator of transcription-3 (pSTAT3), nuclear factor-κB p65, Bax, and caspase-3 in rat testes. DCN significantly ameliorated the changes in the biochemical measurements observed with CdCl2 insult. Additionally, DCN preserved the normal testicular architecture, maintained spermatogenesis, and lowered the expression of NOD-like receptor family protein 3 (NLRP3) inflammasome in testes of rats that received CdCl2. It was concluded that DCN significantly protected the gonads of male rats exposed to cadmium toxicity through modulation of NLRP3/caspase-1/IL-1ß and IL-6/STAT3 pathways of inflammation and apoptosis.

A nongenomic mechanism for "metalloestrogenic" effects of cadmium in human uterine leiomyoma cells through G protein-coupled estrogen receptor.

Cadmium (Cd) is a ubiquitous environmental metal that is reported to be a "metalloestrogen." Uterine leiomyomas (fibroids) are estrogen-responsive gynecologic neoplasms that can be the target of xenoestrogens. Previous epidemiology studies have suggested Cd may be associated with fibroids. We have shown that Cd can stimulate proliferation of human uterine leiomyoma (ht-UtLM) cells, but not through classical estrogen receptor (ER) binding. Whether nongenomic ER pathways are involved in Cd-induced proliferation is unknown. In the present study, by evaluating G protein-coupled estrogen receptor (GPER), ERα36, and phospho-epidermal growth factor receptor (EGFR) expression in human tissues, we found that GPER, ERα36 and phospho-EGFR were all highly expressed in fibroids compared to patient-matched myometrial tissues. In ht-UtLM cells, cell proliferation was increased by low doses of Cd (0.1 µM and 10 µM), and this effect could be inhibited by GPER-specific antagonist (G15) pretreatment, or silencing (si) GPER, but not by siERα36. Cd-activated MAPK was dependent on GPER/EGFR transactivation, through significantly increased phospho-Src, matrix metalloproteinase-2 (MMP2) and MMP9, and heparin-binding EGF-like growth factor (HB-EGF) expression/activation. Also, phospho-Src could interact directly to phosphorylate EGFR. Overall, Cd-induced proliferation of human fibroid cells was through a nongenomic GPER/p-src/EGFR/MAPK signaling pathway that did not directly involve ERα36. This suggests that Cd may be a risk factor for uterine fibroids through cross talk between hormone and growth factor receptor pathways.

Oxidative stress modulation induced by chitosan-glutathione nanoparticles in chondrocytes.

The use of nanometric systems to deliver biologically active substances is a successful tool in different fields. In this study, we investigated nanometric systems with antioxidant capacity to modulate events associated with the redox state in human chondrocytes. We used nanoparticles (NPs) prepared with chitosan and glutathione (GSH) and an in vitro model: primary cultures of human chondrocytes were extracted from hyaline cartilage. The cells were exposed to CdCl2 in the presence or absence of NPs. CdCl2 is a widely known oxidizing agent. Fluorescence and confocal microscopy showed the location of the NPs within the cells. The results obtained showed that the NPs did not significantly affect cell viability. We studied the antioxidant capacity of the NPs by estimating the GSH, TBARs, and Cell Rox content and the enzymatic activity of glutathione peroxidase (GPx). In vitro assays showed that GSH levels, GPx activity and reactive oxygen species (Cell Rox) levels were modified with both concentrations of NPs, while lipoperoxidation (TBARs) decreased when cells exposed to CdCl2 were in contact with the NPs. All these results suggest the ability of NPs to modulate the cell redox state in a dose-dependent manner.

Biodistribution and Systemic Effects in Mice Following Intravenous Administration of Cadmium Telluride Quantum Dot Nanoparticles.

Quantum dots (QDs) are engineered nanoparticles (NPs) of semiconductor structure that possess unique optical and electronic properties and are widely used in biomedical applications; however, their risks are not entirely understood. This study investigated the tissue distribution and toxic effects of cadmium telluride quantum dots (CdTe-QDs) in male BALB/c mice for up to 1 week after single-dose intravenous injections. CdTe-QDs were detected in the blood, lung, heart, liver, spleen, kidney, testis and brain. Most CdTe-QDs accumulated in the liver, followed by the spleen and kidney. At high doses, exposure to CdTe-QDs resulted in mild dehydration, lethargy, ruffled fur, hunched posture, and body weight loss. Histological analysis of the tissues, upon highest dose exposures, revealed hepatic hemorrhage and necrotic areas in the spleen. The sera of mice treated with high doses of CdTe-QDs showed significant increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin levels, as well as a reduction in albumin. CdTe-QD exposure also led to a reduced number of platelets and elevated total white blood cell counts, including monocytes and neutrophils, serum amyloid A, and several pro-inflammatory cytokines. These results demonstrated that the liver is the main target of CdTe-QDs and that exposure to CdTe-QDs leads to hepatic and splenic injury, as well as systemic effects, in mice. By contrast, cadmium chloride (CdCl2), at an equivalent concentration of cadmium, appeared to have a different pharmacokinetic pattern from that of CdTe-QDs, having minimal effects on the aforementioned parameters, suggesting that cadmium alone cannot fully explain the toxicity of CdTe-QDs.

Cadmium-induced hepatocellular injury: Modulatory effects of γ-glutamyl cysteine on the biomarkers of inflammation, DNA damage, and apoptotic cell death.

Cadmium is an extremely toxic pollutant that reaches human body through intake of the industrially polluted food and water as well as through cigarette smoking and exposure to polluted air. Cadmium accumulates in different body organs especially the liver. It induces tissue injury largely through inflammation and oxidative stress-based mechanisms. The aim of the current study was to investigate the ability of γ glutamyl cysteine (γGC) to protect against cadmium-induced hepatocellular injury employing Wistar rats as a mammalian model. The results of the current work indicated that γGC upregulated the level of the anti-inflammatory cytokine IL-10 and downregulated the levels of the pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß) in the cadmium-exposed rats. In addition, γGC reduced the liver tissues cadmium content in the cadmium-treated rats, suppressed the cadmium-induced hepatocellular apoptosis and oxidative modifications of cellular DNA, lipids, and proteins. Additionally, γGC enhanced the antioxidant potential of the liver tissues in the cadmium-treated rats as evidenced by a remarkable increase in the activity of the antioxidant enzymes superoxide dismutase and glutathione peroxidase and significant increase in the levels of the total antioxidant capacity and reduced glutathione as well as a significant reduction in oxidized to reduced glutathione (GSSG/GSH) ratio. Moreover, it effectively improved liver cell integrity in the cadmium-treated rats as demonstrated by a significant reduction in the serum activity of the liver enzymes (ALT and AST) and amelioration of the cadmium-evoked histopathological alterations. Together, these findings underscore, for the first time, the alleviating effects of γGC against cadmium-induced hepatocellular injury that is potentially mediated through reduction of liver tissue cadmium content along with modulation of both hepatocellular redox status and inflammatory cytokines.

Renal toxicity of heavy metals (cadmium and mercury) and their amelioration with ascorbic acid in rabbits.

Cadmium and mercury are among the most toxic and dangerous environmental pollutants that may cause fatal implications. Vitamin C is an important chain-breaking antioxidant and enzyme co-factor against heavy metals. The objective of the present study was to evaluate the toxicological effects of cadmium chloride, mercuric chloride, and their co-administration on biochemical parameters of blood serum and metal bioaccumulation in kidneys and also to elucidate the protective effect of vitamin C in rabbits against these metals. In the current research, cadmium chloride (1.5 mg/kg), mercuric chloride(1.2 mg/kg), and vitamin C (150 mg/kg of body weight) were orally administered to eight treatment groups of the rabbits (1, control; 2, vitamin; 3, CdCl2; 4, HgCl2; 5, vitamin + CdCl2; 6, vitamin + HgCl2; 7, CdCl2 + HgCl2, and 8, vitamin + CdCl2 + HgCl2). After the biometric measurements of all experimental rabbits, biochemical parameters viz. creatinine, cystatin C, uric acid, and alkaline phosphatase (ALP) and metal bioaccumulation were determined using commercially available kits and atomic absorption spectrophotometer, respectively. The levels of creatinine (28.3 ± 1.1 µmol/l), cystatin C (1932.5 ± 38.5 ηg/ml), uric acid (4.8 ± 0.1 mg/day), and ALP (51.6 ± 1.1 IU/l) were significantly (P < 0.05) increased due to administration of mercuric chloride but in the presence of vitamin C, the effects of mercuric chloride on creatinine (21.9 ± 1.4 µmol/l), cystatin C (1676.2 ± 42.2 ηg/ml), uric acid (3.9 ± 0.1 mg/day), and ALP (43.3 ± 0.8 IU/l) were less as compared to metal-exposed specimens. Similar results were found in rabbits treated with cadmium chloride and vitamin C and also with co-administration of both metals and vitamin C. Because of the bio-accumulative nature of cadmium chloride and mercuric chloride, these metals were accumulated in kidneys of rabbits, which might lead to deleterious effects. The results of the present study provide an insight into the toxicity of the cadmium chloride, mercuric chloride, and/or their combination on biochemical parameters as well as kidneys of the rabbits and the ameliorating potential of vitamin C against these metals is also evaluated.

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.