Cadmium sulfide nanoparticles trigger DNA alterations and modify the bioturbation activity of tubificidae worms exposed through the sediment

To address the impact of cadmium sulfide nanoparticles (CdS NPs) in freshwater ecosystems, aquatic oligochaete Tubifex tubifex were exposed through the sediment to a low dose (0.52?mg of 8?nm in size of CdS NPs/kg) for 20 days using microcosms. Cadmium (Cd) was released from the CdS NPs-contaminated sediment to the water column, and during this period the average concentrations of Cd in the filtered water fraction were 0.026?±?0.006?µg/L in presence of oligochaetes. Similar experiments with microparticular CdS and cadmium chloride (CdCl₂) were simultaneously performed for comparative purposes. CdS NPs exposure triggered various effects on Tubifex worms compared to control, microsized and ionic reference, including modification of genome composition as assessed using RAPD-PCR genotoxicity tests. Bioaccumulation levels showed that CdS NPs were less bioavailable than CdCl₂ to oligochaetes and reached 0.08?±?0.01?µg Cd/g for CdS NPs exposure versus 0.76?±?0.3?µg Cd/g for CdCl₂ exposure (fresh weight). CdS NPs altered worm’s behavior by decreasing significantly the bioturbation activity as assessed after the exposure period using conservative fluorescent particulate tracers. This study demonstrated the high potential harm of the CdS nanoparticular form despite its lower bioavailability for Tubifex worms.     

Effects of Detergent Formula Chelating Agents on the Metabolism and Toxicity of Cadmium in Mice

Abstract Chelating agents like NTA (nitrilotriacetic acid) STPP (sodiumtripolyphosphate, Na₅P₃O₁₀) and EDTA (ethylenediaminetetraacetic acid) are used as components of detergents. An increased toxicity of some metal compounds when combined with NTA has led to decreased use of this chelating agent in relation to STPP. In the present studies short-term and long-term effects of these chelating agents on cadmium toxicity in mice were investigated. I: In the short-term study, mice subcutaneously exposed to CdCl₂ (3.2 mg Cd/kg b.wt.) in combination with STPP (32 mg/kg b.wt.) demonstrated a markedly higher mortality compared to animals given CdCl₂ alone. This increase in mortality was similar to the one encountered when CdCl₂ (3.2 mg Cd/kg b.wt.) and NTA (32 mg/kg b.wt.) were combined. Animals exposed subcutaneously to CdCl₂ + STPP or CdCl₂ + NTA showed histological evidence of liver necrosis 24 hrs after exposure not seen in animals given the same dose of CdCl₂ alone and also had markedly lower cadmium concentrations in the livers compared to only Cd-exposed animals. II: In the long-term study, mice were exposed orally to CdSO₄ (50 p.p.m. Cd) alone or in combination with STPP (500 p.p.m.), NTA (500 p.p.m.) or EDTA (50 p.p.m.) by continuous administration via the drinking water for 18 months. A decreased total excretion of urine proteins was seen in all Cd- treated animals irrespectively of the combination with various chelating agents. The conclusion of the present work was that NTA and STPP given by subcutaneous injection to mice markedly increased the toxicity of cadmium but that neither NTA, STPP nor EDTA given orally altered the toxicity of cadmium during a period of long-term exposure of 18 months.     

Genotoxic and oxidative responses in coelomocytes of Eisenia fetida and Hediste diversicolor exposed to lipid‐coated CdSe/ZnS quantum dots and CdCl2

The emerging of Quantum Dots utilization in industrial or medicinal fields involved a potentially increase of these nanoparticles in environment. In this work, the genotoxic (comet assay) and oxidative effects (SOD activity, TBARS) of functionalized‐QDs and cadmium chloride were investigated on Hediste diversicolor and Eisenia fetida coelomocytes. Results demonstrated that functionalized‐QDs (QDNs) and cadmium chloride induced DNA damages through different mechanisms that depended on the nano‐ or ionic nature of Cd. The minimal genotoxic concentrations for H. diversicolor (<0.001ng/g for QDNs and CdCl₂) were lower than for E. fetida (between 0.01 and 0.1 ng/g for QDNs, and between 0.001 and 0.01 ng/g for CdCl₂). These results showed that H. diversicolor was more sensitive than E. fetida. The two contaminants had a low impact on the oxidative stress markers. © 2014 Wiley Periodicals, Inc. Environ Toxicol 30: 918–926, 2015.     

Effects of cadmium on proliferation and self-renewal activity of prostate stem/progenitor cells

Cadmium (Cd) is an occupational and environmental pollutant that induces numerous pathological effects, including injuries to prostate. The aim of the present study was to investigate the effects of Cd on self-renewal and proliferation of prostate stem/progenitor cells (PSPC) and its possible mechanisms. Prostate epithelial cells were prepared from mice to form sphere in Matrigel/PrEGM supplemented with cadmium chloride (CdCl₂). The data showed that CdCl₂ inhibits sphere-forming ability and proliferation of PSPC in a concentration dependent manner. Primary spheres were then passaged to form daughter spheres and we found that CdCl₂ suppressed PSPC self-renewal activity, which recovered after further passaging. We also detected the protein level of androgen receptor (AR) in the spheres of each passage. The results showed that AR in primary spheres is suppressed by CdCl₂ in a concentration dependent manner. However, no obvious change of AR was found in subsequent passages. The in vivo toxicity of CdCl₂ on PSPC was detected by giving mice drinking water with CdCl₂. Our results demonstrated in vivo inhibition effect of CdCl₂ on self-renewal activity of PSPC. Consistent with in vitro results, self-renewal activity of PSPC was recovered after CdCl₂ withdrawal. In addition, CdCl₂ also in vivo suppressed PSPC proliferation as indicated by Ki67 immunostaining. Our finding suggested that Cd may inhibit proliferation and self-renewal activity of PSPC by suppressing AR, which could be important to further understanding the complex mechanism of Cd toxicity in prostate.     

Comparative tissue distributions of cadmium chloride and cadmium-based quantum dot 705 in mice: Safety implications and applications

Abstract

Cadmium (Cd) is a component in quantum dot 705 (QD705). Whether QD705 behaves similar to Cd in vivo is of great concern. We compared the distributional kinetics of cadmium chloride (CdCl₂) and QD705 in mice after intravenous injection. QD705 showed a longer plasma and body retention than CdCl₂ and could be detected in the brain during early exposure. While both the liver and spleen demonstrated a constant Cd concentration for 28 days after QD705 injection, it is likely that this represents intact QD705 stored in mononuclear phagocytes. The kidneys showed a time-dependent accumulation of Cd in the QD705-exposed animals. By day 28, Cd in the kidneys from QD705 was 3-fold that of CdCl₂. QD705 and CdCl₂ have very different kinetics in distribution and metabolism. The long body retention of QD705 in the kidneys may mean that QD705 has even more renal toxicity than CdCl₂.     

Synthesis,characterization and in vivo evaluation of cadmium telluride quantum dots toxicity in mice by toxicometabolomics approach

Quantum dots (QDs) have widespread application in many fields such as medicine and electronics. The need for understanding the potentially harmful side effects of these materials becomes clear. In this study, the toxicity of cadmium telluride quantum dots (CdTe-QDs) and bulk Cd²⁺ has been investigated and compared by applying metabolomics methods. The datasets were ¹H-NMR data from mice plasma which had been taken from four groups of mice in different time intervals. Then, the data were analyzed by applying chemometrics methods and the metabolites were found from Human Metabolome Database (HMDB). The results showed the significant change in the level of some metabolites especially estrogenic steroids in different groups with different amounts of received Cd. The findings also indicated that steroid hormone biosynthesis, lysine biosynthesis and taurine and hypotaurine metabolism are the most affected pathways by CdTe-QDs especially in estrogenic steroids. The over-representation analysis indicated that endoplasmic reticulum, gonads, and hepatocytes are most affected. Since the pattern of metabolite alteration of CdTe-QDs with equivalent Cd²⁺ was similar to those of CdCl₂, it was postulated that beside Cd²⁺ effects, the toxicity of CdTe-QDs is associated with other factors.     

Toxicity of mixtures of zinc oxide and graphene oxide nanoparticles to aquatic organisms of different trophic level: particles outperform dissolved ions

Concomitant releases of various engineered nanoparticles (NPs) into the environment have resulted in concerns regarding their combined toxicity to aquatic organisms. It is however, still elusive to distinguish the contribution to toxicity of components in NP mixtures. In the present study, we quantitatively evaluated the relative contribution of NPs in their particulate form (NP_(particle)) and of dissolved ions released from NPs (NP_(ion)) to the combined toxicity of binary mixtures of ZnO NPs and graphene oxide nanoplatelets (GO NPs) to three aquatic organisms of different trophic levels, including an alga species (Scenedesmus obliquus), a cladoceran species (Daphnia magna), and a freshwater fish larva (Danio rerio). Our results revealed that the effects of ZnO NPs and GO NPs were additive to S. obliquus and D. magna but antagonistic to D. rerio. The relative contribution to toxicity (RCT) of the mixture components to S. obliquus decreased in the order of RCT_{GO NP(particle)} >?RCT_{ZnO NP(particle)}?>?RCT_{ZnO NP(ion)}, while the RCT of the mixture components to D. magna and D. rerio decreased in the order of RCT_{ZnO NP(particle)}?>?RCT_{GO NP(particle)}?>?RCT_{ZnO NP(ion)}. This finding also implies that the suspended particles rather than the dissolved Zn-ions dictated the combined toxicity of binary mixtures of ZnO NPs and GO NPs to the aquatic organisms of different trophic level. The alleviation of the contribution to toxicity of the ionic form of ZnO NPs was caused by the adsorption of the dissolved ions on GO NPs. Furthermore, the ZnO NP_(particle) and GO NP_(particle) displayed a different contribution to the observed mixture toxicity, dependent on the trophic level of the aquatic organisms tested. The difference of the contributions between the two particulate forms was mainly associated with differences in the intracellular accumulation of reactive oxygen species. Our findings highlight the important role of particles in the ecological impact of multi-nanomaterial systems.     

Acute toxicity of two CdSe/ZnSe quantum dots with different surface coating in Daphnia magna under various light conditions

With an increasing use of quantum dots (QDs) in many applications, their potential hazard is of growing concern. However, little is known about their ecotoxicity, especially in vivo. In the present study, we employed freshwater macroinvertebrate, Daphnia magna, to evaluate toxicity characteristics of cadmium selenide/zinc selenide (CdSe/ZnSe) in relation to surface coatings, e.g., mercaptopropionic acid QD (^MPAQD), and gum arabic/tri‐n‐octylphosphine oxide QD (^GA/TOPOQD), and light conditions, i.e., dark, fluorescent light, environmental level of ultraviolet (UV) light, and sunlight. The results of the present study showed that D. magna was more susceptible to ^GA/TOPOQD exposure compared to ^MPAQD. The surface coating of QD appeared to determine the stability of QDs and hence the toxicity, potentially by size change of or the release of toxic components from QDs. However, ^GA/TOPOQD was still less toxic than the equivalent level of CdCl₂. The toxicity of all the tested compounds increased by changing the light condition from dark to white fluorescence to UV‐B light, and to natural sunlight. The effect of light condition on QDs toxicity could also be explained by photostability of the QDs, which would affect size of the particle, release of toxic component ions, and generation of reactive oxygen species. Considering increasing use of QDs in various applications, their environmental fates and corresponding toxic potentials deserve further investigation. © 2009 Wiley Periodicals, Inc. Environ Toxicol 25: 593–600, 2010.     

N-Alkyl-N-dithiocarboxy-d-glucamine analogs as cadmium antagonists: synthesis and evaluation of the n-propyl,n-butyl,and n-amyl derivatives

N-(n-Propyl)-, N-(n-butyl)-, and N-(n-amyl)-N-dithiocarboxy-d-glucamine were newly synthesized by (a) addition of each n-alkylamine to glucose, (b) high-pressure catalytic reduction of each glucosamine thus formed to the corresponding glucamine, and (c) reaction of the resultant secondary amines with CS₂ to form the dithiocarboxy derivatives. Each compound was evaluated as an antagonist of acute cadmium (Cd) toxicity and as a complexing agent for intracellular metallothionein-bound Cd (Cd-MT) in mice. N-Benzyl-N-dithiocarboxy-d-glucamine (BDCG) was used as a positive control compound. Each congener afforded partial or complete protection against the lethal effects of 10.0 mg/kg CdCl₂·2.5 H₂O, and retarded accumulation of Cd in livers and kidneys when given 2 h after the acutely toxic dose of Cd. Each derivative was also effective in mobilizing Cd from MT-bound sites in livers and kidneys of mice which had received a sub-lethal dose of CdCl₂ along with ¹⁰⁹CdCl₂ 2 weeks earlier. Excretion of mobilized Cd was almost exclusively by the fecal route. Potency of the analogs, as well as the octanol/aqueous partition coefficients, increased with the overall length of the N-(n-alkyl) carbon chain. Each compound readily complexed Cd from partially purified Cd-MT in vitro. Serum Cd from mice treated with BDCG was associated principally with proteins of high molecular weight.Supported by the Veterans Administration (G. R. G.), by NIH Grant ES-02638 (M. M. J.), and by VA-NCI Interagency Agreement IGA V101 (134A) P-77014.     

Modulation of cytokines and chemokines expression by NAC in cadmium chloride treated human lung cells

Cadmium (Cd), is one of the most hazardous metals found in the environment. Cd exposure through inhalation has been linked to various diseases in lungs. It was shown that Cd induces proinflammatory cytokines through oxidative stress mechanism. In this report, we studied the immunomodulatory effect of a well known antioxidant, N‐acetylcysteine (NAC) on cadmium chloride (CdCl₂) treated human lung A549 cells through human cytokine array 6. The lung cells were treated with 0 or 75 µM CdCl₂ alone, 2.5 mM NAC alone, or co‐treated with 2.5 mM NAC and 75 µM CdCl₂ for 24 h. The viability of cells was measured by crystal violet dye. The array results were validated by human IL‐1alpha enzyme‐ linked immunosorbent assay (ELISA) kit. The viability of the 75 µM CdCl₂ alone treated cells was decreased to 44.5%, while the viability of the co‐treated cells with 2.5 mM NAC was increased to 84.1% in comparison with untreated cells. In the cell lysate of CdCl₂ alone treated cells, 19 and 8 cytokines were up and down‐regulated, while in the medium 15 and 3 cytokines were up and downregulated in comparison with the untreated cells. In the co‐treated cells, all these cytokines expression was modulated by the NAC treatment. The IL‐1α ELISA result showed the same pattern of cytokine expression as the cytokine array. This study clearly showed the modulatory effect of NAC on cytokines and chemokines expression in CdCl_2‐treated cells and suggests the use of NAC as protective agent against cadmium toxicity. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1612–1619, 2016.     

Acute toxicity to Daphnia magna of effluents containing Cd,Zn, and a mixture Cd‐Zn,after metal removal by Chlorella vulgaris

Daphnia magna was used as a test organism for assessing the toxicity remaining in simulated effluents containing cadmium, zinc, and a cadmium‐zinc mixture, after these metals were removed with suspended and immobilized Chlorella vulgaris cultures. The percentage of removal was higher (84.7%) for cadmium in the metal mixture with immobilized cultures. The LC₅₀ value was lower for the residual cadmium (single and in the mixture) in the effluent after treatment with suspended cultures. The acute toxicity response observed in D. magna, indicates that zinc has an antagonistic effect on cadmium toxicity. According to the results, the treatment system can modify the Cd acute residual toxicity. © 2000 John Wiley & Sons, Inc. Environ Toxicol 15: 160–164, 2000<     

Cadmium exposure increases susceptibility to testicular autoimmunity in mice

Cadmium, one of various environmental toxicants, is known to suppress systemic immunity and to injure the testicular capillary endothelia with resultant necrosis of testicular tissues in mice and rats treated with high doses. Recently, it also became evident that cadmium can affect the integrity of the blood–testis barrier (BTB), the endocrine function of Leydig cells, apoptosis of germ cells and systemic immunity, even on treatment with a low dose that does not induce spermatogenic disturbance. Experimental autoimmune orchitis (EAO), i.e., an organ‐specific autoimmunity of the testis, can be induced by repeated immunization with testicular antigens, and its pathology is characterized by lymphocytic inflammation and spermatogenic disturbance. In the present study, we investigated the morphological and functional changes of testes in mice treated with a low dose of cadmium chloride (CdCl₂) and also examined its toxicity as to susceptibility to EAO. The results showed that exposure to 3 mg CdCl₂ kg^?1 body weight did not affect the spermatogenic state. However, the BTB at the tubuli recti and the rete testis, but not the seminiferous tubules, was slightly weakened, and intra‐testicular mRNA expression of interleukin (IL)‐6, tumor necrosis factor‐α and IL‐1β was significantly increased by the CdCl₂ treatment. Furthermore, immunization with testicular antigens after the CdCl₂ exposure significantly augmented the EAO severity. Therefore, exposure to a low dose of CdCl₂ induces no significant disturbance of spermatogenesis, however, it does change the immunological microcircumstances in the testis, resulting in increased susceptibility to testicular autoimmunity. Copyright © 2012 John Wiley & Sons, Ltd.     

Dietary iron lowers the intestinal uptake of cadmium-metallothionein in rats

It has been shown that addition of extra calcium/phosphorus (Ca/P), zinc (Zn) and iron (Fe²⁺) to the diet results in a significant protection against cadmium (Cd) accumulation and toxicity in rats fed inorganic Cd salt. However, it is not clear whether the presence of these miniral supplements in the diet also protects against the Cd uptake from cadmium-metallothionein. The present study examines the influence of Ca/P, Zn and Fe²⁺ on the Cd disposition in rats fed diets containing either 1.5 and 8 mg Cd/kg diet as cadmium-metallothionein (CdMt) or as cadmium chloride (CdCl₂) for 4 weeks. The feeding of Cd resulted in a dose-dependent increase of Cd in intestine, liver and kidneys. The total Cd uptake in liver and kidneys after exposure to CdMt was lower than after exposure to CdCl₂. At the low dietary Cd level and after addition of the mineral supplement, the kidney/liver concentration ratio increased. However, this ratio was always higher with CdMt than with CdCl₂, suggesting a selective renal disposition of dietary CdMt. The uptake of Cd from CdCl₂ as well as from CdMt was significantly decreased by the presence of a combined mineral supplement of Ca/P, Zn and Fe²⁺. The protection which could be achieved was 72 and 75% for CdMt and 85 and 92% for CdCl₂ after doses of 1.5 mg/kg and 8 mg/kg respectively. In a following experiment it was shown that the protective effect of the mineral mixture against CdMt was mainly due to the presence of Fe²⁺. It seems clear that Cd speciation and the mineral status of the diet have a considerable impact on the extent of Cd uptake in rats.     

Chronic cadmium exposure induced hepatic cellular stress and inflammation in aged female mice

Previous studies have revealed that acute cadmium (Cd) exposure led to inflammation in different organs through an oxidative stress mechanism. However, whether chronic Cd exposure induces inflammation in liver and the mechanistic link between inflammation and cell stress remains unclear. In the present study, we investigated the effects of chronic Cd exposure on hepatic cellular stress and inflammatory responses. Female CD1 mice were administrated with CdCl₂ (10 and 100 mg/L) in drinking water for 57 weeks. Our results showed that the mRNA levels of Inos and the protein content of HO‐1, markers of oxidative stress, were markedly increased in Cd‐treated mice. In addition, the protein level of GRP78, the chaperone of endoplasmic reticulum (ER) stress, was significantly increased in Cd‐treated mice. The expression of the proteins CHOP and peIF2α, two proteins downstream of ER stress, was also upregulated in the Cd‐100 mg/L and Cd‐10 mg/L group, respectively. Moreover, there were increased inflammatory cells existing in liver after Cd administration. Besides, there was a significant elevation in the mRNA level of Mip‐2, Il‐10 and Il‐12 in the Cd‐100 mg/L group. The mRNA level of Tgf‐β was also upregulated in Cd‐treated mice. Moreover, we also found that the number of Ki67‐positive hepatic cells was increased in the Cd‐10 mg/L group. Hence, our results indicated that chronic Cd exposure induced oxidative stress, ER stress, inflammatory responses and proliferation in the liver of aged female mice.     

Cyanobacterial LPS potentiates cadmium toxicity in zebrafish (Danio rerio) embryos

Cyanobacteria are prevalent in the freshwater environment, reaching critical mass in harmful algal blooms. These organisms produce a variety of toxins including endotoxins such as lipopolysaccharides (LPS), which have been previously shown to decrease glutathione‐S‐transferase (GST) activity in zebrafish (Danio rerio) embryos. GST plays a vital role in detoxification response during oxidative stress and provides a first line of defense after toxic heavy metal insult, before increased metallothionein expression. Although some attention has focused on cyanobacterial LPS, little research has focused on effects of concurrent exposures with other toxicants. Because cyanobacterial LPS can alter detoxification enzymes including GST, we hypothesized that cyanobacterial LPS could potentiate metal toxicity. This study investigated the effects of LPS from two cyanobacterial species, Lyngbya spp. and Microcystis aeruginosa, on cadmium toxicity in zebrafish embryos. Forty‐eight‐hour CdCl₂ LC₅₀ values showed that coexposure of cadmium and Lyngbya LPS or Microcystis LPS resulted in significantly increased cadmium toxicity in comparison with cadmium alone. However, increased cadmium toxicity was not due to decreased GST activity as initially hypothesized. In concurrent Microcystis LPS‐cadmium exposures, GST activity was significantly increased in comparison with control embryos at all time points and cadmium concentrations sampled. Concurrent Lyngbya LPS‐cadmium exposures also resulted in increased GST activity at most exposure concentrations. These results indicate that regardless of mechanism, cyanobacterial LPS can potentiate the toxic effects of heavy metals. This represents a significant risk for aquatic organisms exposed to combinations of LPS and metals in the environment. © 2010 Wiley Periodicals, Inc. Environ Toxicol, 2010.     

Co-exposures of TiO2 nanoparticles and cadmium ions at non-lethal doses aggravates liver injury in mice with ConA-induced hepatitis

The wide applications of titanium dioxide nanoparticles (TNP) and ubiquitous cadmium (Cd) pollution increase the chances of their co-existence in the environment and also pose potential health risks to humans. However, toxicological understanding of effects of co-exposures of TNP and Cd to mammals is still lacking. In this study, non-lethal doses of TNP and CdCl₂ were intravenously co-administered to healthy or Concanavalin A (ConA)-induced acute hepatitis mice. Co-exposures of TNP and CdCl₂ increased the accumulation of Cd²⁺ in the liver of hepatitis mice, which was 1.42-fold higher than that of healthy mice. Co-exposures also caused liver damage only in hepatitis mice on the basis of histopathological and biochemical evidence. Further study showed that co-exposure upregulated hepatic oxidative stress, which further induced autophagy and apoptosis only in the liver of hepatitis mice. This finding underlines the potential toxicological consequences of co-exposures of TNP and CdCl₂ in hepatitis sufferers.     

The Influence of Humic Substances on the Absorption and Distribution of Cadmium in Mice

Abstract: The complex binding of cadmium ions to humic and fulvic acids in water may influence the absorption and distribution of drinking-water Cd in humans. Thus, in the present study mice were given a single oral dose of Cd (¹⁰⁹CdCl₂, 25 μg/l) in 100 μl Millipore® water containing different concentrations of humic compounds (0, 1, 10 and 100 mg dissolved organic carbon/l). The complex binding of Cd was studied by dialysis. At neutral pH, 1 mg dissolved organic carbon/l caused complex binding of more than 50% of the Cd, whereas more than 90% of Cd was bound at 10 and 100 mg dissolved organic carbon/l. At pH 3 the complex binding of Cd decreased somewhat, but over 90%) of the Cd was bound at 100 mg dissolved organic carbon/l. Complex binding of Cd increased the lipid solubility of Cd, expressed as an octanol/water partition coefficient, Nevertheless, more than 99% of the bound Cd was present as hydrophilic binding forms. Irrespective of the bound of Cd, the intestinal uptake and intracellular distribution (gel filtration on Sephadex G-75 column) were not affected by the humic substances 6 hr after dosage. Moreover, complex binding did not influence the intestinal absorption of Cd 24 hr after exposure. The median Cd retention in the kidneys of the 100 mg dissolved organic carbon/1 group was 23%> and 46% lower than that of the control group 6 and 24 hr after administration, respectively, indicating alterations in the distribution of Cd after absorption. Thus humic substances may affect the metabolism of toxic heavy metals, such as Cd, in vivo in mice, indicating that the presence of humic and fulvic acids in drinking water should be considered in future risk assessments of metals in drinking water.     

Potential hazards of fenvalerate in massive pollution influence the apoptosis sensitivity

Fenvalerate (Fen), a synthetic pyrethroid insecticide, is widely used in agricultural, domestic and veterinary applications. Fen induces abnormal cell proliferation and apoptosis, which are linked to its hazardous effects. However, this view is controversial and the underlying molecular mechanisms remain elusive. In the present study, the effects of Fen on cadmium (Cd)‐induced apoptosis and the associated molecular mechanisms were investigated in human myeloid leukemia U937 cells. U937 cells were treated with 50 μm cadmium chloride (CdCl₂) with or without Fen pretreatment at 1–50 μm . Apoptosis was evaluated by externalization of phosphatidylserine on the plasma membrane. The expression levels of apoptosis‐related proteins, including Bcl‐2 family members were determined by western blot analysis. The results revealed that pretreatment with Fen at 20 μm for 12 hours significantly inhibited Cd‐induced apoptosis. Decreased expression of pro‐apoptotic Bcl‐2 family proteins (Noxa and Bid) and increased expression of anti‐apoptotic proteins (Bcl‐xL, Mcl‐1 and XIAP) were observed after combined treatment with Fen and CdCl₂. Phosphorylation of ERK and AKT was increased, while phosphorylation of JNK was decreased by the combined treatment, compared with CdCl₂ treatment alone. In conclusion, Fen decreased apoptotic sensitivity induced by Cd in U937 cells. This effect was associated with activation of ERK and AKT, suppression of JNK and changes in expression of Bcl‐2 family proteins and XIAP. The present findings suggest a potential influence of Fen on Cd toxicity via suppression of apoptosis. Fen decreased apoptotic sensitivity induced by Cd, and thus it may contribute carcinogenic risk and influence on cancer therapy.     

Molecular mechanisms involved in the adaptive response to cadmium-induced apoptosis in human myelomonocytic lymphoma U937 cells

We examined the molecular mechanisms involved in the adaptive response to cadmium (Cd)-induced apoptosis in human myelomonocytic lymphoma U937 cells. When U937 cells were treated with 50 μM cadmium chloride (CdCl₂) for 12 h, significant apoptosis occurred. This was associated with an increase in intracellular reactive oxygen species (ROS), sustained phosphorylation of JNK, activation of caspase-3, a decrease in Mcl-1 (anti-apoptotic Bcl-2 proteins), and increases in Bim, Noxa and tBid (a pro-apoptotic protein under the Bcl-2 family). No apoptosis occurred when the cells were treated with 1 μM CdCl₂ for 72 h. However, pretreatment with low-dose CdCl₂ dramatically altered the sensitivity of the cells to 50 μM CdCl₂ with inhibition of apoptosis. Concomitantly, there were significant decreases in the generation of intracellular ROS and the activation of JNK. Pretreatment with 1 μM CdCl₂ also attenuated the decrease in Mcl-1 and the increases in Bim, Noxa and tBid induced by 50 μM CdCl₂. In conclusion, pretreatment with low-dose Cd inhibited apoptosis induced by high-dose Cd. The mechanism involves inhibition of intracellular ROS generation and JNK activation, and modulating the balance between the expression of Mcl-1 and its binding partners, Bim, Noxa and tBid.     

Caffeic acid phenethyl ester,a propolis polyphenolic,attenuates potentially cadmium-induced testicular dysfunction in mice

Abstract

Cadmium (Cd) as environmental pollutant can induce severe damage, particularly to the testis. This study investigated the effects of Caffeic acid phenethyl ester (CAPE) on testicular dysfunction induced by Cd. Adult mice were intraperitoneally injected with cadmium chloride (CdCl₂) with different doses of CAPE pretreatment. After CdCl₂ injection, body/testis weight ratio decreased, Cd levels accumulated and zinc levels decreased in testis. Furthermore, Cd intoxication caused a significant increase of oxidative stress levels, antioxidant enzymes activities, and glutathione levels. Interestingly, significant improvements were observed after the administration of CAPE. Our results demonstrated the protective effect of CAPE, linking Cd testicular dysfunction to oxidative stress.