The environmental application of the carbonized composites of the Zn-containing metal-organic framework MOF-5 and polyaniline (PANI) in its emeraldine salt and base forms (C-(MOF-5/PANI)) was investigated for the first time. Textural properties and particle size distributions revealed that composites are dominantly mesoporous and nanoscale in nature, while Raman spectroscopy revealed the ZnO phase beneath the carbon matrix. Adsorption of pesticide, dye, and metal cation on C-(MOF-5/PANI) composites in aqueous solutions was evaluated and compared with the behavior of the precursor components, carbonized MOF-5 (cMOF), and carbonized PANIs. A lower MOF-5 content in the precursor, a higher specific surface area, and the pore volume of the composites led to improved adsorption performance for acetamiprid (124 mg/g) and Methylene Blue (135 mg/g). The presence of O/N functional groups in composites is essential for the adsorption of nitrogen-rich pollutants through hydrogen bonding with an estimated monolayer capacity twice as high as that of cMOF. The proton exchange accompanying Cd2+ retention was associated with the Zn/Cd ion exchange, and the highest capacity (9.8 mg/g) was observed for the composite synthesized from the precursor with a high MOF-5 content. The multifunctionality of composites was evidenced in mixtures of pollutants where noticeably better performance for Cd2+ removal was found for the composite compared to cMOF. Competitive binding between three pollutants favored the adsorption of pesticide and dye, thereby hindering to some extent the ion exchange necessary for the removal of metal cations. The results emphasize the importance of the PANI form and MOF-5/PANI weight ratio in precursors for the development of surface, porosity, and active sites in C-(MOF-5/PANI) composites, thus guiding their environmental efficiency. The study also demonstrated that C-(MOF-5/PANI) composites retained studied pollutants much better than carbonized precursor PANIs and showed comparable or better adsorption ability than cMOF.

Genetic effects are suspected to influence cadmium internal dose. Our objective was to assess genetic determinants of urine cadmium in American Indian adults participating in the Strong Heart Family Study (SHFS). Urine cadmium levels and genotyped short tandem repeat (STR) markers were available on 1936 SHFS participants. We investigated heritability, including gene-by-sex and smoking interactions, and STR-based quantitative trait locus (QTL) linkage, using a variance-component decomposition approach, which incorporates the genetic information contained in the pedigrees. We also used available single nucleotide polymorphisms (SNPs) from Illumina's Metabochip and custom panel to assess whether promising QTLs associated regions could be attributed to SNPs annotated to specific genes. Median urine cadmium levels were 0.44 μg/g creatinine. The heritability of urine cadmium concentrations was 28%, with no evidence of gene-by-sex or -smoking interaction. We found strong statistical evidence for a genetic locus at chromosome 16 determining urine cadmium concentrations (Logarithm of odds score [LOD] = 3.8). Among the top 20 associated SNPs in this locus, 17 were annotated to ABCC1 (p-values from 0.0002 to 0.02), and attenuated the maximum linkage peak by a ∼40%. Suggestive QTL signals (LOD>1.9) in chromosomes 2, 6, 11, 14, and 19, showed associated SNPs in the genes NDUFA10, PDE10A, PLEKHA7, BAZ1A and CHAF1A, respectively. Our findings support that urinary cadmium levels are heritable and influenced by a QTL on chromosome 16, which was explained by genetic variation in ABCC1. Studies with extended sets of genome-wide markers are needed to confirm these findings and to identify additional metabolism and toxicity pathways for cadmium.

Arsenic (As) occurs naturally and concentrations in water bodies can reach high levels, leading to accumulation in vital organs like the spleen. Being an important organ in immune response and blood development processes, toxic effects of As on the spleen could compromise immunity and cause associated disorders in affected individuals. Splenic detoxification is key to improving the chances of survival but relatively little is known about the mechanisms involved. Essential trace elements like zinc have shown immune-modulatory effects humans and livestock. This study aimed to investigate the mechanisms involved in As-induced splenic toxicity in the common carp (Cyprinus carpio), and the protective effects of zinc (Zn). Our findings suggest that environmental exposure to As caused severe histological injuries and Ca²⁺ accumulation in the spleen of common carp. Additionally, transcriptional and translational profiles of endoplasmic reticulum stress, apoptosis and autophagy-related genes of the spleen showed upward trends under As toxicity. Treatment with Zn appears to offer protection against As-induced splenic injury in common carp and the pathologic changes above were alleviated. Our results provide additional insight into the mechanism of As toxicity in common carp while elucidating the role of Zn, a natural immune-modulator, as a potential antidote against As poisoning.

In this study, the effect of squid liver powder intake on accumulation of cadmium in mice was investigated. Subjects were divided into 4 groups including the control group (CON), squid liver powder group with lipids not removed (SLP100), and squid liver powder groups with lipids removed (LFSLP50 and LFSLP100). Feed intake and food efficiency ratio of squid liver powder groups was significantly higher than the CON. As a result of investigating cadmium content in hair, serum, liver, and kidney during intake of squid liver powder, all groups showed increase in cadmium accumulation through consistent, long-term intake. Especially, cadmium content in liver and kidney of LFSLP100 was significantly higher than the content of SLP100 and CON. As a result of pathological observation on liver and kidney tissues according to squid liver powder diet, LFSLP100 showed most serious pathological symptoms. In case of kidney tissues, degeneration was significantly more severe in LFSLP100 compared to other groups. Such results suggest that cadmium concentration in human body can be increased by ingestion of whole squid including internal organs and that tissues can be damaged by increased cadmium concentration. More specific and systematic studies are deemed necessary.

The current study evaluated acute and subchronic toxicity of arsenite (As(3+)) and zinc (Zn(2+)) to stage 25 tadpoles of Rhinella arenarum in both single and joint laboratory exposures. LC50 values obtained for As(3+) were elevated and remained within the range of 46 to 50 mg/L of As(3+) between 4 and 17 d of exposure. Growth of tadpoles was completely inhibited with 30 mg/L of As(3+), demonstrating the presence of ecologically relevant sublethal effects at concentrations lower than those resulting in lethality. With respect to Zn(2+), a 96-h LC50 value of 2.49 mg/L was calculated in soft water. Contrary to results obtained for As(3+), LC50 values of Zn(2+) gradually decreased with increasing exposure duration, from 2.49 mg/L at 96 h to 1.30 mg/L after 21 d. In joint exposures to both metals, the type of interaction observed between As(3+) and Zn(2+) was concentration dependent. Lethal effects of As(3+) were mitigated, unaffected, or potentiated by 0.01, 0.1, and 1-2 mg/L of Zn(2+), respectively. However, although 0.01 mg/L of Zn(2+) significantly reduced lethality of As(3+)-exposed tadpoles, the same concentration of Zn(2+) did not help to reverse the stunt growth of these animals. Further studies need to examine which are the lowest concentrations As(3+) required to reduce growth and whether Zn(2+) serves to antagonize growth effects in this range of concentrations.

To investigate the relationship between metallothionein induction and zinc-induced tolerance to cadmium cytotoxicity at the cell level, Chang liver cells were pretreated with a wide range of concentrations of zinc sulfate and challenged with toxic levels of cadmium after removal of zinc. It was found that zinc-pretreated cells were significantly resistant even when the extracellular level of zinc was low and metallothionein was not induced by the metal. Pretreatment with zinc resulted in a lesser accumulation of cadmium and metallothionein after challenge with cadmium. In porcine kidney LLC-PK1 cells and bovine aortic smooth muscle cells pretreated with low levels of zinc, the intracellular accumulation of cadmium was significantly less and cadmium-induced decrease in intracellular zinc was significantly prevented without a change of metallothionein content; as the result, the toxic effect of cadmium was significantly diminished. It was therefore concluded that a tolerance to cadmium cytotoxicity is induced by zinc via non-metallothionein mechanisms such as decreasing intracellular cadmium as well as metallothionein induction at the cell level. The non-metallothionein mechanism was postulated to be particularly importatnt when the extracellular concentration of zinc is under the threshold for metallothionein induction.

Response to cadmium cytotoxicity of cultured bovine aortic smooth-muscle cells was compared with that of cultured bovine aortic endothelial cells and porcine kidney epithelial LLC-PK1 cells. The cell damage was evaluated by morphology and the lactate dehydrogenase leakage assay. It was found that vascular smooth-muscle cells are markedly sensitive to cadmium cytotoxicity. The accumulation of intracellular cadmium was much higher but that of metallothionein was much less in vascular smooth-muscle cells than in LLC-PK1 cells; vascular endothelial cells were in between vascular smooth-muscle cells and LLC-PK1 cells. The content of reduced glutathione was slightly increased by cadmium in all three cell types. The present data suggest that a much lower inducibility of metallothionein with a high accumulation of intracellular cadmium in vascular smooth-muscle cells resulted in a marked sensitivity of the cells to cadmium cytotoxicity. Vascular smooth-muscle cells may be one of the critical target of cadmium toxicity.

The effects of cadmium (Cd) on the fatty acid composition and delta 9 desaturation activity were studied in hepatocytes which had been cultured in serum-free medium. The aim of this study was to determine whether the inhibition of delta 9 desaturase seen in Cd-treated rat liver (Kudo et al. (1991) Toxicology, 68, 133-142) is the direct effect of Cd or not. When hepatocytes were cultured in serum-free medium, increases in the proportions of monounsaturated fatty acids such as oleic acid (18:1) were observed in the phospholipid (PL) and triacylglycerol (TG) fractions of hepatocytes, suggesting that delta 9 desaturase was induced. By contrast, essential fatty acids such as linoleic acid (18:2) and arachidonic acid (20:4) decreased. These changes were similar to those seen in the livers of essential fatty acid (EFA)-deficient rats. When hepatocytes were cultured in the presence of CdCl2, the changes in the fatty acid composition were suppressed. The effect of CdCl2 was concentration-dependent. The rate of the conversion of 18:0 to 18:1, which is catalyzed by delta 9 desaturase, was reduced by treatment with Cd, whereas the rate of conversion of 18:2 to 20:4, which is catalyzed by delta 6 desaturase, was slightly increased. Cd did not inhibit liver microsomal delta 9 desaturase activity in vitro. We concluded that Cd suppressed the induction of delta 9 desaturase in cultured hepatocytes. These phenomena can explain the selective inhibition of delta 9 desaturase in the livers of Cd-treated rats.

The effects of cadmium on the peak area of metallothionein (MT) protein were studied by capillary zone electrophoresis with a polyacrylamide-coated tube at neutral pH. When cadmium was added to a commercial standard MT-1 isoform prepared from rabbit liver, the peak are of the MT-1 isoform decreased in a time- and dose-dependent manner. The MT-2 isoform also decreased with time, but the rate of decrease was lower than that of the MT-1 isoform. When ethylene glyco-bis-(beta-aminoethyl ether)-N,N,N'N'-tetraacetic acid (EGTA) was added to a solution containing cadmium and MT-1, the peak area recovered with increasing concentration of EGTA. Zinc caused a slight decrease in the peak areas of MT-1 and MT-2 compared with cadmium, while addition of sodium did not decrease the areas. Furthermore, the peak areas of MT isoforms of the crude extract prepared from zinc-treated mice also decreased with increasing concentration of cadmium. These results indicate that cadmium may changed the charge of MT, which may account for the observed differences in electrophoretic behavior.

We investigated whether or not transforming growth factor beta (TGF beta 1) affects the sensitivity to cadmium of bovine aortic endothelial cell in a culture system. Cadmium cytotoxicity was evaluated by [3H]adenine release assay. It was found that pretreatment with recombinant human TGF beta 1 (rhTGF beta 1) of the confluent cultures resulted in a reduction of cadmium cytotoxicity, suggesting that the cytokine induced a tolerance to cadmium in the cells. Such a tolerance was induced slightly by either recombinant human tumor necrosis factor alpha or recombinant human basic fibroblast growth factor but not by recombinant human interleukin-1 beta and -6; rhTGF beta 1 was the most potent inducer. rhTGF beta 1 failed to induce the tolerance in the presence of anti-rhTGF beta 1 antibody. Pretreatment with the antibody alone caused a significantly sensitive response to cadmium, suggesting that endogenous TGF beta 1 can physiologically contribute to protection against cadmium cytotoxicity in endothelial cells. The accumulation of cadmium was increased in the extracellular fraction but significantly decreased in the intracellular fraction of the cells by pretreatment with rhTGF beta 1. The cadmium content was significantly decreased in the particulate fraction but not in the cytosol fraction. Gel filtration chromatography of the cytosol fraction revealed that cadmium was bound to high-molecular-weight protein and metallothionein; both peaks were slightly increased by pretreatment with rhTGF beta 1. It was concluded that rhTGF beta 1 induces a tolerance to cadmium in cultured endothelial cells, caused by a decrease in the cadmium accumulation in the particulate fraction of the cells. TGF beta 1 may serve as a protective factor against cadmium cytotoxicity in vascular endothelial cells.

We investigated the effect of zinc on cadmium cytotoxicity in vascular endothelial cells in a culture system. The cytotoxicity was evaluated by [3H]adenine release assay. Cadmium at 2 microM concentration and above significantly increased the [3H]adenine release, but zinc at 80 microM and below did not induce such a response after a 24-h incubation. Metallothionein was induced by cadmium at 0.1 microM and above but not by zinc at 300 microM and below; however, zinc at 10 microM and above significantly decreased cadmium-(2 and 5 microM) induced cytotoxicity. Zinc protection against cadmium cytotoxicity was also observed in the presence of 1 microM cycloheximide. Zinc caused significantly less accumulation of cadmium in the cell layer accompanied with a significant accumulation of zinc. The distribution (%) of cadmium in the particulate fraction of the cells was significantly decreased by zinc. In contrast, cadmium in the cytosol fraction was increased in the cells treated with both cadmium and zinc. Gel filtration chromatography of the cytosol showed that cadmium was capable of being bound to high-molecular-weight proteins and metallothionein. The metallothionein-bound cadmium was not increased by zinc; however, the relative distribution of cadmium in the high-molecular-weight fraction in the cytosol was decreased in cadmium plus zinc-treated cells. From these results, it was suggested that the mechanism by which zinc protects endothelial cells from cadmium cytotoxicity was decreased accumulation of cadmium in the particulate fraction and in the high-molecular-weight fraction in the cytosol of the cells. This alteration is postulated to be caused by both zinc-induced decrease in the intracellular cadmium accumulation and the sequestration of cadmium by cadmium-induced metallothionein.

The protective roles of metallothionein (MT) and glutathione (GSH) in acute hepatotoxicity of cadmium (Cd) were investigated in an in vitro system. Liver slices were incubated in a buffer containing cadmium chloride (20-50 ppm) at 37 degrees C for 3 h. Viability of the slices was monitored by measuring intra-cellular potassium (K) content and GSH concentrations. A dose-dependent decrease of intracellular K content of GSH concentrations was observed. Pre-induction of MT (100-fold increase) by injection of zinc sulphate (30 mg Zn/kg body weight) showed protection against decrease in both intracellular K and GSH concentrations in liver slices. Decrease of hepatic GSH (90%) by an injection of buthionine sulfoximine (BSO)(4 mmol/kg body weight) to the rats further enhanced the Cd toxicity in the liver slices. This enhanced toxicity resulting from BSO treatment can be totally overvome by induction of MT by Zn pre-treatment. The cellular uptake of Cd remained unaltered in all experiments. These results demonstrate that hepatic toxicity of Cd may be due to its binding to intracellular sulfhydryl groups and both intracellular GSH and MT levels may provide protection against cytotoxicity of Cd in liver. Moreover, even at low GSH levels, MT could partially protect the hepatic cells from Cd cytotoxicity.

Nulliparous female, 10-day and 20-day pregnant rats were injected intraperitoneally with saline or labelled cadmium-metallothionein (109Cd-MTh) at a single dose of 25 or 250 micrograms Cd as cadmium-metallothionein (Cd-MTh)/kg and sacrificed at 24 h. The renal toxicity was manifested by increased 24-h urinary excretion of beta 2-microglobulin (beta 2-m) and the increased number of damaged convoluted proximal tubules at 24 h. The renal excretion of 109Cd and 109Cd content in the maternal liver and kidney and in the foeto-placental unit were determined. The binding of 109Cd to kidney proteins and the level of intracellular metallothionein (MTh) in livers and kidneys were also determined. It was found that the nephrotoxicity of injected Cd-MTh did not differ in nulliparous and 10-day pregnant rats. This result was consistent with the absence of difference in the renal uptake of 109Cd, its binding to kidney proteins and in the content of endogenous MTh in the kidneys between nulliparous and 10-day pregnant rats. In contrast, 20-day pregnant rats exhibited much more nephrotoxicity than nulliparous rats. The most prominent finding in relation to the extreme sensitivity of 20-day pregnant rats was a lower basal level of intracellular MTh in the kidneys and the accumulation of 109Cd in the high molecular weight proteins in the soluble fraction. It is suggested that the decrease of intracellular MTh in the kidneys of 20-day pregnant rats is the reason for the low protection against the renal toxicity of injected Cd-MTh.

The high reactivity of heavy metals with biological systems is well documented, although some disagreement remains on the precise dose-effect relationships involved. This represents a question of considerable importance, especially in attempts to assess the risks of exposure. The implicit assumption is usually made that a threshold concentration of specific metals exists in the most sensitive target organ, so that an increased frequency of functional lesions will be expected if this threshold is exceeded. The threshold for the metal defines its so-called critical level, and this review was written in order to examine the theoretical and practical difficulties in establishing such a level. Among these may be cited, for instance, the dependence of what constitutes the target tissue on the speciation of the metal, the changes in apparent critical level with rate and route of metal administration, the short half-life of some of the metals as well as their compartmentation in the tissues, and the considerable initiation delay frequently preceding the appearance of lesions. For these and other reasons a useful approximate value for a critical concentration has only been proposed so far for the total Cd concentration in the renal cortex of chronically exposed human adults.

The effect of Zn-induced metallothionein (MT) on the toxicity, uptake, and subcellular distribution of cadmium (Cd) was examined in rat primary hepatocyte cultures and compared to results obtained earlier in this laboratory from intact animals. Hepatocytes were isolated and grown in monolayer culture for 22 h and subsequently treated with ZnCl2 (100 microM) for 24 h, which increased MT concentration about 15-fold. After Zn pretreatment, hepatocytes were exposed to Cd for 24 h. Cytotoxicity was assessed by enzyme leakage, intracellular potassium loss, and cellular glutathione content. The toxicity of Cd was much less in Zn-pretreated cells than in control cells, similar to that previously demonstrated in the intact animal. Zn pretreatment had no appreciable effect on the hepatocellular uptake of 109Cd, but markedly altered its subcellular distribution, with more Cd accumulating in the cytosol and less in the nuclear, mitochondrial, and microsomal fractions. In the cytosol of Zn-pretreated cells, Cd was associated mainly with MT; in contrast, cytosolic Cd in control cells was mainly associated with non-MT macromolecules. Zn-induced changes in the subcellular distribution of Cd in vitro are identical to those observed in vivo in Zn-pretreated rats challenged with Cd. In summary, Zn pretreatment of rat primary hepatocyte cultures protects cells against Cd toxicity. Protection seems to be due to MT-promoted sequestration of Cd and reduction of the amount of Cd associated with critical organelles and proteins. These observations are similar to those noted in the whole animal. These results indicate that cultured hepatocytes are an ideal model for examining MT-induced tolerance to Cd hepatotoxicity.