Induction Of Metallothionein Synthesis Research Articles

Isoproterenol, an adrenergic β receptor agonist, induces metallothionein synthesis followed by canceling amyloid β1-42-induced neurodegeneration.

Adrenergic β receptor activation may ameliorate amyloid β toxicity. We examined whether isoproterenol, an adrenergic β receptor agonist reduces neurodegeneration caused by Aβ1-42, for which intracellular Zn2+ dysregulation is a trigger. Neurodegeneration was assessed in the dentate granule cell layer 14days after intracerebroventricular injection of human Aβ1-42 into the mouse brain. Neurodegeneration was canceled after co-injection of isoproterenol. Isoproterenol did not affect Aβ staining (uptake) in the dentate granule cell layer 1h after Aβ injection. In contrast, isoproterenol reduced intracellular Zn2+ level increased by Aβ. The synthesis of intracellular metallothioneins (MTs), Zn2+-binding proteins was not enhanced in the dentate granule cell layer 24h after Aβ1-42 injection, but significantly enhanced after co-injection of isoproterenol. These data indicate that isoproterenol enhances MT synthesis and cancels neurodegeneration via intracellular Zn2+ toxicity after Aβ1-42 injection. It is likely that MT synthesis enhanced by adrenergic β receptor-mediated signaling contributes to ameliorating Aβ1-42 toxicity in the brain.

Spatial localization of cadmium and metallothionein in the kidneys of mice at the early phase of cadmium accumulation.

Chronic exposure to cadmium (Cd) leads to an accumulation of Cd in the kidneys. Metallothionein (MT) is a low-molecular-weight protein having a high affinity for Cd. Cd bound to MT in serum is filtered through the glomeruli of kidney nephrons and reabsorbed by endocytosis into the proximal tubules from the luminal side. Accumulation of Cd in renal cells induces MT synthesis, leading to long-term deposition of Cd and the suppression of Cd toxicity. Recently, many studies have investigated the tissue distribution of metals using laser ablation ICP-MS (LA-ICP-MS). However, little information has been available regarding renal Cd distribution. Hence, we dually investigated the renal distribution of Cd by LA-ICP-MS and that of MT by immunohistochemistry to clarify the dose- and time-dependent changes in the distributions of Cd and MT in mice exposed to Cd from drinking water for 1, 2, and 4 months. Both Cd and MT exhibited characteristic heterogeneous distribution patterns in the renal cortex. The accumulation of Cd and MT near the surface of the cortex suggests a preferential accumulation of Cd in the surface nephrons. MT distribution was more pronounced in the proximal tubules than in the distal tubules, and there were clear differences in MT immunostaining even among the proximal tubules. The heterogeneous localization of MT may reflect the nephron-specific accumulation of Cd. Combining elemental imaging of Cd with immunostaining of MT proved a successful strategy to reveal the characteristic renal Cd distribution, especially in the early stages of Cd accumulation.

Significance of metallothioneins in differential cadmium accumulation kinetics between two marine fish species.

Impacted marine environments lead to metal accumulation in edible marine fish, ultimately impairing human health. Nevertheless, metal accumulation is highly variable among marine fish species. In addition to ecological features, differences in bioaccumulation can be attributed to species-related physiological processes, which were investigated in two marine fish present in the Canary Current Large Marine Ecosystem (CCLME), where natural and anthropogenic metal exposure occurs. The European sea bass Dicentrarchus labrax and Senegalese sole Solea senegalensis were exposed for two months to two environmentally realistic dietary cadmium (Cd) doses before a depuration period. Organotropism (i.e., Cd repartition between organs) was studied in two storage compartments (the liver and muscle) and in an excretion vector (bile). To better understand the importance of physiological factors, the significance of hepatic metallothionein (MT) concentrations in accumulation and elimination kinetics in the two species was explored. Accumulation was faster in the sea bass muscle and liver, as inferred by earlier Cd increase and a higher accumulation rate. The elimination efficiency was also higher in the sea bass liver compared to sole, as highlighted by greater biliary excretion. In the liver, no induction of MT synthesis was attributed to metal exposure, challenging the relevance of using MT concentration as a biomarker of metal contamination. However, the basal MT pools were always greater in the liver of sea bass than in sole. This species-specific characteristic might have enhanced Cd biliary elimination and relocation to other organs such as muscle through the formation of more Cd/MT complexes. Thus, MT basal concentrations seem to play a key role in the variability observed in terms of metal concentrations in marine fish species.

Altered zinc balance in the Atp7b-/- mouse reveals a mechanism of copper toxicity in Wilson disease.

Wilson disease (WD) is an autosomal recessive disorder caused by mutation in the ATP7B gene that affects copper transport in the body. ATP7B mutation damages copper transporter function, ultimately resulting in excessive copper accumulation and subsequent toxicity in both the liver and brain. Mechanisms of copper toxicity, however, are not well defined. The Atp7b-/- mouse model is well-characterized and presents a hepatic phenotype consistent with WD. In this study, we found that the untreated Atp7b-/- mice accumulate approximately 2-fold excess hepatic zinc compared to the wild type. We used targeted transcriptomics and proteomics to analyze the molecular events associated with zinc and copper accumulation in the Atp7b-/- mouse liver. Altered gene expression of Zip5 and ZnT1 zinc transporters indicated a transcriptional homeostatic response, while increased copper/zinc ratios associated with high levels of metallothioneins 1 and 2, indicated altered Zn availability in cells. These data suggest that copper toxicity in Wilson disease includes effects on zinc-dependent proteins. Transcriptional network analysis of RNA-seq data reveals an interconnected network of transcriptional activators with over-representation of zinc-dependent and zinc-responsive transcription factors. In the context of previous research, these observations support the hypothesis that mechanisms of copper toxicity include disruption of intracellular zinc distribution in liver cells. The translational significance of this work lies in oral zinc supplementation in treatment for WD, which is thought to mediate protective effects through the induction of metallothionein synthesis in the intestine. This work indicates broader impacts of altered zinc-copper balance in WD, including global transcriptional responses and altered zinc balance in the liver.

Bioaccumulation of nickel and its biochemical and genotoxic effects on juveniles of the neotropical fish Prochilodus lineatus

Juveniles of the freshwater fish Prochilodus lineatus were exposed to three concentrations of nickel (Ni): 25, 250 and 2500µgL-1 or water only for periods of 24 and 96h to test for Ni bioaccumulation, its effects on antioxidant defenses and metallothioneins, and the occurrence of DNA damage. After exposure, the fish were sampled and tissue removed from the gills, liver, kidney and muscle to test for Ni accumulation and conduct biochemical (gills and liver) and genotoxic (blood cells and gills) analyses. The results showed that Ni accumulates in the organs in different proportions (kidney>liver>gills>muscle) and accumulation varied according to exposure time. Metallothionein (MT) levels increased in the liver and gills after exposure to Ni, implying that the presence of Ni in these tissues could induce MT synthesis. We also observed that Ni exposure affected antioxidant defenses, increasing lipid peroxidation in the liver of fish exposed to Ni for 96h at the highest concentration tested. DNA damage increased in both blood cells and gills of fish exposed to all Ni concentrations, indicating the genotoxic potential of Ni on fish. We therefore concluded that Ni accumulates in various tissues and results in oxidative and DNA damage in P. lineatus, and that the maximum permitted Ni concentration set in Brazilian legislation (25µgL−1) for freshwaters is not safe for this species.

Induction of renal metallothionein expression by nano-zinc in cadmium-treated rats

Induction of metallothioneins synthesis by cadmium and zinc is an adaptive/defensive mechanism against metal toxicity. In this study, the effect of size and dose of nano-zinc particles administered solely or simultaneously with cadmium to induce the synthesis of renal metallothioneins was investigated in male rats. Levels of renal metallothioneins (MTs) mRNA expression was estimated semiquantitatively after an oral exposure to different sizes (15, 20, and 30 nm) and doses (3, 10, and 100 mg/kg body weight (bw)) of nano-Zn and cadmium (2.5–5 mg/kg bw) using reverse transcription polymerase chain reaction. According to our results, renal MTs were induced significantly in response to the simultaneous use of cadmium and different doses of nano-Zn (20 and 30 nm) exposure (P < 0.005). The expression of MT mRNAs was significantly upregulated by nano-Zn 20 nm depending on the dose (P < 0.001). Our findings suggested that larger sizes and intensive doses of Zn nanoparticles can upregulate MT expression. In conclusion, coadministration of cadmium with nano-Zn particles could improve the induction of renal metallothionein synthesis.

Concentrations and distributions of metals in tissues of stranded green sea turtles (Chelonia mydas) from the southern Atlantic coast of Brazil

Silver (Ag), cadmium (Cd), copper (Cu), lead (Pb) and zinc (Zn) concentrations were analyzed in tissues of juvenile green sea turtles (Chelonia mydas) found stranded along the southern Atlantic coast in Brazil. Green sea turtles were collected (n=29), measured (curved carapace length: CCL) and had their muscle, liver, and kidney dissected for metal concentration measurements. Sex was identified in 18 individuals (10 females and 8 males) through gonad histology. No gender differences in CCL and tissue metal concentrations were observed. In the muscle, there was a negative correlation between CCL and Cd and Cu concentrations. Metal concentrations were lower in the muscle than in the liver and kidney. Zn concentration in the muscle was the highest of all metals analyzed (16.6mg/kg). The kidney showed the highest concentrations of Pb, Cd and Zn (5.4, 28.3 and 54.3mg/kg, respectively), while the liver had the highest values of Ag and Cu (0.8 and 100.9mg/kg, respectively). Tissue Ag, Zn and Cd concentrations were similar to those found in green sea turtles from other regions while Cu and Pb values were elevated, likely due to the metal-rich water and sediment reported in the collection area. In the liver and kidney, concentrations of non-essential (Ag, Cd and Pb) and essential (Cu or Zn) metals were positively correlated, likely due to an induced metallothionein synthesis to protect tissue against the toxic effect of metals. This is the first study to report and correlate the concentrations of essential and non-essential metals in tissues of green sea turtles in the Brazilian southern Atlantic coast, an important feeding and developing area for this turtle species.

The Protective Role of Zinc against Acute Toxicity of Depleted Uranium in Rats

Depleted uranium (DU) has been widely used in both civilian and military activities and contributes to health problems. This study was undertaken to evaluate the protective role of zinc against acute toxicity of DU. Sprague Dawley rats were injected with DU (10 mg/kg, i.p.) to create a toxicity model (DU group). Before and after the injection of DU, zinc sulphate (10 mg/kg, i.p.) was administered once a day for 2 days. The survival rates at 30 days post DU administration and the effects of zinc at 4 days post DU administration were evaluated. Our data indicate that zinc has obvious protective effects, especially pre-treatment with zinc. Rats pre-treated with zinc had significantly higher survival rates than rats in the DU group, with 60.03% more surviving. In addition, at 4 days post DU administration, the former had lower kidney uranium content, insignificant renal tubular epithelial cell necrosis and less transparent tubes. Meanwhile, blood urea nitrogen, creatinine and urine N-acethyl-β-d-glucosaminidase concentrations were significantly decreased; the gene expression levels of metallothionein (MT) in kidney tissues were significantly increased; and catalase levels were increased and malondialdehyde levels were decreased. In conclusion, pre-treatment with zinc significantly alleviated acute toxicity of DU, and the mechanism appeared to be related to the induction of MT synthesis and enhancement of the antioxidant function.

Toxic effect of different ZnO particles on mouse alveolar macrophages

To study the toxicity mechanism of ZnO nanoparticles on mouse macrophages, the toxic effect of different ZnO nanoparticles on mouse alveolar macrophages (MH-S) was investigated in this study. The results showed that the 24h IC50 of four ZnO particles were 48.53, 47.37, 45.43 and 26.74μg/ml for bulk ZnO, 100nm, 30nm and 10–30nm ZnO particles, respectively. At the concentration of 10μg/ml and below, dissolved zinc ions induced metallothionein synthesis, enhanced cellular resistance to oxidative stress. ZnO particles mainly induced cell apoptosis. When the concentration of ZnO particles was 20μg/ml and above, excessive zinc destroyed mitochondrial function and cell membrane, caused cell necrosis. Dissolved zinc ions first cause toxicity in MH-S cells. However, the toxic effect of dissolved zinc ions may exist a threshold on mouse macrophages, inducing about 50% cell death. The toxic difference of different ZnO particles mainly depended on the effect of nondissolved ZnO particles.

Metallothioneins failed to reflect mercury external levels of exposure and bioaccumulation in marine fish – Considerations on tissue and species specific responses

The suitability of metallothioneins (MT) in fish as biomarker of exposure to mercury has been questioned. Therefore, this study aimed at investigating the relationship between external levels of exposure, mercury accumulation and MT content, assessing species and tissue specificities. Two ecologically different fish species –Dicentrarchus labrax and Liza aurata – were surveyed in an estuary historically affected by mercury discharges. Total mercury (T-Hg) and MT content were determined in gills, blood, liver, kidney, muscle and brain. All tissues reflected differences in T-Hg accumulation in both species, although D. labrax accumulated higher levels. Regarding MT, D. labrax revealed a depletion in brain MT content and an incapacity to induce MT synthesis in all the other tissues, whereas L. aurata showed the ability to increase MT in liver and muscle. Tissue-specificities were exhibited in the MT inducing potential and in the susceptibility to MT decrease. L. aurata results presented muscle as the most responsive tissue. None of the investigated tissues displayed significant correlations between T-Hg and MT levels. Overall, the applicability of MT content in fish tissues as biomarker of exposure to mercury was uncertain, reporting limitations in reflecting the metal exposure levels and the subsequent accumulation extent.

The metallothionein genes of Mytilus galloprovincialis: Genomic organization, tissue expression and evolution

Recently, increasing interest has been directed to the study of metallothioneins (MTs), which are small proteins that are able to bind metal ions. The induction of MT synthesis after exposure to metal or other environmental contaminants in a large number of aquatic invertebrates makes these proteins good biomarkers in water monitoring programs. Within bivalves, the species Mytilus galloprovincialis and Mytilus edulis represent model organisms for these types of studies, as well as for molecular studies regarding the expression and characterization of MT encoding genes. In the present paper, we focused on the genomic characterization, evolutionary, and tissue-expression analyses of the MT-10, MT-10 Intronless, and MT-20 genes in M. galloprovincialis. The comparison of the genomic sequences showed the presence of long nucleotide stretches within the introns of the MT genes that are conserved between M. galloprovincialis and M. edulis. These non-coding conserved sequences may contain regulatory motifs. Real-Time RT-PCR experiments revealed that, at the basal conditions, the MT-10 and MT-10 Intronless genes are expressed at levels considerably higher than the MT-20 gene, mainly in the digestive gland and gill tissue. The strong induction of the MT-20 gene expression detected in a field-collected sample is associated with the up-regulation of both the MT-10 and MT-10 Intronless genes. Evolutionary analysis revealed signals of localized positive selection that, together with the tissue-expression data, support a possible functional diversification between the MTs encoded by the MT-10 and MT-10 Intronless genes.

Protective effect of pretreatment with cilostazol on cytotoxicity of cadmium and arsenite in cultured vascular endothelial cells

Cilostazol, an antiplatelet drug, exhibits antiatherogenic effects. The purpose of the present study was to determine the effect of cilostazol on the cytotoxicity of cadmium (Cd) and arsenite (iAs(III)), which involved in the pathogenesis of vascular disorders such as atherosclerosis, in cultured vascular endothelial cells. Cytotoxicity was evaluated by the lactate dehydrogenase leakage assay and morphological observation. Cd (10 µM) -induced cytotoxicity was prevented by pretreatment with cilostazol (30 and 100 µM) and simultaneous treatment with cilostazol (100 µM). On the other hand, iAs(III)-induced cytotoxicity was blocked by pretreatment with cilostazol (30 and 100 µM) but not simultaneous treatment with cilostazol. The mRNA level and the protein level of metallothionein (MT) were significantly increased by cilostazol in the cells. These results suggested, therefore, that pretreatment with cilostazol effectively prevents the cytotoxicity of Cd and iAs(III) in cultured vascular endothelial cells, at least in part through the induction of MT synthesis.

Preventive Effect of Preinduction of Metallothionein on Mutagenicity Caused by Benzo[a]pyrene

The effect of pretreatment with zinc (Zn) compounds on the mutagenicity of benzo[a]pyrene (B[a]P) was investigated using metallothionein (MT)-I/II null mice. MT-I/II null mice and wild-type mice were subcutaneously administered ZnSO4 once a day for 2 days and gavaged B[a]P at 24 hr after the last injection of ZnSO4 .B [a]Pinduced micronucleus frequencies were reduced by Zn pretreatment in the wild-type mice but not in the MT-I/II null mice. Zn administration significantly increased the concentration of MT in the liver and bone marrow cells of wild-type mice, but the statuses of other cellular antioxidants, such as glutathione, catalase and superoxide dismutase, were unchanged. In addition, the activity of a major B[a]P metabolic activation enzyme, cytochrome P450 1A, was unchanged by Zn treatment in both MT-I/II null mice and wild-type mice. These results suggest that Zn pretreatment protects against the mutagenicity of B[a]P through the induction of MT synthesis. The amount of MT produced in animals may determine their sensitivity to B[a]P exposure.

Assessment of low-level metal contamination using the Mediterranean mussel gills as the indicator tissue

The aim of this study was to compare the level of metal contamination in two bays in the middle part of the Eastern Adriatic coastal zone in Croatia using the gills of mussels Mytilus galloprovincialis as indicator tissue. Despite the existing sources of contamination, previous studies with caged mussels only indicated moderate metal contamination of the Kastela Bay, contrary to the Trogir Bay in which marina and shipyard present a probable source of Cu- and Zn-contamination. The measurements of metallothioneins (MTs) and metals that induce MT synthesis (Cu, Zn, and Cd) were performed in the heat-treated gill cytosol and total proteins (TPs) in the untreated gill cytosol. MTs were determined by differential pulse voltammetry, Cu and Zn by flame atomic absorption spectrometry (AAS), Cd by graphite furnace AAS, and TPs by Bradford spectrophotometric procedure. The results collected in four sampling campaigns (autumn periods from 2001 to 2004) indicated that MT levels in mussel gills (expressed on dry mass basis 2.3+/-0.3 mg g(-1)) were comparable with basal levels reported in the literature (2.5+/-0.8 mg g(-1)). Observed interindividual, temporal, and spatial MT variability could be associated with different confounding factors, such as the time of sampling, total protein concentration, and mussel size rather than cytosolic levels of Cu and Zn. Metal levels, expressed on wet mass basis, in the heat-treated gill cytosol ranged from 1.33 to 11.31 microg g(-1) for Zn, from 0.72 to 2.96 microg g(-1) for Cu, and from 0.036 to 0.100 microg g(-1) for Cd. The highest Zn level was measured at Vranjic (Kastela Bay)-the site influenced by untreated domestic wastewater, while somewhat increased Zn and the highest Cu levels were found at marina and shipyard locations (Trogir Bay). The highest Cd level was measured at Inavinil (Kastela Bay). The observed association of gill MT levels with several biotic and abiotic factors limits its use as the biomarker of low-level metal exposure. Therefore, the use of the metal concentrations in the heat-treated gill cytosol of Mediterranean mussels should be considered for the assessment of the low-level metal contamination of coastal marine areas.

Cilostazol Induces Metallothionein Expression in Vascular Cells

Metallothionein (MT) is a cysteine-rich low molecular weight protein and thought to function in the detoxification of heavy metals and reactive oxygen species. We examined the induction of MT synthesis by cilostazol, an antiplatelet drug, in several vascular component cells to find a new pharmacological effect of cilostazol in vascular system. In human coronary artery endothelial cells, cilostazol significantly increased MT-IX and MT-IIA mRNA levels after the treatment for 6 h and endogenous MT-I/II protein levels after the treatment for 24 and 48 h. In addition, cadmium cytotoxicity was prevented by cilostazol in this endothelial cells. Moreover, cilostazol increased MT-IX and MT-IIA mRNA levels in human coronary artery smooth muscle cells, human brain microvascular endothelial cells, human brain microvascular pericytes and human colon carcinoma Caco-2 cells after the treatment for 6 h. Interestingly, cilostazol also increased MT-III mRNA level in brain microvascular endothelial cells more effectively than in other vascular cells. The present results suggest that cilostazol can protect the vascular system from toxic substances such as heavy metals via MT induction in vascular cells.

Oxidative damage effects in the copepod Tigriopus japonicus Mori experimentally exposed to nickel

Tigriopus japonicus Mori has been recognized as a good model for toxicological testing of marine pollutants. Recently, a large number of genes have been identified from this copepod, and their mRNA expression has been studied independently against exposure to marine pollutants; however, biochemical-response information is relatively scarce. The response of T. japonicus to nickel (Ni) additions was examined under laboratory-controlled conditions in 12 days exposure. Superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione-S-transferase (GST), acetylcholinesterase (AchE), reduced glutathione (GSH), the ratio of reduced to oxidized glutathione (GSH/GSSG) and metallothionein (MT) were analyzed for Ni treatments (0, 0.125, 0.25, 0.75 and 3.0 mg/L) after 1, 4, 7 and 12 days. The thiobarbituric reactive species assay was used to evaluate lipid peroxidation (LPO) level in copepods after exposure. The results showed that Ni remarkably affected the biochemical parameters (SOD, GPx, GST, GSH, and GSH/GSSG) after certain exposure durations. However, the copepod's LPO level was significantly decreased under metal treatments after exposure, hinting that the factors involved in LPO might not significantly depend on the operations and functions in the antioxidant system. Ni exhibited the neurotoxicity to copepods, because its use obviously elevated AchE activity. During exposure, Ni initially displayed an inhibition effect but induced MT synthesis in T. japonicus by day 12, probably being responsible for metal detoxification. Thus, Ni had intervened in the detoxification process and antioxidant system of this copepod, and it could be used as a suitable bioindicator of Ni exposure via measuring SOD, GPx, GST, and MT as biomarkers.

Biochemical Response of the Copepod Tigriopus japonicus Mori Experimentally Exposed to Cadmium

The response of the copepod (Tigriopus japonicus Mori) to cadmium (Cd) additions was investigated under laboratory-controlled conditions in a 12-day exposure. Superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione-S-transferase (GST), acetylcholinesterase (AchE), reduced glutathione (GSH), the ratio of reduced to oxidized glutathione (GSH/GSSG), and metallothionein (MT) were analyzed for Cd treatments (0, 10, 20, 40, and 100 microg/L) after exposure for 1, 4, 7, and 12 days. Additionally, thiobarbituric reactive species assay was used to evaluate lipid peroxidation (LPO) of the copepod after the 12-day exposure. The results indicated that Cd treatments significantly influenced the biochemical indexes (SOD, GPx, GST, AchE, GSH, and GSH/GSSG) after certain exposure times. Exposure to Cd induced LPO in the treated copepods, hinting that the copepods had suffered from oxidative damage. During exposure, the Cd initiated an induced MT synthesis in the copepods by day 7, which peaked at day 12 and which was probably responsible for Cd detoxification. Thus, Cd exposure significantly affected the detoxification process and antioxidant system of this copepod, and T. japonicus could be used as a suitable bioindicator of exposure to Cd using SOD, GPx, GST, LPO, and GSH/GSSG as biomarkers.

Inducibility of metallothionein biosynthesis in the whole soft tissue of zebra mussels Dreissena polymorpha exposed to cadmium, copper, and pentachlorophenol

Freshwater mussels Dreissena polymorpha (Pallas, 1771) were exposed to the elevated concentrations of Cd (10, 50, 100, and 500 microg/L), Cu (10, 30, 50, and 80 microg/L), and an organochlorinated pesticide, pentachlorophenol (PCP) (1, 10, and 100 microg/L). Induced synthesis of biomarker metallothionein (MT) and changes in concentrations of cytosolic Cd, Cu, and Zn in the whole soft tissue of mussels were monitored after a 7-day laboratory exposure to the contaminants. A clear dose-dependent elevation in the MT concentration was observed after exposure to Cd at doses of 10-100 microg/L, and this increase of MT content was accompanied with a linear increase of cytosolic Cd. Cd concentration of 500 microg/L caused no additional increase of MT and Cd in mussel cytosol, suggesting possible toxic effects due to exceeding cellular inducible/defense capacity. Cu exposure resulted with variable changes in MT concentrations, with no clear linear relationship between MT and Cu concentrations in water, although a progressive dose-dependent accumulation of Cu in the soluble fraction of mussel tissues was recorded. A decrease of cytosolic Zn was evident at higher exposure concentrations of both metals used. PCP in concentrations applied was unable to induce MT synthesis, but the higher concentrations of PCP influenced the cytosolic metal concentrations. In conclusion, the results obtained confirm the specificity of MT induction in D. polymorpha as an biological response on metal stimulation, especially by cadmium, being more closely correlated to MT than copper within the ecologically relevant concentration range. The strong induction potential of cadmium as well as an absence of MT induction following exposure to PCP as an organic chemical contaminant are supporting evidences for usage of zebra mussel MT as a specific biomarker of Cd exposure in biomonitoring programs.

Endoplasmic Reticulum Stress and Metallothionein

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Endoplasmic Reticulum Stress and Metallothionein

Much attention has been paid to lifestyle-related diseases including type 2 diabetes mellitus, cardiovascular disease, hypertension, and hyperlipidemia because the incidence rates of these diseases are increasing in developed countries. Elucidation of factors contributing to the development of obesity and insulin resistance is needed. Metallothionein (MT), a ubiquitous metal-binding protein, is induced not only by heavy metals but also by various kinds of stresses. Endoplasmic reticulum (ER) stress is caused by accumulation of misfolded proteins in ER. Recently, increased ER stress by obesity and impairment of insulin action by ER stress have been reported. Exposure to ER stress increased induction of MT synthesis, and an enhanced response to ER stress evaluated as expression of Bip/GRP78mRNA was observed in the liver of MT-null mice, suggesting that MT attenuates expression of ER stress. MT may prevent ER stress and thereby modulate the development of obesity and insulin resistance. A possible role of metallothionein in response reaction for ER stress is discussed.