Showing papers on "Zinc toxicity published in 2008"

Modeling the toxicity of copper and zinc salts to wheat in 14 soils

Abstract: Interest is mounting in developing and utilizing soil-specific soil quality guidelines. This requires quantifying the effects that soil physicochemical properties have on various ecotoxicological endpoints, including phytotoxicity. To this end, 14 agricultural soils from Australia with differing soil properties were spiked with copper (Cu) and zinc (Zn) salts and used to conduct 21-d plant growth inhibition tests using wheat (Triticum aestivum L.) in pot trials. The toxicity of Cu and Zn was similar with 10% effect concentration (EC10) values ranging from 110 to 945 and from 235 to 965 mg/kg, respectively, while the corresponding median effect concentration (EC50) values ranged from 240 to 1,405 and 470 to 1,745 mg/kg, respectively. Copper toxicity values (EC10, EC20, and EC50) were best modeled by the logarithm of cation exchange capacity (CEC) and either soil pH or electrical conductivity. Zinc EC50 and EC20 values were best modeled using the logarithm of CEC, while the EC10 data were best modeled using soil pH and the logarithm of organic carbon. These models generally estimated toxicity within a factor of two of the measured values.

Expression of ZnT and ZIP zinc transporters in the human RPE and their regulation by neurotrophic factors.

Abstract: Expression of ZnT and ZIP Zinc Transporters in the Human RPE and Their Regulation by Neurotrophic Factors Kar Wah Leung, 1 Mugen Liu, 2 Xuming Xu, 2 Magdalene J. Seiler, 3 Colin J. Barnstable, 1,2 and Joyce Tombran-Tink 1,2 P URPOSE . Zinc is an essential cofactor for normal cell function. Altered expression and function of zinc transporters may con- tribute to the pathogenesis of neurodegenerative disorders including macular degeneration. The expression and regula- tion of zinc transporters in the RPE and the toxicity of zinc to these cells were examined. M ETHODS . Zinc transporters were identified in a human RPE cell line, ARPE19, using a 28K human array, and their expression was confirmed by PCR, immunocytochemistry, and Western blot analysis in primary human RPE cultures and ARPE19. Zinc toxicity to ARPE19 was determined using monotetrazolium, propidium iodide, and TUNEL assays, and Zn 2⫹ uptake was visualized with Zinquin ethyl ester. The effect of various growth factors on zinc transporter expression also was exam- ined. R ESULTS . Transcripts for 20 of 23 zinc transporters are ex- pressed in fetal human RPE, 16 of 23 in adult human RPE, and 21 of 23 in ARPE19. Zn transporter proteins were also detected in ARPE19. ZnT5 expression was not observed, whereas ZnT6, ZIP1, and ZIP13 were the most abundantly expressed in all RPE samples. The addition of low concentrations of Zn 2⫹ to cul- tures resulted in a dose-dependent increase in intracellular Zn 2⫹ content in ARPE19, and ⬎30 nM Zn 2⫹ induced necrosis with an LC 50 of 117.4 nM. Brain-derived neurotrophic factor, ciliary neurotrophic factor, glial-derived neurotrophic factor (GDNF), and pigment epithelial-derived neurotrophic factor (PEDF) increased ZIP2 expression, GDNF and PEDF increased ZnT2 expression, and PEDF increased ZnT3 and ZnT8 expres- sion. These neurotrophic factors also promoted Zn 2⫹ uptake in the RPE. C ONCLUSIONS . The array of zinc transporters expressed by the RPE may play a key role in zinc homeostasis in the retina and in ocular health and diseases. (Invest Ophthalmol Vis Sci. 2008;49:1221–1231) DOI:10.1167/iovs.07-0781 From the 1 Department of Neural and Behavioral Sciences, Penn- sylvania State University College of Medicine, Hershey, Pennsylvania; Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut; and 3 Department of Ophthalmology, Doheny Retina Institute, Keck School of Medicine, University of Southern California, Los Angeles, California. Supported by The David Woods Kemper Foundation, by grants from the National Institutes of Health and the Macular Vision Research Foundation, and by the Ben Franklin Award from the Pennsylvania Department of Community and Economic Development. Submitted for publication June 26, 2007; revised September 7, 2007; accepted January 9, 2008. Disclosure: K.W. Leung, None; M. Liu, None; X. Xu, None; M.J. Seiler, None; C.J. Barnstable, None; J. Tombran-Tink, None The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked “advertise- ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact. Corresponding author: Joyce Tombran-Tink, Department of Neu- ral and Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, PA 17033; jttink@aol.com. D isruption in zinc homeostasis is strongly implicated in the pathophysiology of many chronic neurodegenerative dis- eases and acute neural injuries. Excessive and inadequate levels of bioavailable zinc are detrimental to the health of neurons. 1 For example, increased concentration of Zn 2⫹ is associated with aggregation of ␤ -amyloid protein in patients with Alzhei- mer disease. 2–5 Zinc enrichment in the cerebrovasculature may be an underlying factor in the development of cerebral amyloid angiopathy, a condition characterized by ␤ -amyloid deposits in perivascular spaces of the brain. 6 Intense presynaptic activity in epilepsy, ischemia, or traumatic lesions can trigger the release of Zn 2⫹ to neurotoxic levels in surrounding tissues. This release may account for the unusually high Zn 2⫹ content in the somata of neurons degenerating after severe episodes of ischemia or seizure activity. 2,7–14 A deficiency in Zn 2⫹ , on the other hand, promotes brain malformations during development and has other adverse con- sequences in the nervous system. 15 Depleted pools of intracel- lular zinc in primary retinal cell cultures induce the caspase- dependent death of photoreceptors and other retinal neurons 16 in the eye, and decreased levels of zinc in the retina contribute to the pathogenesis of age-related macular degen- eration (AMD). The zinc–AMD connection is supported by the findings that retinas from monkeys with early-onset macular degeneration contain fourfold less Zn 2⫹ than monkeys with normal vision 17,18 and that levels of zinc in drusen and sub-RPE deposits 19 are increased, suggesting that the risk for or severity of AMD increases with the depletion of available intracellular zinc pools in the retina. Newsome et al. 20 were the first to report that replenishing Zn 2⫹ by oral administration has a positive effect on AMD. The 2004 AREDS report and other studies confirm that replacing zinc with a dietary supplement has beneficial effects against AMD. 21–23 Normal ocular tissues contain relatively high levels of zinc, ranging from approximately 25 ␮ g/g wet weight in the RPE/ choroid to 100 ␮ g/g dry weight in the retina, 24,25 with a high percentage of this localized in the photoreceptors and RPE cells. Recent studies show that intracellular localization of Zn 2⫹ pools in photoreceptors changes with light exposure, with the greatest intensity of zinc staining observed in the perikarya of photoreceptors of dark-adapted retinas and in the inner segments of light-adapted retinas. 25 Zn 2⫹ movement be- tween RPE and photoreceptors is also light dependent, sug- gesting that Zn 2⫹ is critical to normal visual function. The importance of Zn 2⫹ in biological processes is not re- stricted to the nervous system. It is the second most abundant trace element in the human body and is critical to housekeep- ing roles in physiology, cellular metabolism, protein structure, and gene expression. It provides structural stability to the Zn 2⫹ finger domains of many DNA-binding proteins and is a cofactor for more than 300 metalloenzymes, in which it is an essential element for the catalytic site of the enzymes or serves in a structural capacity to facilitate enzymatic function. 26 For ex- ample, mutations in the copper-zinc superoxide dismutase (SOD1), an anti-oxidative Zn-binding enzyme, promote loss of Investigative Ophthalmology & Visual Science, March 2008, Vol. 49, No. 3 Copyright © Association for Research in Vision and Ophthalmology Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/Journals/IOVS/933445/ on 05/29/2016

Impact of zinc-tolerant plant growth-promoting rhizobacteria on lentil grown in zinc-amended soil

Abstract: Though zinc is a plant nutrient at low levels, Zn ions can be highly phytotoxic at higher concentrations found in contaminated soils. Plant growth-promoting rhizobacteria can be used to decrease this toxicity. Indeed, in addition to their role in plant-growth promotion, rhizobacteria also reduce the toxicity of heavy metals. In turn, they can be effective for crops grown in metal-contaminated soils. Here, we isolated a zinc-tolerant plant growth-promoting rhizobacterium, Rhizobium species RL9, from a zinc-contaminated soil and assayed its plant growth-promoting activities in vitro. We found that the rhizobacterium strain RL9 tolerated zinc up to a concentration of 400 μg mL−1 on yeast extract mannitol agar medium. It produced 33 μg mL−1 of indole acetic acid in Luria Bertani broth at 100 μg mL−1 of tryptophan and was positive for siderophore, hydrogen cyanide and ammonia. Such phytohormones released by this strain could help in promoting the growth of legumes. We further tested the effect of rhizobacterium strain RL9 on lentils grown in zinc-amended soil. We found that when the rhizobacterium strain RL9 was added to soil contaminated with Zn at 4890 mg/kg, lentil dry matter increased by 150%, nodule numbers by 15%, nodule dry mass by 27%, leghaemogloblin by 30%, seed yield by 10% and grain protein by 8%, compared with uninoculated plants. We also found that the concentration of zinc was higher in uninoculated plant organs than in the inoculated counterpart. Our findings thus suggest that rhizobacterium strain RL9 could be exploited for bacteria-assisted reduction of zinc toxicity in zinc-contaminated soils due to its intrinsic abilities of expressing growth-promoting substances and reduction of the toxic effects of zinc.

Acute toxicity of aqueous copper, cadmium, and zinc to the mayfly Rhithrogena hageni.

Abstract: Heptageniid mayfly nymphs have been suggested as sensitive indicators of metal contamination in streams based on biomonitoring studies, experimentation in situ, and experimentation in microcosm. Laboratory tests were conducted to evaluate the sensitivity of Rhithrogena hageni, a heptageniid mayfly, to waterborne copper, cadmium, and zinc. Tests were conducted with soft water (hardness = 40–50 mg/L) at about 12°C. Toxicity endpoints were survival and moulting (%/day). Median 96 hr lethal concentrations were 0.137, 10.5, and 50.5 mg/L for copper, cadmium and zinc, respectively. The average daily moulting rate of survivors significantly decreased after exposure to these metals in solution.

Essential Role for Zinc-Triggered p75NTR Activation in Preconditioning Neuroprotection

Abstract: Ischemic preconditioning (PC) of the brain is a phenomenon by which mild ischemic insults render neurons resistant to subsequent strong insults. Key steps in ischemic PC of the brain include caspase-3 activation and poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, but upstream events have not been clearly elucidated. We have tested whether endogenous zinc is required for ischemic PC of the brain in rats. Mild, transient zinc accumulation was observed in certain neurons after ischemic PC. Moreover, intraventricular administration of CaEDTA during ischemic PC abrogated both zinc accumulation and the protective effect against subsequent full ischemia. To elucidate the mechanism of the zinc-triggered PC (Zn PC) effect, cortical cultures were exposed to sublethal levels of zinc, and 18 h later to lethal levels of zinc or NMDA. Zn PC exhibited the characteristic features of ischemic PC, including caspase-3 activation, PARP-1 cleavage, and HSP70 induction, all of which are crucial for subsequent neuroprotection against NMDA or zinc toxicity. HSP70 induction was necessary for protection, as it halted caspase-3 activation before apoptosis. Interestingly, in both Zn PC in vitro and ischemic PC in vivo , p75 NTR was necessary for neuroprotection. These results suggest that caspase-3 activation during ischemic PC, a necessary event for subsequent neuroprotection, may result from mild zinc accumulation and the consequent p75 NTR activation in neurons.

Identification of Mutations in Caenorhabditis Elegans That Cause Resistance to High Levels of Dietary Zinc and Analysis Using a Genomewide Map of Single Nucleotide Polymorphisms Scored by Pyrosequencing

Abstract: Zinc plays many critical roles in biological systems: zinc bound to proteins has structural and catalytic functions, and zinc is proposed to act as a signaling molecule Because zinc deficiency and excess result in toxicity, animals have evolved sophisticated mechanisms for zinc metabolism and homeostasis However, these mechanisms remain poorly defined To identify genes involved in zinc metabolism, we conducted a forward genetic screen for chemically induced mutations that cause Caenorhabditis elegans to be resistant to high levels of dietary zinc Nineteen mutations that confer significant resistance to supplemental dietary zinc were identified To determine the map positions of these mutations, we developed a genomewide map of single nucleotide polymorphisms (SNPs) that can be scored by the high-throughput method of DNA pyrosequencing This map was used to determine the approximate chromosomal position of each mutation, and the accuracy of this approach was verified by conducting three-factor mapping experiments with mutations that cause visible phenotypes This is a generally applicable mapping approach that can be used to position a wide variety of C elegans mutations The mapping experiments demonstrate that the 19 mutations identify at least three genes that, when mutated, confer resistance to toxicity caused by supplemental dietary zinc These genes are likely to be involved in zinc metabolism, and the analysis of these genes will provide insights into mechanisms of excess zinc toxicity

Longitudinal changes in zinc transport kinetics, metallothionein, and zinc transporter expression in a blood-brain barrier model in response to a moderately excessive zinc environment

Abstract: A blood-brain barrier (BBB) model composed of porcine brain capillary endothelial cells (BCEC) was exposed to a moderately excessive zinc environment (50 µmol Zn/L) in cell culture and longitudinal measurements were made of zinc transport kinetics, ZnT-1 (SLC30A1) expression, and changes in the protein concentration of metallothionein (MT), ZnT-1, ZnT-2 (SLC30A2), and Zip1 (SLC39A1). Zinc release by cells of the BBB model was significantly increased after 12–24 h of exposure, but decreased back to control levels after 48–96 h, as indicated by transport across the BBB from both the ablumenal (brain) and lumenal (blood) directions. Expression of ZnT-1, the zinc export protein, increased 169% within 12 h, but was no longer different from controls after 24 h. Likewise, ZnT-1 protein content increased transiently after 12 h of exposure but returned to control levels by 24 h. Capacity for zinc uptake and retention increased from both the lumenal and ablumenal directions within 12–24 h of exposure and remained elevated. MT and ZnT-2 were elevated within 12 h and remained elevated throughout the study. Zip1 was unchanged by the treatment. The BBB’s response to a moderately high zinc environment was dynamic and involved multiple mechanisms. The initial response was to increase the cell’s capacity to sequester zinc with additional MT and increase zinc export with the ZnT-1 protein. But, the longer term strategy involved increasing ZnT-2 transporters, presumably to sequester zinc into intracellular vesicles as a mechanism to protect the brain and maintain brain zinc homeostasis.

Zinc induces motor neuron death via a selective inhibition of brain-derived neurotrophic factor activity

Abstract: Amyotrophic lateral sclerosis is a debilitating disease that results from the deterioration and loss of motor neurons. The neurotoxic potential of Zn(2+), both in vitro and in vivo, has been well established; however, the mechanism(s) of zinc's toxicity remain unclear. Our laboratory has demonstrated that Zn(2+)-mediated inhibition of neurotrophins can induce cell death. The present study investigates the neurotoxic mechanism(s) of this metal ion by assessing zinc's selectivity in altering the neurotrophin BDNF, but not the neural cytokine CNTF, with respect to motor neuron survival. Embryonic day 15 rat spinal motor neuron cultures were maintained in either BDNF or CNTF. Terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) staining showed that exposure to 100microM Zn(2+) significantly increased the number of pro-apoptotic neurons in cultures maintained with BDNF, while these conditions had no effect on cultures maintained with CNTF. We also demonstrate that BDNF protomer cross-linking efficiency and TrkB receptor cross-linking to BDNF are significantly inhibited by Zn(2+), suggesting that a Zn(2+)-induced change in BDNF conformation inhibits receptor-binding activity. This study reveals a mechanism by which zinc toxicity is mediated via a selective loss in neurotrophin activity resulting in motor neuron death.

Nickel limitation and zinc toxicity in a urea‐grown diatom

Abstract: When growing on urea as a nitrogen source, diatoms must accumulate nickel (Ni), a cofactor in the urease enzyme, which hydrolyzes urea. The uptake of Ni at low ambient concentrations is particularly challenging in view of the slow rate of reaction of the Ni2+ ion with uptake ligands. As expected, cultures of the model diatoms Thalassiosira weissflogii and Thalassiosira pseudonana become limited at very low Ni concentrations when growing on urea but not on nitrate or ammonium as a nitrogen source. At high Ni concentrations, urea-grown cultures of T. weissflogii exhibit similar accumulation of various other metals to nitrate-grown cultures and the same sensitivity to zinc and copper (Zn and Cu) concentrations. But at low Ni concentrations, T. weissflogii cells growing on urea accumulate excess Zn and exhibit extreme sensitivity to Zn toxicity. It appears that Zn accumulates in cells growing at low Ni concentrations by uptake through the up-regulated Ni transport system. The resulting sensitivity of Ni-limited cells to Zn (or to other metals that may be taken up via the Ni transport system) may limit the use of urea as a source of nitrogen in the oceans by some phytoplankton species.

Zinc Toxicity among Galvanization Workers in the Iron and Steel Industry

Abstract: Galvanization is the process of coating steel or cast iron pieces with zinc, allowing complete protection against corrosion The ultimate goal of this work was to assess the effect of occupational exposure to zinc in the galvanization process on different metals in the human body and to detect the association between zinc exposure and its effect on the respiratory system This study was conducted in 111 subjects in one of the major companies in the iron and steel industry There were 61 subjects (workers) who were involved in the galvanization process Fifty adult men were chosen as a matched reference group from other departments of the company All workers were interviewed using a special questionnaire on occupational history and chest diseases Ventilatory functions and chest X rays were assessed in all examined workers Also, complete blood counts were performed, and serum zinc, iron, copper, calcium, and magnesium levels were tested This study illustrated the relation between zinc exposure in the galvanization process and high zinc levels among exposed workers, which was associated with a high prevalence rate of metal fume fever (MFF) and low blood copper and calcium levels There was no statistically significant difference between the exposed and control groups with regards to the magnesium level No long-term effect of metals exposure was detected on ventilatory functions or chest X rays among the exposed workers

Impact of overexpression of metallothionein-1 on cell cycle progression and zinc toxicity

Abstract: Metallothioneins (MTs) have an important role in zinc homeostasis and may counteract the impact of oversupply. Both intracellular zinc and MT expression have been implicated in proliferation control and resistance to cellular stress, although the interdependency is unclear. The study addresses the consequences of a steady-state overexpression of MT-1 for intracellular zinc levels, cell cycle progression, and protection from zinc toxicity using a panel of cell lines with differential expression of MT-1. The panel comprised parental Chinese hamster ovary-K1 cells with low endogenous expression of MT and transfectants with enhanced expression of mouse MT-1 on an autonomously replicating expression vector with a noninducible promoter. Cell cycle progression, determined by flow cytometry and time-lapse microscopy, revealed that enhanced cytoplasmic expression of MT-1 does not impact on normal cell cycle operation, suggesting that basal levels of MT-1 expression are not limiting for background levels of oxidative stress. MT-1 overexpression correlated with a steady-state increase in cytoplasmic free Zn2+, assessed using the fluorescent zinc-sensor Zinquin, particularly at high levels of overexpression, further suggesting that zinc availability is normally not limiting for cell cycle progression. Enhanced MT-1 expression, over a 10-fold range, had a clear impact on resistance to Cd2+ and Zn2+ toxicity. In the case of Zn2+, the degree of protection afforded was less, indicating that MT-1 has a limited range and saturable capacity for effecting resistance. The results have implications for the use of cellular stress responses to exogenously supplied zinc and zinc-based systemic therapies.

Enhancing Glutathione Synthesis can Decrease Zinc-Mediated Toxicity

Abstract: Zinc toxicity has been linked to cellular glutathione: A decrease in glutathione is followed by an increase in zinc-mediated toxicity. The question arises whether an increase in glutathione synthesis might decrease zinc-mediated cytotoxicity. We incubated five cell lines (hepatoma and lung-derived) with zinc chloride and 2 mmol/l N-acetyl-l-cysteine (NAC) to support glutathione synthesis. In all but one hepatic cell line, the glutathione content was increased by NAC as compared to the d-enantiomere NADC, whereas NADC did not increase GSH content as compared to not treated controls. In both alveolar epithelial cell lines, an increase in zinc tolerance was observed due to NAC as compared to NADC. In native fibroblast-like and the hepatoma cell lines, no changes in zinc tolerance were found due to NAC. In the fibroblast-like cells, zinc tolerance was increased due to NAC only after cellular glutathione had been previously decreased (by lowered cysteine concentrations in the medium). Enhancing glutathione synthesis can antagonize zinc-mediated toxicity in the alveolar epithelial cell lines, whereas some other characteristics than glutathione synthesis might be more important in other cell types. Furthermore, NAC acted as a GSH precursor only at cysteine medium concentrations of 10 µmol/l or below and therefore might be described as a poor cysteine repletor for glutathione synthesis.

Alterations in metal toxicity and metal-induced metallothionein gene expression elicited by growth medium calcium concentration

Abstract: The calcium content of the growth medium has been shown to influence the growth and differentiation of primary epithelial cells in culture. The goal of the present study was to determine if growth medium calcium concentration could influence the susceptibility to metal toxicity and metallothionein gene expression of an immortalized human prostate-derived epithelial cell line (RWPE-1). The RWPE-1 cell line was grown in medium containing either 0.1 or 1.4 mM calcium. Confluent cells were exposed to either Zn(+2) (50, 100, or 150 microM) or Cd(+2) (3, 6, or 12 microM) for 13 days, and cell toxicity and MT gene expression were determined along the time course of exposure. It was demonstrated that the calcium content of the growth medium had a marked influence on Zn(+2) toxicity and a lesser but significant effect on Cd(+2) toxicity to the RWPE-1 cells. Calcium concentration of the growth medium was also shown to alter the accumulation of MT-1/2 protein and MT-1E, MT-1X, and MT-2A mRNAs. It was shown that MT-1/2 protein was markedly increased for metal-exposed cells grown in medium containing 0.1 mM calcium; however, the increased expression did not cause an increase in the resistance of the cells to Zn(+2) or Cd(+2) exposure. These observations show that growth medium calcium concentration can influence metal toxicity and the pattern of expression of the MT mRNAs and protein for RWPE-1 cells. The results suggest that caution should be exercised when comparing toxicological responses between cell lines that may be grown in growth formulations differing in calcium concentration.

FTIR study of zinc-induced biochemical changes in the liver of Indian carp Labeo rohita

Abstract: Zinc is an essential metal for different physiological functions and becomes toxic when elevated concentrations are introduced into the environment. In the present study, an attempt is made to analyze zinc-induced biochemical changes in the liver tissues of freshwater fingerlings of Labeo rohita using Fourier Transformation Infrared Spectroscopy. Several important features have been observed in the FTIR spectra of zinc-intoxicated liver tissues, namely, altered membrane lipid, altered protein profile, and increased glycogen content, indicating an alteration in the lipid and protein profiles leading to modification in membrane composition. Further, it is observed that acute exposure to zinc causes some alteration in protein profile with a decrease in α-helix and an increase in random coil structure. Treatment with the chelating agent D-penicillamine reduces the biochemical contents in the liver tissues. This shows that D-penicillamine is a good antidote for zinc toxicity.

Effect of zinc ion on peroxidase activity of serum in cow.

Abstract: In this study, for clarifying some possible mechanism of zinc toxicity, the effect of increasing amounts of Zn2+ ion on peroxidase activity was investigated in vitro in serum of cow. The H2O2-mediated oxidation of o-dianisidine was used to assess the peroxidase activity. Results show that after preincubation of serum with 0.2-20 mM Zn2+ concentration for 5 min, peroxidase activity was inhibited compared to the control and decreased rapidly with increasing metal concentrations. The enzyme was completely inhibited after 5 min preincubation in 30 mM Zn2+. When the preincubation of serum and Zn2+ was prolonged to 30 and 60 min, the enzymatic activity decreased more rapidly with increasing metal concentration. Extended exposure of the enzyme to lower concentrations of the metal brought about the same effect as shorter exposure to higher metal concentrations.