Tolerance to cadmium cytotoxicity is induced by zinc through non-metallothionein mechanisms as well as metallothionein induction in cultured cells

Mishima, Atsushi; Yamamoto, Chika; Fujiwara, Yasuyuki; Kaji, Tatsuru

doi:10.1016/s0300-483x(96)03565-2

Cited by 26 publications

(9 citation statements)

References 24 publications

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“…Zinc is protective against Cd by the induction of metallothionein and other unspecified mechanisms (Mishima et al. ), and zinc can improve clinical symptoms of asthma in children such as cough, wheezing, and pulmonary function (Ghaffari et al. ).…”

Section: Discussionmentioning

confidence: 99%

Low-dose oral cadmium increases airway reactivity and lung neuronal gene expression in mice

et al. 2016

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Inhalation of cadmium (Cd) is associated with lung diseases, but less is known concerning pulmonary effects of Cd found in the diet. Cd has a decades‐long half‐life in humans and significant bioaccumulation occurs with chronic dietary intake. We exposed mice to low‐dose CdCl2 (10 mg/L in drinking water) for 20 weeks, which increased lung Cd to a level similar to that of nonoccupationally exposed adult humans. Cd‐treated mice had increased airway hyperresponsiveness to methacholine challenge, and gene expression array showed that Cd altered the abundance of 443 mRNA transcripts in mouse lung. In contrast to higher doses, low‐dose Cd did not elicit increased metallothionein transcripts in lung. To identify pathways most affected by Cd, gene set enrichment of transcripts was analyzed. Results showed that major inducible targets of low‐dose Cd were neuronal receptors represented by enriched olfactory, glutamatergic, cholinergic, and serotonergic gene sets. Olfactory receptors regulate chemosensory function and airway hypersensitivity, and these gene sets were the most enriched. Targeted metabolomics analysis showed that Cd treatment also increased metabolites in pathways of glutamatergic (glutamate), serotonergic (tryptophan), cholinergic (choline), and catecholaminergic (tyrosine) receptors in the lung tissue. Protein abundance measurements showed that the glutamate receptor GRIN2A was increased in mouse lung tissue. Together, these results show that in mice, oral low‐dose Cd increased lung Cd to levels comparable to humans, increased airway hyperresponsiveness and disrupted neuronal pathways regulating bronchial tone. Therefore, dietary Cd may promote or worsen airway hyperresponsiveness in multiple lung diseases including asthma.

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Section: Discussionmentioning

confidence: 99%

Low-dose oral cadmium increases airway reactivity and lung neuronal gene expression in mice

et al. 2016

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“…Our analyses showed that vascular endothelial cells are sensitive to cadmium cytotoxicity (Kaji et al, 1996); cadmium influences the synthesis of heparan sulfate proteoglycans (Ohkawara et al, 1997) and lowers fibrinolytic activity by promoting the synthesis and secretion of plasminogen activator inhibitor-1 (Yamamoto et al, 1993;Yamamoto and Kaji, 2002). Endothelial cells can be protected from cadmium cytotoxicity by zinc (Kaji et al, 1992;Mishima et al, 1997). In general, zinc-induced MT provides protection against cadmium; however, in vascular endothelial cells, zinc does not induce MT protein expression, despite reducing the accumulation of cadmium within the cells (Kaji et al, 1992).…”

Section: Introductionmentioning

confidence: 82%

Zinc diethyldithiocarbamate as an inducer of metallothionein in cultured vascular endothelial cells

et al. 2016

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-Vascular endothelial cells are in direct contact with blood. Inorganic zinc is thought to be incapable of inducing metallothionein, which protects cells from heavy metal toxicity and oxidative stress, in vascular endothelial cells. Here, we aimed to further characterize the induction of metallothionein in vascular endothelial cells. Our results confirmed that inorganic zinc could not induce metallothionein in vascular endothelial cells. Moreover, ZnSO 4 could not activate both the metal response element (MRE) transcription factor 1 (MTF-1)/MRE and Nrf2/antioxidant response element (ARE) pathways and was incapable of inducing metallothionein. In addition, bis(L-cysteinato)zincate(II), a zinc complex that activates the MTF-1/MRE pathway, increased MRE promoter activity but failed to induce metallothionein, suggesting that vascular endothelial metallothionein was not induced only by activation of the MTF-1/MRE pathway. Further analysis of a library of zinc complexes showed that zinc(II) bis(diethyldithiocarbamate) activated the MTF-1/MRE pathway but not the Nrf2/ARE pathway, increased MT-1A, MT-1E, and MT-2A mRNA levels, and induced metallothionein proteins. These data indicated that zinc complexes may be excellent tools to analyze metallothionein induction in vascular endothelial cells.

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“…For mercury, humoral parameters (Ig level and lysozyme activity), phagocyte activity, and the proliferative response of thymocytes were no longer significantly affected. That zinc protects cadmium‐ or mercury‐induced toxicity has been shown in several toxicological [27,31,32] and immunotoxicological studies [33,34].…”

Section: Discussionmentioning

confidence: 99%

“…Zinc can protect cells from cadmium‐induced toxicity by (1) inducing the synthesis of metallothionein, a metal protein complex that sequesters and reduces the amount of free metal in the tissues, thereby reducing their potential toxicity; (2) preventing the entry of cadmium into the cell; and (3) competing with cadmium for intracellular binding sites [32]. The induction of metallothionein and glutathione by cadmium is probably one of the most important mechanisms of cellular protection against this metal.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulation by heavy metals tested individually or in mixtures in rainbow trout (Oncorhynchus mykiss) exposed in vivo

Sanchez-Dardon

Voccia

Hontela

et al. 1999

Enviro Toxic and Chemistry

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Abstract-The objective of this study was to evaluate the effect of heavy metals, at environmentally relevant concentrations, on the immune response of rainbow trout. Trout were exposed for 30 d to cadmium chloride (CdCl 2 ), mercuric chloride (HgCl 2 ), or zinc chloride (ZnCl 2 ) either individually or in combinations: CdCl 2 /HgCl 2 , CdCl 2 /ZnCl 2 , HgCl 2 /ZnCl 2 , or CdCl 2 /HgCl 2 /ZnCl 2 . Following the 30-d exposure, parameters of the nonspecific cellular immune response (phagocytosis, respiratory burst, and lymphoblastic proliferation) and of the nonspecific humoral immune response (lysozyme activity and the level of immunoglobulin) were measured. The results obtained indicate that individually, all three metals tested induce significant immunomodulations. However, the toxicity of mercury or cadmium is significantly reduced in fish simultaneously exposed to zinc, indicating that a protection is afforded by zinc against cadmium-and mercury-induced immunotoxicity.

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Tolerance to cadmium cytotoxicity is induced by zinc through non-metallothionein mechanisms as well as metallothionein induction in cultured cells

Cited by 26 publications

References 24 publications

Low-dose oral cadmium increases airway reactivity and lung neuronal gene expression in mice

Low-dose oral cadmium increases airway reactivity and lung neuronal gene expression in mice

Zinc diethyldithiocarbamate as an inducer of metallothionein in cultured vascular endothelial cells

Immunomodulation by heavy metals tested individually or in mixtures in rainbow trout (Oncorhynchus mykiss) exposed in vivo

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