Reduction in cadmium‐induced toxicity and c‐Jun N‐terminal kinase activation by glutathione in cultured mouse embryonic cells

MacKinnon, Yolanda; Kapron, Carolyn M.

doi:10.1002/bdra.20703

Cited by 9 publications

(3 citation statements)

References 54 publications

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“…Furthermore, cadmium toxicity is modulated in part by GSH levels [19], [20]. Additionally, oxidative stress and subsequent GSH depletion may be an integral component of the pro-inflammatory potential of heavy metal containing nanoparticles [3], [21].…”

Section: Resultsmentioning

confidence: 99%

The Glutathione Synthesis Gene Gclm Modulates Amphiphilic Polymer-Coated CdSe/ZnS Quantum Dot–Induced Lung Inflammation in Mice

et al. 2013

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Quantum dots (QDs) are unique semi-conductor fluorescent nanoparticles with potential uses in a variety of biomedical applications. However, concerns exist regarding their potential toxicity, specifically their capacity to induce oxidative stress and inflammation. In this study we synthesized CdSe/ZnS core/shell QDs with a tri-n-octylphosphine oxide, poly(maleic anhydride-alt-1-tetradecene) (TOPO-PMAT) coating and assessed their effects on lung inflammation in mice. Previously published in vitro data demonstrated these TOPO-PMAT QDs cause oxidative stress resulting in increased expression of antioxidant proteins, including heme oxygenase, and the glutathione (GSH) synthesis enzyme glutamate cysteine ligase (GCL). We therefore investigated the effects of these QDs in vivo in mice deficient in GSH synthesis (Gclm +/− and Gclm −/− mice). When mice were exposed via nasal instillation to a TOPO-PMAT QD dose of 6 µg cadmium (Cd) equivalents/kg body weight, neutrophil counts in bronchoalveolar lavage fluid (BALF) increased in both Gclm wild-type (+/+) and Gclm heterozygous (+/−) mice, whereas Gclm null (−/−) mice exhibited no such increase. Levels of the pro-inflammatory cytokines KC and TNFα increased in BALF from Gclm +/+ and +/− mice, but not from Gclm −/− mice. Analysis of lung Cd levels suggested that QDs were cleared more readily from the lungs of Gclm −/− mice. There was no change in matrix metalloproteinase (MMP) activity in any of the mice. However, there was a decrease in whole lung myeloperoxidase (MPO) content in Gclm −/− mice, regardless of treatment, relative to untreated Gclm +/+ mice. We conclude that in mice TOPO-PMAT QDs have in vivo pro-inflammatory properties, and the inflammatory response is dependent on GSH synthesis status. Because there is a common polymorphism in humans that influences GCLM expression, these findings imply that humans with reduced GSH synthesis capabilities may be more susceptible to the pro-inflammatory effects of QDs.

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Section: Resultsmentioning

confidence: 99%

The Glutathione Synthesis Gene Gclm Modulates Amphiphilic Polymer-Coated CdSe/ZnS Quantum Dot–Induced Lung Inflammation in Mice

et al. 2013

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“…In the chick embryo, Cd exposure is associated with high levels of ROS production and apoptosis in the ectoderm, neural tube, lateral plate mesoderm, and somites within 4 to 8 h after Cd exposure (Thompson et al, 2005). Although not directly implicated in murine teratogenesis, the role of Cd in inducing oxidative stress in adult tissue is implicated by the tissue-specific induction of apoptosis and activation of heat shock proteins (Papaconstantinou et al, 2003) and the protective effect of vitamin E (Warren et al, 2000) and glutathione (MacKinnon and Kapron, 2010). The cell death in the ectoderm and AER is in contrast to the cell death caused by retinoic acid that is localized to the mesoderm, but results in morphologically similar defects (Liao et al, 2007).…”

Section: Ethanolmentioning

confidence: 99%

Prenatal exposure to environmental factors and congenital limb defects

Alexander

Clark

Tuan

2016

Birth Defects Research Pt C

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Limb congenital defects afflict approximately 0.6:1000 live births. In addition to genetic factors, prenatal exposure to drugs and environmental toxicants, represents a major contributing factor to limb defects. Examples of well-recognized limb teratogenic agents include thalidomide, warfarin, valproic acid, misoprostol, and phenytoin. While the mechanism by which these agents cause dymorphogenesis is increasingly clear, prediction of the limb teratogenicity of many thousands of as yet uncharacterized environmental factors (pollutants) remains inexact. This is limited by the insufficiencies of currently available models. Specifically, in vivo approaches using guideline animal models have inherently deficient predictive power due to genomic and anatomic differences that complicate mechanistic comparisons. On the other hand, in vitro two-dimensional (2D) cell cultures, while accessible for cellular and molecular experimentation, do not reflect the three-dimensional (3D) morphogenetic events in vivo nor systemic influences. More robust and accessible models based on human cells that accurately replicate specific processes of embryonic limb development are needed to enhance limb teratogenesis prediction and to permit mechanistic analysis of the adverse outcome pathways. Recent advances in elucidating mechanisms of normal development will aid in the development of process-specific 3D cell cultures within specialized bioreactors to support multicellular microtissues or organoid constructs that will lead to increased understanding of cell functions, cell-to-cell signaling, pathway networks, and mechanisms of toxicity. The promise is prompting researchers to look to such 3D microphysiological systems to help sort out complex and often subtle interactions relevant to developmental malformations that would not be evident by standard 2D cell culture testing. Birth Defects Research (Part C) 108:243-273, 2016. © 2016 Wiley Periodicals, Inc.

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“…Cell differentiation (chondrogenesis) was determined by staining the proteoglycans in cell cultures with Alcian blue as described by Paulsen and Solursh (), with modifications as described in MacKinnon and Kapron (). After 5 days of treatment, cells were fixed and stained overnight with 0.5% Alcian Blue 8GX dye (Sigma, ON) in 0.1 N HCl.…”

Section: Methodsmentioning

confidence: 99%

Reduction in cadmium‐induced toxicity by c‐Jun modulation in mouse embryo limb bud cells

Kapron

Cheng

2015

Birth Defects Research

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Reduction in cadmium‐induced toxicity and c‐Jun N‐terminal kinase activation by glutathione in cultured mouse embryonic cells

Abstract: Exogenous GSH protects cultured embryonic limb bud cells from Cd(2+)-induced inhibition of cell proliferation and differentiation, which is associated with the activation of JNK.

Cited by 9 publications

References 54 publications

The Glutathione Synthesis Gene Gclm Modulates Amphiphilic Polymer-Coated CdSe/ZnS Quantum Dot–Induced Lung Inflammation in Mice

The Glutathione Synthesis Gene Gclm Modulates Amphiphilic Polymer-Coated CdSe/ZnS Quantum Dot–Induced Lung Inflammation in Mice

Prenatal exposure to environmental factors and congenital limb defects

Reduction in cadmium‐induced toxicity by c‐Jun modulation in mouse embryo limb bud cells

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