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

Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, United States of America.
PLoS ONE (Impact Factor: 3.23). 05/2013; 8(5):e64165. DOI: 10.1371/journal.pone.0064165
Source: PubMed


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.

Download full-text


Available from: Chad S Weldy, Oct 05, 2015
49 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Glutathione (GSH) is the most abundant cellular thiol antioxidant and it exhibits numerous and versatile functions. Disturbances in GSH homeostasis have been associated with liver diseases induced by drugs, alcohol, diet and environmental pollutants. Until recently, our laboratories and others have developed mouse models with genetic deficiencies in glutamate-cysteine ligase (GCL), the rate-limiting enzyme in the GSH biosynthetic pathway. This review focuses on regulation of GSH homeostasis and, specifically, recent studies that have utilized such GSH-deficient mouse models to investigate the role of GSH in liver disease processes. These studies have revealed a differential hepatic response to distinct profiles of hepatic cellular GSH concentration. In particular, mice engineered to not express the catalytic subunit of GCL in hepatocytes [Gclc(h/h) mice] experience almost complete loss of hepatic GSH (to 5% of normal) and develop spontaneous liver pathologies characteristic of various clinical stages of liver injury. In contrast, mice globally engineered to not express the modifier subunit of GCL [Gclm(-/-) mice] show a less severe hepatic GSH deficit (to ≈15% of normal) and exhibit overall protection against liver injuries induced by a variety of hepatic insults. Collectively, these transgenic mouse models provide interesting new insights regarding pathophysiological functions of GSH in the liver.
    Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 07/2013; 60. DOI:10.1016/j.fct.2013.07.008 · 2.90 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ferritin (Ftn) undergoes photo-induced charge separation reactions that oxidize organic substrates. The liberated electrons are transferred through the protein shell to reduce Au ions to gold nanoparticles (AuNPs). We systematically varied the concentrations of citrate (electron donor), Au3+ or Au+ (electron acceptor), and ferritin (photo catalyst) to determine if careful control of these reactant concentrations would: (1) provide size control; (2) alter the morphology of the resulting AuNPs; and (3) alter the catalytic activity of the resulting AuNPs. The size and phosphate content of the ferritin iron core was also evaluated for its influence in this photocatalysis reaction. We report that as the Ftn concentration was increased to an optimal range, the number of AuNPs increased and showed smaller size, more spherical shape, and narrower distribution. Increasing the citrate concentration (electron donor) increased the rate of AuNP formation producing more spherical, uniform sized AuNPs. Increasing the Au3+ concentrations increased the number and sizes of the AuNPs. Since Au3+ reduction requires 3-electrons we proposed that using Au+ would increase the rate of the reaction. The photochemical reaction with Au+ was faster and produced 2.4 +/- 1.0 nm diameter AuNPs providing another method of size control. AuNPs were tested as reduction catalysts to convert 4-nitrophenol into 4-aminophenol. The smaller spherical AuNPs were better reduction catalysts than the larger AuNPs. In summary, using a single photochemical synthesis method we can reproducibly control the size, uniformity and catalytic activity of the resulting AuNPs simply by varying the concentrations or oxidation states of the reactants.
    RSC Advances 01/2014; 4(7):3472-3481. DOI:10.1039/C3RA46520A · 3.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Quantum dots (QDs), as advanced nanotechnology products, are widely used in the bio-medical field for diagnostic and therapeutic purposes due to their unique properties. Therefore, it becomes important for researchers to elucidate the adverse effects of QDs on human beings. This essay provides an overview of the toxic effects of QDs on respiratory system, which are summarized into two main parts: in vitro toxicity, including reduction of cell viability, genetic material damage and disordered immune cell reactions; as well as in vivo toxicity, involving accumulation of QDs, lung injury and inflammation, and potential long-term adverse effects. As the toxic severity of a QD type depends on its composition, dose, size, surface chemistry and structure, it is a big challenge to determine a benchmark of QDs. Thus, we have to remember that each QD type is a unique nanocrystal, which needs to be assessed individually. However, there are still some feasible recommendations for minimizing the toxicity provided in this review. Overall, more and more large-scale well-organized toxicity studies of different QD types on different species need to be conducted in order to provide guidelines of QDs' safety application.
    Inhalation Toxicology 02/2014; 26(2):128-39. DOI:10.3109/08958378.2013.871762 · 2.26 Impact Factor
Show more