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

Abstract

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.

Toxicity of quantum dots on respiratory system

“…McConnachie et al (2013) used real-time PCR and observed an increased mRNA expression level of genes involved in both oxidative stress signaling and inflammatory pathways in QD-treat mice. Moreover, Nagy et al investigated the up-regulation and down-regulation of genes by real-time PCR analysis to explore the mechanisms of cadmium-containing QDs driving normal human bronchial epithelial (NHBE) cell death, mitochondrial function and inflammation.…”

“…Jacobsen et al (2009) detected a slight insignificant increase in neutrophils and relative decrease in macrophages among apolipoproein E knockout (ApoEÀ/À) mice exposed to broncho-alveolar lavage (BAL) fluid. McConnachie et al (2013) showed that QDs elicited a stronger and statistically significant neutrophil influx in lungs of both mice with normal or slightly diminished capacity for glutathione (GSH) synthesis 8 h after bronchoalveolar lavage (BAL).…”

“…There are several studies suggesting that QD deposition in lung tissues results in lung damage (Ho et al, 2013;Jacobsen et al, 2009;McConnachie et al, 2013). However, there are other plausible explanations in the literature to elucidate mechanisms of QD-induced lung injury.…”

Role of Glutathione Biosynthesis in Endothelial Dysfunction and Fibrosis

“…Human polymorphisms of GCLc and/or GCLm may also result in decreased GSH synthesis and severe pathological phenotypes [16,17]. Genetic ablation of Gclm in mice is associated with impaired vascular reactivity [18], ovarian failure [19], lung inflammation [20] and mitochondrial dysfunction [21]. Of interest, the relationship between alterations in the redox status and fibrogenesis is intimately related to GSH homeostasis [14].…”

Metal ion doped CdSe quantum dots prepared by hydrothermal synthesis: enhanced photocatalytic activity and stability under visible light

“…Hence, it is necessary for us to take steps to overcome their drawbacks. Fortunately, the defects of CdSe QDs can be improved by further modification [21,22] via loading [23,24], doping [15,25], and so on.…”