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.
Highlights
Engineering efforts over the last several years have resulted in stunning advances in the production of nanomaterials that can be utilized for a wide variety of applications
Neutrophil Influx into the Lungs as Assessed by Bronchoalveolar Lavage To investigate the potential pro-inflammatory properties of tri-n-octylphosphine oxide (TOPO)-poly(maleic anhydride-alt-tetradecene) (PMAT) quantum dots (QDs) when dosed via nasal instillation, we determined the percentage of neutrophils present in bronchoalveolar lavage fluid (BALF) 8 hours after QD administration
Several interesting findings arose from these studies, namely that (1) glutamate cysteine ligase modifier subunit (Gclm) status is a major determinant of the degree of pulmonary inflammation following TOPO-PMAT QD exposure via nasal instillation and (2) despite all mice receiving equivalent doses of TOPO-PMAT
Summary
Engineering efforts over the last several years have resulted in stunning advances in the production of nanomaterials that can be utilized for a wide variety of applications. These advances, leading to a broad array of novel nanomaterials, have occurred at such a rapid pace that efforts to understand and characterize the impact of nanomaterial exposure on human health are lagging. Pelley et al [1] and Botrill and Green [2] present excellent reviews of recent QD toxicity studies In these reviews, the authors cite several examples whereby QDs elicit toxicity in a variety of in vitro systems, via the generation of reactive oxygen intermediates [3]. Previous in vitro work in our lab indicated that heme oxygenase-1 is a highly robust and reproducible biomarker of QD exposure indicating activation of oxidative stress signaling across a variety of cell types of either human or murine origin [4]
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