Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, United States of America.
PLoS One. 2013 May 27;8(5):e64165. doi: 10.1371/journal.pone.0064165. Print 2013.
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.
量子点 (QDs) 是一种独特的半导体荧光纳米粒子，具有在多种生物医学应用中的潜在用途。然而，人们对其潜在毒性表示担忧，特别是它们诱导氧化应激和炎症的能力。在这项研究中，我们合成了具有三辛基氧化膦 (TOPO) 涂层的 CdSe/ZnS 核/壳量子点，并评估了它们对小鼠肺部炎症的影响。先前发表的体外数据表明，这些 TOPO-PMAT 量子点会引起氧化应激，导致抗氧化蛋白表达增加，包括血红素加氧酶和谷胱甘肽 (GSH) 合成酶谷氨酸半胱氨酸连接酶 (GCL)。因此，我们在 GSH 合成缺陷 (Gclm +/- 和 Gclm -/- 小鼠) 的小鼠体内研究了这些量子点的影响。当通过鼻腔滴注将 TOPO-PMAT 量子点以 6 µg 镉 (Cd) 当量/公斤体重的剂量暴露于小鼠时，肺泡灌洗液 (BALF) 中的中性粒细胞计数在 Gclm 野生型 (+/+) 和 Gclm 杂合型 (+/-) 小鼠中均增加，而 Gclm 缺失 (-/-) 小鼠则没有增加。促炎细胞因子 KC 和 TNFα 的水平在 Gclm +/+ 和 +/- 小鼠的 BALF 中增加，但在 Gclm -/- 小鼠中没有增加。对肺中 Cd 水平的分析表明，量子点更容易从 Gclm -/- 小鼠的肺部清除。在任何小鼠中，基质金属蛋白酶 (MMP) 活性均无变化。然而，无论是否接受治疗，Gclm -/- 小鼠的全肺髓过氧化物酶 (MPO) 含量均较未接受治疗的 Gclm +/+ 小鼠降低。我们得出的结论是，在小鼠中，TOPO-PMAT 量子点具有体内促炎特性，并且炎症反应取决于 GSH 合成状态。由于人类中存在影响 GCLM 表达的常见多态性，这些发现意味着 GSH 合成能力降低的人可能更容易受到量子点的促炎作用的影响。
