title: 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.
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, United States of America.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: McConnachie
authors.forename: Dianne
authors.initials: D
authors.lastname: Botta
authors.forename: Collin C
authors.initials: CC
authors.lastname: White
authors.forename: Chad S
authors.initials: CS
authors.lastname: Weldy
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Wilkerson
authors.forename: Jianbo
authors.initials: J
authors.lastname: Yu
authors.forename: Russell
authors.initials: R
authors.lastname: Dills
authors.forename: Xiaozhong
authors.initials: X
authors.lastname: Yu
authors.forename: William C
authors.initials: WC
authors.lastname: Griffith
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Faustman
authors.forename: Federico M
authors.initials: FM
authors.lastname: Farin
authors.forename: Sean E
authors.initials: SE
authors.lastname: Gill
authors.forename: William C
authors.initials: WC
authors.lastname: Parks
authors.forename: Xiaoge
authors.initials: X
authors.lastname: Hu
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Gao
authors.forename: David L
authors.initials: DL
authors.lastname: Eaton
authors.forename: Terrance J
authors.initials: TJ
authors.lastname: Kavanagh
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D019187:Cadmium Compounds / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005721:Glutamate-Cysteine Ligase / Q000235:genetics*; D005978:Glutathione / Q000096:biosynthesis; D018836:Inflammation Mediators / Q000276:immunology; D015603:Keratinocytes / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology; D009195:Peroxidase / Q000378:metabolism; D011014:Pneumonia / Q000209:etiology*; D011108:Polymers / Q000737:chemistry* / Q000633:toxicity; D045663:Quantum Dots / Q000737:chemistry* / Q000633:toxicity; D012333:RNA, Messenger / Q000235:genetics; D018036:Selenium Compounds / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D013312:Stress, Physiological / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019287:Zinc Sulfate / Q000737:chemistry
chemical_list: D019187:Cadmium Compounds; D016207:Cytokines; D018836:Inflammation Mediators; D011108:Polymers; D012333:RNA, Messenger; D018036:Selenium Compounds; D014409:Tumor Necrosis Factor-alpha; D019287:Zinc Sulfate; C058667:cadmium selenide; D009195:Peroxidase; D020782:Matrix Metalloproteinases; C560749:GCLM protein, mouse; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione