Assessment of myocardial fibrosis in the left ventricle wall of FA Sham (A), <i>in utero</i> DE Sham (B), FA TAC (C), and <i>in utero</i> DE TAC (D) mice.

<p>Blue staining indicates fibrotic regions. Percentage of LV area that is highly fibrotic was quantified (E). FA sham (n = 4), FA TAC (n = 6), DE sham (n = 5), DE TAC (n = 6). Scale bars = 200 µm.</p

Systolic (A), diastolic (B), and mean (C) arterial pressure as measured by tail-cuff in 10-week old male mice.

<p>(D) Linear regression between body weight and mean BP. FA males (n = 10), DE males (n = 9).</p

Images of placental cross-sections with immunohistochemistry staining against CD45 in FA (A and C) and <i>in utero</i> DE (B and D).

<p>Number of CD45+ cells normalized to decidua cross sectional area is quantified (E). FA dams (n = 3), FA placentas (n = 3 per dam), DE dams (n = 4), DE placentas (n = 3 per dam). Scale bars = 100 µm (panels A and B) and 50 µm (panels C and D).</p

Assessment of individual cardiomyocyte hypertrophy in the left ventricle wall of FA Sham (A), <i>in utero</i> DE Sham (B), FA TAC (C), and <i>in utero</i> DE TAC (D) mice.

<p>Average myocyte area was quantified (E). FA sham (n = 4), FA TAC (n = 6), DE sham (n = 5), DE TAC (n = 6). Scale bars = 50 µm.</p

Baseline left ventricular wall thickness and contractile function in 12 week old male mice as measured by echocardiography.

<p>(A) Left ventricular anterior wall thickness at diastole, (B) left ventricular internal diameter at diastole, (C) percentage fractional shortening. FA males (n = 10), DE males (n = 9).</p

Images of placental cross sections stained with hematoxylin and eosin.

<p>(A) FA – Decidua layer, (B) DE – Decidua layer, excessive densely packed fibrin and enmeshed red cells and nuclear debris deep in the spongiotrophoblast layer, (C) FA – spongiotrophoblast layer, (D) DE – spongiotrophoblast layer, focal-extensive area of necrosis, congestion and hemorrhage at the labyrinth/spongiotrophoblast interface, (E) FA – labyrinth layer, (F) DE – labyrinth layer, increased stromal density and compaction of the vascular spaces. Scale bars = panels A–D, 100 µm; panels E and F, 50 µm.</p

Placental 3-nitrotyrosine (3-NT) staining by immunofluorescence and adjacent H&E stained sections.

<p>Representative images from sagittal cross-section from (A and B) FA exposed dam, (C and D) DE exposed dam showing perivascular 3-NT staining, (E and F) DE exposed dam showing perivascular 3-NT staining, and (G) quantification of relative 3-NT fluorescence. FA dams (n = 3), FA placentas (n = 3 per dam), DE dams (n = 4), DE placentas (n = 3 per dam). Scale bars = 50 µm.</p

Effects of <i>in utero</i> DE exposure on adult body weight.

<p>(A) Male 10-week body weight, (B) body weight normalized to tibia length, and (C) tibia length. FA males (n = 10), DE males (n = 9).</p

Embryonic day 17.5 (E17.5) embryo collection in FA and DE exposed dams.

<p>(A) Number of dams with resorbed embryos and (B) number of embryos resorbed vs number of viable embryos in FA and DE exposed dams. (C) Average fetus weight per dam and (D) individual fetus weights. (E) Average placental weight per dam and (F) individual placental weights. FA dams (n = 3), DE dams (n = 4).</p

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

<div><p>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 <i>in vitro</i> 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 <i>in vivo</i> in mice deficient in GSH synthesis (<i>Gclm</i> +/− and <i>Gclm</i> −/− 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 <i>Gclm</i> wild-type (+/+) and <i>Gclm</i> heterozygous (+/−) mice, whereas <i>Gclm</i> null (−/−) mice exhibited no such increase. Levels of the pro-inflammatory cytokines KC and TNFα increased in BALF from <i>Gclm</i> +/+ and +/− mice, but not from <i>Gclm</i> −/− mice. Analysis of lung Cd levels suggested that QDs were cleared more readily from the lungs of <i>Gclm</i> −/− 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 <i>Gclm</i> −/− mice, regardless of treatment, relative to untreated <i>Gclm</i> +/+ mice. We conclude that in mice TOPO-PMAT QDs have <i>in vivo</i> 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.</p></div