Vasomotor function in rat arteries after ex vivo and intragastric exposure to food-grade titanium dioxide and vegetable carbon particles

Abstract Background Humans are continuously exposed to particles in the gastrointestinal tract. Exposure may occur directly through ingestion of particles via food or indirectly by removal of inhaled material from the airways by the mucociliary clearance system. We examined the effects of food-grade particle exposure on vasomotor function and systemic oxidative stress in an ex vivo study and intragastrically exposed rats. Methods In an ex vivo study, aorta rings from naïve Sprague-Dawley rats were exposed for 30 min to food-grade TiO2 (E171), benchmark TiO2 (Aeroxide P25), food-grade vegetable carbon (E153) or benchmark carbon black (Printex 90). Subsequently, the vasomotor function was assessed in wire myographs. In an in vivo study, lean Zucker rats were exposed intragastrically once a week for 10 weeks to vehicle, E171 or E153. Doses were comparable to human daily intake. Vasomotor function in the coronary arteries and aorta was assessed using wire myographs. Tetrahydrobiopterin, ascorbate, malondialdehyde and asymmetric dimethylarginine were measured in blood as markers of oxidative stress and vascular function. Results Direct exposure of E171 to aorta rings ex vivo increased the acetylcholine-induced vasorelaxation and 5-hydroxytryptamine-induced vasocontraction. E153 only increased acetylcholine-induced vasorelaxation, and Printex 90 increased the 5-hydroxytryptamine-induced vasocontraction, whereas Aeroxide P25 did not affect the vasomotor function. In vivo exposure showed similar results as ex vivo exposure; increased acetylcholine-induced vasorelaxation in coronary artery segments of E153 and E171 exposed rats, whereas E171 exposure altered 5-hydroxytryptamine-induced vasocontraction in distal coronary artery segments. Plasma levels of markers of oxidative stress and vascular function showed no differences between groups. Conclusion Gastrointestinal tract exposure to E171 and E153 was associated with modest albeit statistically significant alterations in the vasocontraction and vasorelaxation responses. Direct particle exposure to aorta rings elicited a similar type of response. The vasomotor responses were not related to biomarkers of systemic oxidative stress

Problems of B1-Avitaminosis in the Knee-Jeak-Method of Measuring Fatigue

Inflammation and oxidative stress are considered the main drivers of vasomotor dysfunction and progression of atherosclerosis after inhalation of particulate matter. In addition, new studies have shown that particle exposure can induce the level of bioactive mediators in serum, driving vascular- and systemic toxicity. We aimed to investigate if pulmonary inflammation would accelerate nanoparticle-induced atherosclerotic plaque progression in Apolipoprotein E knockout (ApoE-/-) mice. ApoE -/- mice were exposed to vehicle, 8.53 or 25.6 μg nanosized carbon black (CB) alone or spiked with LPS (0.2 μg/mouse/exposure; once a week for 10 weeks). Inflammation was determined by counting cells in bronchoalveolar lavage fluid. Serum Amyloid A3 (Saa3) expression and glutathione status were determined in lung tissue. Plaque progression was assessed in the aorta and the brachiocephalic artery. The effect of vasoactive mediators in plasma of exposed ApoE-/- mice was assessed in aorta rings isolated from naïve C57BL/6 mice. Pulmonary exposure to CB and/or LPS resulted in pulmonary inflammation with a robust influx of neutrophils. The CB exposure did not promote plaque progression in aorta or BCA. Incubation with 0.5% plasma extracted from CB-exposed ApoE-/- mice caused vasoconstriction in aorta rings isolated from naïve mice; this effect was abolished by the treatment with the serotonin receptor antagonist Ketanserin. In conclusion, repeated pulmonary exposure to nanosized CB and LPS caused lung inflammation without progression of atherosclerosis in ApoE-/- mice. Nevertheless, plasma extracted from mice exposed to nanosized CB induced vasoconstriction in aortas of naïve wild-type mice, an effect possibly related to increased plasma serotonin

The applicability of the GHS classification criteria to nanomaterials

The report reviews the applicability of the Globally Harmonised System of Classification and Labelling of Chemicals (GHS) hazard classification criteria to manufactured nanomaterials considering the recent data generated and compiled in the nanomaterial testing program under the OECD Working Party on Manufactured Nanomaterials. In addition, data from the EU NANoREG project, the EU NanoSafety Cluster projects, REACH registrations and publicly available literature were used. The project focused on four nanomaterials and selected health hazard classes. The available test data were evaluated with respect to applicability of the test methods, applicability of the GHS criteria, identified data gaps and uncertainties and need for revision of GHS criteria or guidance. The report also highlights specific issues to be considered when classifying nanomaterials

Role of oxidative stress in carbon nanotube-generated health effects

The development of products containing carbon nanotubes (CNTs) is a major achievement of nanotechnology, although concerns regarding risk of toxic effects linger if the hazards associated with these materials are not thoroughly investigated. Exposure to CNTs has been associated with depletion of antioxidants, increased intracellular production of reactive oxygen species and pro-inflammatory signaling in cultured cells with primary function in the immune system as well as epithelial, endothelial and stromal cells. Pre-treatment with antioxidants has been shown to attenuate these effects, indicating a dependency of oxidative stress on cellular responses to CNT exposure. CNT-mediated oxidative stress in cell cultures has been associated with elevated levels of lipid peroxidation products and oxidatively damaged DNA. Investigations of oxidative stress endpoints in animal studies have utilized pulmonary, gastrointestinal, intravenous and intraperitoneal exposure routes, documenting elevated levels of lipid peroxidation products and oxidatively damaged DNA nucleobases especially in the lungs and liver, which to some extent occur concomitantly with altered levels of components in the antioxidant defense system (glutathione, superoxide dismutase or catalase). CNTs are biopersistent high aspect ratio materials, and some are rigid with lengths that lead to frustrated phagocytosis and pleural accumulation. There is accumulating evidence showing that pulmonary exposure to CNTs is associated with fibrosis and neoplastic changes in the lungs, and cardiovascular disease. As oxidative stress and inflammation responses are implicated in the development of these diseases, converging lines of evidence indicate that exposure to CNTs is associated with increased risk of cardiopulmonary diseases through generation of a pro-inflammatory and pro-oxidant milieu in the lungs

Progression of atherosclerotic plaques in the aorta and brachiocephalic artery from <i>ApoE</i>^<i>-/-</i> mice exposed to carbon black (CB) and/or lipopolysaccharide (LPS) by i.t. instillation.

<p>A) Atherosclerotic plaque area is expressed as the percentage of the luminal surface of the aorta covered with plaques. Calculations were made on whole aorta preparations from ascending aorta to the iliac bifurcation. B) Atherosclerotic plaque area expressed as the percentage of the lumen occupied by plaques in BCA. Six sections of BCA per animal were analyzed; three sections at 100 μm and three sections at 200 μm after the branch from the aortic arch (n = 6–10 mice per group). C) The intima-media ratio in BCA is calculated by dividing the area of the intima with the area of the media layer (n = 6–10 mice per group). Black bars represent the groups that did not receive LPS and white bars the groups that did receive LPS. Minus (-) denotes no exposure, plus denotes low (+) or high-dose (++) exposure. Data are presented as mean and SEM. Asterisks denote statistical significance *P<0.05, using one-way ANOVA with Tukey’s post-hoc test, and **P<0.01, two-factor ANOVA with Fisher’s LSD post-hoc test.</p

Glutathione status in lung tissue of <i>ApoE</i>^<i>-/-</i> mice after repeated i.t. instillations of carbon black (CB) or lipopolysaccharide (LPS).

<p>Total and reduced glutathione was measured at 24 h post-exposure in lung homogenate from <i>ApoE</i>^<i>-/-</i> mice of study 1 and 2. Data is presented as mean and SEM (n = 10 mice per group).</p