Abstract
BackgroundThere is growing evidence that exposure to small size particulate matter increases the risk of developing cardiovascular disease.MethodsWe investigated plaque progression and vasodilatory function in apolipoprotein E knockout (ApoE-/-) mice exposed to TiO2. ApoE-/- mice were intratracheally instilled (0.5 mg/kg bodyweight) with rutile fine TiO2 (fTiO2, 288 nm), photocatalytic 92/8 anatase/rutile TiO2 (pTiO2, 12 nm), or rutile nano TiO2 (nTiO2, 21.6 nm) at 26 and 2 hours before measurement of vasodilatory function in aorta segments mounted in myographs. The progression of atherosclerotic plaques in aorta was assessed in mice exposed to nanosized TiO2 (0.5 mg/kg bodyweight) once a week for 4 weeks. We measured mRNA levels of Mcp-1, Mip-2, Vcam-1, Icam-1 and Vegf in lung tissue to assess pulmonary inflammation and vascular function. TiO2-induced alterations in nitric oxide (NO) production were assessed in human umbilical vein endothelial cells (HUVECs).ResultsThe exposure to nTiO2 was associated with a modest increase in plaque progression in aorta, whereas there were unaltered vasodilatory function and expression levels of Mcp-1, Mip-2, Vcam-1, Icam-1 and Vegf in lung tissue. The ApoE-/- mice exposed to fine and photocatalytic TiO2 had unaltered vasodilatory function and lung tissue inflammatory gene expression. The unaltered NO-dependent vasodilatory function was supported by observations in HUVECs where the NO production was only increased by exposure to nTiO2.ConclusionRepeated exposure to nanosized TiO2 particles was associated with modest plaque progression in ApoE-/- mice. There were no associations between the pulmonary TiO2 exposure and inflammation or vasodilatory dysfunction.
Highlights
The investigation of toxicological effects of nanoparticles is increasingly important due to their growing occupational use and presence as compounds in consumer products
We hypothesised that pulmonary exposure to nanosized particles, compared to fine particle would evoke larger cardiovascular effects, whereas altered vasodilatory function would be blunted by ex vivo treatment with the superoxide dismutase mimic tempol. To this end we investigate plaque progression and vasodilatory function in dyslipidemic and atherosclerosis prone apolipoprotein E knockout (ApoE-/-) mice exposed by intratracheal instillation (i.t.) to three physicochemically different TiO2 particles including nanometer-size coated rutile TiO2, nanometer-size and highly photocatalytic anatase-rich TiO2, and sub-micrometer-size coated rutile TiO2
In this study we show that four repeated i.t. instillations of nanometer-size coated rutile TiO2 (nTiO2) were associated with a modest increase in plaque progression in the aorta of ApoE-/- mice, whereas there was little pulmonary inflammation and only minor effects on vasodilatory function of endothelial and smooth muscle cells in segments after two instillations
Summary
The investigation of toxicological effects of nanoparticles is increasingly important due to their growing occupational use and presence as compounds in consumer products. Pulmonary exposure to carbon-based particles can accelerate plaques progression in animal models [6,7]. Associations between exposure to TiO2 particles and progression of atherosclerosis have not been assessed, whereas pulmonary exposure has been associated with vasomotor dysfunction [8]. Methods: We investigated plaque progression and vasodilatory function in apolipoprotein E knockout (ApoE-/-) mice exposed to TiO2. ApoE-/- mice were intratracheally instilled (0.5 mg/kg bodyweight) with rutile fine TiO2 (fTiO2, 288 nm), photocatalytic 92/8 anatase/rutile TiO2 (pTiO2, 12 nm), or rutile nano TiO2 (nTiO2, 21.6 nm) at 26 and 2 hours before measurement of vasodilatory function in aorta segments mounted in myographs. The progression of atherosclerotic plaques in aorta was assessed in mice exposed to nanosized TiO2 (0.5 mg/kg bodyweight) once a week for 4 weeks. TiO2-induced alterations in nitric oxide (NO) production were assessed in human umbilical vein endothelial cells (HUVECs)
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