Pulmonary and hemostatic toxicity of multi-walled carbon nanotubes and zinc oxide nanoparticles after pulmonary exposure in Bmal1 knockout mice

Abstract

BackgroundPulmonary exposure to nanoparticles (NPs) may affect, in addition to pulmonary toxicity, the cardiovascular system such as procoagulant effects, vascular dysfunction and progression of atherosclerosis. However, only few studies have investigated hemostatic effects after pulmonary exposure.MethodsWe used Bmal1 (brain and muscle ARNT-like protein-1) knockout (Bmal1−/−) mice which have a disturbed circadian rhythm and procoagulant phenotype, to study the pulmonary and hemostatic toxicity of multi-walled carbon nanotubes (MWCNTs) and zinc oxide (ZnO) NPs after subacute pulmonary exposure. Bmal1−/− and wild-type (Bmal1+/+) mice were exposed via oropharyngeal aspiration, once a week, during 5 consecutive weeks, to a cumulative dose of 32 or 128 μg MWCNTs or 32 or 64 μg ZnO NPs.ResultsMWCNTs caused a pronounced inflammatory response in the lung with increased cell counts in the broncho-alveolar lavage and increased secretion of interleukin-1β and cytokine-induced neutrophil chemo-attractant (KC), oxidative stress (increased ratio of oxidized versus reduced glutathione and decreased total glutathione) as well as anemic and procoagulant effects as evidenced by a decreased prothrombin time with increased fibrinogen concentrations and coagulation factor (F)VII. In contrast, the ZnO NPs seemed to suppress the inflammatory (decreased neutrophils in Bmal1−/− mice) and oxidative response (increased total glutathione in Bmal1−/− mice), but were also procoagulant with a significant increase of FVIII. The procoagulant effects, as well as the significant correlations between the pulmonary endpoints (inflammation and oxidative stress) and hemostasis parameters were more pronounced in Bmal1−/− mice than in Bmal1+/+ mice.ConclusionsThe Bmal1−/− mouse is a sensitive animal model to study the procoagulant effects of engineered NPs. The MWCNTs and ZnO NPs showed different pulmonary toxicity but both NPs induced procoagulant effects, suggesting different mechanisms of affecting hemostasis. However, the correlation analysis suggests a causal association between the observed pulmonary and procoagulant effects.

Bio‐effect of nanoparticles in the cardiovascular system

“…Importantly, there was a close association between the level of pulmonary inflammation and cardiac damage, such as myocarditis and myocardial cell swelling, and the lesions of the coronary artery. 19,30 Luyts et al 132 reported that MWCNTs induced anemic and procoagulant effects characterized by a decreased prothrombin time and increased Fbg and coagulation factor (F)VII levels were in Bmal1 (brain and muscle ARNT-like protein-1) knockout (Bmal1(-/-)) mice, which was accompanied by a profound inflammatory response in the lung, as [75] reflected by the increased cell counts in the BALF, and elevated release of IL-1b and the cytokine-induced neutrophil chemo-attractant (KC). ZnO NPs elicited an increase in the levels of the total number of cells, neutrophils, LDH levels and total protein levels in the BALF, and caused pulmonary inflammatory pathology in SD rats.…”

Nanotechnology based anti-infectives to fight microbial intrusions

“…It has property to get aggregated into microscopic bundles followed by formation of small agglomerate (Pauluhn and Rosenbruch 2014). These particles if inhaled causes the inflammation (Luyts et al 2014), epithelioid granulomas (Sanchez et al 2011), and fibrosis in lungs, pulmonary blockage and asphyxiation (Siddiqui et al 2012;Mercer et al 2013). In the past, studies performed on rat lung inhalation toxicity of carbon nanotube indicated that their toxicity increase with the decrease in their sizes and increasing surface area (Madani et al 2013).…”

Pulmonary and hemostatic toxicity of multi-walled carbon nanotubes and zinc oxide nanoparticles after pulmonary exposure in Bmal1 knockout mice

“…Thereafter, the stock concentrations were diluted to obtain the final concentrations for exposure: 160 and 640 μg/ml MWCNT (corresponding to 6.4 and 25.6 μg/dosing) and 256 and 512 μg/ml ZnO (corresponding to 6.4 and 12.8 μg/dosing). Based on preliminary studies, we chose to lower the dose of ZnO NPs exposure since the pulmonary administration of 25 μg ZnO NPs induced an acute mortality, whereas a dose of 12.5 μg did not [63].…”