Changes in cholesterol homeostasis and acute phase response link pulmonary exposure to multi-walled carbon nanotubes to risk of cardiovascular disease

Abstract

Adverse lung effects following pulmonary exposure to multi-walled carbon nanotubes (MWCNTs) are well documented in rodents. However, systemic effects are less understood. Epidemiological studies have shown increased cardiovascular disease risk after pulmonary exposure to airborne particles, which has led to concerns that inhalation exposure to MWCNTs might pose similar risks. We analyzed parameters related to cardiovascular disease, including plasma acute phase response (APR) proteins and plasma lipids, in female C57BL/6 mice exposed to a single intratracheal instillation of 0, 18, 54 or 162μg/mouse of small, entangled (CNTSmall, 0.8±0.1μm long) or large, thick MWCNTs (CNTLarge, 4±0.4μm long). Liver tissues and plasma were harvested 1, 3 and 28days post-exposure. In addition, global hepatic gene expression, hepatic cholesterol content and liver histology were used to assess hepatic effects. The two MWCNTs induced similar systemic responses despite their different physicochemical properties. APR proteins SAA3 and haptoglobin, plasma total cholesterol and low-density/very low-density lipoprotein were significantly increased following exposure to either MWCNTs. Plasma SAA3 levels correlated strongly with pulmonary Saa3 levels. Analysis of global gene expression revealed perturbation of the same biological processes and pathways in liver, including the HMG-CoA reductase pathway. Both MWCNTs induced similar histological hepatic changes, with a tendency towards greater response following CNTLarge exposure. Overall, we show that pulmonary exposure to two different MWCNTs induces similar systemic and hepatic responses, including changes in plasma APR, lipid composition, hepatic gene expression and liver morphology. The results link pulmonary exposure to MWCNTs with risk of cardiovascular disease.

Surface modification does not influence the genotoxic and inflammatory effects of TiO2nanoparticles after pulmonary exposure by instillation in mice

“…Pulmonary Saa3 mRNA levels were used as a biomarker of pulmonary acute phase response (23,24), and hepatic Saa1 mRNA levels were used as biomarker of hepatic acute phase response (25,37). …”

“…Interestingly, an accompanying hepatic acute phase response was observed following i.t. to two different carbon nanotubes (25) and to a much lesser extent after exposure to another TiO 2 NPs (10) and even less after pulmonary exposure to carbon black NPs (28). Taken together, our results may support the notion that pulmonary and systemic acute phase responses constitute a signalling pathway between particle-induced lung inflammation and cardiovascular health effects (24).…”

“…Genotoxicity was assessed as DNA strand breaks determined by comet assay in BAL cells, lung and liver. The biological markers and time points were chosen to enable comparison of adverse health effect with other NPs tested in our lab with the same set-up and increase knowledge of prediction the adverse effects of other NMs (2,10,15,17,25–31). …”

Acute and subacute pulmonary toxicity and mortality in mice after intratracheal instillation of ZnO nanoparticles in three laboratories

“…Preparation of broncho-alveolar lavage fluid (BALF) was performed as previously described [30] . Briefly, exsanguination was caused by withdrawal of blood from a heart puncture.…”

2-amino-1-methyl-6-phenylimidazo(4,5-b) pyridine (PhIP) induces gene expression changes in JAK/STAT and MAPK pathways related to inflammation, diabetes and cancer

“…SAA1 encodes a member of the serum amyloid A family of apolipoproteins, which is a major acute phase protein that is highly expressed in response to inflammation and tissue injury [38, 39]. SAA1 also plays an important role in high density lipoprotein (HDL) metabolism and cholesterol homeostasis [40]. High levels of this protein are associated with chronic inflammatory diseases [38].…”