Multi-walled carbon nanotube-physicochemical properties predict the systemic acute phase response following pulmonary exposure in mice

Abstract

Pulmonary exposure to multi-walled carbon nanotubes (MWCNTs) has been linked to an increased risk of developing cardiovascular disease in addition to the well-documented physicochemical-dependent adverse lung effects. A proposed mechanism is through a strong and sustained pulmonary secretion of acute phase proteins to the blood. We identified physicochemical determinants of MWCNT-induced systemic acute phase response by analyzing effects of pulmonary exposure to 14 commercial, well-characterized MWCNTs in female C57BL/6J mice pulmonary exposed to 0, 6, 18 or 54 μg MWCNT/mouse. Plasma levels of acute phase response proteins serum amyloid A1/2 (SAA1/2) and SAA3 were determined on day 1, 28 or 92. Expression levels of hepatic Saa1 and pulmonary Saa3 mRNA levels were assessed to determine the origin of the acute phase response proteins. Pulmonary Saa3 mRNA expression levels were greater and lasted longer than hepatic Saa1 mRNA expression. Plasma SAA1/2 and SAA3 protein levels were related to time and physicochemical properties using adjusted, multiple regression analyses. SAA3 and SAA1/2 plasma protein levels were increased after exposure to almost all of the MWCNTs on day 1, whereas limited changes were observed on day 28 and 92. SAA1/2 and SAA3 protein levels did not correlate and only SAA3 protein levels correlated with neutrophil influx. The multiple regression analyses revealed a protective effect of MWCNT length on SAA1/2 protein level on day 1, such that a longer length resulted in lowered SAA1/2 plasma levels. Increased SAA3 protein levels were positively related to dose and content of Mn, Mg and Co on day 1, whereas oxidation and diameter of the MWCNTs were protective on day 28 and 92, respectively. The results of this study reveal very differently controlled pulmonary and hepatic acute phase responses after MWCNT exposure. As the responses were influenced by the physicochemical properties of the MWCNTs, this study provides the first step towards designing MWCNT that induce less SAA.

Occupational exposure during handling and loading of halloysite nanotubes – A case study of counting nanofibers

“…Unmodified HNTs have shown to induce very low cytotoxicity in the following human cell types: carcinoma cells, peripheral blood lymphocytes, primary umbilical vein endothelial cells, intestinal cells, and epithelial cells (Ahmed et al, 2015;Vergaro et al, 2010;Nan et al, 2008;Lai et al, 2013). However, as HNTs have similar dimensions as short carbon nanotubes (CNTs), they may potentially cause pulmonary inflammation and acute phase response following pulmonary exposure as previously reported for CNTs (Saber et al, 2013(Saber et al, , 2014Poulsen et al, 2015Poulsen et al, , 2017Jaurand, 2017).…”

“…For mineral fibers with a diameter in the range of 0.15 and 2 μm and a length above 2 μm, fibrosis correlated with the surface area of the fibers (Lippmann, 1988(Lippmann, , 2014Stayner et al, 2008Stayner et al, , 2013Hwang et al, 2014). While airway exposure to short carbon nanotubes,~0.3 μm in length, was shown to cause fibrosis and long lasting inflammation (Pauluhn, 2010;Poulsen et al, 2015Poulsen et al, , 2016Poulsen et al, , 2017.…”

From the Roundabout of Molecular Events to Nanomaterial-Induced Chronic Inflammation Prediction

“…This indicates an important interaction between nanoparticles and cholesterol, which is reflected in strongly upregulated cholesterol and lipid synthesis pathways in epithelial cells in vitro ( Fig. 2d heatmap, SI section S2d), as well as in mouse lungs in vivo (SI section S2d) 26,30,31 . In the case of cholesterol-depleted plasma membranes, the majority of nanoparticles cross the plasma membranes on a timescale of minutes, resulting in a fine distribution of particles inside the cell.…”

Physicochemical predictors of Multi‐Walled Carbon Nanotube–induced pulmonary histopathology and toxicity one year after pulmonary deposition of 11 different Multi‐Walled Carbon Nanotubes in mice

“…Some MWCNT induced fibrosis or changes related to fibrosis, but these changes were largely dose‐dependent . In addition, increased plaque progression, increased blood levels of proteins related to plaque progression and changes in secondary organs such as the liver have also been reported after pulmonary exposure to MWCNT . However, in order to identify persistent pathological changes, long‐term studies are needed.…”

“…The portfolio of MWCNT was selected to include a broad variety of physicochemical properties: a set of thin and entangled, a set of longer and needlelike, and a set of surface modified vs pristine MWCNT. Several of these MWCNT have previously been included in our 90‐day studies, thus enabling comparison across time‐points. These studies used the same route of exposure as in the present study, and they investigated physicochemical determinants of more acute toxicological effects in terms of pulmonary neutrophil influx, genotoxicity and induction of the acute phase response.…”