title: 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.
authors.affiliation: National Research Centre for the Working Environment, DK-2100 Copenhagen, Denmark; Department of Science, Systems and Models, Roskilde University, DK-4000 Roskilde, Denmark. Electronic address: spo@nrcwe.dk.
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Poulsen
authors.affiliation: National Research Centre for the Working Environment, DK-2100 Copenhagen, Denmark. Electronic address: ats@nrcwe.dk.
authors.forename: Anne T
authors.initials: AT
authors.lastname: Saber
authors.affiliation: National Food Institute, Technical University of Denmark, Søborg, Denmark. Electronic address: almo@food.dtu.dk.
authors.forename: Alicja
authors.initials: A
authors.lastname: Mortensen
authors.affiliation: Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland. Electronic address: szarek@uwm.edu.pl.
authors.forename: Józef
authors.initials: J
authors.lastname: Szarek
authors.affiliation: Environmental and Radiation Health Sciences Directorate, Health Canada, Ottawa, Ontario K1A 0K9, Canada. Electronic address: dongmei.wu@hc-sc.gc.ca.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wu
authors.affiliation: Environmental and Radiation Health Sciences Directorate, Health Canada, Ottawa, Ontario K1A 0K9, Canada. Electronic address: andrew.williams@hc-sc.gc.ca.
authors.forename: Andrew
authors.initials: A
authors.lastname: Williams
authors.affiliation: Department of Science, Systems and Models, Roskilde University, DK-4000 Roskilde, Denmark. Electronic address: oa@ruc.dk.
authors.forename: Ole
authors.initials: O
authors.lastname: Andersen
authors.affiliation: National Research Centre for the Working Environment, DK-2100 Copenhagen, Denmark. Electronic address: nrj@nrcwe.dk.
authors.forename: Nicklas R
authors.initials: NR
authors.lastname: Jacobsen
authors.affiliation: Environmental and Radiation Health Sciences Directorate, Health Canada, Ottawa, Ontario K1A 0K9, Canada. Electronic address: carole.yauk@hc-sc.gc.ca.
authors.forename: Carole L
authors.initials: CL
authors.lastname: Yauk
authors.affiliation: National Research Centre for the Working Environment, DK-2100 Copenhagen, Denmark; Department of Public Health, University of Copenhagen, DK-1014 Copenhagen K, Denmark. Electronic address: hwa@nrcwe.dk.
authors.forename: Håkan
authors.initials: H
authors.lastname: Wallin
authors.affiliation: Environmental and Radiation Health Sciences Directorate, Health Canada, Ottawa, Ontario K1A 0K9, Canada. Electronic address: sabina.halappanavar@hc-sc.gc.ca.
authors.forename: Sabina
authors.initials: S
authors.lastname: Halappanavar
authors.affiliation: National Research Centre for the Working Environment, DK-2100 Copenhagen, Denmark; Department of Micro- and Nanotechnology, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark. Electronic address: ubv@nrcwe.dk.
authors.forename: Ulla
authors.initials: U
authors.lastname: Vogel
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism*; D000210:Acute-Phase Reaction / Q000097:blood / Q000139:chemically induced* / Q000235:genetics; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood / Q000139:chemically induced* / Q000235:genetics; D002784:Cholesterol / Q000097:blood*; D005260:Female; D005786:Gene Expression Regulation; D006706:Homeostasis; D018836:Inflammation Mediators / Q000097:blood; D019570:Inhalation Exposure / Q000009:adverse effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D037742:Nanotubes, Carbon / Q000633:toxicity*; D010316:Particle Size; D012333:RNA, Messenger / Q000378:metabolism; D018570:Risk Assessment; D013997:Time Factors
chemical_list: D000209:Acute-Phase Proteins; D015415:Biomarkers; D018836:Inflammation Mediators; D037742:Nanotubes, Carbon; D012333:RNA, Messenger; D002784:Cholesterol
keywords: Acute phase response; Atherosclerosis; Histology; Liver; Nanotoxicology; Toxicogenomics