Systemic distribution of single-walled carbon nanotubes in a novel model: alteration of biochemical parameters, metabolic functions, liver accumulation, and inflammation in vivo.
The increasing use of carbon nanotubes (CNTs) in several industrial applications raises concerns on their potential toxicity due to factors such as tissue penetrance, small dimensions, and biopersistence. Using an in vivo model for CNT environmental exposure, mimicking CNT exposition at the workplace, we previously found that CNTs rapidly enter and disseminate in the organism, initially accumulating in the lungs and brain and later reaching the liver and kidneys via the bloodstream in CD1 mice. Here, we monitored and traced the accumulation of single-walled CNTs (SWCNTs), administered systemically in mice, in different organs and the subsequent biological responses. Using the novel in vivo model, MITO-Luc bioluminescence reporter mice, we found that SWCNTs induce systemic cell proliferation, indicating a dynamic response of cells of both bone marrow and the immune system. We then examined metabolic (water/food consumption and dejections), functional (serum enzymes), and morphological (organs and tissues) alterations in CD1 mice treated with SWCNTs, using metabolic cages, performing serum analyses, and applying histological, immunohistochemical, and ultrastructural (transmission electron microscopy) methods. We observed a transient accumulation of SWCNTs in the lungs, spleen, and kidneys of CD1 mice exposed to SWCNTs. A dose- and time-dependent accumulation was found in the liver, associated with increases in levels of aspartate aminotransferase, alanine aminotransferase and bilirubinemia, which are metabolic markers associated with liver damage. Our data suggest that hepatic accumulation of SWCNTs associated with liver damage results in an M1 macrophage-driven inflammation.
Vascular Biology and Angiogenesis, Scientific and Technology Pole, IRCCS MultiMedica, Milano.
Elisa
E
Principi
Department of Biotechnology and Life Sciences, University of Insubria, Varese.
Rossana
R
Girardello
Vascular Biology and Angiogenesis, Scientific and Technology Pole, IRCCS MultiMedica, Milano.
Antonino
A
Bruno
Department of Research, Advanced Diagnosis and Innovation, Regina Elena National Cancer Institute, Rome.
Isabella
I
Manni
Department of Biotechnology and Life Sciences, University of Insubria, Varese.
Elisabetta
E
Gini
Vascular Biology and Angiogenesis, Scientific and Technology Pole, IRCCS MultiMedica, Milano.
Arianna
A
Pagani
Department of Biotechnology and Life Sciences, University of Insubria, Varese.
Annalisa
A
Grimaldi
Department of Neuroscience, Ophthalmology and Genetics, University of Genoa, Genoa.
Federico
F
Ivaldi
Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
Terenzio
T
Congiu
Vascular Biology and Angiogenesis, Scientific and Technology Pole, IRCCS MultiMedica, Milano.
Daniela
D
De Stefano
Department of Research, Advanced Diagnosis and Innovation, Regina Elena National Cancer Institute, Rome.
Giulia
G
Piaggio
Department of Biotechnology and Life Sciences, University of Insubria, Varese.
Magda
M
de Eguileor
Vascular Biology and Angiogenesis, Scientific and Technology Pole, IRCCS MultiMedica, Milano; Department of Biotechnology and Life Sciences, University of Insubria, Varese.
Douglas M
DM
Noonan
Vascular Biology and Angiogenesis, Scientific and Technology Pole, IRCCS MultiMedica, Milano.
Adriana
A
Albini
D000818:Animals; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D037742:Nanotubes, Carbon / Q000737:chemistry* / Q000633:toxicity*; D060888:Real-Time Polymerase Chain Reaction; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution
D037742:Nanotubes, Carbon; D008156:Luciferases
Kupffer cells; hepatic function; inflammation; metabolism; mouse models; nanotoxicity; single-walled carbon nanotubes