title: Titanium dioxide nanoparticles promote arrhythmias via a direct interaction with rat cardiac tissue.
abstract: BACKGROUND
  In light of recent developments in nanotechnologies, interest is growing to better comprehend the interaction of nanoparticles with body tissues, in particular within the cardiovascular system. Attention has recently focused on the link between environmental pollution and cardiovascular diseases. Nanoparticles <50 nm in size are known to pass the alveolar-pulmonary barrier, enter into bloodstream and induce inflammation, but the direct pathogenic mechanisms still need to be evaluated. We thus focused our attention on titanium dioxide (TiO₂) nanoparticles, the most diffuse nanomaterial in polluted environments and one generally considered inert for the human body.
  
  
  METHODS
  We conducted functional studies on isolated adult rat cardiomyocytes exposed acutely in vitro to TiO₂ and on healthy rats administered a single dose of 2 mg/Kg TiO₂ NPs via the trachea. Transmission electron microscopy was used to verify the actual presence of TiO₂ nanoparticles within cardiac tissue, toxicological assays were used to assess lipid peroxidation and DNA tissue damage, and an in silico method was used to model the effect on action potential.
  
  
  RESULTS
  Ventricular myocytes exposed in vitro to TiO₂ had significantly reduced action potential duration, impairment of sarcomere shortening and decreased stability of resting membrane potential. In vivo, a single intra-tracheal administration of saline solution containing TiO₂ nanoparticles increased cardiac conduction velocity and tissue excitability, resulting in an enhanced propensity for inducible arrhythmias. Computational modeling of ventricular action potential indicated that a membrane leakage could account for the nanoparticle-induced effects measured on real cardiomyocytes.
  
  
  CONCLUSIONS
  Acute exposure to TiO₂ nanoparticles acutely alters cardiac excitability and increases the likelihood of arrhythmic events.
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy. monia.savi@unipr.it.|CERT, Center of Excellence for Toxicological Research, Department of Clinical and Experimental Medicine, Via Gramsci 14, Parma, 43126, Italy. monia.savi@unipr.it.
authors.forename: Monia
authors.initials: M
authors.lastname: Savi
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy. stefano.rossi@unipr.it.|CERT, Center of Excellence for Toxicological Research, Department of Clinical and Experimental Medicine, Via Gramsci 14, Parma, 43126, Italy. stefano.rossi@unipr.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Rossi
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy. leonardo.bocchi@unipr.it.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Bocchi
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy. laura.gennaccaro@studenti.unipr.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Gennaccaro
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy. francesca.cacciani@unipr.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cacciani
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy. alessio.perotti@nemo.unipr.it.
authors.forename: Alessio
authors.initials: A
authors.lastname: Perotti
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy. davide.amidani@unipr.it.
authors.forename: Davide
authors.initials: D
authors.lastname: Amidani
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. rossella.alinovi@unipr.it.|CERT, Center of Excellence for Toxicological Research, Department of Clinical and Experimental Medicine, Via Gramsci 14, Parma, 43126, Italy. rossella.alinovi@unipr.it.
authors.forename: Rossella
authors.initials: R
authors.lastname: Alinovi
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. matteo.goldoni@unipr.it.|CERT, Center of Excellence for Toxicological Research, Department of Clinical and Experimental Medicine, Via Gramsci 14, Parma, 43126, Italy. matteo.goldoni@unipr.it.
authors.forename: Matteo
authors.initials: M
authors.lastname: Goldoni
authors.affiliation: Department of Physics and Earth Science, University of Parma, Parma, Italy. irene.aliatis@studenti.unipr.it.
authors.forename: Irene
authors.initials: I
authors.lastname: Aliatis
authors.affiliation: Department of Physics and Earth Science, University of Parma, Parma, Italy. pierpaolo.lottici@unipr.it.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Lottici
authors.affiliation: Department of Physics and Earth Science, University of Parma, Parma, Italy. danilo.bersani@unipr.it.
authors.forename: Danilo
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authors.affiliation: National Research Council- IMEM-CNR, Parma, Italy. mcampani@area.bo.cnr.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Campanini
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. silvana.pinelli@unipr.it.|CERT, Center of Excellence for Toxicological Research, Department of Clinical and Experimental Medicine, Via Gramsci 14, Parma, 43126, Italy. silvana.pinelli@unipr.it.
authors.forename: Silvana
authors.initials: S
authors.lastname: Pinelli
authors.affiliation: Italian Worker Compensation Authority INAIL, ex-ISPESL Monteporzio Catone, Roma, Italy. m.petyx@inail.it.
authors.forename: Marta
authors.initials: M
authors.lastname: Petyx
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. caterina.frati@unipr.it.
authors.forename: Caterina
authors.initials: C
authors.lastname: Frati
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T), University of Parma, Parma, Italy. andrea.gervasi@mail.com.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gervasi
authors.affiliation: Department of Pharmacology, Second University of Naples, Naples, Italy. corrado_urbanek@hotmail.com.
authors.forename: Konrad
authors.initials: K
authors.lastname: Urbanek
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. federico.quaini@unipr.it.
authors.forename: Federico
authors.initials: F
authors.lastname: Quaini
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy. annamaria.buschini@unipr.it.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Buschini
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy. donatella.stilli@unipr.it.
authors.forename: Donatella
authors.initials: D
authors.lastname: Stilli
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy. claudio.rivetti@unipr.it.
authors.forename: Claudio
authors.initials: C
authors.lastname: Rivetti
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy. emilio.macchi@unipr.it.|CERT, Center of Excellence for Toxicological Research, Department of Clinical and Experimental Medicine, Via Gramsci 14, Parma, 43126, Italy. emilio.macchi@unipr.it.
authors.forename: Emilio
authors.initials: E
authors.lastname: Macchi
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. antonio.mutti@unipr.it.|CERT, Center of Excellence for Toxicological Research, Department of Clinical and Experimental Medicine, Via Gramsci 14, Parma, 43126, Italy. antonio.mutti@unipr.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Mutti
authors.affiliation: CERT, Center of Excellence for Toxicological Research, Department of Clinical and Experimental Medicine, Via Gramsci 14, Parma, 43126, Italy. michele.miragoli@humanitasresearch.it.|Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, Milan, 20090, Italy. michele.miragoli@humanitasresearch.it.
authors.forename: Michele
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authors.lastname: Miragoli
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy. massimiliano.zaniboni@unipr.it.|CERT, Center of Excellence for Toxicological Research, Department of Clinical and Experimental Medicine, Via Gramsci 14, Parma, 43126, Italy. massimiliano.zaniboni@unipr.it.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Zaniboni
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D003198:Computer Simulation; D004249:DNA Damage; D056966:Excitation Contraction Coupling / Q000187:drug effects; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects* / Q000503:physiopathology / Q000648:ultrastructure; D019570:Inhalation Exposure / Q000009:adverse effects*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D053768:Metal Nanoparticles / Q000008:administration & dosage / Q000633:toxicity*; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000648:ultrastructure; D017208:Rats, Wistar; D014025:Titanium / Q000008:administration & dosage / Q000633:toxicity*; D023382:Toxicity Tests, Acute
chemical_list: D000393:Air Pollutants; C009495:titanium dioxide; D014025:Titanium