title: TiO2 nanoparticles tested in a novel screening whole human blood model of toxicity trigger adverse activation of the kallikrein system at low concentrations.
abstract: There is a compelling need to understand and assess the toxicity of industrially produced nanoparticles (NPs). In order to appreciate the long-term effects of NPs, sensitive human-based screening tests that comprehensively map the NP properties are needed to detect possible toxic mechanisms. Animal models can only be used in a limited number of test applications and are subject to ethical concerns, and the interpretation of experiments in animals is also distorted by the species differences. Here, we present a novel easy-to-perform highly sensitive whole-blood model using fresh non-anticoagulated human blood, which most justly reflects complex biological cross talks in a human system. As a demonstrator of the tests versatility, we evaluated the toxicity of TiO2 NPs that are widely used in various applications and otherwise considered to have relatively low toxic properties. We show that TiO2 NPs at very low concentrations (50 ng/mL) induce strong activation of the contact system, which in this model elicits thromboinflammation. These data are in line with the finding of components of the contact system in the protein corona of the TiO2 NPs after exposure to blood. The contact system activation may lead to both thrombotic reactions and generation of bradykinin, thereby representing fuel for chronic inflammation in vivo and potentially long-term risk of autoimmunity, arteriosclerosis and cancer. These results support the notion that this novel whole-blood model represents an important contribution to testing of NP toxicity.
authors.affiliation: Division of CBRN Defence and Security, Swedish Defence Research Agency, Sweden.
authors.forename: Barbro
authors.initials: B
authors.lastname: Ekstrand-Hammarström
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden.
authors.forename: Jaan
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden.
authors.forename: Padideh
authors.initials: P
authors.lastname: Davoodpour
authors.affiliation: Linnæus Centre for Biomaterials Chemistry, Linnæus University, SE-391 82 Kalmar, Sweden.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Sandholm
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden; Linnæus Centre for Biomaterials Chemistry, Linnæus University, SE-391 82 Kalmar, Sweden.
authors.forename: Kristina N
authors.initials: KN
authors.lastname: Ekdahl
authors.affiliation: Division of CBRN Defence and Security, Swedish Defence Research Agency, Sweden; Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Bucht
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden. Electronic address: bo.nilsson@igp.uu.se.
authors.forename: Bo
authors.initials: B
authors.lastname: Nilsson
mesh_terms: D000327:Adsorption; D000990:Antithrombin III / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D003165:Complement System Proteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007610:Kallikreins / Q000097:blood*; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity* / Q000648:ultrastructure; D010447:Peptide Hydrolases / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013997:Time Factors; D014025:Titanium / Q000737:chemistry / Q000633:toxicity*
chemical_list: D001798:Blood Proteins; C046193:antithrombin III-protease complex; C009495:titanium dioxide; D000990:Antithrombin III; D003165:Complement System Proteins; D014025:Titanium; D010447:Peptide Hydrolases; D007610:Kallikreins
keywords: Complement; Contact system; Nanoparticles; P25; Platelets