Tissue biodistribution of intravenously administrated titanium dioxide nanoparticles revealed blood-brain barrier clearance and brain inflammation in rat.
BACKGROUND
Notwithstanding increasing knowledge of titanium dioxide nanoparticles (TiO2 NPs) passing through biological barriers, their biodistribution to the central nervous system (CNS) and potential effects on blood-brain barrier (BBB) physiology remain poorly characterized.


METHODS
Here, we report time-related responses from single-dose intravenous (IV) administration of 1 mg/kg TiO2 NPs to rats, with particular emphasis on titanium (Ti) quantification in the brain. Ti content in tissues was analyzed using inductively coupled plasma mass spectrometry. Integrity and functionality of the BBB as well as brain inflammation were characterized using a panel of methods including RT-PCR, immuno-histo chemistry and transporter activity evaluation.


RESULTS
Biokinetic analysis revealed Ti biopersistence in liver, lungs and spleen up to one year after TiO2 NPs administration. A significant increase of Ti in the brain was observed at early end points followed by a subsequent decrease. In-depth analysis of Ti in the total brain demonstrated quantitative Ti uptake and clearance by brain microvasculature endothelial cells (BECs) with minimal translocation in the brain parenchyma. The presence of Ti in the BECs did not affect BBB integrity, despite rapid reversible modulation of breast cancer resistance protein activity. Ti biopersistence in organs such as liver was associated with significant increases of tight junction proteins (claudin-5 and occludin), interleukin 1β (IL-1β), chemokine ligand 1 (CXCL1) and γ inducible protein-10 (IP-10/CXCL10) in BECs and also increased levels of IL-1β in brain parenchyma despite lack of evidence of Ti in the brain. These findings mentioned suggest potential effect of Ti present at a distance from the brain possibly via mediators transported by blood. Exposure of an in vitro BBB model to sera from TiO2 NPs-treated animals confirmed the tightness of the BBB and inflammatory responses.


CONCLUSIONS
Overall, these findings suggest the clearance of TiO2 NPs at the BBB with persistent brain inflammation and underscore the role of Ti biopersistence in organs that can exert indirect effects on the CNS dependent on circulating factors.
CEA, Direction des Sciences du Vivant, iBiTec-S, Service de Pharmacologie et d'Immunoanalyse, Equipe Pharmacologie Neurovasculaire, 91191, Gif-sur-Yvette, France.
Clémence
C
Disdier
INRS, Département Polluants et Santé, Rue du Morvan, CS 60027, 54519, Vandœuvre Cedex, France.
Jérôme
J
Devoy
CEA, Direction des Sciences du Vivant, iBiTec-S, Service de Pharmacologie et d'Immunoanalyse, Equipe Pharmacologie Neurovasculaire, 91191, Gif-sur-Yvette, France.
Anne
A
Cosnefroy
INRS, Département Polluants et Santé, Rue du Morvan, CS 60027, 54519, Vandœuvre Cedex, France.
Monique
M
Chalansonnet
DSM, IRAMIS, NIMBE (UMR 3685), laboratory of Nanometric Structures, CEA Saclay, 91191, Gif/Yvette, France.
Nathalie
N
Herlin-Boime
Laboratoire de Chimie Physique, UMR CNRS 8000, Université de Paris-Sud, 91405, Orsay, France.
Emilie
E
Brun
Department of Biological Sciences, University of North Texas, Denton, TX, USA.
Amie
A
Lund
CEA, Direction des Sciences du Vivant, iBiTec-S, Service de Pharmacologie et d'Immunoanalyse, Equipe Pharmacologie Neurovasculaire, 91191, Gif-sur-Yvette, France. aloise.mabondzo@cea.fr.
Aloïse
A
Mabondzo
D000818:Animals; D001812:Blood-Brain Barrier; D004660:Encephalitis / Q000139:chemically induced*; D007275:Injections, Intravenous; D053768:Metal Nanoparticles; D051381:Rats; D014018:Tissue Distribution; D014025:Titanium / Q000008:administration & dosage / Q000493:pharmacokinetics*
C009495:titanium dioxide; D014025:Titanium