Abstract

BackgroundNotwithstanding 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.MethodsHere, 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.ResultsBiokinetic 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.ConclusionOverall, 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-015-0102-8) contains supplementary material, which is available to authorized users.

Highlights

  • 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

  • Characterization of titanium dioxide nanoparticles Morphology and size of TiO2 NPs in stock suspensions were determined by Transmission Electron Microscopy (TEM)

  • Those measurements highlight the important tendency of TiO2 NPs to aggregate/agglomerate as soon as they are in suspension

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Summary

Introduction

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. The brain is well protected by the blood brain barrier (BBB), which contains cells of several types: brain endothelial cells (BECs), astrocytes, and pericytes [7,8,9,10,11] These cells communicate closely to guarantee a physical and functional barrier between the blood and the central nervous system (CNS): tight junctions connecting endothelial cells and many transporters including two major ATP-driven drug efflux pumps, the P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) [12,13,14]. This neurovascular unit regulates distribution of xenobiotics to the brain

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