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.

Notwithstanding potential neurotoxicity of inhaled titanium dioxide nanoparticles (TiO2 NPs), the toxicokinetics and consequences on blood-brain barrier (BBB) function remain poorly characterized. To improve risk assessment, we need to evaluate the impact on BBB under realistic environmental conditions and take into account vulnerability status such as age. 12–13 week and 19-month-old male rats were exposed by inhalation to 10 mg/m3 of TiO2 nano-aerosol (6 hrs/day, 5 day/week, for 4 weeks). We showed an age-dependent modulation of BBB integrity parameters suggesting increased BBB permeability in aging rats. This alteration was associated with a significant increase of cytokines/chemokines in the brain, including interleukin-1β, interferon-γ, and fractalkine as well as a decreased expression of synaptophysin, a neuronal activity marker. These observations, in absence of detectable titanium in the brain suggest that CNS-related effects are mediated by systemic-pathway. Moreover, observations in terms of BBB permeability and brain inflammation underline age susceptibility. Even if TiO2 NPs were not evidenced in the brain, we observed an association between the exposure to TiO2 NPs and the dysregulation of BBB physiology associated with neuroinflammation and decreased expression of neuronal activity marker, which was further exacerbated in the brain of aged animal’s.

We investigated in adult rats whether a relatively short exposure to a novel odour can lead to changes in reactivity of olfactory bulb principal neurons. Naive rats were exposed to isoamyl acetate for 20 min per day either for 6 consecutive days or for a single 20-min exposure. Control group was non-exposed. Under anaesthesia, responsiveness of each recorded single mitral/tufted cell was tested towards isoamyl acetate and four other odours. Results show that the proportion of responding cells in the exposed groups decreased drastically when compared to controls. In the two experimental groups recorded 24 h following the last exposure, mitral/tufted cells show a significant decrease in the number of excitatory responses. In parallel, the number of non-responsive cells increased by at least a fourfold factor. This decrease in reactivity was not selective towards the odour used during the exposure but concerned any of the five test-odours presented during recordings. Finally, this lower responsiveness was long lasting as it was still observed 10 days after the end of the last exposure. This preliminary study points out the importance of even limited sensory experience in neural representation of odours.

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