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. 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. 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. 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.

中文翻译：

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静脉给予二氧化钛纳米颗粒的组织生物分布显示大鼠血脑屏障清除和脑部炎症。

尽管对通过生物屏障的二氧化钛纳米粒子（TiO2 NPs）的了解不断增加，但它们在中枢神经系统（CNS）中的生物分布以及对血脑屏障（BBB）生理学的潜在影响仍然不明确。在这里，我们报告了从1毫克/千克TiO2 NP的单剂量静脉内（IV）给药到大鼠的与时间有关的反应，特别强调了大脑中钛（Ti）的定量。使用感应耦合等离子体质谱法分析组织中的钛含量。使用包括RT-PCR，免疫组织化学和转运蛋白活性评估在内的一系列方法对BBB的完整性和功能性以及脑部炎症进行了表征。生物动力学分析表明，施用TiO2 NP后长达一年的时间，钛在肝脏，肺和脾脏中的生物持久性。在早期终点观察到大脑中Ti的显着增加，随后下降。对全脑中Ti的深入分析表明，脑微脉管内皮细胞（BEC）可定量定量摄取和清除Ti，且在脑实质中的转运极少。尽管快速可逆地调节了乳腺癌抗性蛋白的活性，但BEC中Ti的存在并未影响BBB的完整性。钛在肝脏等器官中的生物持久性与紧密连接蛋白（claudin-5和occludin），白介素1β（IL-1β），趋化因子配体1（CXCL1）和γ诱导型蛋白10（IP-10 / CXCL10）的显着增加有关尽管缺乏大脑中Ti的证据，但在BEC中也是如此，并且脑实质中IL-1β的水平也升高。提到的这些发现表明，距大脑较远的位置存在Ti的潜在作用，可能是通过血液转运的介体。从TiO2 NPs处理的动物的血清中暴露体外BBB模型，证实了BBB的紧密性和炎症反应。总体而言，这些发现表明，BBB处的TiO2 NPs清除具有持续性脑部炎症，并强调了Ti生物持久性在器官中的作用，这种作用可对依赖循环因素的CNS产生间接影响。