Brain Inflammation, Blood Brain Barrier dysfunction and Neuronal Synaptophysin Decrease after Inhalation Exposure to Titanium Dioxide Nano-aerosol in Aging Rats

International audienceNotwithstanding potential neurotoxicity of inhaled titanium dioxide nanoparticles (TiO 2 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/m 3 of TiO 2 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 TiO 2 NPs were not evidenced in the brain, we observed an association between the exposure to TiO 2 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. Due to their remarkable properties, nanoparticles (NPs) could potentially be used in a large array of applications , from electronics to medicine. Nanomaterials are currently being used in the production or manufacturing processes of a number of commercial products 1. In this context, there are increasing concerns regarding the potential adverse effects of NPs on human health. Among the wide variety of nanomaterials, titanium dioxide NPs (TiO 2 NPs) are produced in a large industrial scale and can be found in commercial products such as paints, food additives 2 , cosmetics 3 , and environmental decontamination systems 4. Published data from studies in rodents show that TiO 2 NPs can cross the epithelial barriers (nasal, bronchial, alveolar, gastro-intestinal) and enter the blood circulation from the respiratory and the gastro-intestinal tracts 5–10. After inhalation exposure , there is larger concern about translocation of NPs into the brain, either directly via the olfactory pathway or indirectly across the blood brain barrier (BBB). Indeed, ambient air particles and NPs have been previously demonstrated to translocate into the brain after inhalation, and thus may potentially influence the central nervous system (CNS). For example, translocation of 36 nm 13 C particles was observed in the olfactory bulb of rats, most likely originating from entry via the olfactory mucosa of the nose 11. Brain translocation of gold NPs were also observed in a rat exposure model 12 , and 15–20 nm iridium NPs could be detected in the rat brain up to 6 months after inhalation exposure 13,14. Despite these observations, the effects of NPs on the CNS under realisticMalgré les études suggérant une neurotoxicité potentielle des nanoparticules de dioxyde de titane (NPs TiO2), peu de données portent sur la toxico-cinétique de ces nanoparticules et sur leur impact sur la barrière hémato-encéphalique (BHE). Afin d’améliorer cette évaluation du risque, il est nécessaire d’étudier l’impact des NPs TiO2 sur la BHE dans des conditions d’exposition réalistes et de prendre en considération un paramètre important qui est la vulnérabilité liée à l’âge. Des rats âgés de 12 à 13 semaines et de 19 mois ont été exposés par inhalation à un nano-aérosol de TiO2 à la concentration de 10 mg/m3, 6 heures/jour, 5 jours/semaine pendant 4 semaines. Il a été montré, une modulation des paramètres d’intégrité de la BHE en fonction de l’âge de l’animal. En effet, chez les rats âgés, il a été constaté une augmentation de la perméabilité de la BHE. Cette altération est associée à une augmentation significative des cytokines/chimiokines dans le cerveau (interleukine 1 b, interféron g, et fractalkine) mais également à une diminution de l’expression de la synaptophysine, marqueur de l’activité neuronale. En l’absence de titane détectable dans le cerveau, ces données suggèrent que les effets observés au niveau du système nerveux central sont transmis par voie systémique. Malgré l’absence de translocation cérébrale, un lien existe entre l’exposition aux NPs TIO2 et au dysfonctionnement de la BHE associé à une neuro-inflammation et une diminution de l’expression de l’activité neuronale qui est exacerbée chez les rats âgés