Biokinetic comparison after single I.V. administration or chronic aerosol inhalation of TiO2 nanoparticles : impact on blood-brain barrier

Notwithstanding the translocation of reported TiO2 nanoparticles (NPs) through biological barriers, the bio-distribution of TiO2NPs to the CNS and impact on the functions of the BBB remain poorly characterized. We report such evidence.
Adult rats received a single 1mg/kg iv dose of TiO2NPs or inhaled for 28 days, 5 days a week, 6h per days a 10mg/m3 concentration of aerosol. Blood and tissues were collected at various times. Ti levels were measured using ICP-MS. In vivo permeability and transport activities of the BBB were evaluated. The expression of structural components of the BBB and the brain inflammatory profile were assessed by RTPCR on isolated brain micro-vessels.
After iv administration, data revealed a rapid bio-distribution of Ti to all the tissues with a bioaccumulation in liver up to one year; we also demonstrated a Ti uptake until 24h followed clearance by brain endothelial cells (BECs) without translocation in the CNS. After chronic inhalation (CI), Ti was only found in the lungs. Despite lack of Ti in the brains 24h after IV and at all-time point after inhalation, modification of the BBB physiology was highlighted. In the case of iv, the BBB integrity was maintained whereas we noticed a modulation in BECs of claudin-5, occludin, IL-1 and CXCl1 mRNAs expression as well as a BCRP activity. After CI, we also noticed a reversible modulation of BCRP activity at early time point and 28 days after the end of exposition, an increase in the BBB impermeability.
These data indicate a different target organ depending on the administration route. In both exposure routes, we highlighted a lack of TiO2NPs translocation to the CNS with dysfunction of the BBB as well as cytokines/chemokines up regulation suggesting a relationship between BBB modulation and Ti bioaccumulation in other tissues through secretion of mediators.