Brain inflammation and Blood Brain Barrier disruption after sub-acute inhalation exposure to titanium dioxide nanoparticle aerosol in aging rats

Notwithstanding potential neurotoxicity of Titanium dioxide nanoparticles (TiO2 NPs), the toxicokinetics and consequences on blood brain barrier (BBB) functions remain poorly characterized. We previously described the biodistribution of intravenous administered TiO2 NPs and highlighted a modulation of BBB physiology associated with neuro-vascular inflammation. To improve risk assessment we needed to evaluate impact on BBB under realistic environmental conditions and to take into account vulnerability status such as age.
Adult and aging rats inhaled a 10mg/m3 concentration of TiO2 NPs aerosol for 28 days, 5 days a week, 6 hours per day. Blood and tissues were collected at various times and Ti levels were measured. In vivo BBB permeability was evaluated as well as expression of structural BBB components on isolated brain micro-vessels. The brain inflammatory profile was assessed by multiplex analysis, RT-PCR and localized on brain slides by immuno-fluorescence.
After a 4-week inhalation period, TiO2 NPs were observed to accumulate in the lungs, with a gradual clearance over the time points measured. No age-related differences in biodistribution were noted in the current studies. Moreover, we reported an age dependent increase in BBB permeability which underscores the brain vulnerability of aging population. We also noted an age-dependent modulation of BBB integrity parameters suggesting a BBB breakdown in vulnerable aging rats. Modulation in expressions of ABC and SLC transporters at the BBB level were highlighted suggesting alteration of detoxification function of the BBB. Ti biopersistence in lung tissues was associated with significant increase of cytokines/chemokines in the brain such as interleukine 1â, interferon ã or fractalkine. These brain inflammation markers suggest indirect induction of brain inflammation that seems dependent on circulating mediators. Despite lack of CNS translocation, we suggested a link between the presence of TiO2 NPs in organs and dysregulation of BBB physiology.