The unique physico-chemical properties of engineered nanomaterials influence their ability to aerosolize, and thus inhalation exposure is of major occupational concern. Inhaled nanoparticles can potentially translocate to the brain via olfactory sensory neurons or through systemic circulation and cause irreversible damage to the nervous system. To determine if engineered nanomaterials pose a neurological risk, we evaluated the effects of multi-walled carbon nanotubes (MWCNT) in a murine model. Male C57BL/6J mice were exposed to MWCNT either by pharyngeal aspiration (single dose of 10-80ug/mouse; 1, 7, 28, or 56d post-exposure) or whole-body inhalation (10mg/m3 x 5h/d x 2, 4, 8 or 12d; 1d post-exposure). MWCNT exposure elicited neuroinflammation, altered blood-brain barrier (BBB) integrity and induced cellular stress in discrete brain areas. Specifically, MWCNT induced (2 to 16-fold) the mRNA expression of several proinflammatory chemokines (Ccl2, Ccl3, Ccl4, Cxcl2), cytokines (Il-1beta, Il-6, Tnfalpha), selectins (Sele, Selp) and markers of cellular stress (Hspb2, Mt1, Mt2). Exposure to MWCNT also decreased the expression of BBB-related markers (Edn2, Vegfa), suggestive of alterations in BBB integrity. In the hippocampus, MWCNT altered the expression of certain Alzheimer's-related genes (Aplp2, Apba2, Apba3, Bace1, Bace2, Ctsc, Ctsd), which interact with or are involved in the processing of amyloid-precursor protein. The neurotoxic responses were comparable between the two routes of exposure and some of the effects persisted until 56d post-exposure. Taken together, our findings suggest that exposure to an engineered nanomaterial like MWCNT, can elicit neuroinflammation, disrupt BBB integrity and cause cellular/molecular changes that could potentially culminate in neurodegeneration.
Airborne-particles; Biological-effects; Biological-factors; Cell-alteration; Cell-biology; Cell-damage; Cell-metabolism; Cell-morphology; Cell-wall-permeability; Cellular-transport-mechanism; Cellular-reactions; Cytology; Exposure-assessment; Exposure-levels; Exposure-methods; Inhalation-studies; Irritants; Laboratory-animals; Lung-cells; Lung-irritants; Occupational-exposure; Microscopic-analysis; Metal-compounds; Metal-fumes; Metal-industry; Metal-industry-workers; Metal-oxides; Metal-workers; Metallic-fumes; Nervous-system-disorders; Nervous-system-function; Neurological-reactions; Neurological-system; Neuropathology; Neuropathy; Neurotoxic-effects; Particle-aerodynamics; Particulates; Pulmonary-function; Pulmonary-disorders; Pulmonary-system-disorders; Respiratory-irritants; Respiratory-hypersensitivity; Risk-factors; Statistical-analysis; Tissue-culture; Toxic-effects; Nanotechnology
The Toxicologist. Society of Toxicology 48th Annual Meeting and ToxExpo, March 15-19, 2009, Baltimore, Maryland