Long-term inhalation exposure to nickel nanoparticles exacerbated atherosclerosis in a susceptible mouse model.

BACKGROUND: Because associations have been reported between inhaled ambient ultrafine particles and increased risk of cardiopulmonary disease, it has been suggested that inhaled engineered nanoparticles (NPs) may also induce adverse effects on the cardio-vascular system. Objective: We examined the long-term cardio-vascular effects of inhaled nickel hydroxide NPs (nano-NH) using a sensitive mouse model. METHODS: Hyperlipidemic, apoprotein E-deficient (ApoE(-/-)) mice were exposed to nano-NH at either 0 or 79 mu g Ni/m(3), via a whole-body inhalation system, for 5 hr/day, 5 days/week, for either 1 week or 5 months. We measured various indicators of oxidative stress and inflammation in the lung and cardio-vascular tissue, and we determined plaque formation on the ascending aorta. RESULTS: Inhaled nano-NH induced significant oxidative stress and inflammation in the pulmonary and extrapulmonary organs, indicated by up-regulated mRNA levels of certain anti-oxidant enzyme and inflammatory cytokine genes; increased mitochondrial DNA damage in the aorta; significant signs of inflammation in bronchoalveolar lavage fluid; changes in lung histopathology; and induction of acute-phase response. In addition, after 5-month exposures, nano-NH exacerbated the progression of atherosclerosis in ApoE(-/-) mice. CONCLUSIONS: This is the first study to report long-term cardio-vascular toxicity of an inhaled nanomaterial. Our results clearly demonstrate that long-term exposure to inhaled nano-NH can induce oxidative stress and inflammation, not only in the lung but also in the cardio-vascular system, and that this stress and inflammation can ultimately contribute to progression of atherosclerosis in ApoE(-/-) mice.