Long-term effects of inhaled nickel hydroxide nanoparticles on the progression of atherosclerosis

There is growing interest in engineered nanoparticles (NPs; particles with a diameter < 100 nm) for various medical and technological applications, but the environmental and health effects of these NPs are yet largely unknown. Since there have been associations reported between inhaled ambient ultrafine particles and increased risk of cardiopulmonary disease, it has been suggested that inhaled NPs may also induce adverse effects on the cardiovascular system. I hypothesized that long-term exposure to inhaled nickel (Ni) NPs could induce oxidative stress and inflammation, not only in the lung, but also in the cardiovascular system, which can ultimately contribute to progression of atherosclerosis in a susceptible mouse model.;Nickel hydroxide nanoparticles (nano-NH) was used as a test material and thoroughly characterized for various physicochemical properties related to toxicity. A series of preliminary studies were conducted using wild-type C57BL/6 mice to identify acute toxic potential of nano-NH. For sub-acute and sub-chronic exposure, 5-month-old male apoprotein E knockout (ApoE -/-) mice were exposed either to filtered air or nano-NH (diameter of primary particle: 5nm, count median diameter of agglomerates: ~40nm) at ~ 80 mug Ni/m3 (less than 10% of the current occupational standard), for 5h/d, 5d/w for either 1 week or 5 months. Various indicators of oxidative stress and inflammation were measured in the lung and cardiovascular tissue, and plaque formation on the ascending aorta was determined after 5m of exposure.;The results indicated that: (1) nano-NH could induce acute pulmonary toxicity in a dose-related manner, and particle characteristics might play key roles in understanding potential mechanisms of these responses; (2) inhaled nano-NH could result in significant oxidative stress in the pulmonary and extra-pulmonary organs; and (3) exposure to inhaled nano-NH could induce pulmonary and systemic inflammation and, in the long term, exacerbate atherosclerosis in ApoE-/- mice.;These findings will contribute to further understanding potential risks and mechanisms of NPs-induced toxicity and also establishing a database for nanoparticle-specific regulations in occupational and environmental settings.