The long-term central nervous system effects of inhaled nickel hydroxide nanoparticles in mice.

摘要

Exposure to inhaled nanoparticles (NPs) is not a new phenomenon, but with the advent of nanotechnology there is great concern about increased exposure to airborne particles in this size range, specifically engineered NPs. The majority of NP based toxicological studies assessing secondary effects have focused on cardiopulmonary responses with little attention paid to the central nervous system (CNS). The aim of this study was to examine if inhalation exposure to nano-Ni(OH)2 would induce oxidative stress (OS) and inflammatory responses not only in the lung, but in three distinct brain regions as well: olfactory bulb (OLB), midbrain (MB), and cerebellum (CRBL); and in the long-term, lead to dysfunction and/or damage to cells within these brain tissues. Utilizing a whole body exposure system, short and long-term exposures to inhaled nano-Ni(OH) 2 (CMD=40 nm) in C57BL/6 mice were conducted. For short-term studies mice were exposed for 4 h to nominal concentrations of 100, 500, and 1000 mug/m 3. For long-term studies mice were exposed for 5h/d, 5d/w, for up to 5 m to a nominal concentration of 100 mug/m3. Intransanal and intravenous studies were conducted to determine nano-Ni(OH)2 transport mechanism(s) and in these studies mice received 12 mug Ni/mouse. Markers of OS, inflammation, and injury were examined in the lungs, OLB, MB, and CRBL of mice. Data indicated in the lungs, following short-term exposures, a dose-dependent OS and inflammatory response. In the long-term, in the lungs, pronounced OS and inflammatory events occurred following 3 m of exposure with histological changes noted after 5 m of exposure. In the brain, following short and long-term studies, unique transcriptional responses of OS and inflammatory related genes were observed in the OLB, MB, and CRBL with evidence of a neurotoxic event in the MB. Nickel was found in the respiratory tract; and transport of nano-Ni(OH) 2 to the OLB was detected. Comparative toxicity studies between nano-Ni(OH) 2, nano-NiSO4, copper, manganese and carbon based NPs demonstrated that solubility and the material (metal) of NPs influenced adverse responses in these tissues. These results collectively contribute to the current NP toxicological database and highlight the importance of investigating CNS effects of inhaled NPs.