title: Role of engineered metal oxide nanoparticle agglomeration in reactive oxygen species generation and cathepsin B release in NLRP3 inflammasome activation and pulmonary toxicity.
abstract: Incomplete understanding of the contributions of dispersants and engineered nanoparticles/materials (ENM) agglomeration state to biological outcomes presents an obstacle for toxicological studies. Although reactive oxygen species (ROS) production is often regarded as the primary indicator of ENM bioactivity and toxicity, it remains unclear whether ENM produce ROS or whether ROS is an outcome of ENM-induced cell injury. Phagolysosomal disruption and cathepsin B release also promote bioactivity through inflammasome activation. Therefore, specific particle parameters, i.e. preexposure dispersion status and particle surface area, of two ENM (NiO and CeO2) were used to evaluate the role of ROS generation and cathepsin B release during ENM-induced toxicity. Male C57BL/6J mice were exposed to 0, 20, 40, or 80 μg of poorly or well-dispersed NiO-NP or CeO2-NP in four types of dispersion media. At 1- and 7-day postexposure, lung lavage fluid was collected to assess inflammation, cytotoxicity, and inflammasome activation. Results showed that preexposure dispersion status correlated with postexposure pulmonary bioactivity. The differences in bioactivity of NiO-NP and CeO2-NP are likely due to NiO-NP facilitating the release of cathepsin B and in turn inflammasome activation generating proinflammatory cytokines. Further, both metal oxides acted as free radical scavengers. Depending on the pH, CeO2-NP acted as a free radical scavenger in an acidic environment (an environment mimicking the lysosome) while the NiO-NP acted as a scavenger in a physiological pH (an environment that mimics the cytosol of the cell). Therefore, results from this study suggest that ENM-induced ROS is not likely a mechanism of inflammasome activation.
authors.affiliation: a Center for Environmental Health Sciences, University of Montana , Missoula , MT , USA.|b Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health , Morgantown , WV , USA , and.
authors.forename: Tina M
authors.initials: TM
authors.lastname: Sager
authors.affiliation: b Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health , Morgantown , WV , USA , and.
authors.forename: Michael
authors.initials: M
authors.lastname: Wolfarth
authors.affiliation: b Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health , Morgantown , WV , USA , and.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Leonard
authors.affiliation: b Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health , Morgantown , WV , USA , and.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Morris
authors.affiliation: b Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health , Morgantown , WV , USA , and.
authors.forename: Dale W
authors.initials: DW
authors.lastname: Porter
authors.affiliation: b Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health , Morgantown , WV , USA , and.|c Department of Pharmaceutical Sciences , West Virginia University School of Pharmacy , Morgantown , WV , USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Castranova
authors.affiliation: a Center for Environmental Health Sciences, University of Montana , Missoula , MT , USA.
authors.forename: Andrij
authors.initials: A
authors.lastname: Holian
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002401:Cathepsin B / Q000378:metabolism*; D002452:Cell Count; D002563:Cerium / Q000737:chemistry / Q000633:toxicity*; D058847:Inflammasomes / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D053768:Metal Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D009532:Nickel / Q000737:chemistry / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013499:Surface Properties
chemical_list: C587672:IL1B protein, mouse; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D002563:Cerium; C030583:ceric oxide; D009532:Nickel; C028007:nickel monoxide; D007770:L-Lactate Dehydrogenase; D002401:Cathepsin B; C533915:Ctsb protein, mouse
keywords: ROS; activation; agglomeration; cytotoxicity; engineered nanoparticles; inflammasome; inflammation; pulmonary toxicity