title: Physicochemical properties of iron oxide nanoparticles that contribute to cellular ROS-dependent signaling and acellular production of hydroxyl radical.
abstract: While nanoparticles (NPs) are increasingly used in a variety of consumer products and medical applications, some of these materials have potential health concerns. Macrophages are the primary responders to particles that initiate oxidative stress and inflammatory reactions. Here, we utilized six flame-synthesized, engineered iron oxide NPs with various physicochemical properties (e.g. Fe oxidation state and crystal size) to study their interactions with RAW 264.7 macrophages, their iron solubilities, and their abilities to produce hydroxyl radical in an acellular assay. Both iron solubility and hydroxyl radical production varied between NPs depending on crystalline diameter and surface area of the particles, but not on iron oxidation state. Macrophage treatment with the iron oxide NPs showed a dose-dependent increase of heme oxygenase 1 (HO-1) and NAD(P)H:quinone oxidoreductase (NQO-1). The nuclear factor (NF)-erythroid-derived 2 (E2)-related factor 2 (Nrf2) modulates the transcriptional activity of antioxidant response element (ARE)-driven genes, such as HO-1 and NQO-1. Here, we show that the iron oxide NPs activate Nrf2, leading to its increased nuclear accumulation and enhanced Nrf2 DNA-binding activity in NP-treated RAW 264.7 macrophages. Iron solubility and acellular hydroxyl radical generation depend on the physical properties of the NPs, especially crystalline diameter; however, these properties are weakly linked to the activation of cellular signaling of Nrf2 and the expression of oxidative stress markers. Overall, our work shows for the first time that iron oxide nanoparticles induce cellular marker genes of oxidative stress and that this effect is transcriptionally mediated through the Nrf2-ARE signaling pathway in macrophages.
authors: a Department of Environmental Toxicology , University of California , Davis , CA , USA.|b Center for Health and the Environment , University of California , Davis , CA , USA.
authors: Christoph F A
authors: CF
authors: Vogel
authors: c Department of Land, Air and Water Resources , University of California , Davis , CA , USA.
authors: Jessica G
authors: JG
authors: Charrier
authors: b Center for Health and the Environment , University of California , Davis , CA , USA.
authors: Dalei
authors: D
authors: Wu
authors: c Department of Land, Air and Water Resources , University of California , Davis , CA , USA.
authors: Alexander S
authors: AS
authors: McFall
authors: b Center for Health and the Environment , University of California , Davis , CA , USA.
authors: Wen
authors: W
authors: Li
authors: d Department of Mechanical and Aeronautical Engineering , University of California , Davis , CA , USA.
authors: Aamir
authors: A
authors: Abid
authors: d Department of Mechanical and Aeronautical Engineering , University of California , Davis , CA , USA.
authors: Ian M
authors: IM
authors: Kennedy
authors: c Department of Land, Air and Water Resources , University of California , Davis , CA , USA.
authors: Cort
authors: C
authors: Anastasio
mesh_terms: D002470:Cell Survival / Q000187:drug effects*; D005290:Ferric Compounds / Q000378:metabolism*; D017665:Hydroxyl Radical; D008264:Macrophages; D053758:Nanoparticles / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D014162:Transfection
chemical_list: D005290:Ferric Compounds; D017382:Reactive Oxygen Species; C000499:ferric oxide; D017665:Hydroxyl Radical
keywords: Hydroxyl radical; Nrf2; macrophage; nanoparticles; oxidative stress