title: Iron Oxide Nanoparticles Induce Dopaminergic Damage: In vitro Pathways and In Vivo Imaging Reveals Mechanism of Neuronal Damage.
abstract: Various iron-oxide nanoparticles have been in use for a long time as therapeutic and imaging agents and for supplemental delivery in cases of iron-deficiency. While all of these products have a specified size range of ∼ 40 nm and above, efforts are underway to produce smaller particles, down to ∼ 1 nm. Here, we show that after a 24-h exposure of SHSY-5Y human neuroblastoma cells to 10 μg/ml of 10 and 30 nm ferric oxide nanoparticles (Fe-NPs), cellular dopamine content was depleted by 68 and 52 %, respectively. Increases in activated tyrosine kinase c-Abl, a molecular switch induced by oxidative stress, and neuronal α-synuclein expression, a protein marker associated with neuronal injury, were also observed (55 and 38 % percent increases, respectively). Inhibition of cell-proliferation, significant reductions in the number of active mitochondria, and a dose-dependent increase in reactive oxygen species (ROS) were observed in neuronal cells. Additionally, using a rat in vitro blood-brain barrier (BBB) model, a dose-dependent increase in ROS accompanied by increased fluorescein efflux demonstrated compromised BBB integrity. To assess translational implications, in vivo Fe-NP-induced neurotoxicity was determined using in vivo MRI and post-mortem neurochemical and neuropathological correlates in adult male rats after exposure to 50 mg/kg of 10 nm Fe-NPs. Significant decrease in T 2 values was observed. Dynamic observations suggested transfer and retention of Fe-NPs from brain vasculature into brain ventricles. A significant decrease in striatal dopamine and its metabolites was also observed, and neuropathological correlates provided additional evidence of significant nerve cell body and dopaminergic terminal damage as well as damage to neuronal vasculature after exposure to 10 nm Fe-NPs. These data demonstrate a neurotoxic potential of very small size iron nanoparticles and suggest that use of these ferric oxide nanoparticles may result in neurotoxicity, thereby limiting their clinical application.
authors.affiliation: Division of Neurotoxicology, US FDA/National Center for Toxicological Research, Jefferson, AR, USA, Syed.Imam@fda.hhs.gov.
authors.forename: Syed Z
authors.initials: SZ
authors.lastname: Imam
authors.forename: Susan M
authors.initials: SM
authors.lastname: Lantz-McPeak
authors.forename: Elvis
authors.initials: E
authors.lastname: Cuevas
authors.forename: Hector
authors.initials: H
authors.lastname: Rosas-Hernandez
authors.forename: Serguei
authors.initials: S
authors.lastname: Liachenko
authors.forename: Yongbin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sumit
authors.initials: S
authors.lastname: Sarkar
authors.forename: Jaivijay
authors.initials: J
authors.lastname: Ramu
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Robinson
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Jones
authors.forename: Bobby
authors.initials: B
authors.lastname: Gough
authors.forename: Merle G
authors.initials: MG
authors.lastname: Paule
authors.forename: Syed F
authors.initials: SF
authors.lastname: Ali
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Binienda
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002395:Catecholamines / Q000032:analysis; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects; D059290:Dopaminergic Neurons / Q000737:chemistry / Q000187:drug effects* / Q000648:ultrastructure; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D058185:Magnetite Nanoparticles / Q000633:toxicity*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D054118:Nanospheres; D009447:Neuroblastoma / Q000473:pathology; D018384:Oxidative Stress; D010316:Particle Size; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000032:analysis; D013052:Spectrometry, X-Ray Emission
chemical_list: D002395:Catecholamines; D058185:Magnetite Nanoparticles; D017382:Reactive Oxygen Species; D020169:Caspases