title: In vitro screening of metal oxide nanoparticles for effects on neural function using cortical networks on microelectrode arrays.
abstract: Nanoparticles (NPs) may translocate to the brain following inhalation or oral exposures, yet higher throughput methods to screen NPs for potential neurotoxicity are lacking. The present study examined effects of 5 CeO2 (5- 1288 nm), and 4 TiO2 (6-142 nm) NPs and microparticles (MP) on network function in primary cultures of rat cortex on 12 well microelectrode array (MEA) plates. Particles were without cytotoxicity at concentrations ≤50 µg/ml. After recording 1 h of baseline activity prior to particle (3-50 µg/ml) exposure, changes in the total number of spikes (TS) and # of active electrodes (#AEs) were assessed 1, 24, and 48 h later. Following the 48 h recording, the response to a challenge with the GABAA antagonist bicuculline (BIC; 25 µM) was assessed. In all, particles effects were subtle, but 69 nm CeO2 and 25 nm TiO2 NPs caused concentration-related decreases in TS following 1 h exposure. At 48 h, 5 and 69 nm CeO2 and 25 and 31 nm TiO2 decreased #AE, while the two MPs increased #AEs. Following BIC, only 31 nm TiO2 produced concentration-related decreases in #AEs, while 1288 nm CeO2 caused concentration-related increases in both TS and #AE. The results indicate that some metal oxide particles cause subtle concentration-related changes in spontaneous and/or GABAA receptor-mediated neuronal activity in vitro at times when cytotoxicity is absent, and that MEAs can be used to screen and prioritize nanoparticles for neurotoxicity hazard.
authors.affiliation: a Office of Research and Development, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park , NC , USA.
authors.forename: Jenna D
authors.initials: JD
authors.lastname: Strickland
authors.affiliation: a Office of Research and Development, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park , NC , USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Lefew
authors.affiliation: a Office of Research and Development, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park , NC , USA.
authors.forename: James
authors.initials: J
authors.lastname: Crooks
authors.affiliation: a Office of Research and Development, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park , NC , USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Hall
authors.affiliation: a Office of Research and Development, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park , NC , USA.
authors.forename: Jayna N R
authors.initials: JN
authors.lastname: Ortenzio
authors.affiliation: a Office of Research and Development, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park , NC , USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Dreher
authors.affiliation: a Office of Research and Development, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park , NC , USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Shafer
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D002563:Cerium / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D008839:Microelectrodes; D053758:Nanoparticles / Q000633:toxicity*; D009415:Nerve Net / Q000187:drug effects*; D010316:Particle Size; D061251:Primary Cell Culture; D051381:Rats; D020318:Rats, Long-Evans; D013499:Surface Properties; D014025:Titanium / Q000633:toxicity*
chemical_list: C009495:titanium dioxide; D002563:Cerium; C030583:ceric oxide; D014025:Titanium
keywords: Nanoparticles; nanotoxicology; particle toxicology