title: A multi-laboratory evaluation of microelectrode array-based measurements of neural network activity for acute neurotoxicity testing.
abstract: There is a need for methods to screen and prioritize chemicals for potential hazard, including neurotoxicity. Microelectrode array (MEA) systems enable simultaneous extracellular recordings from multiple sites in neural networks in real time and thereby provide a robust measure of network activity. In this study, spontaneous activity measurements from primary neuronal cultures treated with three neurotoxic or three non-neurotoxic compounds was evaluated across four different laboratories. All four individual laboratories correctly identifed the neurotoxic compounds chlorpyrifos oxon (an organophosphate insecticide), deltamethrin (a pyrethroid insecticide) and domoic acid (an excitotoxicant). By contrast, the other three compounds (glyphosate, dimethyl phthalate and acetaminophen) considered to be non-neurotoxic ("negative controls"), produced only sporadic changes of the measured parameters. The results were consistent across the different laboratories, as all three neurotoxic compounds caused concentration-dependent inhibition of mean firing rate (MFR). Further, MFR appeared to be the most sensitive parameter for effects of neurotoxic compounds, as changes in electrical activity measured by mean frequency intra burst (MFIB), and mean burst duration (MBD) did not result in concentration-response relationships for some of the positive compounds, or required higher concentrations for an effect to be observed. However, greater numbers of compounds need to be tested to confirm this. The results obtained indicate that measurement of spontaneous electrical activity using MEAs provides a robust assessment of compound effects on neural network function.
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy; Department of Infomatics Bioengineering, Robotics, SystemEngeneering, University of Genova, Genova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vassallo
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Chiappalone
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy; Department of Clinical Engineering, University Hospital of Santa Maria, Av. Roraima, 1000-Predio 22, Bairro Camobi, Santa Maria, CEP: 97105-900 RS, Brazil.
authors.forename: Ricardo
authors.initials: R
authors.lastname: De Camargos Lopes
authors.affiliation: Institute for Health and Consumer Protection, European Commission Joint Research Centre, Ispra, Italy.
authors.forename: Bibiana
authors.initials: B
authors.lastname: Scelfo
authors.affiliation: Alternative Toxicity Service Unit-ETT SpA, via Sestri 37, 16154 Genova, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Novellino
authors.affiliation: Alternative Toxicity Service Unit-ETT SpA, via Sestri 37, 16154 Genova, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Defranchi
authors.affiliation: Institute for Health and Consumer Protection, European Commission Joint Research Centre, Ispra, Italy.
authors.forename: Taina
authors.initials: T
authors.lastname: Palosaari
authors.affiliation: Experimental Toxicology and Ecology, BASF, Carl Bosch-Strasse, 67056 Ludwigshafen am Rhein, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Weisschu
authors.affiliation: Experimental Toxicology and Ecology, BASF, Carl Bosch-Strasse, 67056 Ludwigshafen am Rhein, Germany.
authors.forename: Tzutzuy
authors.initials: T
authors.lastname: Ramirez
authors.affiliation: Department of Infomatics Bioengineering, Robotics, SystemEngeneering, University of Genova, Genova, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Martinoia
authors.affiliation: National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: Andrew F M
authors.initials: AFM
authors.lastname: Johnstone
authors.affiliation: National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: Cina M
authors.initials: CM
authors.lastname: Mack
authors.affiliation: Experimental Toxicology and Ecology, BASF, Carl Bosch-Strasse, 67056 Ludwigshafen am Rhein, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Landsiedel
authors.affiliation: Institute for Health and Consumer Protection, European Commission Joint Research Centre, Ispra, Italy.
authors.forename: Maurice
authors.initials: M
authors.lastname: Whelan
authors.affiliation: Institute for Health and Consumer Protection, European Commission Joint Research Centre, Ispra, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Bal-Price
authors.affiliation: National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA. Electronic address: Shafer.tim@epa.gov.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Shafer
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation / Q000379:methods*; D020128:Inhibitory Concentration 50; D007306:Insecticides / Q000494:pharmacology*; D008839:Microelectrodes; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology*; D051381:Rats; D014116:Toxicology / Q000379:methods*
chemical_list: D007306:Insecticides; D009498:Neurotoxins
keywords: Cross-laboratory comparison; Microelectrode array; Screening