title: Metabolomics-on-a-chip and predictive systems toxicology in microfluidic bioartificial organs.
abstract: The world faces complex challenges for chemical hazard assessment. Microfluidic bioartificial organs enable the spatial and temporal control of cell growth and biochemistry, critical for organ-specific metabolic functions and particularly relevant to testing the metabolic dose-response signatures associated with both pharmaceutical and environmental toxicity. Here we present an approach combining a microfluidic system with (1)H NMR-based metabolomic footprinting, as a high-throughput small-molecule screening approach. We characterized the toxicity of several molecules: ammonia (NH(3)), an environmental pollutant leading to metabolic acidosis and liver and kidney toxicity; dimethylsulfoxide (DMSO), a free radical-scavenging solvent; and N-acetyl-para-aminophenol (APAP, or paracetamol), a hepatotoxic analgesic drug. We report organ-specific NH(3) dose-dependent metabolic responses in several microfluidic bioartificial organs (liver, kidney, and cocultures), as well as predictive (99% accuracy for NH(3) and 94% for APAP) compound-specific signatures. Our integration of microtechnology, cell culture in microfluidic biochips, and metabolic profiling opens the development of so-called "metabolomics-on-a-chip" assays in pharmaceutical and environmental toxicology.
authors.affiliation: Université de Lyon, UMR 5280 CNRS/ENS-Lyon/UCBL1 Centre de RMN à Très Hauts Champs, 5 rue de la Doua, 69100 Villeurbanne, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Shintu
authors.forename: Régis
authors.initials: R
authors.lastname: Baudoin
authors.forename: Vincent
authors.initials: V
authors.lastname: Navratil
authors.forename: Jean-Matthieu
authors.initials: JM
authors.lastname: Prot
authors.forename: Clément
authors.initials: C
authors.lastname: Pontoizeau
authors.forename: Marianne
authors.initials: M
authors.lastname: Defernez
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blaise
authors.forename: Céline
authors.initials: C
authors.lastname: Domange
authors.forename: Alexandre R
authors.initials: AR
authors.lastname: Péry
authors.forename: Pierre
authors.initials: P
authors.lastname: Toulhoat
authors.forename: Cécile
authors.initials: C
authors.lastname: Legallais
authors.forename: Céline
authors.initials: C
authors.lastname: Brochot
authors.forename: Eric
authors.initials: E
authors.lastname: Leclerc
authors.forename: Marc-Emmanuel
authors.initials: ME
authors.lastname: Dumas
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000641:Ammonia / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity; D000818:Animals; D021522:Bioartificial Organs; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D004285:Dogs; D064420:Drug-Related Side Effects and Adverse Reactions; D056945:Hep G2 Cells; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D055432:Metabolomics; D044085:Microfluidics / Q000295:instrumentation* / Q000379:methods*; D008958:Models, Molecular; D012372:ROC Curve
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D000641:Ammonia