title: GABAA receptor and cell membrane potential as functional endpoints in cultured neurons to evaluate chemicals for human acute toxicity.
abstract: Toxicity risk assessment for chemical-induced human health hazards relies mainly on data obtained from animal experimentation, human studies and epidemiology. In vitro testing for acute toxicity based on cytotoxicity assays predicts 70-80% of rodent and human toxicity. The nervous system is particularly vulnerable to chemical exposure which may result in different toxicity features. Acute human toxicity related to adverse neuronal function is usually a result of over-excitation or depression of the nervous system. The major molecular and cellular mechanisms involved in such reactions include GABAergic, glutamatergic and cholinergic neurotransmission, regulation of cell and mitochondrial membrane potential, and those critical for maintaining central nervous system functionality, such as controlling cell energy. In this work, a set of chemicals that are used in pharmacy, industry, biocide treatments or are often abused by drug users are tested for their effects on GABA(A) receptor activity, GABA and glutamate transport, cell membrane potential and cell viability in primary neuronal cultures. GABA(A) receptor function was inhibited by compounds for which seizures have been observed after severe human poisoning. Commonly abused drugs inhibit GABA uptake but not glutamate uptake. Most neurotoxins altered membrane potential. The GABA(A) receptor, GABA uptake and cell membrane potential assays were those that identified the highest number of chemicals as toxic at low concentrations. These results show that in vitro cell assays may identify compounds that produce acute neurotoxicity in humans, provided that in vitro models expressing neuronal targets relevant for acute neural dysfunctions are used.
authors: Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas, CSIC-IDIBAPS, Barcelona, Spain.
authors: Mireia
authors: M
authors: Galofré
authors: Zoila
authors: Z
authors: Babot
authors: Daniel A
authors: DA
authors: García
authors: Susana
authors: S
authors: Iraola
authors: Eduard
authors: E
authors: Rodríguez-Farré
authors: Anna
authors: A
authors: Forsby
authors: Cristina
authors: C
authors: Suñol
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000187:drug effects*; D018675:Toxicity Tests / Q000379:methods*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D011963:Receptors, GABA-A; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid