title: Evaluation of aggregating brain cell cultures for the detection of acute organ-specific toxicity.
abstract: As part of the ACuteTox project aimed at the development of non-animal testing strategies for predicting human acute oral toxicity, aggregating brain cell cultures (AGGR) were examined for their capability to detect organ-specific toxicity. Previous multicenter evaluations of in vitro cytotoxicity showed that some 20% of the tested chemicals exhibited significantly lower in vitro toxicity as expected from in vivo toxicity data. This was supposed to be due to toxicity at supracellular (organ or system) levels. To examine the capability of AGGR to alert for potential organ-specific toxicants, concentration-response studies were carried out in AGGR for 86 chemicals, taking as endpoints the mRNA expression levels of four selected genes. The lowest observed effect concentration (LOEC) determined for each chemical was compared with the IC20 reported for the 3T3/NRU cytotoxicity assay. A LOEC lower than IC20 by at least a factor of 5 was taken to alert for organ-specific toxicity. The results showed that the frequency of alerts increased with the level of toxicity observed in AGGR. Among the chemicals identified as alert were many compounds known for their organ-specific toxicity. These findings suggest that AGGR are suitable for the detection of organ-specific toxicity and that they could, in conjunction with the 3T3/NRU cytotoxicity assay, improve the predictive capacity of in vitro toxicity testing.
authors.affiliation: Department of Physiology, University of Lausanne, Rue du Bugnon 7, CH-1005 Lausanne, Switzerland. Marie-Gabrielle.ZurichFontanellaz@unil.ch
authors.forename: Marie-Gabrielle
authors.initials: MG
authors.lastname: Zurich
authors.forename: Sven
authors.initials: S
authors.lastname: Stanzel
authors.forename: Annette
authors.initials: A
authors.lastname: Kopp-Schneider
authors.forename: Pilar
authors.initials: P
authors.lastname: Prieto
authors.forename: Paul
authors.initials: P
authors.lastname: Honegger
mesh_terms: D000826:Animal Testing Alternatives; D000818:Animals; D001921:Brain / Q000166:cytology*; D002478:Cells, Cultured; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics; D004676:Myelin Basic Protein / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D016900:Neurofilament Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D023382:Toxicity Tests, Acute
chemical_list: C436006:Mbp protein, rat; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D012333:RNA, Messenger; C051774:neurofilament protein H; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat