title: Toxicogenomic profile of apoptotic and necrotic SN56 basal forebrain cholinergic neuronal loss after acute and long-term chlorpyrifos exposure.
abstract: Chlorpyrifos (CPF) is an organophosphate insecticide reported to induce, both after acute and repeated exposure, learning and memory dysfunctions, although the mechanism is not completely known. CPF produces basal forebrain cholinergic neuronal loss, involved on learning and memory regulation, which could be the cause of such cognitive disorders. This effect was reported to be induced through apoptotic process, partially mediated by AChE overexpression, although neuronal necrosis was also described after CPF exposure. Accordingly, we hypothesized that CPF induces apoptotic and necrotic basal forebrain cholinergic cell death. We evaluated, in septal SN56 basal forebrain cholinergic neurons, the CPF effect after 24h and 14days exposure on apoptosis and necrosis induction and the apoptotic and necrotic gene expression pathways. This study shows that CPF induces, after acute and long-term exposure, apoptosis and necrosis, partially mediated through AChE overexpression. Evaluation of cell death pathways supports the necrosis and apoptosis data and revealed that some genes are altered at lower concentrations than those at which the effects observed are produce and below the No Observed Adverse Effect Level (NOAEL). The present finding suggests that the use of gene expression profile could be a more sensitive and accurate way to determine the CPF's NOAEL.
authors.affiliation: Department of Toxicology and Legal Medicine, Medical School, Complutense University of Madrid, 28041 Madrid, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Moyano
authors.affiliation: Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain. Electronic address: jdelpino@pdi.ucm.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Del Pino
authors.affiliation: Department of Toxicology and Legal Medicine, Medical School, Complutense University of Madrid, 28041 Madrid, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Anadon
authors.affiliation: Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Díaz
authors.affiliation: Department of Toxicology and Legal Medicine, Medical School, Complutense University of Madrid, 28041 Madrid, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Gómez
authors.affiliation: Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Frejo
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D066187:Basal Forebrain / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004390:Chlorpyrifos / Q000633:toxicity*; D059329:Cholinergic Neurons / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects*; D007306:Insecticides / Q000633:toxicity; D051379:Mice; D009336:Necrosis; D015398:Signal Transduction / Q000187:drug effects; D043922:Toxicogenetics
chemical_list: D007306:Insecticides; D000110:Acetylcholinesterase; D004390:Chlorpyrifos
keywords: Apoptosis; Basal forebrain cholinergic neurons; Chlorpyrifos; NOAEL; Necrosis; Toxicogenomic profile