title: Acute and long-term exposure to chlorpyrifos induces cell death of basal forebrain cholinergic neurons through AChE variants alteration.
abstract: Chlorpyrifos (CPF) is one of the most widely used organophosphates insecticides that has been reported to induce cognitive disorders both after acute and repeated administration similar to those induced in Alzheimer's disease (AD). However, the mechanisms through which it induces these effects are unknown. On the other hand, the cholinergic system, mainly basal forebrain cholinergic neurons, is involved in learning and memory regulation, and an alteration of cholinergic transmission or/and cholinergic cell loss could induce these effects. In this regard, it has been reported that CPF can affect cholinergic transmission, and alter AChE variants, which have been shown to be related with basal forebrain cholinergic neuronal loss. According to these data, we hypothesized that CPF could induce basal forebrain cholinergic neuronal loss through cholinergic transmission and AChE variants alteration. To prove this hypothesis, we evaluated in septal SN56 basal forebrain cholinergic neurons, the CPF toxic effects after 24h and 14 days exposure on neuronal viability and the cholinergic mechanisms related to it. This study shows that CPF impaired cholinergic transmission, induced AChE inhibition and, only after long-term exposure, increased CHT expression, which suggests that acetylcholine levels alteration could be mediated by these actions. Moreover, CPF induces, after acute and long-term exposure, cell death in cholinergic neurons in the basal forebrain and this effect is independent of AChE inhibition and acetylcholine alteration, but was mediated partially by AChE variants alteration. Our present results provide a new understanding of the mechanisms contributing to the harmful effects of CPF on neuronal function and viability, and the possible relevance of CPF in the pathogenesis of neurodegenerative diseases.
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: Paula
authors.initials: P
authors.lastname: Moyano
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 Legal Medicine, Medical School, Complutense University of Madrid, 28041 Madrid, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: García
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 Pharmacolgy, Health Sciences School, Alfonso X University, 28691 Madrid, Spain.
authors.forename: Jimena
authors.initials: J
authors.lastname: García
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: D000109:Acetylcholine / Q000032:analysis; D000110:Acetylcholinesterase / Q000187:drug effects*; D000818:Animals; D066187:Basal Forebrain / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004390:Chlorpyrifos / Q000633:toxicity*; D002795:Choline O-Acetyltransferase / Q000187:drug effects; D059329:Cholinergic Neurons / Q000737:chemistry / Q000187:drug effects*; D007306:Insecticides / Q000633:toxicity*; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D007306:Insecticides; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; D004390:Chlorpyrifos; D000109:Acetylcholine
keywords: Acetylcholine; Acetylcholine esterase; Acetylcholine transferase; Basal forebrain neurons; Cell death; Chlorpyrifos; High-affinity choline transporter