title: Delayed reduction of hippocampal synaptic transmission and spines following exposure to repeated subclinical doses of organophosphorus pesticide in adult mice.
abstract: Agricultural and household organophosphorus (OP) pesticides inhibit acetylcholinesterase (AchE), resulting in increased acetylcholine (Ach) in the central nervous system. In adults, acute and prolonged exposure to high doses of AchE inhibitors causes severe, clinically apparent symptoms, followed by lasting memory impairments and cognitive dysfunction. The neurotoxicity of repeated environmental exposure to lower, subclinical doses of OP pesticides in adults is not as well studied. However, repeated exposure to acetylcholinesterase inhibitors, such as chlorpyrifos (CPF), pyridostigmine, and sarin nerve agent, has been epidemiologically linked to delayed onset symptoms in Gulf War Illness and may be relevant to environmental exposure in farm workers among others. We treated adult mice with a subclinical dose (5 mg/kg) of CPF for 5 consecutive days and investigated hippocampal synaptic transmission and spine density early (2-7 days) and late (3 months) after CPF administration. No signs of cholinergic toxicity were observed at any time during or after treatment. At 2-7 days after the last injection, we found increased synaptic transmission in the CA3-CA1 region of the hippocampus of CPF-treated mice compared with controls. In contrast, at 3 months after CPF administration, we observed a 50% reduction in synaptic transmission likely due to a corresponding 50% decrease in CA1 pyramidal neuron synaptic spine density. This study is the first to identify a biphasic progression of synaptic abnormalities following repeated OP exposure and suggests that even in the absence of acute cholinergic toxicity, repeated exposure to CPF causes delayed persistent damage to the adult brain in vivo.
authors.affiliation: Department of Neurology & Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-8813, USA.
authors.forename: Haley E
authors.initials: HE
authors.lastname: Speed
authors.forename: Cory A
authors.initials: CA
authors.lastname: Blaiss
authors.forename: Ahleum
authors.initials: A
authors.lastname: Kim
authors.forename: Michael E
authors.initials: ME
authors.lastname: Haws
authors.forename: Neal R
authors.initials: NR
authors.lastname: Melvin
authors.forename: Michael
authors.initials: M
authors.lastname: Jennings
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Eisch
authors.forename: Craig M
authors.initials: CM
authors.lastname: Powell
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D002452:Cell Count; D004390:Chlorpyrifos / Q000633:toxicity*; D049229:Dendritic Spines / Q000187:drug effects* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018408:Patch-Clamp Techniques; D010575:Pesticides / Q000633:toxicity*; D017966:Pyramidal Cells / Q000187:drug effects* / Q000473:pathology; D009435:Synaptic Transmission / Q000187:drug effects*; D013997:Time Factors
chemical_list: D010575:Pesticides; D000110:Acetylcholinesterase; D004390:Chlorpyrifos