title: Mechanisms of organophosphate insecticide-induced airway hyperreactivity.
abstract: It has been suggested that pesticide exposure may be a contributing factor underlying the increased incidence of asthma in the United States and other industrialized nations. To test this hypothesis, airway hyperreactivity was measured in guinea pigs exposed to chlorpyrifos, a widely used organophosphate pesticide. Electrical stimulation of the vagus nerves caused frequency-dependent bronchoconstriction that was significantly potentiated in animals 24 h or 7 days after a single subcutaneous injection of either 390 mg/kg or 70 mg/kg of chlorpyrifos, respectively. Mechanisms by which chlorpyrifos may cause airway hyperreactivity include inhibition of acetylcholinesterase (AChE) or dysfunction of M3 muscarinic receptors on airway smooth muscle or of autoinhibitory M2 muscarinic receptors on parasympathetic nerves in the lung. AChE activity in the lung was significantly inhibited 24 h after treatment with 390 mg/kg of chlorpyrifos, but not 7 days after injection of 70 mg/kg of chlorpyrifos. Acute exposure to eserine (250 microg/ml) also significantly inhibited lung AChE but did not potentiate vagally induced bronchoconstriction. Neuronal M2 receptor function was tested using the M2 agonist pilocarpine, which inhibits vagally induced bronchoconstriction in control animals. In chlorpyrifos-treated animals, pilocarpine dose-response curves were shifted significantly to the right, demonstrating decreased responsiveness of neuronal M2 receptors. In contrast, chlorpyrifos treatment did not alter methacholine-induced bronchoconstriction, suggesting that chlorpyrifos does not alter M3 muscarinic receptor function on airway smooth muscle. These data demonstrate that organophosphate insecticides can cause airway hyperreactivity in the absence of AChE inhibition by decreasing neuronal M2 receptor function.
authors.affiliation: National Institutes of Health National Institute of Neurological Disorders and Stroke, 6001 Executive Blvd. NSC, Suite 2149, MSC 9535, Bethesda, MD 20892-9835, USA.
authors.forename: Allison D
authors.initials: AD
authors.lastname: Fryer
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Lein
authors.forename: Angela S
authors.initials: AS
authors.lastname: Howard
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Yost
authors.forename: Rondell A
authors.initials: RA
authors.lastname: Beckles
authors.forename: David A
authors.initials: DA
authors.lastname: Jett
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced* / Q000503:physiopathology*; D004390:Chlorpyrifos / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D007306:Insecticides / Q000633:toxicity*; D007700:Kinetics; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010830:Physostigmine / Q000633:toxicity*; D010862:Pilocarpine / Q000494:pharmacology; D043587:Receptor, Muscarinic M3 / Q000187:drug effects / Q000502:physiology; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology
chemical_list: D002800:Cholinesterase Inhibitors; D007306:Insecticides; D043587:Receptor, Muscarinic M3; D010862:Pilocarpine; D010830:Physostigmine; D004390:Chlorpyrifos