title: Neuropathy target esterase in mouse whole blood as a biomarker of exposure to neuropathic organophosphorus compounds.
abstract: The adult hen is the standard animal model for testing organophosphorus (OP) compounds for organophosphorus compound-induced delayed neurotoxicity (OPIDN). Recently, we developed a mouse model for biochemical assessment of the neuropathic potential of OP compounds based on brain neuropathy target esterase (NTE) and acetylcholinesterase (AChE) inhibition. We carried out the present work to further develop the mouse model by testing the hypothesis that whole blood NTE inhibition could be used as a biochemical marker for exposure to neuropathic OP compounds. Because brain NTE and AChE inhibition are biomarkers of OPIDN and acute cholinergic toxicity, respectively, we compared NTE and AChE 20-min IC50 values as well as ED50 values 1 h after single intraperitoneal (i.p.) injections of increasing doses of two neuropathic OP compounds that differed in acute toxicity potency. We found good agreement between the brain and blood for in vitro sensitivity of each enzyme as well for the ratios IC50 (AChE)/IC50 (NTE). Both OP compounds inhibited AChE and NTE in the mouse brain and blood dose-dependently, and brain and blood inhibitions in vivo were well correlated for each enzyme. For both OP compounds, the ratio ED50 (AChE)/ED50 (NTE) in blood corresponded to that in the brain despite the somewhat higher sensitivity of blood enzymes. Thus, our results indicate that mouse blood NTE could serve as a biomarker of exposure to neuropathic OP compounds. Moreover, the data suggest that relative inhibition of blood NTE and AChE provide a way to assess the likelihood that OP compound exposure in a susceptible species would produce cholinergic and/or delayed neuropathic effects. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Laboratory of Molecular Toxicology, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Moscow Region, 142432, Russia.
authors.forename: Galina F
authors.initials: GF
authors.lastname: Makhaeva
authors.affiliation: Laboratory of Molecular Toxicology, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Moscow Region, 142432, Russia.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Rudakova
authors.affiliation: Laboratory of Postgenomic Chemistry, Division of Chemical Enzymology, Chemistry Department, M.V. Lomonosov Moscow State University, 119991, Leninskie Gory, Moscow, Russia.
authors.forename: Larisa V
authors.initials: LV
authors.lastname: Sigolaeva
authors.affiliation: Laboratory of Postgenomic Chemistry, Division of Chemical Enzymology, Chemistry Department, M.V. Lomonosov Moscow State University, 119991, Leninskie Gory, Moscow, Russia.
authors.forename: Ilya N
authors.initials: IN
authors.lastname: Kurochkin
authors.affiliation: Toxicology Program, Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan, 48109, USA. rjrich@umich.edu.|Department of Neurology, University of Michigan, Ann Arbor, Michigan, 48109, USA. rjrich@umich.edu.
authors.forename: Rudy J
authors.initials: RJ
authors.lastname: Richardson
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000097:blood* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D008815:Mice, Inbred Strains; D020258:Neurotoxicity Syndromes / Q000097:blood* / Q000201:enzymology / Q000209:etiology; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000633:toxicity*
chemical_list: D015415:Biomarkers; D009943:Organophosphorus Compounds; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D000110:Acetylcholinesterase
keywords: OPIDN; acetylcholinesterase (AChE); biomarkers; blood; brain; mouse; neuropathy target esterase (NTE); organophosphorus (OP) compounds; poly(N,N-dimethylaminoethyl methacrylate)