Loss of neuropathy target esterase in mice links organophosphate exposure to hyperactivity.
Neuropathy target esterase (NTE) is involved in neural development and is the target for neurodegeneration induced by selected organophosphorus pesticides and chemical warfare agents. We generated mice with disruptions in Nte, the gene encoding NTE. Nte(-/-) mice die after embryonic day 8, and Nte(+/-) mice have lower activity of Nte in the brain and higher mortality when exposed to the Nte-inhibiting compound ethyl octylphosphonofluoridate (EOPF) than do wild-type mice. Nte(+/-) and wild-type mice treated with 1 mg per kg of body weight of EOPF have elevated motor activity, showing that even minor reduction of Nte activity leads to hyperactivity. These studies show that genetic or chemical reduction of Nte activity results in a neurological phenotype of hyperactivity in mammals and indicate that EOPF toxicity occurs directly through inhibition of Nte without the requirement for Nte gain of function or aging.
Winrow
Christopher J
CJ
The Salk Institute for Biological Studies, The Laboratory of Genetics, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Hemming
Matthew L
ML
Allen
Duane M
DM
Quistad
Gary B
GB
Casida
John E
JE
Barlow
Carrolee
C
D000110:Acetylcholinesterase / Q000378:metabolism; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D001921:Brain / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000235:genetics* / Q000502:physiology*; D019992:Databases as Topic; D020224:Expressed Sequence Tags; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D006948:Hyperkinesis / Q000139:chemically induced*; D017404:In Situ Hybridization, Fluorescence; D007306:Insecticides / Q000633:toxicity*; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000633:toxicity; D010641:Phenotype; D011233:Precipitin Tests; D017386:Sequence Homology, Amino Acid; D013997:Time Factors; D014018:Tissue Distribution; D001616:beta-Galactosidase / Q000378:metabolism
D007306:Insecticides; D009943:Organophosphorus Compounds; C100419:ethyl octylphosphonofluoridate; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D000110:Acetylcholinesterase; D001616:beta-Galactosidase