Loss of neuropathy target esterase in mice links organophosphate exposure to hyperactivity

• Published in: Nature genetics Vol. 33; no. 4; pp. 477 - 485
• Main Authors: Barlow, Carrolee, Winrow, Christopher J, Hemming, Matthew L, Allen, Duane M, Quistad, Gary B, Casida, John E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01-04-2003
• Subjects: Acetylcholinesterase - metabolism; Aging; Alleles; Amino Acid Sequence; Animals; Artificial chromosomes; beta-Galactosidase - metabolism; Biological and medical sciences; Blotting, Northern; Body weight; Brain - metabolism; Carboxylic Ester Hydrolases - genetics; Carboxylic Ester Hydrolases - physiology; Chemical reduction; Cloning; Complications and side effects; Databases as Topic; Esterases; Expressed Sequence Tags; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Gene loci; Genotype; Humans; Hyperactivity; Hyperkinesis - chemically induced; Hypotheses; In Situ Hybridization, Fluorescence; Insecticides - toxicity; Laboratories; Mammals; Mice; Mice, Transgenic; Models, Genetic; Molecular and cellular biology; Molecular Sequence Data; Mortality; Nervous system diseases; Neurodegeneration; Neurons - drug effects; Organophosphates; Organophosphorus Compounds - toxicity; Organophosphorus pesticides; Pesticides; Phenotype; Physiological aspects; Precipitin Tests; Risk factors; Sequence Homology, Amino Acid; Time Factors; Tissue Distribution; Toxicity; United States; United States > US; California; Genetics
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1131

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.