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Article
Nature Genetics  33, 477 - 485 (2003)
Published online: 17 March 2003; | doi:10.1038/ng1131

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

Christopher J. Winrow1, 3, Matthew L. Hemming1, Duane M. Allen1, Gary B. Quistad2, John E. Casida2 & Carrolee Barlow1, 3

1  The Salk Institute for Biological Studies, The Laboratory of Genetics, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.

2  Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, 115 Wellman Hall, University of California, Berkeley, California 94720-3112, USA.

3  Present address: Merck Research Laboratories, 3535 General Atomics Court, San Diego, California 92121, USA.

Correspondence should be addressed to Carrolee Barlow carrolee_barlow@merck.com
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.

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Nature Genetics Correspondence (01 Jul 2003)

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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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