Nature Genetics
34, 235 (2003)
doi:10.1038/ng0703-235b
Reply to "Association between organophosphate exposure and hyperactivity?"Christopher J Winrow1, 3, John E Casida2
& Carrolee Barlow1, 31 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. In reply
We appreciate the interest and enthusiasm resulting from our report describing the generation of Nte-haploinsufficient (Nte+/-) mice. In their letter, Bus et al. conclude that "the hypothesis that organophosphate-induced inhibition of Nte is causally related to hyperactivity is not plausible". We disagree on the basis of four lines of evidence. First, they did not note that the earlier study used Swiss-Webster mice and the present study used 129S6/SvEvTac mice. We know that the activity of Nte in the brain is different in these two strains, and differences in detoxifying enzymes might also contribute to any apparent dose-response discrepancy. Second, we show that Nte+/- mice have elevated motor activity relative to Nte+/+ littermates. These mice are genetically identical except for Nte haploinsufficiency. The power of mouse genetics enables analysis of the effects resulting from manipulating a single gene through comparisons with a littermate that is otherwise genetically identical. As noted in their letter, the Nte+/- mice have a 40% reduction in Nte activity in brain homogenates. From these results, it can be concluded that a decrease in Nte levels and activity leads to an increase in motor activity. Third, when Nte+/+ mice are exposed to 1 mg of EOPF per kg body weight, we again see an increase in motor activity similar to that seen with Nte+/- mice. EOPF has been shown to be a potent Nte inhibitor both in vitro and in vivo in Swiss-Webster mice and hens. Finally, Nte+/- mice are more sensitive than their Nte+/+ littermates to the toxic effects of EOPF at 6−10 mg per kg body weight. The overlap between the genetic and EOPF exposure experiments leads directly to the hypothesis that inhibition of Nte, either chemically or genetically, can lead to hyperactivity.
See Association between organophosphate exposure and hyperactivity? by Bus et al.
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