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John W. Newman,¹ Debra L. Denton,² Christophe Morisseau,¹ Cory S. Koger,³ Craig E. Wheelock,¹ David E. Hinton,³ and Bruce D. Hammock^1,4

¹Department of Entomology, ²Department of Land, Air, and Water Resources, and ³Department of Anatomy, Physiology, and Cell Biology, University of California, Davis, California, USA
⁴University of California Davis Cancer Center, Sacramento, California, USA

Abstract

Substituted ureas and carbamates are mechanistic inhibitors of the soluble epoxide hydrolase (sEH) . We screened a set of chemicals containing these functionalities in larval fathead minnow (Pimphales promelas) and embryo/larval golden medaka (Oryzias latipes) models to evaluate the utility of these systems for investigating sEH inhibition in vivo. Both fathead minnow and medaka sEHs were functionally similar to the tested mammalian orthologs (murine and human) with respect to substrate hydrolysis and inhibitor susceptibility. Low lethality was observed in either larval or embryonic fish exposed to diuron [N-(3,4-dichlorophenyl) , N´-dimethyl urea], desmethyl diuron [N-(3,4-dichlorophenyl) , N´-methyl urea], or siduron [N-(1-methylcyclohexyl) , N´-phenyl urea]. Dose-dependent inhibition of sEH was a sublethal effect of substituted urea exposure with the potency of siduron < desmethyl diuron = diuron, differing from the observed in vitro sEH inhibition potency of siduron > desmethyl diuron > diuron. Further, siduron exposure synergized the toxicity of trans-stilbene oxide in fathead minnows. Medaka embryos exposed to diuron, desmethyl diuron, or siduron displayed dose-dependent delays in hatch, and elevated concentrations of diuron and desmethyl diuron produced developmental toxicity. The dose-dependent toxicity and in vivo sEH inhibition correlated, suggesting a potential, albeit undefined, relationship between these factors. Additionally, the observed inversion of in vitro to in vivo potency suggests that these fish models may provide tools for investigating the in vivo stability of in vitro inhibitors while screening for untoward effects. Key words: epoxide hydrolase, fish, in vivo models, mammals, urea pesticides. Environ Health Perspect 109:61-66 (2001) . [Online 13 December 2000]

http://ehpnet1.niehs.nih.gov/docs/2001/109p61-66newman/ abstract.html

Address correspondence to B.D. Hammock, 303 Briggs Hall, Department of Entomology, University of California, 1 Shields Avenue, Davis, CA 95616 USA. Telephone: (530) 752-8465. Fax: (530) 752-1537. E-mail: bdhammock@ucdavis.edu

We thank M. Goodrow for providing compounds I and III.

This research was funded by NIEHS training grant 732ES07059, UC Davis/NIEHS Superfund Basic Research Program project P42ES04699, the UC Systemwide Ecotoxicology Program, the California Statewide Integrated Pest Management Program (CALFED contract 97-C12, project B81609) , NCI grant CA 45131, and NIEHS grant R01ES02710.

Received 10 January 2000 ; accepted 19 September 2000.