Evaluation of Fish Models of Soluble Epoxide Hydrolase Inhibition

John W. Newman, Debra L. Denton, Christophe Morisseau, Cory S. Koger, Craig E. Wheelock, David E. Hinton, Bruce D. Hammock
2001 Environmental Health Perspectives  
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
more » ... s 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 dosedependent 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
doi:10.2307/3434922 fatcat:ep2atheogzf6hpblqsx4a2zcj4