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ANDROGEN RECEPTOR ANTAGONISM BY THE ORGANOPHOSPHATE INSECTICIDE FENITROTHION
Citation:
Tamura, H., S. C. Maness, K. Reischmann, D. C. Dorman, L. E. Gray Jr., AND K. W. Gaido. ANDROGEN RECEPTOR ANTAGONISM BY THE ORGANOPHOSPHATE INSECTICIDE FENITROTHION. TOXICOLOGICAL SCIENCES 60(1):56-62, (2001).
Description:
Androgen receptor antagonism by the organophosphate insecticide fenitrothion. Tamura, H., Maness, S.C., Reischmann, K. Dorman, D.C., Gray, L.E., and Gaido, K.W. (2000). Toxicol. Sci.
Organophosphate insecticides represent one of the most widely used classes of pesticides with high potential for human exposure in both rural and residential environments. We investigated the interaction of the organophosphothioate pesticide fenitrothion [O,O-dimethyl O-(4-nitro-m-tolyl) phosphorothioate] with the human androgen receptor (AR). Motor activity and acetylcholinesterase activity in whole blood and brain were also assessed. Fenitrothion blocked dihydrotestosterone-dependent AR activity in a dose-responsive and competitive manner in HepG2 human hepatoma liver cells transiently transfected with human AR and an AR-dependent luciferase reporter gene. Schild regression analysis yielded an equilibrium dissociation constant value of 2.18 X 10-8 M. To determine the antiandrogenic potential of fenitrothion in vivo, Seven-week old castrated Sprague-Dawley rats, were dosed once a day for 7 days with testosterone propionate (50 :g/day, sq) plus gavage doses of either corn oil vehicle or fenitrothion (15 or 30 mg/kg/day). An additional group of rats was given testosterone propionate and flutamide (50 mg/kg/day). Fenitrothion caused significant dose-dependent decreases in the ventral prostate, seminal vesicle, and levator ani plus bulbocavernosus muscles tissue weights. In contrast, blood acetylcholinesterase activity, a standard biomarker of organophosphate poisoning, was only inhibited at the higher dose of fenitrothion (30 mg/kg). Our result demonstrate that fenitrothion is a potent, competitive AR antagonist. The high potential for human exposure together with the continued concern over endocrine active chemicals in the environment indicates the need for further study of this class of compounds.