Androgen receptor antagonism by the organophosphate insecticide fenitrothion

Organophosphate insecticides represent one of the most widely used classes of pesticides with high potential for human exposure in both rural and resi dential environments. We investigated the interaction of the organophosphot hioate pesticide fenitrothion (O,O-dimethyl O-(4-nitro-m-tolyl) phosphoroth ioate) with the human androgen receptor (AR). Fenitrothion blocked dihydrot estosterone-dependent AR activity in a concentration-dependent and competit ive manner in HepG2 human hepatoma liver cells transiently transfected with human AR and an AR-dependent luciferase reporter gene. Schild regression a nalysis yielded an equilibrium dissociation constant value of 2.18 x 10(-8) M. To determine the antiandrogenic potential of fenitrothion in vivo, 7-we ek-old castrated Sprague-Dawley rats were dosed once a day for 7 days with testosterone propionate (50 mug/day, sc) plus gavage doses of either corn o il vehicle or fenitrothion (15 or 30 mg/kg/day). An additional group of rat s was given testosterone propionate and flutamide (50 mg/kg/day). Motor act ivity and acetylcholinesterase activity in whole blood and brain were also assessed. Both fenitrothion and the reference antiandrogen flutamide caused significant decreases in the ventral prostate, seminal vesicle, and levato r ani plus bulbocavernosus muscles tissue weights. In contrast, blood acety lcholinesterase activity, a standard biomarker of organophosphate poisoning , was only inhibited at the higher dose of fenitrothion (30 mg/kg). Our res ults demonstrate that fenitrothion is a competitive AR antagonist, comparab le in potency to the pharmaceutical antiandrogen flutamide and more potent, based on in vitro assays, than the known environmental antiandrogens linur on and p,p'-, 2,2-bis(p-hydroxyphenyl)-1,1-dichloroethylene (p,p'-DDE).