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Antiandrogenic activity and metabolism of the organophosphorus pesticide fenthion and related compounds. (Research).

We investigated the endocrine-disrupting actions of the organophosphorus or·gan·o·phos·pho·rus  
An organophosphate.

 pesticide fenthion and related compounds and the influence of metabolic transformation on the activities of these compounds. Fenthion acted as an antagonist of the androgenic activity of dihydrotestosterone dihydrotestosterone /di·hy·dro·tes·tos·te·rone/ (DHT) (-tes-tos´te-ron) an androgenic hormone formed in peripheral tissue by the action of 5 on testosterone; thought to be the androgen responsible for development of male primary sex  ([10.sup.-7] M) in the concentration range of [10.sup.-6]-[10.sup.4] M in an androgen-responsive element-luciferase reporter-responsive assay using NIH "Not invented here." See digispeak.

NIH - The United States National Institutes of Health.
3T3 cells. The antiandrogenic activity of fenthion was similar in magnitude to that of flutamide. Fenthion also tested positive in the Hershberger assay using castrated cas·trate  
tr.v. cas·trat·ed, cas·trat·ing, cas·trates
1. To remove the testicles of (a male); geld or emasculate.

2. To remove the ovaries of (a female); spay.

 male rats. Marked estrogenic and antiestrogenic activities of fenthion and related compounds were not observed in MCF-7 cells. When fenthion was incubated with rat liver microsomes in the presence of NADPH NADPH the reduced form of NADP.

The reduced form of NADP.


reduced form of nicotinamide adenine dinucleotide phosphate (NADP) used in a number of reductive synthesis such as fatty
, the antiandrogenic activity markedly decreased, and fenthion sulfoxide sulf·ox·ide
Any of various compounds that contain a sulfinyl group.


1. the divalent radical =SO.

2. an organic compound intermediate between a sulfide and a sulfone.
 was detected as a major metabolite. The oxidase oxidase /ox·i·dase/ (ok´si-das) any enzyme of the class of oxidoreductases in which molecular oxygen is the hydrogen acceptor.

 activity toward fenthion was exhibited by cytochrome P450 and flavin-containing monooxygenase. Fenthion sulfoxide was negative in the screening test for antiandrogens, as was fenthion sulfone sulfone /sul·fone/ (sul´fon)
1. the radical SO2.

2. a compound containing two hydrocarbon radicals attached to the —SO2— group, especially dapsone and its derivatives, which are potent antibacterials effective
. However, when fenthion sulfoxide was incubated with liver cytosol cytosol /cy·to·sol/ (sit´ah-sol) the liquid medium of the cytoplasm, i.e., cytoplasm minus organelles and nonmembranous insoluble components.cytosol´ic

 in the presence of 2-hydroxypyrimidine, an electron donor of aldehyde oxidase, the extract of the incubation mixture exhibited antiandrogenic activity. In this case, fenthion was detected as a major metabolite of the sulfoxide. Metabolic interconversion in·ter·con·ver·sion  
Mutual conversion.

inter·con·vert v.
 between fenthion and fenthion sulfoxide in the body seems to maintain the antiandrogenic activity. Key words: aldehyde oxidase, antiandrogenic activity, cytochrome P450, endocrine disruption, fenthion, fenthion sulfoxide.


Fenthion [O, O-dimethyl-O-(4-methylmercapto)-3-methylphenylthio-phosphate] is an organophosphorus pesticide widely used throughout the world as a broad-spectrum insecticide for numerous crops and also as an ectoparasiticide for farm animals (Roberts and Hutson 1999). Fenthion inhibits acetylcholine acetylcholine (əsēt'əlkō`lēn), a small organic molecule liberated at nerve endings as a neurotransmitter. It is particularly important in the stimulation of muscle tissue.  esterase esterase /es·ter·ase/ (es´ter-as) any enzyme which catalyzes the hydrolysis of an ester into its alcohol and acid.

Any of various enzymes that catalyze the hydrolysis of an ester.
 and is thought to be a safe pesticide because it is not easily converted to the possibly highly toxic oxon derivative in animal species. However, toxic effects such as ultrastructural change in testes testes
 or testicles

Male reproductive organs (see reproductive system). Humans have two oval-shaped testes 1.5–2 in. (4–5 cm) long that produce sperm and androgens (mainly testosterone), contained in a sac (scrotum) behind the penis.
 of gobiid fish, reduction in larval production in sand fiddler crabs, chronic toxicity in hens, acute toxicity in birds, reptiles, and fish, and decreases in muscarinic muscarinic /mus·ca·rin·ic/ (mus?kah-rin´ik) denoting the cholinergic effects of muscarine on postganglionic parasympathetic neural impulses.  receptor function in rat retina have been reported (Mullie et al. 1999; Schoor et al. 2000; Tandon et al. 1994; Tuler and Bowen 1999; Zutshi and Murthy 2001). Furthermore, it has been reported that fenthion and its oxidation products, fenthion sulfoxide and fenthion oxon, contaminate olives, mosquitos, fish, and the environment (Cavanna and Molinari 1998; Fukushima 1991; Kitamura et al. 2000; Lacorte et al. 1997; Meyer et al. 1998; Peiris and Hemingway 1996; Pereira and Hostettler 1993; Prasad et al. 1997; Tsuda et al. 1996). The relationship between the toxicity and metabolism of fenthion has been examined in human neuroblastoma Neuroblastoma Definition

Neuroblastoma is a type of cancer that usually originates either in the tissues of the adrenal gland or in the ganglia of the abdomen or in the ganglia of the nervous system.
 cell lines, birds, and fish, and either an increase or a decrease in toxicity as a result of metabolism was found (Cova et al. 1995; Kitamura et al. 2000; Roux et al. 1995).

Many environmental xenobiotics exert hormonal effects at the cellular and organismal levels. These compounds can mimic the biologic activity of sex hormones and thyroid hormone and are called "endocrine-disrupting chemicals." The estrogenic chemicals include chlorinated chlorinated /chlo·ri·nat·ed/ (klor´i-nat?ed) treated or charged with chlorine.


charged with chlorine.

chlorinated acids
some, e.g.
 insecticides such as kepone, o,p'-DDT, dieldrin dieldrin: see insecticides. , methoxychlor methoxychlor

one of the group of chlorinated hydrocarbon insecticides which cause typical signs of that poisoning.
, and nonchlorinated compounds used in the plastics and detergent industries, such as alkylphenols and bisphenol A (Andersen et al. 1999; Gaido et al. 1997; Soto et al. 1994). We demonstrated that fenthion does not have estrogenic activity, based on the finding that vitellogenin Vitellogenin (Vg) (from latin vitellus = yolk and gener = to produce) is a synonymous term for the gene and the expressed protein. The molecule is classified as a glyco-lipo-protein, having properties of a sugar, fat and protein.  levels in male goldfish were not enhanced when the fish were kept in fenthion solution (Kitamura et al. 1999). However, the estrogenic activity of fenthion has not been examined in mammalian cell lines. Further, the antiandrogenic activity of fenthion has not been examined, even though some pesticides are known to have antiandrogenic properties. The pesticide vinclozolin is known to exhibit antiandrogenic activity after metabolic activation (Gray et al. 1994; Kelce et al. 1994). Flutamide, a diuretic agent, must also be metabolically activated before it can exert effects (Wong et al. 1995). The widespread use of these pesticides and fungicides in the environment may generate antiandrogens by metabolic activation and may alter male sexual development and reproductive processes (Kelce and Wilson 1997).

To clarify the endocrine-disrupting action of fenthion and related compounds, we examined their androgenic and antiandrogenic activities in this study using androgen-responsive element (ARE)-luciferase reporter-transfected mouse fibroblast fibroblast /fi·bro·blast/ (fi´bro-blast)
1. an immature fiber-producing cell of connective tissue capable of differentiating into chondroblast, collagenoblast, or osteoblast.

 cell line NIH3T3 in vitro and the Hershberger assay in vivo. We also examined the estrogenic and antiestrogenic activities using estrogen-responsive element (ERE)-luciferase reporter-transfected human breast cancer cell line MCF-7. The influence of the metabolism of fenthion on these endocrine-disrupting activities was investigated using rat liver preparations.

Materials and Methods

Chemicals. Fenthion (98% pure), fenthion sulfoxide (99%), fenthion sulfone (99%), fensulfothion (98%), fenitrothion (98%), trichlorfon trichlorfon

an organophosphorus insecticide and anthelmintic, used in horses, often in combination with other anthelmintics, for treatment of endoparasites and cutaneous habronemiasis. Also used in dogs against whipworms and as a pour-on in cattle for control of warble flies.
 (98%), malathion (99%), and EPN EPN

ethyl p-nitrophenyl benzenethiophosphanate; a nonsystemic organophosphorus insecticide and acaricide.
 (ethyl p-nitrophenyl benzenethiophosphonate, 98%) were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). Dihydrotestosterone (DHT (Distributed Hash Table) A method for storing hash tables in geographically distributed locations in order to provide a failsafe lookup mechanism for distributed computing. ), 2-hydroxypyrimidine, and menadione menadione /men·a·di·one/ (men?ah-di´on) vitamin K3.
1. a synthetic fat-soluble vitamin that can be converted in the body to active vitamin K.

 were obtained from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). SKF SKF Svenska Kullagerfabriken
SKF Svenska Klätterförbundet (Sweden)
SKF Smithsonian Kite Festival
SKF San Antonio Kelly Field Annex (Lackland AFB, Texas) 
 525-A, [alpha]-naphthoflavone, 17[beta]-estradiol ([E.sub.2]), and [alpha]-naphthylthiourea were purchased from Sigma Chemical Co. (St. Louis, MO, USA).

Animals. Male rats were housed at 22[degrees]C with a 12-hr light/dark cycle, with free access to tap water and a standard pellet diet MM-3 (Funabashi Farm, Funabashi, Japan). All experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals of Hiroshima University.

Cell culture. NIH3T3 and MCF-7 cells were maintained in Dulbecco's Modified Eagle's Medium (DMEM DMEM Dulbecco's Modified Eagle's Medium (for cell culture growth)
DMEM Design Manufacture and Engineering Management Department
) (Sigma) plus 5% calf serum (Gibco/Invitrogen Corp., Carlsbad, CA, USA) and DMEM plus 5% fetal bovine serum Fetal bovine serum ( or foetal bovine serum) is serum taken from the fetuses of cows. Fetal Bovine Serum (or FBS) is the most widely used serum in the culturing of cells. In some papers the expression foetal calf serum is used.  (Gibco/Invitrogen), respectively, containing penicillin and streptomycin streptomycin (strĕp'tōmī`sĭn), antibiotic produced by soil bacteria of the genus Streptomyces and active against both gram-positive and gram-negative bacteria (see Gram's stain), including species resistant to other . For assays, the medium was changed to phenol red-free DMEM (Sigma) containing the same antibiotics along with dextran-charcoal-treated calf serum or fetal bovine serum for a week.

Plasmids. The p[(ARE).sub.2]-luc plasmid was constructed with pGL3-enhancer (Promega Co., Madison, WI, USA) by inserting a synthetic double-strand oligo-DNA containing the consensus androgen-responsive element 5'-CATAGTACGTGATGTTCTAGGCCTAGTACGTGATGTTCTCTATAC (with Sac I/Xho I ends). For pSG5-hAR, human androgen receptor cDNA was amplified from human prostate cDNA by polymerase chain reaction polymerase chain reaction (pŏl`ĭmərās') (PCR), laboratory process in which a particular DNA segment from a mixture of DNA chains is rapidly replicated, producing a large, readily analyzed sample of a piece of DNA; the process is  with LA-Taq (Takara) and introduced into pCR2.1 with a TA Cloning Kit (Invitrogen). The EcoRI fragment was then inserted into the EcoRI site in the pSG5 plasmid. The p(ERE)3-SV40-luc plasmid, which contains three tandem copies of the consensus ERE, was a gift from M. Kudoh of Yamanouchi Pharmaceutical Co. (Tsukuba, Japan). pRL-CMV Renilla luciferase luciferase
n an enzyme present in certain luminous organisms that act to bring about the oxidation of luciferins; energy produced in the
 derived with the CMV enhancer/promoter (Promega Co., Madison, WI, USA) was used as the internal control.

Liver preparations. Male rats (160-190 g, Slc:Wistar/ST strain) obtained from Japan SLC, Inc. (Shizuoka, Japan) were used. Livers were excised from exsanguinated rats and immediately perfused with 1.15% KCl. The livers were homogenized ho·mog·e·nize  
v. ho·mog·e·nized, ho·mog·e·niz·ing, ho·mog·e·niz·es
1. To make homogeneous.

a. To reduce to particles and disperse throughout a fluid.

 in 4 volumes of 1.15% KCl. The homogenate homogenate /ho·mog·e·nate/ (ho-moj´in-at) material obtained by homogenization.


material obtained by homogenization.
 was centrifuged for 20 min at 9,000 x g. We further separated the supernatant fraction into cytosol and microsomes by centrifugation for 60 min at 105,000 x g. The microsomes were washed by resuspension Noun 1. resuspension - a renewed suspension of insoluble particles after they have been precipitated
suspension - a mixture in which fine particles are suspended in a fluid where they are supported by buoyancy
 in 2 volumes of the KCl solution and resedimentation for 60 min at 105,000 x g. The washed microsomes were suspended in a volume of 1.15% KCl equivalent to the original liver weight. The microsomal microsomal

pertaining to or emanating from microsome.
 fraction was stored at -80[degrees]C before use.

Purification of aldehyde oxidase from livers of rats. We purified aldehyde oxidase from rat livers according to the reported method (Sugihara et al. 1995). The cytosol obtained from 14 g of rat liver was used for the purification. The active fractions showed a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

Assay of androgenic and antiandrogenic activities in vitro. We measured androgenic activity using the ARE-luciferase reporter assay in NIH3T3 cells. Cells were plated at 5 x [10.sup.4]/well in 24-well plates and transiently transfected with 0.1 [micro]g of pS[G.sub.5]-hAR, 0.5 [micro]g of p[(ARE).sub.2]-luc with TransFast transfection trans·fec·tion
Infection of a bacterium or cell with DNA or RNA isolated from a bacteriophage or from an animal or a plant virus, resulting in replication of the complete virus.
 reagent containing a synthetic cationic cationic

having qualities dependent on having free cations available.

cationic detergents
are wetting agents that disrupt or damage cell membranes, denature proteins and inactivate enzymes.
 lipid (Promega), following the supplied protocol. The weight ratio of TransFast reagent to DNA DNA: see nucleic acid.
 or deoxyribonucleic acid

One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes.
 was 1:1. After 24-hr incubation with samples, cells were harvested with 50 [micro]L of cell lysis buffer (Promega) and the firefly and renilla luciferase activities were determined with the dual luciferase assay kit (Promega) by measuring luminescence luminescence, general term applied to all forms of cool light, i.e., light emitted by sources other than a hot, incandescent body, such as a black body radiator.  with a Wallac Micro-Beta scintillation scintillation /scin·til·la·tion/ (sin?ti-la´shun)
1. an emission of sparks.

2. a subjective visual sensation, as of seeing sparks.

 counter (PerkinElmer Life Sciences, Boston, MA, USA). Firefly luciferase reporter activity was normalized to renilla luciferase activity from pRL-CMV. To assess antiandrogenic activity, the inhibitory effects of test compounds on the androgenic activity of DHT at the concentrations of [10.sup.-11] and [10.sup.-10] M was examined. Because androgen, progesterone, and glucocorticoid receptors share the same hormone-responsive element, the reporter responses to progesterone and glucocorticoid glucocorticoid /glu·co·cor·ti·coid/ (-kor´ti-koid)
1. any of the group of corticosteroids predominantly involved in carbohydrate metabolism, and also in fat and protein metabolism and many other activities (e.g.
 were examined and confirmed to be negative (data not shown). Data are expressed as the means [+ or -] SD of four experiments using independent transfected cells.

In the assay of the antiandrogenic activity of the metabolites produced from fenthion or fenthion sulfoxide, substrates (0.1 [micro]mol) were incubated with 0.1 mL rat liver microsomes in the presence of 1 [micro]mol of NADPH, or with 0.2 mL liver cytosol in the presence of 2-hydroxypyrimidine for 30 min in a final volume of 1 mL 0.1 M phosphate buffer. After the incubation, the mixture was extracted with 5 mL ethyl acetate and evaporated to dryness. The residue was dissolved in 1 mL ethanol, and an aliquot aliquot (al-ee-kwoh) adj. a definite fractional share, usually applied when dividing and distributing a dead person's estate or trust assets. (See: share)  was used for the antiandrogenic activity assay described above. We calculated the total concentration of the substrate and its metabolites from the original amount of the substrate.

Assay of androgenic and antiandrogenic activities in vivo (Hershberger assay). We used F344 male rats obtained from Charles River Co. (Kanagawa, Japan). They were surgically castrated at 5 weeks of age. At 7 weeks of age, they were divided into five groups consisting of seven animals each, except six in the control. We treated the rats once a day for 7 days with subcutaneous doses of 0.2 mL of vehicle (Panacete 810; Nippon Oils and Fats Co., Ltd., Tokyo, Japan), testosterone propionate propionate /pro·pi·o·nate/ (pro´pe-o-nat) any salt of propionic acid.

A salt or ester of propionic acid.


any salt of propionic acid.
 (500 [micro]g/kg/day), testosterone propionate plus flutamide (6 mg/kg/day), or testosterone plus fenthion (25 or 50 mg/kg/day). We sacrificed animals under anesthesia and dissected and weighed the ventral prostate and seminal vesicles.

Assay of estrogenic and antiestrogenic activities in vitro. We assayed estrogenic activity according to the previously reported method using an ERE-luciferase reporter in MCF-7 cells (Sugihara et al. 2000). Briefly, transient transfections in MCF-7 cells were performed using TransFast in 12-well plates at 1 x [10.sup.5] cells/well with 1.9 [micro]g p[(ERE).sub.3]-SV40-luc and 0.1 [micro]g pRL-CMV as an internal standard. Twenty-four hours after addition of the sample, the assay was performed with a dual luciferase assay kit. We measured antiestrogenic activity in terms of the inhibitory effect of the test compounds on the estrogenic activity of [E.sub.2] at the concentrations of 1 x [10.sup.-10] and 1 x [10.sup.-9] M. Data are expressed as the means [+ or -] SD of four experiments using independent transfected cells.

Metabolizing activities of rat liver preparations. The incubation mixture consisted of 0.2 [micro]mol fenthion or fenthion sulfoxide, 1 [micro]mol of an electron donor and liver microsomes (2-3 mg protein) or cytosol (1-2 mg protein) in a final volume of 1 mL of 0.1 M K,Na-phosphate buffer (pH 7.4). The incubation was continued for 30 min at 37[degrees]C. In the case of reduction of fenthion sulfoxide, the incubation was performed using a Thunberg tube under anaerobic anaerobic /an·aer·o·bic/ (an?ah-ro´bik)
1. lacking molecular oxygen.

2. growing, living, or occurring in the absence of molecular oxygen; pertaining to an anaerobe.
 conditions. The side arm contained an electron donor, and the body contained all other components. The tube was gassed for 3 min with nitrogen, evacuated with an aspirator as·pi·ra·tor
An apparatus for removing fluid from a body cavity, consisting usually of a hollow needle and a cannula, connected by tubing to a container in which a vacuum is created by a syringe or a suction pump.
 for 5 min, and again gassed with nitrogen. The reaction was started by mixing the components of the side arm and the body together. After the incubation, the mixture, after addition of 10 nmol benzophenone ben·zo·phe·none  
A white crystalline compound, C6H5COC6H6, used in perfumery and in medicine. Also called diphenylketone.
 as an internal standard and two volumes of acetonitrile acetonitrile /ac·e·to·ni·trile/ (as?e-to-ni´tril) a colorless liquid with an etherlike odor used as an extractant, solvent, and intermediate; ingestion or inhalation yields cyanide as a metabolic product. , was centrifuged, and an aliquot of the supernatant was subjected to analysis by high-performance liquid chromatography (HPLC HPLC high-performance liquid chromatography.


high performance liquid chromatography.

HPLC High-performance liquid chromatography Lab instrumentation A highly sensitive analytic method in which analytes are placed
). The time-course of the formation of the metabolite in the presence of NADPH with 1.5 mg protein of liver microsomes of rats was linear to 60 min. The dependency on amount of liver microsomes was linear up to 10 mg protein. Data are expressed as the means [+ or -] SD of four experiments using independent rats.

HPLC. HPLC was performed in a Hitachi L-7110 high-performance liquid chromatograph chromatograph /chro·mato·graph/ (kro-mat´o-graf)
1. the apparatus used in chromatography.

2. to analyze by chromatography.


1. to analyze by chromatography.

 (Tokyo, Japan) equipped with an ultraviolet absorption detector. The instrument was fitted with a 4 x 125 mm Inertsil ODS-3 column (GL-Science, Tokyo, Japan). The mobile phase was acetonitrile-0.1 M K[H.sub.2]P[O.sub.4] (6:4, vol/vol, pH 5.4). The chromatograph was operated at a flow rate of 0.5 mL/min and at a wavelength of 254 nm. Elution elution /elu·tion/ (e-loo´shun) in chemistry, separation of material by washing; the process of pulverizing substances and mixing them with water in order to separate the heavier constituents, which settle out in solution, from the  times of fenthion sulfoxide, fenthion sulfone, benzophenone, and fenthion were 5.8, 8.8, 15.2, and 25.4 min, respectively. We determined the amounts of metabolites formed from the peak areas. In some experiments for the determination of metabolites, a Beckman 168 photodiode array ultraviolet (UV) detector (Beckman Instruments, Inc., Fullerton, CA, USA) was fitted to the HPLC unit to identify the metabolites of fenthion and fenthion sulfoxide.

GC-MS GC-MS Gas chromatography-mass spectroscopy. See there. . Gas chromatography-mass spectrometry (GC-MS) was performed using a Shimadzu GC-17A/QP-5000 (Kyoto, Japan) in the electron impact mode. A DB-5 fused-silica capillary column (30 m x 0.25 mm i.d.; J & W Scientific Inc., Folsom, CA, USA) was used. The column temperature was held at 100[degrees]C for 5 min, then increased at a rate of 10[degrees]C/min to 200[degrees]C. We injected 1 [micro]L of sample into the injection port at 220[degrees]C. Splitless injection was used. The retention times of fenthion sulfoxide and fenthion were 12.2 and 14.7 min, respectively.


Androgenic and antiandrogenic activities of fenthion and metabolites. Androgenic and antiandrogenic activities of fenthion, fenthion sulfoxide, and fenthion sulfone were examined using an ARE-luciferase reporter in NIH3T3 cells. These compounds had no detectable androgenic activity in the concentration range of [10.sup.-7]-[10.sup.-4] M. In contrast, DHT at [10.sup.-11]-[10.sup.-9] M exhibited marked androgenic activity (Figure 1A). When fenthion was added to the assay system at [10.sup.-7]-[10.sup.-5] M, the activity of DHT at a concentration of [10.sup.-11] M was inhibited concentration dependently. This antiandrogenic effect of fenthion was also observed at a concentration of [10.sup.-10] M DHT. The antiandrogenic activity of fenthion is comparable to that of flutamide. However, fenthion sulfoxide and fenthion sulfone did not show such antiandrogenic effects in the concentration range of [10.sup.-7]-[10.sup.-5] M (Figure 1B,C).


Antiandrogenic activities of fenthion-related compounds. Antiandrogenic activities of fenthion and related compounds were comparatively examined with an ARE-luciferase reporter in NIH3T3 cells. Figure 2 shows the I[C.sub.50] (concentration for 50% inhibition) values of fenthion, fenthion sulfoxide, fenthione sulfone, fenitrothion, fensulfothion, EPN, trichlorfon, and malathion against the androgenic activity of DHT at a concentration of [10.sup.-10] M. The highest activity among organophosphorus compounds was observed in fenitrothion, followed by fenthion and EPN. However, fenthion sulfoxide, fenthion sulfone, fensulfothion, trichlorfon, and malathion did not show such activity. These results indicate that some organophosphorus insecticides have antiandrogenic but not androgenic activity.


Estrogenic and antiestrogenic activities of fenthion and metabolites. Estrogenic activities of fenthion, fenthion sulfoxide, and fenthion sulfone were examined using ERE-luciferase reporter-transfected MCF-7 cells. [E.sub.2] exhibited estrogenic activity at [10.sup.-12]-[10.sup.-9] M. In contrast, no estrogenic activity of fenthion, fenthion sulfoxide, or fenthion sulfone was observed in the concentration range of [10.sup.-7]-[10.sup.4] M, except for a marginal effect at [10.sup.-4] M (data not shown). When fenthion, fenthion sulfoxide, or fenthion sulfone was added to the assay system of [E.sub.2] in the concentration range of [10.sup.-8]-[10.sup.-5] M, the estrogenic activity of [E.sub.2] at the concentrations of [10.sup.-11] M and [10.sup.-10] M was not inhibited (data not shown). Thus, no significant estrogenic or antiestrogenic effect of fenthion and related compounds was observed.

Antiandrogenic activity of fenthion after metabolism with rat liver microsomes. The effect of the metabolism of fenthion by rat liver microsomes on the antiandrogenic activity of the compound was examined. When fenthion was incubated with rat liver microsomes in the presence of NADPH, the inhibitory effect of the extract on the androgenic activity of DHT at the concentrations of [10.sup.11] and [10.sup.-10] M was markedly decreased compared with the original activity of fenthion. The decrease of antiandrogenic activity was minimal when the incubation was performed without liver microsomes (Figure 3A, B). Fenthion sulfoxide was detected by HPLC as a major metabolite in the complete incubation mixture. The mass and UV spectra of the metabolite confirmed that it was fenthion sulfoxide (data not shown).


Antiandrogenic activity of fenthion sulfoxide after metabolism with rat liver cytosol. When fenthion sulfoxide was incubated with rat liver cytosol in the presence of 2-hydroxypyrimidine, an electron donor of aldehyde oxidase, under anaerobic conditions, the extract of the incubation mixture inhibited the androgenic activity of DHT on NIH3T3 cells in the range of [10.sup.-7]-[10.sup.-5] M. The antiandrogenic activity was not observed after incubation without liver cytosol (Figure 3C, D). Such metabolic activation did not occur after the incubation of fenthion sulfoxide with liver microsomes in the presence of NADPH. When fenthion sulfoxide was incubated with liver cytosol of rats in the presence of 2-hydroxypyrimidine, one metabolite, of which the retention time corresponded to that of fenthion, was detected in HPLC of the extract. The metabolite was identified by comparison of the mass and UV spectra with those of authentic fenthion, as described in "Materials and Methods." Fenthion was not detected in HPLC of the incubation mixture of fenthion sulfoxide with rat liver microsomes (data not shown). These results suggest that the oxidation of fenthion acts as a detoxification pathway and the reduction of fenthion sulfoxide to fenthion as an activation step, and this inter-conversion between fenthion and fenthion sulfoxide in the body functions to maintain the antiandrogenic activity of fenthion.

Metabolism of fenthion and fenthion sulfoxide by rat liver preparations. In the conversion of fenthion to fenthion sulfoxide by rat liver microsomes, NADPH was effective as an electron donor. The NADPH-linked oxidizing activity in liver microsomes of rats toward fenthion was significantly inhibited by [alpha]-naphthylthiourea and partially inhibited by SKF 525-A, [alpha]-naphthoflavone, and quinidine quinidine (kwĭn`ĭdēn'), heart muscle relaxant used to maintain regular heart rhythm patterns. It is an alkaloid chemically similar to quinine and, like quinine, occurs naturally in some species of cinchona trees.  (Figure 4A). This suggests that the oxidizing activity to the sulfoxide is due to both cytochromes P450 (CYPs) and flavin-containing monooxygenase (FMO FMO For Members Only
FMO Flavin-Containing Monooxygenase
FMO Financierings-Maatschappij voor Ontwikkelingslanden (Dutch: Netherlands Development Finance Company)
FMO Fire Management Officer (National Park Service) 
) in the rats.


Fenthion was formed from fenthion sulfoxide by rat liver cytosol when 2-hydroxypyrimidine or benzaldehyde benzaldehyde (bĕnzăl`dəhīd) or benzenecarbonal (bĕn'zēnkär`bənəl), C6H5CHO, colorless liquid aldehyde with a characteristic almond odor. , which are electron donors of aldehyde oxidase, was added under anaerobic conditions. However, xanthine xanthine /xan·thine/ (-then) a purine base found in most body tissues and fluids, certain plants, and some urinary calculi; it is an intermediate in the degradation of AMP to uric acid. Methylated xanthine compounds (e.g. , an electron donor of xanthine oxidase, was not effective for the reduction. In the cytosolic reduction, NADPH and NADH NADH the reduced form of NAD.

The reduced form of NAD.

NADH, a coenzyme that incorporates niacin and involved in the Krebs cycle.
 were also much less effective than 2-hydroxypyrimidine. The 2-hydroxypyrimidine-dependent activity in rat liver was inhibited by menadione, which is an inhibitor of aldehyde oxidase, but not by oxypurinol, an inhibitor of xanthine oxidase (Figure 4B). This suggests that the reducing activity is due to aldehyde oxidase in rat liver cytosol. Indeed, purified aldehyde oxidase from rats exhibited a significant sulfoxide reductase reductase /re·duc·tase/ (-tas) a term used in the names of some of the oxidoreductases, usually specifically those catalyzing reactions important solely for reduction of a metabolite.  activity (64.7 nmol/min/mg protein) in the presence of 2-hydroxypyrimidine. In contrast, liver microsomes exhibited no reductase activity even in the presence of NADPH, indicating that CYP CYP

In currencies, this is the abbreviation for the Cyprus Pound.

The currency market, also known as the Foreign Exchange market, is the largest financial market in the world, with a daily average volume of over US $1 trillion.
 was not involved in the fenthion sulfoxide reduction (data not shown). The cytosolic reductase activity toward fenthion sulfoxide was higher than the NADPH-dependent microsomal oxidase activity toward fenthion.

Hershberger assay of fenthion. Antiandrogenic potential of fenthion in vivo was further investigated by means of the Hershberger assay using Fischer 344 rats according to the Hershberger protocol (Hershberger et al. 1953). Body weight was decreased by 25% in the group administered the higher dose of fenthion, but there were no significant differences among other groups. Teststerone treatment significantly increased the weights of the prostate and seminal vesicles, and these increases were completely blocked by flutamide administration. Fenthion also significantly suppressed the effect of testosterone on the weight of both glands (Figure 5). Thus, the antiandrogenic effect of fenthion was also observed in vivo.



In this study we examined the endocrine-disrupting action of fenthion and its metabolites, focusing on antiandrogenic and estrogenic actions. No estrogenic or antiestrogenic activity of fenthion was detected using estrogen-responsive reporter assay. However, we demonstrated that fenthion is a potent antiandrogen antiandrogen /an·ti·an·dro·gen/ (-an´dro-jen) any substance capable of inhibiting the biological effects of androgens.

, though fenthion sulfoxide and fenthion sulfone lack this activity. Antiandrogenic activity of fenthion using ARE-luciferase reporter assay in NIH3T3 cells was comparable to that of the reference antiandrogen, flutamide. The Hershberger assay has been used to screen chemicals for androgenic and antiandrogenic activities in vivo. In the Hershberger assay used in this study, fenthion could block androgen-dependent tissue growth. Fenthion's effect on androgen-dependent tissue weights was significant. The antiandrogenic activity shown by the reporter assay in NIH3T3 cells is supported by the result of this in vivo assay. It is known that fenthion is accumulated in the environment (Fukushima 1991; Lacorte et al. 1997; Pereira and Hostettler 1993). Fenthion and its metabolites were detected in rice and olive oil at concentrations of about 10 and 1 ppm, respectively (Cabras et al. 1993; Fukuda et al. 1962). These compounds were also detected in river water near Osaka, Japan at 20-70 ng/L (Yamaguchi and Fukushima 1994). The concentration detected in the river water is three orders of magnitude lower than the concentration of fenthion that causes antiandrogenic activity. However, the concentrations detected in rice and olive oil are sufficient to exert antiandrogenic action. Fenthion may accumulate to a level in the body sufficient to cause antiandrogenic action. Further, fenthion in combination with other pesticides may exhibit antiandrogenic activity. Lacorte et al. (1997) reported that fenthion was oxidized oxidized

having been modified by the process of oxidation.

oxidized cellulose
see absorbable cellulose.
 to the sulfoxide in the environment. This conversion would contribute to the inactivation inactivation /in·ac·ti·va·tion/ (in-ak?ti-va´shun) the destruction of biological activity, as of a virus, by the action of heat or other agent.  of fenthion in terms of antiandrogenic action. However, the effect of fenthion on reproductive tissues in rats in vivo shown in this study cannot be neglected.

In this study, we demonstrated that fenitrothion and EPN, in addition to fenthion, are antiandrogenic, but fensulfothion, trichlorfon, and malathion are not. Antiandrogenic compounds so far reported include vinclozolin, linuron linuron

a methyl urea herbicide. Sprayed plants may contain higher than normal amounts of nitrate and cause nitrite poisoning.
, iprodione, chlozolinate, procymidone, flutamide, p,p'-DDE, and ketoconazole ketoconazole /ke·to·co·na·zole/ (ke?to-kon´ah-zol) a derivative of imidazole used as an antifungal agent.

 (Gray et al. 1999a, 1999b; Lambright et al. 2000; McIntyre et al. 2000; Ostby et al. 1999; You et al. 1999). In contrast, both positive and negative results on the antiandrogenic activity of fenitrothion, a relative of fenthion, have been reported (Ashby and Lefevre 2000; Curtis 2001; Sohoni et al. 2001; Sunami et al. 2000; Tamura et al. 2001). The significant antiandrogenic activity of fenitrothion found in our study supports previous findings that fenitrothion has antiandrogenic properties. The structures of fenthion and fenitrothion are the same except for their para substituents. These structures closely resemble that of flutamide. It is difficult to understand the structural differences between antiandrogenic and non-antiandrogenic organophosphorus insecticides. Further study of the structure requirements for, and the mechanism of action of, antiandrogenic activity of organophosphorus insecticides is needed.

Several reports have indicated that sulfide compounds are metabolized mainly by oxidation to the corresponding sulfoxide and sullone compounds, and some sulfoxide compounds are reduced in the sulfide compounds in mammalian species (Benoit et al. 1992; DeBaun and Menn 1976; McLane et al. 1983; Mitchell and Waring 1986; Tatsumi et al. 1983). However, the metabolism of fenthion and fenthion sulfoxide has not been extensively examined in mammalian species. Brady and Arthur (1961) briefly reported that fenthion was transformed to the oxidized metabolites in rats in vivo. In the current study, we showed that fenthion was oxidized to fenthion sulfoxide, and the sulfoxide was reduced back to the parent fenthion. However, fenthion sulfone was not formed from fenthion in rat liver. We also demonstrated the inactivation of the antiandrogenic activity of fenthion upon metabolic oxidation and the activation of fenthion sulfoxide by reductive metabolism, and we suggest that the interconversion between fenthion and fenthion sulfoxide in the body functions to maintain antiandrogenic activity (Figure 6).


Fenthion was oxidized to fenthion sulfoxide by rat liver microsomes. The oxidizing activity to the sulfoxide appears to be exhibited by both CYP and FMO in rats. In our preliminary study, microsomal preparations from cells expressing recombinant human CYP 1A1, 1A2, 2B6, 2C9, and 3A4 and FMO I expressed in a human B lymphoblastoid cell line, exhibited sulfoxide oxidase activities toward fenthion amounting to 3.6, 0.4, 0.4, 0.3, 1.0, and 62.4 nmol/min/mg protein, respectively. In contrast, the reductive metabolism of fenthion sulfoxide was catalyzed by a cytosolic enzyme, aldehyde oxidase but not CYP. The velocity of this reverse reaction is about the same as that of fenthion oxidation (1.1 and 0.8 nmol/min/mg protein, respectively).

Metabolic modification of the activity of endocrine disrupters is an important factor influencing the toxicity of these compounds. For example, vinclozolin, an antifungal agent, was activated to antiandrogenic compounds by hydrolysis of the amide linkage in animals (Kelce et al. 1994). p,p'-DDT is metabolized to p,p'-DDD and p,p'-DDE by reductive dechlorination and dehydrochlorination, respectively (Esaac and Matsumura 1980; Kitamura et al. 2002). p,p'-DDD shows estrogenic activity and p,p'-DDE shows antiandrogenic activity (Chen et al. 1997; Kelce et al. 1995). Polychlorinated biphenyls are converted to hydroxylated metabolites in animals, and some hydroxylated polychlorinated biphenyls show estrogenic and/or antithyroid hormonal activity (Connor et al. 1997; Garner et al. 1999; Korach et al. 1988). Further, methoxychlor, trans-stilbene, benzophenone, and benzo[a]pyrene are proestrogens that require metabolic activation by liver microsomal mixed-function oxidase in animals (Charles et al. 2000; Fertuck et al. 2001; Gaido et al. 1999; Nakagawa and Suzuki 2002; Sugihara et al. 2000). In contrast, the estrogen screening test of fenthion and related compounds in this study was negative, and these compounds were not metabolically activated to estrogens Estrogens
Hormones produced by the ovaries, the female sex glands.

Mentioned in: Acne, Polycystic Ovary Syndrome

estrogens (es´trōjenz),
 (data not shown). Much further work is needed to examine the metabolic modification of potentially hazardous endocrine disrupters in the environment.


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A necklace of precious stones, generally set in one strand.

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Any of a class of highly stable organic compounds prepared by the reaction of chlorine with biphenyl, a two-ring compound.
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n. 1. (Chem.) A salt of sulphonic acid.
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Foreign to the body or to living organisms. Used of chemical compounds.

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Shigeyuki Kitamura, (1) Tomoharu Suzuki, (1) Shigeru Ohta, (1) and Nariaki Fujimoto (2)

(1) Graduate School of Biomedical Sciences Graduate School of Biomedical Sciences may refer to:
  • Texas A&M University Graduate School of Biomedical Sciences in College Station, Texas
  • University of Medicine and Dentistry of New Jersey Graduate School of Biomedical Sciences in Newark, New Jersey
, and (2) Department of Developmental Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

Address correspondence to S. Kitamura, Graduate School of Biomedical Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551, Japan. Fax: 81 82 257 5329. E-mail:

This work was supported by a grant-in-aid for Scientific Research on a Priority Area (13027256) from the Japanese Ministry of Education, Science, Sports and Culture, and a grant-in-aid for Scientific Research (C13672343) from the Japan Society for the Promotion of Science.

Received 29 July 2002; accepted 25 October 2002.
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