Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 5-day Hershberger assay using young mature male rats to detect compounds interfering with androgen receptor (AR)-mediated mechanisms was evaluated for ability to identify p,p'-DDE (a weak AR antagonist) and methyltestosterone (MT, an AR agonist). Fenitrothion, an organophosphate pesticide, was also evaluated in this validated assay. Castrated male Crj:CD(SD)IGS rats (1 week after castration, 11 weeks of age) were subjected to experiments. To determine a suitable value of testosterone propionate (TP) as a reference androgen for detection of antiandrogenic chemicals, castrated male rats were treated daily with TP (0, 0.06, 0.25, 1, 4, or 16 mg/kg/day, s.c.). TP produced increases in weights of ventral prostate, seminal vesicles and levator ani plus bulbocavernosus muscles. Serum androgen level measured by RIA kit (mostly TP) were elevated in a dose-related manner, while the weights of organs with 1 mg/kg/day of TP were nearly equivalent to the maximum responses (i.e., sub-maximal). One hundred mg/kg/day of p,p'-DDE significantly attenuated TP 0.1 mg/kg-induced increases in weights of seminal vesicles and muscles, and TP 1 mg/kg-induced increases in weights of ventral prostate, seminal vesicles and muscles, but did not affect the weight of these organs in either TP 16 mg/kg-treated or intact rats, demonstrating that the dose range of 0.1-1 mg/kg TP is suitable for reference androgen. Oral treatment with 100 mg/kg of MT increased the weights of ventral prostate, seminal vesicles and muscles as strongly as did subcutaneous injection of 1 mg/kg of TP. These findings demonstrate that the 5-day Hershberger assay using young mature as well as immature male rats is a sensitive and valid short-term screening method for the detection of chemicals interfering with AR-mediated mechanisms. To determine whether fenitrothion interferes with AR-mediated mechanisms in vivo, fenitrothion (0, 0.75, 1.5 or 3 mg/kg/day) was administered by gavage for 5 days to castrated rats for androgenicity, or to castrated rats treated with 1 mg/kg TP for antiandrogenicity. Treatment with fenitrothion had no adverse effects on clinical signs, body weight, or liver or kidney weights, but cholinesterase activities in the brain and erythrocytes were significantly suppressed by fenitrothion to, respectively, 77-81% and 66-67% of control levels. In the antiandrogenicity experiment, serum androgen levels of TP-treated, castrated rats did not differ among groups. Treatment with 100 mg/kg of p,p'-DDE as a positive control again significantly attenuated TP-induced increases in weights of the ventral prostate and seminal vesicles, while fenitrothion had no effect on the weights of any organs. In the androgenicity experiment, treatment with 100 mg/kg of MT significantly increased weights of ventral prostate, seminal vesicles and muscles, but fenitrothion had no effects on the weights of any of these organs. These findings yield no evidence that fenitrothion interferes with AR-mediated mechanisms in vivo, consistent with the result of several toxicological bioassays.
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PMID:Evaluation of a 5-day Hershberger assay using young mature male rats: methyltestosterone and p,p'-DDE, but not fenitrothion, exhibited androgenic or antiandrogenic activity in vivo. 1120 Nov 71

Fenitrothion is a broad-spectrum organophosphate insecticide. Recently, it has been reported to exert androgenic or anti-androgenic activity in in vitro and in vivo screening assays, although the effects appear equivocal in vivo. To provide a conclusive and comprehensive evaluation of fenitrothion, especially regarding its anti-androgenic activity in the reproductive and endocrine systems, we conducted a one-generation reproductive toxicity study at appropriately toxic dose levels with a number of sensitive endpoints for endocrine disruption. Fenitrothion was administered to Crj:CD(SD)IGS parental animals (P) at concentrations of 10, 20, and 60 ppm in the diet for 10 weeks prior to mating, and throughout mating, gestation and lactation. Their offspring (F1) were exposed from weaning until maturation at the age of 10 weeks. In the P generation, brain cholinesterase activity was remarkably reduced in the 60 ppm males and in the 20 and 60 ppm females. Reproductive performance, organ weights, histopathology, and sperm analytical parameters were not affected. In the F1 generation, no general toxicity or effects on anogenital distance, retention of areolae/nipples, onset of puberty, organ weights, histopathological findings, and sperm parameters were observed. In conclusion, fenitrothion had no effects on the reproductive or endocrine systems of the P and F1 generations, even at toxic doses that markedly suppressed brain cholinesterase activity in P animals. The results suggest that fenitrothion at in-use levels in the environment is unlikely to cause disruption of human endocrine systems.
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PMID:Lack of evidence for endocrine disrupting effects in rats exposed to fenitrothion in utero and from weaning to maturation. 1559 Jan 6