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
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概要
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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.
- 2000-12-25
著者
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YAMADA Tomoya
Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd.
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OKUNO Yasuyoshi
Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd.
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SEKI Takaki
Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd.
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MIYATA Kaori
Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd.
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KAMITA Yusuke
Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd.
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Seki Takaki
Environmental Health Science Laboratory Sumitomo Chemical Co. Ltd.
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Sukata Tokuo
Environmental Health Science Lab. Sumitomo Chemical Co. Ltd.
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Miyata Kaori
Environmental Health Science Laboratory Sumitomo Chemical Company Ltd.
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Miyata Kaori
Corporate R&d Sumitomo Metal Industries Ltd.
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Kamita Yusuke
Environmental Health Science Laboratory Sumitomo Chemical Co. Ltd.
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SHIRAI Tomoyuki
Nagoya City University Medical School
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YABUSHITA Setsuko
Environmental Health Sciece Lab., Sumitomo Chemical Co., Ltd.
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MATSUO Masatoshi
Environmental Health Science Lab., Sumitomo Chemical Co., Ltd.
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Matsuo Masatoshi
Cooperative Research Center For Advanced Science And Technology Osaka University
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Kunimatsu Takeshi
Environmental Health Science Laboratry Sumitomo Chem. Co. Ltd.
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Yamada T
Environmental Health Science Laboratory Sumitomo Chemical Co. Ltd.
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SUNAMI Osamu
Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd.
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NAKATSUKA Iwao
Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd.
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Sunami Osamu
Environmental Health Science Laboratry Sumitomo Chem. Co. Ltd.
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Nakatsuka Iwao
Environmental Health Science Laboratory Sumitomo Chemical Co. Ltd.
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Nakatsuka Iwao
Environmental Health Science Laboratory Sumitomo Chemical Company Ltd.
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Yanai T
United Graduate School Of Veterinary Sciences Gifu University
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Okuno Yasuyoshi
Environmental Health Science Laboratory Sumitomo Chemical Company Ltd.
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Okuno Yasuyoshi
Environmental Health Science Laboratory Sumitomo Chemical Co. Ltd.
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Yabushita Setsuko
Environmental Health Science Lab. Sumitomo Chemical Co. Ltd.
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Seki Takaki
Environmental Health Science Laboratory Sumitomo Chem. Co. Ltd.
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Miyata Kaori
Environmental Health Science Laboratory Sumitomo Chemical Co. Ltd
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Okuno Yasuyoshi
Environmental Health Science Laboratory Sumitomo Chemical Co. Ltd
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Sukata Tokuo
Safety Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd.
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