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ToxSci Advance Access published online on February 19, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh093
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received October 7, 2003; accepted January 28, 2004
© 2004 Society of Toxicology

Endocrine Toxicology

Enhanced Rat Hershberger Assay Appears Reliable for Detection of Not Only (Anti-)Androgenic Chemicals but Also Thyroid Hormone Modulators

Tomoya Yamada 1*, Takeshi Kunimatsu 1, Kaori Miyata 1, Setsuko Yabushita 1, Tokuo Sukata 1, Satoshi Kawamura 1, Takaki Seki 1, Yasuyoshi Okuno 1, and Nobuyoshi Mikami 1

1 Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-8558, Japan

* To whom correspondence should be addressed. E-mail: yamadat8{at}sc.sumitomo-chem.co.jp.


  Abstract

Development of an internationally recognized standard for the Hershberger assay as a screening tool to detect potential (anti-)androgenic chemicals is in progress. In the present preliminary study, we evaluated the reliability of the enhanced Hershberger assay to detect thyroid hormone modulating activity, while concentrating attention on possible confounding influence on evaluation of (anti-)androgenic activity. Castrated or testosterone propionate (TP, 0.2 or 0.25 mg/kg/day)-injected castrated male Crj:CD(SD)IGS rats (7 weeks old) were dosed for 10 days by oral gavage with vehicle (corn oil) or the following chemicals: propylthiouracil (PTU, 2.5 mg/kg/day), a potent inhibitor of thyroid hormone synthesis, phenobarbital (PB, 125 mg/kg/day) and 2,2-bis(4-chlorophenyl)-1,1-dichloroethylene (p,p'-DDE, 100 mg/kg/day), two hepatic enzyme inducers that enhance the clearance of thyroid hormones. PTU markedly increased thyroid weights, and decreased serum T3 and T4, and increased serum TSH, also causing marked microscopic alteration of the thyroid gland. Whereas PB and DDE only significantly affect serum T4 and revealed some histopathological findings. The alterations appeared to be more robust at the presence of TP. Furthermore, data for p,p'-DDE demonstrated its anti-androgenic effects, whereas PTU and PB had little or no effects on the weights of androgen-related accessory glands/tissues: the ventral prostate, dorso-lateral prostate, seminal vesicles with coagulating glands, glans penis, Cowper's glands, and levator ani plus bulbocavernosus (LABC) muscles. Weight of the LABC muscles was decreased by PB treatment in TP-treated castrated rats. These findings in the present study suggests that the enhanced Hershberger assay, with evaluation of thyroid histopathology and weights, and hormone levels, appears to be reliable for screening for not only (anti-)androgenic chemicals but also thyroid hormone modulators. In order to evaluate whether the sensitivity and specificity of such a thyroid assay is great enough for routine screening purposes, future experiments including dose-response studies using lower dose levels have to be performed.

Key Words: endocrine disruptor, Hershberger assay, thyroid hormone, screening .


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