ToxSci Advance Access published online on July 14, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh225
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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1 School of Pharmaceutical Sciences and COE Program in the 21st Century, University of Shizuoka, 52-1, Yada, Shizuoka 422-8526, Japan
* To whom correspondence should be addressed. E-mail: kato{at}ys7.u-shizuoka-ken.ac.jp.
We have previously demonstrated that in mice, the decrease in serum thyroxine (T4) level by polychlorinated biphenyls (PCBs) occurs without increase in the UDP-glucuronosyltransferase (T4-UDP-GT) for T4 glucuronidation, although the PCB-induced decrease in rats is generally thought to occur through induction of the T4-UDP-GT, UGT1A1 and UGT1A6. In the present study, to further clarify the relationship between the decrease in serum T4 level and the increase in the UGT1A activity by PCB in rats, we examined the relationship using Wistar and Gunn rats, a mutant strain of Wistar rats deficient in UGT1A isoforms. Serum total T4 level was markedly decreased in not only Wistar rats but also Gunn rats 4 days after treatment with a PCB, Kanechlor-500 (KC500, 100 mg/kg) or 2,2',4,5,5'-pentachlorobiphenyl (PentaCB, 112 mg/kg), and there was no significant difference in magnitude of the decrease between Wistar and Gunn rats. On the other hand, the level and activity of T4-UDP-GT were significantly increased by treatment with either KC500 or PentaCB in Wistar rats but not in Gunn rats. In addition, no significant change in the level of serum total triiodothyronine (T3) and thyroid-stimulating hormone by the KC500 treatment was observed in either Wistar or Gunn rats. Furthermore, significant decrease in the activity of hepatic type-I deiodinase, which mediates the deiodization of T4 and T3, by the treatment with KC500 or PentaCB was observed in both Wistar and Gunn rats. From the serum of KC500- or PentaCB-treated Wistar and Gunn rats, mono- and di-hydroxylated PCB metabolites, which would bind to T4 binding serum protein (transthyretin), were detected. In conclusion, the present results suggest that the decrease in serum total T4 level by either KC500 or PentaCB in Gunn rats was not dependent on the increase in hepatic T4-UDP-GT activity and further suggest that the PCB-mediated decrease in serum T4 level might occur, at least in part, through formation of the hydroxylated PCB metabolites. Furthermore, even in Wistar rats, the PCB-mediated decrease in serum T4 level might occur through not only increase in hepatic T4-UDP-GT but also formation of the hydroxylated PCB metabolites.
Accepted June 22, 2004
Endocrine Toxicology
A Possible Mechanism for Decrease in Serum Thyroxine Level by Polychlorinated Biphenyls in Wistar and Gunn Rats
2 Graduate School of Life Science, University of Hyogo, 3-2-1 Kouto, Kamigori-cho, Ako-gun, Hyogo 678-1297, Japan
3 Daiichi College of Pharmaceutical Sciences, 22-1, Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan
4 Center for Biological Safety & Research, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
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