A Possible Mechanism for Decrease in Serum Thyroxine Level by Polychlorinated Biphenyls in Wistar and Gunn Rats

Abstract

We have previously demonstrated that in mice, the decrease in serum thyroxine (T(4)) level by polychlorinated biphenyls (PCBs) occurs without an increase in the UDP-glucuronosyltransferase (T(4)-UDP-GT) for T(4) glucuronidation, although the PCB-induced decrease in rats is generally thought to occur through induction of T(4)-UDP-GT, UGT1A1, and UGT1A6. In the present study, to further clarify the relationship between the decrease in serum T(4) level and the increase in UGT1A activity by PCB in rats, we examined the relationship using Wistar rats and Gunn rats, a mutant strain of Wistar rats deficient in UGT1A isoforms. The serum total T(4) level was markedly decreased not only in the Wistar rats but also in the 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 the two rat strains. At the same time, the level and activity of T(4)-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 (T(3)) 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 T(4) and T(3), by 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 T(4) binding serum protein (transthyretin), were detected. In conclusion, the present results suggest that the decrease in serum total T(4) level by either KC500 or PentaCB in Gunn rats was not dependent on the increase in hepatic T(4)-UDP-GT activity. The findings further suggest that the PCB-mediated decrease in serum T(4) 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 T(4) level might occur not only through the increase in hepatic T(4)-UDP-GT but also via formation of hydroxylated PCB metabolites.

A Novel Mechanism for Polychlorinated Biphenyl-Induced Decrease in Serum Thyroxine Level in Rats

“…Thus, a decrease in the level of serum total T 4 is also observed in the Wistar and Gunn rats treated with KC500 (a single i.p. administration at a dose of 100 mg/kg) (Kato et al, 2004). In addition, constitutive levels of serum total T 4 and T 3 were higher in Gunn rats than in Wistar rats, and the results were identified with those as previously described by Benathan et al (1983).…”

“…However, among the experimental animals treated with a T 4 -UDP-GT inducer, the difference in magnitude of decrease in the level of serum total T 4 is not necessarily correlated with that of hepatic T 4 -UDP-GT activity (Craft et al, 2002;Hood et al, 2003;Kato et al, 2003). Our present and previous results (Kato et al, 2004 using Wistar and Gunn rats support a hypothesis that significant decrease in the level of serum total thyroid hormones by either PCB or phenobarbital occurs primarily in a hepatic T 4 -UDP-GT-independent pathway.…”

“…As the factors regulating the level of serum total T 4 , serum TSH, hepatic type I iodothyronine deiodinase, and TTR are known. However, no significant change in the level of serum TSH occurs in the PCBtreated rats (Liu et al, 1995;Hood et al, 1999;Hallgren et al, 2001;Kato et al, 2004). Hepatic type I iodothyronine deiodinase activity was significantly decreased in Wistar and Gunn rats by KC500 (Kato et al, 2004).…”

“…Furthermore, we have reported that in Kanechlor-500 (KC500)-treated mice, serum T 4 level decreased without an increase in T 4 -UDP-GT activity (Kato et al, 2003) and that the decrease in serum total T 4 level by a single administration of either KC500 or 2,2Ј,4,5,5Ј-pentachlorobiphenyl occurred even in UGT1A-deficient Wistar (Gunn) rats (Kato et al, 2004). Thus, an exact mechanism for the PCB-induced decrease in the level of serum thyroid hormone remains unclear.…”

Environmental Thyroid Disruptors and Human Endocrine Health

“…This is supported by animal data that PCBs reduce the TH levels (Gauger et al, 2004;Kato et al, 2004;Zoeller et al, 2000). PCBs may also exert direct actions on the TR independently from their effects on the TH secretion (Zoeller, 2002;Zoeller, 2003 Gauger et al, 2004;Zoeller et al, 2000).…”