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The Effects of In Vivo Acute Exposure to Polychlorinatedbiphenyls on Free and Total Thyroxine in Rats
Citation:
HEDGE, J. M., M. J. DEVITO, AND K. M. CROFTON. The Effects of In Vivo Acute Exposure to Polychlorinatedbiphenyls on Free and Total Thyroxine in Rats. INTERNATIONAL JOURNAL OF TOXICOLOGY. Taylor & Francis, Inc., Philadelphia, PA, 28(5):382-391, (2009).
Impact/Purpose:
This manuscript reports data from investigations on whether acute exposure to polychlorinatedbiphenyls results in hypothyroxenemia due to displacement of free thyroxine from transport proteins. A single oral dose of 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153 at 60mg/kg) or 3,3',4,4',5,5'-hexaxchlorobiphenyl (PCB 169 at 1 mg/kg) was administered to female Hooded Long-Evans rats at 28 or 76 days old. Serum total thyroxine (TT4) and FT4 were measured at 0.5, 1, 2, 4, 8, 24 or 48 hrs post dosing. Microsomal ethoxy- and pentoxy-resorufin-O-deethylase (EROD and PROD) activity and uridine diphosphoglucuronosyl transferase (UGT) activity were determined from rats that liver samples at these same times. In summary, these data show that in both young and adult in vivo exposure to PCB 153 and PCB 169 did not increase serum FT4. Increased UGT and EROD activity following exposure to PCB169 and increased PROD activity after exposure to PCB 153, indicate that the decreases seen in thyroid hormones may be due to increased metabolism and/or biliary excretion. The lack of serum FT4 increases, even in the presence of up to a 36% decrease in TT4 after acute exposure to PCB 153 and 169 suggest that the in vitro interactions of these compounds with transport proteins do not predict the in vivo effects on serum TT4 concentrations. These data support the conclusion that neither PCB 153 nor PCB169 displace much of T4 from it’s binding proteins in vivo, if it occurs, it does not result in increased serum FT4.
Description:
Hypothyroxinemia in rats has been well documented as a result of either developmental or adult exposure to polychlorinated biphenyls (PCBs). Hypothetical mechanisms for this include induction of hepatic catabolic enzymes and cellular hormone transporters, and/or interference with plasma transport proteins. We hypothesized that if thyroxine (T4) displacement from transport proteins by PCBs occurs in vivo, it would result in increased free thyroxine (FT4) concentrations in the blood. This study investigates the effects of a single oral dose of 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153 at 60 mg/kg) or 3,3',4,4',5,5'-hexaxchlorobiphenyl (PCB 169 at 1 mg/kg) on female Hooded Long-Evans rats at 28 or 76 days of age. Serum total thyroxine (TT4) and FT4 were measured at 0.5, 1, 2, 4, 8, 24 or 48 hrs post-dosing. Microsomal ethoxy- and pentoxy-resorufin-O-deethylase (EROD and PROD) activity and uridine diphosphoglucuronosyl transferase (UGT) activity were determined from liver samples at these same time points. No significant increase in TT4 or FT4 concentrations was seen at any time point as a result of PCB 153 or PCB 169 exposure. PCB 153 significantly decreased TT4 and FT4 in young and adult rats as a result of treatment, with young rats showing a time-by-treatment interaction from 2 to 48 hours post-dosing in serum FT4. With PCB 169 exposure, young rats showed a decrease in FT4 only, while adult rats showed decreases in TT4 only. Hepatic EROD and PROD activities were both dramatically increased following PCB 169 and 153, respectively. UGT activity towards T4 was increased only after PCB 169 exposure. These data demonstrate that neither PCB 153 nor PCB169 increased FT4 which supports the conclusion that these PCBs do not displace T4 from serum TTR, or if it does occur there is no subsequent increase in serum FT4 in vivo.
