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ToxSci Advance Access originally published online on December 9, 2005
Toxicological Sciences 2006 90(1):87-95; doi:10.1093/toxsci/kfj069
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Effect of PCB 126 on Hepatic Metabolism of Thyroxine and Perturbations in the Hypothalamic-Pituitary-Thyroid Axis in the Rat

Jeffrey W. Fisher*,1, Jerry Campbell*, Srinivasa Muralidhara*, James V. Bruckner*, Duncan Ferguson*, Moiz Mumtaz{dagger}, Barry Harmon{ddagger}, Joan M. Hedge§, Kevin M. Crofton, Hekap Kim|| and Tara L. Almekinder*

* University of Georgia, Interdisciplinary Toxicology Program, Athens, Georgia 30602; {dagger} Agency for Toxic Substances and Disease Registry (ATSDR), NCEH/ATSDR/DT, Chamblee, GA 30341; {ddagger} University of Georgia, College of Veterinary Medicine, Department of Pathology, Athens, GA 30602; § USEPA/ORD/NHEERL, Neurotoxicology Division, Research Triangle Park, NC 27711; U.S. Environmental Protection Agency (USEPA/ORD/NHEERL) Neurotoxicology Division; and || Visiting Scientist, Department of Environmental Science, College of Natural Sciences, Kangwon, National University, Churcheon, Gangwon Do 200-701 South Korea

Received August 27, 2005; accepted November 23, 2005

The objective of this research was to examine the time- and dose- dependent disturbances in the hypothalamic-pituitary-thyroid (HPT) axis of adult male rats administered a potent coplanar (non-ortho) PCB, 3,3',4,4',5-pentachlorobiphenyl (PCB 126). Adult male Sprague-Dawley rats were administered a single oral bolus dose of 0, 7.5, 75, or 275 µg PCB 126/kg bw dissolved in corn oil. The rats were sacrificed periodically over 22 days. The 7.5-µg/kg dose induced hepatic ethoxyresorufin-O-deethylation EROD activity, but no changes were observed in hepatic uridine diphosphate glucuronyl transferases (UDPGTs) activity or serum TSH, T4, or fT4 concentrations. The two highest doses caused a modest decline in weight gain, induced hepatic EROD and UDPGT activities, increased serum TSH concentrations, and decreased serum T4 and fT4 concentrations. The amount of thyroxine glucuronide formed daily (pM/mg protein) increased linearly with the area-under-the-concentration-curve (AUCC) for PCB 126 in liver (µg/kg/day) and then slowed at the 275-µg/kg PCB 126 dose. Perturbations in the HPT axis were nonlinear with respect to PCB 126 dosing. As expected, an inverse relationship between the AUCC for serum T4 (µg/dl/day) and the AUCC for serum TSH (ng/dl/day) was observed; however, the relationship was highly nonlinear. These data support a mode of action for PCB 126 involving induction of hepatic UDPGTs by the aryl hydrocarbon receptor AhR. However, the dose-response characteristics of the HPT axis are nonlinear and complex, requiring sophisticated tools, such as PBPK models, to characterize dose response.

Key Words: PCB 126; thyroid hormones; P450, EROD; rat; TSH; UDPGT.


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