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ToxSci Advance Access published online on December 9, 2005
Toxicological Sciences, 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
Received August 27, 2005
Accepted November 23, 2005

Endocrine Toxicology

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

J W Fisher 1 *, J Campbell 1, S Muralidhara 1, J V Bruckner 2, D Ferguson 2, M Mumtaz 3, B Harmon 4, J M Hedge 5, K M Crofton 6, H Kim 7, and T L Almekinder 1

1 University of Georgia, Interdisciplinary Toxicology Program
2 University of Georgia, Dept of Pharmaceutical and Biomedical Sciences
3 University of Georgia, Dept of Physiology and Pharmacology
4 Agency for Toxic Substances and Disease Registry (ATSDR)
5 University of Georgia, Dept of Pathology
6 US Environmental Protection Agency (USEPA/ORD/NHEERL) Neurotoxicology Division
7 Visiting Scientist, Kangwon National University

* To whom correspondence should be addressed.
J W Fisher, E-mail: jwfisher{at}uga.edu


  Abstract

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 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-theconcentration-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 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.

Keywords: PCB 126; Thyroid Hormones; P450; EROD; Rat; TSH; UDPGT.
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