Effect of PCB 126 on hepatic metabolism of thyroxine and perturbations in the hypothalamic-pituitary-thyroid axis in the rat.
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 microg PCB 126/kg bw dissolved in corn oil. The rats were sacrificed periodically over 22 days. The 7.5-microg/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 (microg/kg/day) and then slowed at the 275-microg/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 (microg/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.
Fisher
Jeffrey W
JW
University of Georgia, Interdisciplinary Toxicology Program, Athens, Georgia 30602, USA. jwfisher@uga.edu
Campbell
Jerry
J
Muralidhara
Srinivasa
S
Bruckner
James V
JV
Ferguson
Duncan
D
Mumtaz
Moiz
M
Harmon
Barry
B
Hedge
Joan M
JM
Crofton
Kevin M
KM
Kim
Hekap
H
Almekinder
Tara L
TL
D000818:Animals; D019540:Area Under Curve; D001835:Body Weight / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D004965:Estrogen Antagonists / Q000494:pharmacology / Q000633:toxicity*; D014453:Glucuronosyltransferase / Q000096:biosynthesis; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D011078:Polychlorinated Biphenyls / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000378:metabolism*
D004965:Estrogen Antagonists; D013972:Thyrotropin; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1; D014453:Glucuronosyltransferase; D013974:Thyroxine; C023035:3,4,5,3',4'-pentachlorobiphenyl