ToxSci Advance Access published online on March 22, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm063
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Low-Dose Effects of Ammonium Perchlorate on the Hypothalamic-Pituitary-Thyroid (HPT) Axis of Adult Male Rats Pretreated with PCB126
* University of Georgia, Interdisciplinary Toxicology Program, Athens, Georgia 30602
University of Georgia, College of Veterinary Medicine, Department of Pathology, Athens, Georgia 30602 (Deceased)
USEPA/ORD/NHEERL, Neurotoxicology Division, Research Triangle Park, North Carolina 27711
AFRL/HEPB, Wright-Patterson Air Force Base, Ohio 45433
¶ Boston Medical Center, Section of Endocrinology, Diabetes, and Nutrition Center, Boston, Massachusetts 02118
|| Consultant, Statistics and Modeling Supporting Informed Decisions, Athens, GA 30606
||| Agency for Toxic Substances and Disease Registry (ATSDR), Division of Toxicology, Atlanta, Georgia 30333
1 To whom correspondence may be addressed: 206 Environmental Health Sciences Department, University of Georgia, Athens, GA 30602-2102, USA, Phone: 706-542-2454, Fax: 706-542-7472, e-mail: evad{at}uga.edu
Received January 18, 2007; revision received March 7, 2007; accepted March 16, 2007
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Abstract |
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The objective of this research was to characterize the disturbances in the hypothalamic-pituitary-thyroid (HPT) axis resulting from exposure to a binary mixture, PCB126 and perchlorate (ClO
), known to cause hypothyroidism by different modes of action. Two studies were conducted to determine the HPT axis effects of ClO on adult male Sprague-Dawley rats pretreated with PCB126. In Dosing Study I, rats were administered a single oral dose of PCB126 (0, 7.5, or 75 µg/kg) on Day 0 and nine days later ClO (0, 0.01, 0.1, or 1 mg/kg-day) was added to the drinking water until euthanasia on Day 22. Significant dose-dependent trends were found for all thyroid function indices measured following ClO in drinking water for 14 days. 75 µg PCB126/kg resulted in a significant increase in hepatic T4-glucuronide (T4-G) formation, causing a decline in serum T4 and fT4, and resulting in increased serum TSH. Serum TSH was also increased in animals that received 7.5 µg PCB126/kg; no other HPT axis alterations were found in these animals. When pretreated with PCB126 the ClO dose trends disappeared, suggesting a less than additive effect on the HPT axis. In Dosing Study II, animals were given lower doses of PCB126 (0, 0.075, 0.75, or 7.5 µg/kg) on Day 0, and followed with ClO (0 or 0.01 mg/kg-day) in drinking water beginning on Day 1 and continuing for several days to explore transient HPT axis effects. No statistical effects were seen for PCB126 or ClO alone, and no perturbations were found when administered sequentially in Dosing Study II. In conclusion, these studies demonstrate that HPT axis disturbances following exposure to ClO are less than additive when pretreated with relatively high doses of PCB126. At relatively low doses, at or near the NOEL for PCB126 and ClO, no interactions between the chemicals occur.
Key Words: PCB126; perchlorate; rat; thyroid; T4; TSH; UDPGT.
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