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Toxicologic Pathology
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Role of Thyroid Hormones in Hepatic Effects of Peroxisome Proliferators

Richard T. Miller

College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606, Department of Pathology, Glaxo Wellcome Inc, Research Triangle Park, North Carolina 27709

Lori A. Scappino

College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606

Sarah M. Long

College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606

J. Christopher Corton

Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709

Peroxisome proliferators are endocrine disrupting chemicals that cause liver tumors in rodents but not humans. Although the receptor that mediates key hepatic effects, the peroxisome proliferator-activated receptor alpha (PPAR-{alpha}), and its endogenous ligands have been identified, the mechanism whereby these commonly used chemicals cause liver tumors in rodents has yet to be elucidated. Species differences in PPAR-{alpha} and DNA response elements may explain some of the variability in response upon exposure to peroxisome proliferators. The possibility that thyroid-modulating effects of peroxisome proliferators may contribute to the hepatic effects of peroxisome proliferators has yet to be fully explored. When the potent peroxisome proliferator, WY-14,643, was given to hypothyroid rats, there was a blunting of the hepatomegaly and hepatocyte proliferative responses seen in thyroid-intact animals. Acyl-CoA oxidase activity was unaltered by changes in thyroid hormone status. In addition, preliminary evidence indicates that peroxisome proliferators increased hepatic thyroid receptor (TR{alpha}1) expression, but TR{alpha}1 levels in liver tumors were similar to those in unexposed animals. Significant differences between humans and rodents with respect to thyroid hormone physiology and metabolism, in conjunction with the results of these studies, may be indicative of yet another mechanism to explain differential sensitivity to hepatic effects of peroxisome proliferators.

Key Words: Liver • cell replication • hepatocarcinogenesis • thyroid receptor • acyl-CoA oxidase • hepatomegaly

Toxicologic Pathology, Vol. 29, No. 1, 149-155 (2001)
DOI: 10.1080/019262301301418964
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