Role of thyroid hormones in hepatic effects of peroxisome proliferators

Peroxisome proliferators are endocrine disrupting chemicals that cause live r tumors in rodents but not humans. Although the receptor that mediates key hepatic effects, the peroxisome proliferator-activated receptor alpha (PPA R-alpha). and its endogenous ligands have been identified. the mechanism wh ereby these commonly used chemicals cause liver tumors in rodents has yet t o be elucidated. Species differences in PPAR-alpha and DNA response element s may explain some of the variability in response upon exposure to peroxiso me proliferators. The possibility that thyroid-modulating effects of peroxi some proliferators may contribute to the hepatic effects of peroxisome prol iferators has yet to be fully explored. When the potent peroxisome prolifer ator. 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 hor mone status. In addition, preliminary evidence indicates that peroxisome pr oliferators increased hepatic thyroid receptor (TR alpha1) expression, but TR alpha1 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 thes e studies, may be indicative of yet another mechanism to explain differenti al sensitivity to hepatic effects of peroxisome proliferators.