The Ah receptor (AHR) and peroxisome proliferator-activated receptor alpha (PPARalpha) are ligand-dependent transcription factors that are known to bind to xenobiotic chemicals and induce target gene expression. Some of their ligands are also potent non-genotoxic carcinogens in rodent model systems. The physiological functions of these receptors are being evaluated through the study of null mouse phenotypes. The AHR-null and PPARalpha-null mice are fertile but exhibit phenotypes varying severity suggesting that they have important functions and possible endogenous ligands. The AHR-null mice are generally in ill health due to an immune deficiency and tissue fibrosis, particularly in the liver. There has been considerable progress in unraveling the mechanism of AHR action. Livers of AHR-null mice have unusually high levels of retinoic acid (RA) due to a defect in RA catabolism which leads to high level expression of retinoic acid receptor (RAR) responsive genes and activation of transforming growth factor beta (TGFbeta) by the RAR-controlled transglutaminase II enzyme. This results in TGFbeta-stimulated accelerated apoptosis during development and the resultant small fibrotic livers of the AHR-null mice. These data indicate that AHR has an influence on cell cycle control and suggest a possible mechanism for the toxic and teratogenic effects of certain AHR ligands such as 2,4,7.8-tetrachlorodibenzo-p- dioxin (TCDD). The phenotype of the PPARalpha-null mice is considerable less severe than the AHR-null. These animals have an abnormal capacity to metabolize fatty acids which is particularly notable under certain dietary conditions leading to high serum lipids or starvation. These results establish an important role for PPARalpha in physiological homeostasis. PPARalpha null mice are also resistant to peroxisome proliferator-induced hepatocarcinogenesis. This is due in part to an effect of PPARalpha on cell cycle control and the production of oxidative stress through high level expression of the peroxisomal enzyme acyl-CoA oxidase that yields hydrogen peroxide as a byproduct. Further study of mice lacking AHR and PPAR-alpha should lead to a more complete understanding of the physiological roles of these receptors and clues to the mechanisms of action on non-genotoxic carcinogens. - Dioxin, Peroxisome proliferation, Receptors, Toxicity, Cancer susceptibility,
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