PPARα Agonist-Induced Rodent Tumors: Modes of Action and Human Relevance

• Published in: Critical reviews in toxicology 2003, Vol.33 (6), p.655-780
• Main Authors: Klaunig, James E., Babich, Michael A., Baetcke, Karl P., Cook, Jon C., Corton, J. Chris, David, Raymond M., DeLuca, John G., Lai, David Y., McKee, Richard H., Peters, Jeffrey M., Roberts, Ruth A., Fenner-Crisp, Penelope A.
• Format: Article
• Language: English
• Subjects: carcinogenic mode of action; clofibrate; DEHP; human relevance of animal tumors; Leydig-cell tumor; liver tumor; oxadiazon; pancreatic acinar-cell tumor; perfluorooctanoic acid (PFOA); peroxisome proliferator; PPARα agonist; risk assessment
• ISSN: 1040-8444; 1547-6898
• DOI: 10.1080/713608372

Widely varied chemicals-including certain herbicides, plasticizers, drugs, and natural products-induce peroxisome proliferation in rodent liver and other tissues. This phenomenon is characterized by increases in the volume density and fatty acid oxidation of these organelles, which contain hydrogen peroxide and fatty acid oxidation systems important in lipid metabolism. Research showing that some peroxisome proliferating chemicals are nongenotoxic animal carcinogens stimulated interest in developing mode of action (MOA) information to understand and explain the human relevance of animal tumors associated with these chemicals. Studies have demonstrated that a nuclear hormone receptor implicated in energy homeostasis, designated peroxisome proliferator-activated receptor alpha (PPARα), is an obligatory factor in peroxisome proliferation in rodent hepatocytes. This report provides an in-depth analysis of the state of the science on several topics critical to evaluating the relationship between the MOA for PPARα agonists and the human relevance of related animal tumors. Topics include a review of existing tumor bioassay data, data from animal and human sources relating to the MOA for PPARα agonists in several different tissues, and case studies on the potential human relevance of the animal MOA data. The summary of existing bioassay data discloses substantial species differences in response to peroxisome proliferators in vivo, with rodents more responsive than primates. Among the rat and mouse strains tested, both males and females develop tumors in response to exposure to a wide range of chemicals including DEHP and other phthalates, chlorinated paraffins, chlorinated solvents such as trichloroethylene and perchloroethylene, and certain pesticides and hypolipidemic pharmaceuticals. MOA data from three different rodent tissues-rat and mouse liver, rat pancreas, and rat testis-lead to several different postulated MOAs, some beginning with PPARα activation as a causal first step. For example, studies in rodent liver identified seven "key events," including three "causal events"-activation of PPARα, perturbation of cell proliferation and apoptosis, and selective clonal expansion-and a series of associative events involving peroxisome proliferation, hepatocyte oxidative stress, and Kupffer-cell-mediated events. Similar in-depth analysis for rat Leydig-cell tumors (LCTs) posits one MOA that begins with PPARα activation in the liver, but two possible pathways, one s