Key issues in the role of peroxisome proliferator-activated receptor agonism and cell signaling in trichloroethylene toxicity.

Peroxisome proliferator-activated receptor alpha (PPARalpha) is thought to be involved in several different diseases, toxic responses, and receptor pathways. The U.S. Environmental Protection Agency 2001 draft trichloroethylene (TCE) risk assessment concluded that although PPAR may play a role in liver tumor induction, the role of its activation and the sequence of subsequent events important to tumorigenesis are not well defined, particularly because of uncertainties concerning the extraperoxisomal effects. In this article, which is part of a mini-monograph on key issues in the health risk assessment of TCE, we summarize some of the scientific literature published since that time on the effects and actions of PPARalpha that help inform and illustrate the key scientific questions relevant to TCE risk assessment. Recent analyses of the role of PPARalpha in gene expression changes caused by TCE and its metabolites provide only limited data for comparison with other PPARalpha agonists, particularly given the difficulties in interpreting results involving PPARalpha knockout mice. Moreover, the increase in data over the last 5 years from the broader literature on PPARalpha agonists presents a more complex array of extraperoxisomal effects and actions, suggesting the possibility that PPARalpha may be involved in modes of action (MOAs) not only for liver tumors but also for other effects of TCE and its metabolites. In summary, recent studies support the conclusion that determinations of the human relevance and susceptibility to PPARalpha-related MOA(s) of TCE-induced effects cannot rely on inferences regarding peroxisome proliferation per se and require a better understanding of the interplay of extraperoxisomal events after PPARalpha agonism.