| Key Issues in the Role of Peroxisome Proliferator–Activated Receptor Agonism and Cell Signaling in Trichloroethylene Toxicity Nagalakshmi Keshava and Jane C. Caldwell National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC, USA Abstract
Peroxisome proliferator–activated receptor  (PPAR) 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 PPAR that help inform and illustrate the key scientific questions relevant to TCE risk assessment. Recent analyses of the role of PPAR in gene expression changes caused by TCE and its metabolites provide only limited data for comparison with other PPAR agonists, particularly given the difficulties in interpreting results involving PPAR knockout mice. Moreover, the increase in data over the last 5 years from the broader literature on PPAR agonists presents a more complex array of extraperoxisomal effects and actions, suggesting the possibility that PPAR 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 PPAR-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 PPAR agonism. Key words: dichloroacetic acid, peroxisome proliferator–activated receptor, PPAR, trichloroacetic acid, trichloroethylene. Environ Health Perspect 114:1464–1470 (2006) . doi:10.1289/ehp.8693 available via http://dx.doi.org/ [Online 9 May 2006]
This article is part of the mini-monograph "Trichloroethylene Health Risks: Key Scientific Issues." Address correspondence to N. Keshava, U.S. EPA, 1200 Pennsylvania Ave., Mail Code 8623D, Washington, DC 20460 USA. Telephone: (202) 564-3311. Fax: (202) 565-0076. E-mail: keshava.nagu@epa.gov We thank J. Blancato, C. Chen, M. Evans, J. Jinot, J. Lipscomb, M. Okino, F. Power, J. Schaum, and C. Siegel Scott for their insightful, constructive input. We especially thank W. Chiu, TCE team chemical manager, for key assistance in completing this review and coordinating this mini-monograph. The views expressed in this article are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency. The authors declare they have no competing financial interests. Received 27 September 2005 ; accepted 28 March 2006.
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