Evaluation of the Role of Peroxisome Proliferator-Activated Receptor α (PPARα in Mouse Liver Tumor Induction by Trichloroethylene and Metabolites

Abstract

Trichloroethylene (TCE) is an industrial solvent and a widespread environmental contaminant. Induction of liver cancer in mice by TCE is thought to be mediated by two metabolites, dichloroacetate (DCA) and trichloroacetate (TCA), both of which are themselves mouse liver carcinogens. TCE, TCA, and DCA are relatively weak peroxisome proliferators (PP), a group of rodent hepatocarcinogens that activate a nuclear receptor, PP-activated receptor α (PPARα. The objective of this review is to assess the weight of evidence (WOE) that PPARα is or is not mechanistically involved in mouse liver tumor induction by TCE and metabolites. Based on similarities of TCE and TCA to typical PP, including dose-response characteristics showing PPARα-dependent responses coincident with liver tumor induction and abolishment of TCE and TCA effects in PPARα-null mice, the WOE supports the hypothesis that PPARα plays a dominant role in TCE- and TCA-induced hepatocarcinogenesis. Data indicates that the MOA for DCA tumor induction is PPARα-independent. Uncertainties remain regarding the genesis of the TCE-induced tumors. In contrast to the TCA-induced tumors, which have molecular features similar to those induced by typical PP, there is evidence, albeit weak, that TCE tumors arise by a mode of action (MOA) different from that of TCA tumors, based largely on dissimilarities in molecular markers found in TCE versus TCA-induced tumors. In summary, the WOE indicates that TCA-induced liver tumors arise by a PPARα-dependent MOA. Although the TCE MOA is likely dominated by a PPARα-dependent contribution from TCA, the contribution of a PPARα-independent MOA from DCA cannot be ruled out.

Keywords:

• chloral hydrate
• dichloroacetic acid
• liver tumors
• perchloroethylene
• PPARα
• trichloroacetic acid
• trichloroethylene

ACKNOWLEDGMENTS

I thank Drs. Hugh Barton, Tony DeAngelo, Dick Bull, and Jeff Fisher for their thoughtful review of this article and John Havel and Peggy Zieman for assistance in preparing the review.

The information in this document has been subjected to review by the National Health and Environmental Effects Research Laboratory of the U.S. EPA and approved for publication. Approval does not signify that the contents reflect the views of the agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.