Evaluation of the role of peroxisome proliferator-activated receptor alpha (PPARalpha) in mouse liver tumor induction by trichloroethylene and metabolites

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 alpha (PPARalpha. The objective of this review is to assess the weight of evidence (WOE) that PPARalpha 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 PPARalpha-dependent responses coincident with liver tumor induction and abolishment of TCE and TCA effects in PPARalpha-null mice, the WOE supports the hypothesis that PPARalpha plays a dominant role in TCE- and TCA-induced hepatocarcinogenesis. Data indicates that the MOA for DCA tumor induction is PPARalpha-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 PPARalpha-dependent MOA. Although the TCE MOA is likely dominated by a PPARalpha-dependent contribution from TCA, the contribution of a PPARalpha-independent MOA from DCA cannot be ruled out.