Science Inventory

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

Citation:

CORTON, C. Evaluation of the Role of Peroxisome Proliferator-Activated Receptor α (PPARα) in Mouse Liver Tumor Induction by Trichloroethylene and Metabolites. CRITICAL REVIEWS IN TOXICOLOGY. CRC Press LLC, Boca Raton, FL, 38(11/10/2008):857 - 875, (2008).

Impact/Purpose:

A peroxisome proliferator-type mode of action of mouse liver tumor induction has been proposed for trichloroethylene and metabolites trichloroacetate and dichloroacetate. This review uses a weight of evidence approach to show that TCA and likely TCE are heavily dependent on PPARalpha for mouse liver tumor induction. In contrast, the evidence indicates that DCA works through a PPARalpha-independent mode of action.

Description:

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. TCA is also an important metabolite in the induction of mouse liver tumors by perchloroethylene (PERC), widely used in the dry-cleaning industry and chloral hydrate (CH), a sedative and drinking water contaminant. 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 mode of action (MOA) by which exposure to PPARα activators leads to rodent liver tumors has been postulated to be irrelevant to humans based largely on evidence that functional PPARα is at much lower levels in human liver. 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 MOA different than 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.

Record Details:

Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Product Published Date: 11/10/2008
Record Last Revised: 03/26/2009
OMB Category: Other
Record ID: 188388