Role of the peroxisome proliferator-activated receptor α (PPARα) in responses to trichloroethylene and metabolites, trichloroacetate and dichloroacetate in mouse liver

• Published in: Toxicology (Amsterdam) Vol. 203; no. 1; pp. 83 - 98
• Main Authors: Laughter, Ashley R., Dunn, Corrie S., Swanson, Cynthia L., Howroyd, Paul, Cattley, Russell C., Christopher Corton, J.
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 15.10.2004; Amsterdam Elsevier Science
• Subjects: Animals; Biological and medical sciences; Body Weight - drug effects; Cell Division - physiology; Chemical and industrial products toxicology. Toxic occupational diseases; Dichloroacetate; Dichloroacetic Acid - toxicity; Gene Expression Regulation - drug effects; Hepatocarcinogenesis; Hepatocytes - drug effects; Liver - drug effects; Liver - enzymology; Liver - metabolism; Medical sciences; Mice; Organ Size - drug effects; Oxidoreductases - metabolism; Peroxisome proliferation; PPAR alpha - physiology; PPARα; Protein Array Analysis; Solvents; Toxicology; Transcript profiling; Trichloroacetate; Trichloroacetic Acid - toxicity; Trichloroethylene; Trichloroethylene - toxicity; PP; Dichloroacetate; WY; DCA; SDS; Transcript profiling; Trichloroethylene; PAGE; Peroxisome proliferation; PPARα; ACO; RXR; Trichloroacetate; TCA; PPAR; Hepatocarcinogenesis; DEHP; PBST; PPRE; TCE; Cyp; PCR; Metabolite; Liver; Carcinogenesis; Peroxisome proliferator; Liver cancer; PPAR-α receptor; Messenger RNA; Gene; Chlorine Organic compounds; Ethylene(trichloro); Digestive system; Rodentia; Organic solvent; Vertebrata; Mammalia; General anesthetic; Mouse; Animal
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2004.06.014

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 carcinogenic metabolites, dichloroacetate (DCA) and trichloroacetate (TCA). TCE is considered to be a relatively weak peroxisome proliferator (PP), a group of rodent hepatocarcinogens that cause adaptive responses in liver through the PP-activated receptor alpha (PPARα). The objectives of this study were to determine whether effects of TCE, TCA and DCA in the liver associated with carcinogenesis are mediated by PPARα. Male wild-type and PPARα-null mice were given TCE by gavage for 3 days or 3 weeks; TCA or DCA were given in the drinking water for 1 week. Increases in relative liver and kidney weights by TCE were dependent on PPARα whereas liver weight increases by DCA were PPARα-independent. Dose-dependent increases in hepatocyte proliferation observed in wild-type mice after TCE exposure as determined by BrdU-labeling of hepatocytes were PPARα-dependent. Transcript profiling using macroarrays containing ∼1200 genes showed that 93% (40 out of 43) of all expression changes observed in wild-type mice upon TCE exposure were dependent on PPARα and included known targets of PP (Cyp4a12, epidermal growth factor receptor) and additional genes involved in cell growth. Increases in enzymes that catalyze β- and ω-oxidation of fatty acids were dependent on PPARα after exposure to TCE, TCA or DCA. TCE altered a unique set of genes in the livers of PPARα-null mice compared to wild-type mice including those that respond to different forms of stress. These data support the hypothesis that PPARα plays a dominant role in mediating the effects associated with hepatocarcinogenesis upon TCE exposure.