Role of the peroxisome proliferator-activated receptor alpha (PPARalpha) in responses to trichloroethylene and metabolites, trichloroacetate and dichloroacetate in mouse liver.
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 (PPARalpha). The objectives of this study were to determine whether effects of TCE, TCA and DCA in the liver associated with carcinogenesis are mediated by PPARalpha. Male wild-type and PPARalpha-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 PPARalpha whereas liver weight increases by DCA were PPARalpha-independent. Dose-dependent increases in hepatocyte proliferation observed in wild-type mice after TCE exposure as determined by BrdU-labeling of hepatocytes were PPARalpha-dependent. Transcript profiling using macroarrays containing approximately 1200 genes showed that 93% (40 out of 43) of all expression changes observed in wild-type mice upon TCE exposure were dependent on PPARalpha and included known targets of PP (Cyp4a12, epidermal growth factor receptor) and additional genes involved in cell growth. Increases in enzymes that catalyze beta- and omega-oxidation of fatty acids were dependent on PPARalpha after exposure to TCE, TCA or DCA. TCE altered a unique set of genes in the livers of PPARalpha-null mice compared to wild-type mice including those that respond to different forms of stress. These data support the hypothesis that PPARalpha plays a dominant role in mediating the effects associated with hepatocarcinogenesis upon TCE exposure.
Laughter
Ashley R
AR
CIIT Centers for Health Research, Research Triangle Park, NC, USA.
Dunn
Corrie S
CS
Swanson
Cynthia L
CL
Howroyd
Paul
P
Cattley
Russell C
RC
Corton
J Christopher
JC
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000502:physiology; D003999:Dichloroacetic Acid / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism; D047493:PPAR alpha / Q000502:physiology*; D040081:Protein Array Analysis; D014238:Trichloroacetic Acid / Q000633:toxicity; D014241:Trichloroethylene / Q000633:toxicity*
D047493:PPAR alpha; D014241:Trichloroethylene; D014238:Trichloroacetic Acid; D003999:Dichloroacetic Acid; D010088:Oxidoreductases; C028427:palmitoyl CoA oxidase