PMID- 15363585
OWN - NLM
STAT- MEDLINE
DCOM- 20041119
LR  - 20131121
IS  - 0300-483X (Print)
IS  - 0300-483X (Linking)
VI  - 203
IP  - 1-3
DP  - 2004 Oct 15
TI  - Role of the peroxisome proliferator-activated receptor alpha (PPARalpha) in 
      responses to trichloroethylene and metabolites, trichloroacetate and 
      dichloroacetate in mouse liver.
PG  - 83-98
AB  - 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.
FAU - Laughter, Ashley R
AU  - Laughter AR
AD  - CIIT Centers for Health Research, Research Triangle Park, NC, USA.
FAU - Dunn, Corrie S
AU  - Dunn CS
FAU - Swanson, Cynthia L
AU  - Swanson CL
FAU - Howroyd, Paul
AU  - Howroyd P
FAU - Cattley, Russell C
AU  - Cattley RC
FAU - Corton, J Christopher
AU  - Corton JC
LA  - eng
PT  - Journal Article
PL  - Ireland
TA  - Toxicology
JT  - Toxicology
JID - 0361055
RN  - 0 (PPAR alpha)
RN  - 290YE8AR51 (Trichloroethylene)
RN  - 5V2JDO056X (Trichloroacetic Acid)
RN  - 9LSH52S3LQ (Dichloroacetic Acid)
RN  - EC 1.- (Oxidoreductases)
RN  - EC 1.3.3.- (palmitoyl CoA oxidase)
SB  - IM
MH  - Animals
MH  - Body Weight/drug effects
MH  - Cell Division/physiology
MH  - Dichloroacetic Acid/toxicity
MH  - Gene Expression Regulation/drug effects
MH  - Hepatocytes/drug effects
MH  - Liver/drug effects/enzymology/*metabolism
MH  - Mice
MH  - Organ Size/drug effects
MH  - Oxidoreductases/metabolism
MH  - PPAR alpha/*physiology
MH  - Protein Array Analysis
MH  - Trichloroacetic Acid/toxicity
MH  - Trichloroethylene/*toxicity
EDAT- 2004/09/15 05:00
MHDA- 2004/12/16 09:00
CRDT- 2004/09/15 05:00
PHST- 2004/02/26 00:00 [received]
PHST- 2004/05/18 00:00 [revised]
PHST- 2004/06/01 00:00 [accepted]
PHST- 2004/09/15 05:00 [pubmed]
PHST- 2004/12/16 09:00 [medline]
PHST- 2004/09/15 05:00 [entrez]
AID - S0300483X04003099 [pii]
AID - 10.1016/j.tox.2004.06.014 [doi]
PST - ppublish
SO  - Toxicology. 2004 Oct 15;203(1-3):83-98. doi: 10.1016/j.tox.2004.06.014.