PMID- 12965124
OWN - NLM
STAT- MEDLINE
DCOM- 20031028
LR  - 20190819
IS  - 0300-483X (Print)
IS  - 0300-483X (Linking)
VI  - 191
IP  - 2-3
DP  - 2003 Sep 30
TI  - Role of the peroxisome proliferator-activated receptor alpha in responses to 
      diisononyl phthalate.
PG  - 211-25
AB  - Diisononyl phthalate (DINP) is a compound widely used as a plasticizer in the 
      production of polyvinyl chloride products. Chronic exposure to DINP leads to 
      liver cancer in rats and mice. Many phthalates are considered to be relatively 
      weak peroxisome proliferators (PP), a group of rodent hepatocarcinogens that 
      cause a variety of adaptive responses in liver through the PP-activated receptor 
      alpha (PPARalpha). The objectives of this study were to determine whether 
      DINP-induced effects in the liver associated with carcinogenesis are mediated by 
      PPARalpha and to identify novel gene targets of DINP. Male and female SV129 
      wild-type, SV129 PPARalpha-null, and B6C3F1 mice were administered DINP by gavage 
      or in the feed. Transcript profile technology and reverse transcriptase 
      (RT)-polymerase chain reaction (PCR) were used to identify gene targets. 
      Dose-dependent increases in relative liver weights were dependent on PPARalpha in 
      10- or 12-week-old male and female mice and 30-week-old male mice. Female 
      30-week-old mice exhibited PPARalpha-independent increases in relative liver 
      weights. Increases in hepatocyte proliferation, palmitoyl-CoA oxidase (PCO) 
      activity, and levels of enzymes involved in beta- and omega-oxidation of fatty 
      acids were shown to be dependent on PPARalpha. Five novel genes were shown to be 
      altered in the livers of female wild-type mice after a 3-week exposure, but not 
      in PPARalpha-null, mice. These genes included those involved in DNA repair and 
      recombination (ATP-dependent helicase and Endonuclease III homolog), drug 
      metabolism (Cyp2a4) and protein trafficking (FKBP-1, FKBP-13). An additional gene 
      (Cyp2d9) was shown to be down-regulated in wild-type mice but up-regulated in 
      PPARalpha-null mice indicating more complex regulation by PPARalpha and 
      additional factors. These data support the hypothesis that PPARalpha plays a 
      dominant role in mediating the effects associated with hepatocarcinogenesis after 
      DINP exposure.
FAU - Valles, Edith G
AU  - Valles EG
AD  - CIIT Centers for Health Research, Research Triangle Park, NC 27709, USA.
FAU - Laughter, Ashley R
AU  - Laughter AR
FAU - Dunn, Corrie S
AU  - Dunn CS
FAU - Cannelle, Sabine
AU  - Cannelle S
FAU - Swanson, Cynthia L
AU  - Swanson CL
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 (Carcinogens)
RN  - 0 (Phthalic Acids)
RN  - 0 (Plasticizers)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Transcription Factors)
RN  - 4010KIX4CK (diisononyl phthalate)
RN  - 63231-63-0 (RNA)
RN  - EC 1.- (Oxidoreductases)
RN  - EC 1.3.3.- (palmitoyl CoA oxidase)
RN  - G34N38R2N1 (Bromodeoxyuridine)
SB  - IM
MH  - Animals
MH  - Body Weight/drug effects
MH  - Bromodeoxyuridine/metabolism
MH  - Carcinogens/toxicity
MH  - Cell Division/drug effects
MH  - Crosses, Genetic
MH  - Female
MH  - Hepatocytes/drug effects/metabolism
MH  - Liver Neoplasms, Experimental/*chemically induced/enzymology/genetics/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C3H
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Oligonucleotide Array Sequence Analysis
MH  - Organ Size/drug effects
MH  - Oxidoreductases/metabolism
MH  - Phthalic Acids/*toxicity
MH  - Plasticizers/*toxicity
MH  - RNA/chemistry/genetics
MH  - Receptors, Cytoplasmic and Nuclear/*metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Transcription Factors/*metabolism
EDAT- 2003/09/11 05:00
MHDA- 2003/10/29 05:00
CRDT- 2003/09/11 05:00
PHST- 2003/09/11 05:00 [pubmed]
PHST- 2003/10/29 05:00 [medline]
PHST- 2003/09/11 05:00 [entrez]
AID - S0300483X03002609 [pii]
AID - 10.1016/s0300-483x(03)00260-9 [doi]
PST - ppublish
SO  - Toxicology. 2003 Sep 30;191(2-3):211-25. doi: 10.1016/s0300-483x(03)00260-9.