Role of the peroxisome proliferator-activated receptor alpha in responses to diisononyl phthalate.
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.
Valles
Edith G
EG
CIIT Centers for Health Research, Research Triangle Park, NC 27709, USA.
Laughter
Ashley R
AR
Dunn
Corrie S
CS
Cannelle
Sabine
S
Swanson
Cynthia L
CL
Cattley
Russell C
RC
Corton
J Christopher
JC
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D003433:Crosses, Genetic; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism; D010795:Phthalic Acids / Q000633:toxicity*; D010968:Plasticizers / Q000633:toxicity*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism*
D002273:Carcinogens; D010795:Phthalic Acids; D010968:Plasticizers; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C012125:diisononyl phthalate; D012313:RNA; D010088:Oxidoreductases; C028427:palmitoyl CoA oxidase; D001973:Bromodeoxyuridine