Role of the peroxisome proliferator-activated receptor α 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 (PPARα). The objectives of this study were to determine whether DINP-induced effects in the liver associated with carcinogenesis are mediated by PPARα and to identify novel gene targets of DINP. Male and female SV129 wild-type, SV129 PPARα-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 PPARα in 10- or 12-week-old male and female mice and 30-week-old male mice. Female 30-week-old mice exhibited PPARα-independent increases in relative liver weights. Increases in hepatocyte proliferation, palmitoyl-CoA oxidase (PCO) activity, and levels of enzymes involved in β- and ω-oxidation of fatty acids were shown to be dependent on PPARα. Five novel genes were shown to be altered in the livers of female wild-type mice after a 3-week exposure, but not in PPARα-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 PPARα-null mice indicating more complex regulation by PPARα and additional factors. These data support the hypothesis that PPARα plays a dominant role in mediating the effects associated with hepatocarcinogenesis after DINP exposure