Role of PPARalpha in mediating the effects of phthalates and metabolites in the liver.

Phthalate esters belong to a large class of compounds known as peroxisome proliferators (PP). PP include chemicals that activate different subtypes of the peroxisome proliferator-activated receptor (PPAR) family. The ability of phthalate esters and their metabolites to activate responses through different PPAR subtypes is not fully characterized. We investigated the ability of two phthalate esters di-(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP) and selected metabolites to activate PPAR (alpha, beta/delta, gamma) using a transient transfection assay. The monoester of DEHP, mono-(2-ethylhexyl) phthalate (MEHP) activated all three subtypes of PPAR, but preferentially activated PPARalpha. A second metabolite of DEHP, 2-ethylhexanoic acid (2-EHXA) was a weaker activator of all three subtypes. DBP, but not the primary metabolite mono-n-butyl phthalate weakly activated all three PPAR subtypes. MEHP and DBP but not DEHP and MBP interacted directly with human PPARalpha and PPARgamma as determined by scintillation proximity assays. Both DEHP and DBP activated expression of PP-inducible gene products in wild-type but not PPARalpha-null mice suggesting that both of these phthalates exert their effects by activation of PPARalpha in vivo. The preferential activation of PPARalpha by phthalate ester metabolites suggests that these phthalates mediate their toxic effects in rodent liver in a manner indistinguishable from other PP.

Decreased longevity and enhancement of age-dependent lesions in mice lacking the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha).

The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) is activated by peroxisome proliferators (PP), a large class of structurally diverse xenobiotic chemicals, hypolipidemic drugs, and endogenous lipids. PPARalpha alters the transcriptional programs of genes whose functions include lipid metabolism, inflammation, cell fate, and stress responses in liver, heart, kidney, and skin. Many of these genes are also under control of PPARalpha in the absence of exogenous peroxisome proliferator exposure. Mice that lack PPARalpha (PPARalpha-null mice) exhibit a number of defects in lipid metabolism and accumulate lipids in the liver. Here, we compared the age-dependent lesions in the liver, kidney, and heart in PPARalpha-null mice with those observed in wild-type SV129 mice, in the absence of exogenous chemical exposure. Groups of mice were sacrificed, at 6, 12, 18, 21, or 24 months of age, or allowed to age until moribund or found dead. PPARalpha-null mice had decreased longevity, due to a variety of causes. Statistically significant differences in the occurrence of a number of lesions between strains was observed. Hepatocellular carcinomas and multiple hepatocellular adenomas occurred in PPARa-null mice but not wild type mice. Various nonneoplastic spontaneous aging lesions occurred at higher incidence, shorter latency, or increased severity in PPARalpha-null mice compared with wild-type mice. In the liver, these included vacuolated hepatocytes and sinusoidal cells and mixed cell inflammation. The kidneys of PPARalpha-null mice exhibited higher incidences and severities of cortical mineralization. Minimal myocardial mineralization occurred at a higher incidence in PPARalpha-null mice. Our results imply that PPARalpha delays the development of some spontaneous lesions associated with aging in the liver, kidney, and heart of SV129 mice.