Estrogen-induced Production of a Peroxisome Proliferator-activated Receptor (PPAR) Ligand in a PPARγ-expressing Tissue

Peroxisome proliferation has been associated with carcinogenesis in the liver, and estrogen intake has been associated with increased risk of cancer in the hormone target tissues. Estrogen-induced peroxisome proliferation has been observed in an estrogen target tissue, the uropygial gland in the duck. To elucidate the molecular mechanism of this process, we previously isolated the cDNA of peroxisome proliferator-activated receptor γ1 (PPARγ1) from the duck uropygial gland and found that its expression was high exclusively in this tissue of duck. However, the nature of the ligand for PPARγ1 and how estrogen might enhance PPARγ1-regulated gene expression were not known. Here we demonstrate that estrogen treatment of animals enhanced the metabolism of arachidonic acid in the uropygial gland. Conversion of prostaglandin D 2 to a metabolite was induced by estradiol treatment preceding peroxisome proliferation. High performance liquid chromatography and TLC analyses showed that the metabolite behaved chromatographically similar to prostaglandin J 2 and Δ 12 -prostaglandin J 2 . Gas chromatography/mass spectrometry revealed a striking similarity of the metabolite to Δ 12 -prostaglandin J 2 , the only form among the J 2 series whose natural occurrence has been detected. Furthermore, this metabolite was able to activate duck PPARγ1 to the same extent as the same concentrations of Δ 12 -prostaglandin J 2 and 15-deoxy-Δ 12,14 -prostaglandin J 2 , whereas under the same conditions, prostaglandin D 2 was not effective. The results suggest that estrogen treatment induced the formation of a prostaglandin D 2 metabolite that activated duck PPARγ1, causing the induction of peroxisome proliferation in the duck uropygial gland.