title: Activation of peroxisome proliferators-activated receptor δ (PPARδ) promotes blastocyst hatching in mice.
abstract: Prostaglandins participate in a variety of female reproductive processes, including ovulation, fertilization, embryo implantation and parturition. In particular, maternal prostacyclin (PGI(2)) is critical for embryo implantation and the action of PGI(2) is not mediated via its G-protein-coupled membrane receptor, IP, but its nuclear receptor, peroxisome-proliferator-activated receptor δ (PPARδ). Recently, several studies have shown that PGI(2) enhances blastocyst development and/or hatching rate in vitro, and subsequently implantation and live birth rates in mice. However, the mechanism by which PGI(2) improves preimplantation embryo development in vitro remains unclear. Using molecular, pharmacologic and genetic approaches, we show that PGI(2)-induced PPARδ activation accelerates blastocyst hatching in mice. mRNAs for PPARδ, retinoid X receptor (heterodimeric partners of PPARδ) and PGI(2) synthase (PGIS) are temporally induced after zygotic gene activation, and their expression reaches maximum levels at the blastocyst stage, suggesting that functional complex of PPARδ can be formed in the blastocyst. Carbaprostacyclin (a stable analogue of PGI(2)) and GW501516 (a PPARδ selective agonist) significantly accelerated blastocyst hatching but did not increase total cell number of cultured blastocysts. Whereas U51605 (a PGIS inhibitor) interfered with blastocyst hatching, GW501516 restored U51605-induced retarded hatching. In contrast to the improvement of blastocyst hatching by PPARδ agonists, PPAR antagonists significantly inhibited blastocyst hatching. Furthermore, deletion of PPARδ at early stages of preimplantation mouse embryos caused delay of blastocyst hatching, but did not impair blastocyst development. Taken together, PGI(2)-induced PPARδ activation accelerates blastocyst hatching in mice.
authors.affiliation: Laboratory of Reproductive Biology & Infertility, Cheil General Hospital & Women's Healthcare Center, Kwandong University College of Medicine, Seoul, Korea.
authors.forename: Hee Jung
authors.initials: HJ
authors.lastname: Kang
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Jung Ah
authors.initials: JA
authors.lastname: Yoon
authors.forename: Jin Hyun
authors.initials: JH
authors.lastname: Jun
authors.forename: Hyunjung Jade
authors.initials: HJ
authors.lastname: Lim
authors.forename: Tae Ki
authors.initials: TK
authors.lastname: Yoon
authors.forename: Haengseok
authors.initials: H
authors.lastname: Song
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001755:Blastocyst / Q000502:physiology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics; D010064:Embryo Implantation / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D047494:PPAR delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011247:Pregnancy; D011463:Prostaglandins H / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors / Q000096:biosynthesis / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D001549:Benzamides; D065607:Cytochrome P-450 Enzyme Inhibitors; C425931:GW 501516; D047494:PPAR delta; D011463:Prostaglandins H; D011725:Pyridines; D012333:RNA, Messenger; D047488:Retinoid X Receptors; C458508:T 0070907; D013844:Thiazoles; C015014:azo analog I; C026678:carboprostacyclin; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase