title: Glucose deprivation, oxidative stress and peroxisome proliferator-activated receptor-alpha (PPARA) cause peroxisome proliferation in preimplantation mouse embryos.
abstract: Ex vivo two-cell mouse embryos deprived of glucose in vitro can develop to blastocysts by increasing their pyruvate consumption; however, zygotes when glucose-deprived cannot adapt this metabolic profile and degenerate as morulae. Prior to their death, these glucose-deprived morulae exhibit upregulation of the H+-monocarboxylate co-transporter SLC16A7 and catalase, which partly co-localize in peroxisomes. SLC16A7 has been linked to redox shuttling for peroxisomal beta-oxidation. Peroxisomal function is unclear during preimplantation development, but as a peroxisomal transporter in embryos, SLC16A7 may be involved and influenced by peroxisome proliferators such as peroxisome proliferator-activated receptor-alpha (PPARA). PCR confirmed Ppara mRNA expression in mouse embryos. Zygotes were cultured with or without glucose and with the PPARA-selective agonist WY14643 and the developing embryos assessed for expression of PPARA and phospho-PPARA in relation to the upregulation of SLC16A7 and catalase driven by glucose deprivation, indicative of peroxisomal proliferation. Reactive oxygen species (ROS) production and relationship to PPARA expression were also analysed. In glucose-deprived zygotes, ROS was elevated within 2 h, as were PPARA expression within 8 h and catalase and SLC16A7 after 12-24 h compared with glucose-supplied embryos. Inhibition of ROS production prevented this induction of PPARA and SLC16A7. Selective PPARA agonism with WY14643 also induced SLC16A7 and catalase expression in the presence of glucose. These data suggest that glucose-deprived cleavage stage embryos, although supplied with sufficient monocarboxylate-derived energy, undergo oxidative stress and exhibit elevated ROS, which in turn upregulates PPARA, catalase and SLC16A7 in a classical peroxisomal proliferation response.
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Jansen
authors.forename: Kara
authors.initials: K
authors.lastname: Cashman
authors.forename: Jeremy G
authors.initials: JG
authors.lastname: Thompson
authors.forename: Marie
authors.initials: M
authors.lastname: Pantaleon
authors.forename: Peter L
authors.initials: PL
authors.lastname: Kaye
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000187:drug effects / Q000378:metabolism*; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005947:Glucose / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020025:Peroxisome Proliferators / Q000494:pharmacology; D020675:Peroxisomes / Q000187:drug effects / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D027501:Monocarboxylic Acid Transporters; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D017382:Reactive Oxygen Species; C490426:Slc16a7 protein, mouse; C006253:pirinixic acid; D002374:Catalase; D005947:Glucose