title: Mitochondrial inhibition during preimplantation embryogenesis shifts the transcriptional profile of fetal mouse brain.
abstract: Environmental stress results in perturbations to mitochondrial function in the preimplantation embryo and hinders subsequent embryo and possibly offspring development. Global gene expression in fetal mouse brain was investigated following targeted mitochondrial inhibition by amino-oxyacetate (AOA) from the 2-cell to the blastocyst stage. Blastocysts were transferred to pseudopregnant recipients and RNA extracted from Day 18 fetal brains for microarray interrogation. Exposure to 5 μM AOA during preimplantation embryo development induced differential expression of 166 genes (>1.25 fold) in the fetal brain, relative to control medium-cultured embryos. Altered expression pathways included carbohydrate metabolism, neurological development, cellular proliferation and death, DNA replication, recombination and repair. Of 28 genes exhibiting the greatest change in expression, qPCR confirmed that 16 were significantly altered. Targeted qPCR assessment of a further 20 genes associated with methylation, acetylation and mitochondrial dysfunction revealed that three were significantly altered (Immp1l, Nars2, Sat2) and Dmap1 exhibited a sex-specific response to AOA exposure. Only 2/48 genes had significantly altered expression by qPCR (Nola3, Timm8b) in fetal brains exposed to 50 μM AOA embryo culture, excluding an AOA dose-dependent response. It was concluded that perturbation of mitochondrial function induced by 5 μM AOA during preimplantation embryo development alters gene expression in the neonatal brain in a manner that suggests that proper brain development may be compromised.
authors.affiliation: Discipline of Obstetrics & Gynaecology, School of Paediatrics & Reproductive Health, North Terrace Campus, The University of Adelaide, Adelaide, SA 5005, Australia. tod.fullston@adelaide.edu.au
authors.forename: Tod
authors.initials: T
authors.lastname: Fullston
authors.forename: Megan
authors.initials: M
authors.lastname: Mitchell
authors.forename: Sarah
authors.initials: S
authors.lastname: Wakefield
authors.forename: Michelle
authors.initials: M
authors.lastname: Lane
mesh_terms: D000625:Aminooxyacetic Acid / Q000494:pharmacology*; D000818:Animals; D001755:Blastocyst / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D046149:Embryo Culture Techniques; D004624:Embryo Transfer; D044127:Epigenesis, Genetic / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D053263:Gene Regulatory Networks / Q000187:drug effects; D005865:Gestational Age; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D012333:RNA, Messenger; D000625:Aminooxyacetic Acid