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Advanced maternal age affects hippocampal gene expression in adult mouse offspring

ABSTRACT: Advanced Maternal Age (AMA) is a risk factor for neurological and neuropsychiatric disorders in offspring. We developed a mouse model to investigate whether pregnancy at advanced age may provoke behavioral and brain gene expression changes in offspring. Mice conceived by 15- to 18-month-old (15-18M) or 3M control females were delivered by cesarean section and were all fostered after birth by 3M dams. Genome-wide mRNA expression was analyzed using microarrays in the hippocampus of 4M male offspring. In conclusion, pregnancy at advanced age yields offspring with altered patterns of gene expression in the hippocampus, typical of human neuropsychiatric and neurodegenerative disorders. The effects were not reversed by the postnatal maternal care provided by young foster mothers. This suggests that prenatal conditions associated with AMA may negatively affect fetal brain development and hence postnatal behaviors. This work was supported by the Polish National Science Center (2014/15/D/NZ4/04274 to SS and 2011/03/N/NZ29/05222 to AMS) and European Union Seventh Framework Programme (FP7/2007-2013-n 312097 to GEP). This work was also partially supported by Institute of Genetics and Animal Breeding of the Polish Academy of Sciences (S.III.1.3 to JAM) and by the Polish Ministry of Science and Higher Education (N N519 657940 to JG). SS, FZ and GEP are participating in the COST action FA1201 ‘Epiconcept’ - Epigenetic and Periconception Environment.

ORGANISM(S): Mus musculus

PROVIDER: GSE82325 | GEO | 2016/06/08

SECONDARY ACCESSION(S): PRJNA324656

REPOSITORIES: GEO

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Project description:Background: Early embryonic development is governed by maternal transcripts stored within the oocyte during oogenesis. Transcriptional activity of the oocyte ultimately dictates its developmental potential and may be influenced by maternal age, resulting in reduced competence of oocytes derived from women of advanced age, compared with the young. In the current study, RNA-Seq was used to perform transcriptome profiling of human GV and MII oocytes derived from young and advanced maternal age women. Participants/Materials and Methods: Cumulus dissection from donated oocytes was performed. GV and MII oocytes underwent deep RNA sequencing using the SMART-Seq v4 Ultra Low Input RNA protocol (Takara-Clontech, USA) and Nextera XT DNA library preparation kit (Illumina, USA). Data processing, quality assessment and bioinformatics analysis were performed using source-software, including FastQC, HISAT2, StringTie, edgeR and DAVID. Results: Following deep single-cell RNA-Seq on GV and MII oocytes, hundreds of transcripts were significantly differentially expressed between young maternal age (YMA) and advanced maternal age (AMA) groups, with the most significant biological processes relating to mitochondrial reserves. The GV to MII transition shares common biological processes between young and AMA groups, however, some genes involved in mitochondria function were altered during ageing. A decrease in mitochondrial-related transcripts was also observed during the GV to MII transition. However, there was a much greater reduction of mitochondrial-related transcripts in MII oocytes of AMA. This observation was confirmed when YMA MII oocytes were compared with the AMA MII group with mitochondrial-related transcripts being significantly higher expressed in the YMA group, including biological processes, such as mitochondrial electron transport and ATP biosynthetic process. These results indicate a higher energy potential in YMA MII oocytes that is decreased with age. Other significantly higher biological processes in the YMA MII group include transcripts involved in the regulation of ubiquitin-dependent degradation. Lack of these transcripts could lead to a non-appropriate removal of oogenesis remnants following fertilisation in the AMA MII group. Discussion: Understanding reproductive ageing effects at the RNA level in human oocytes may reveal differences in the mechanisms regulating the GV to MII transition that impact on oocyte quality in YMA and AMA patients. Further investigations of the up-/down-regulated transcripts during ageing could guide and improved IVF outcomes for AMA patients.

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Advanced maternal age affects hippocampal gene expression in adult mouse offspring

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