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Advanced maternal age perturbs mouse embryo development and alters the phenotype of derived embryonic stem cells

Lookup NU author(s): Dr Miguel Velazquez

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Advanced maternal age (AMA) is known to reduce fertility, increases aneuploidy in oocytes and early embryos and leads to adverse developmental consequences which may associate with offspring lifetime health risks. However, investigating underlying effects of AMA on embryo developmental potential is confounded by the inherent senescence present in maternal body systems further affecting reproductive success. Here, we describe a new model for the analysis of early developmental mechanisms underlying AMA by the derivation and characterisation of mouse embryonic stem cell (mESC-like) lines from naturally conceived embryos. Young (7–8 weeks) and Old (7–8 months) C57BL/6 female mice were mated with young males. Preimplantation embryos from Old dams displayed developmental retardation in blastocyst morphogenesis. mESC lines established from these blastocysts using conventional techniques revealed differences in genetic, cellular and molecular criteria conserved over several passages in the standardised medium. mESCs from embryos from AMA dams displayed increased incidence of aneuploidy following Giemsa karyotyping compared with those from Young dams. Moreover, AMA caused an altered pattern of expression of pluripotency markers (Sox2, OCT4) in mESCs. AMA further diminished mESC survival and proliferation and reduced the expression of cell proliferation marker, Ki-67. These changes coincided with altered expression of the epigenetic marker, Dnmt3a and other developmental regulators in a sex-dependent manner. Collectively, our data demonstrate the feasibility to utilise mESCs to reveal developmental mechanisms underlying AMA in the absence of maternal senescence and with reduced animal use.


Publication metadata

Author(s): Khurana P, Smyth N, Sheth B, Velazquez MA, Eckert JJ, Fleming TP

Publication type: Article

Publication status: Published

Journal: Journal of Developmental Origins of Health and Disease

Year: 2021

Pages: Epub ahead of print

Online publication date: 01/07/2021

Acceptance date: 16/05/2021

Date deposited: 01/07/2021

ISSN (print): 2040-1744

ISSN (electronic): 2040-1752

Publisher: Cambridge University Press

URL: https://doi.org/10.1017/S2040174421000325

DOI: 10.1017/S2040174421000325


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Funding

Funder referenceFunder name
317146
278418
BB/F007450/1

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