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

Advanced maternal age perturbs mouse embryo development and alters the phenotype of derived embryonic stem cells
Advanced maternal age perturbs mouse embryo development and alters the phenotype of derived embryonic stem cells
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.
Advanced maternal age, blastocyst, mouse embryonic stem cells
2040-1744
1-11
Khurana, Pooja
c383f4cc-30dd-417a-b7bb-7999b3c73d9a
Smyth, Neil
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Sheth, Bhavwanti
2ca6ed58-a992-47b7-b3a5-3c5df82aada7
Velazquez, Miguel abraham A
3b67a037-eed3-4268-92f8-7a4b58473472
Eckert, Judith
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Fleming, Thomas
2abf761a-e5a1-4fa7-a2c8-12e32d5d4c03
Khurana, Pooja
c383f4cc-30dd-417a-b7bb-7999b3c73d9a
Smyth, Neil
0eba2a40-3b43-4d40-bb64-621bd7e9d505
Sheth, Bhavwanti
2ca6ed58-a992-47b7-b3a5-3c5df82aada7
Velazquez, Miguel abraham A
3b67a037-eed3-4268-92f8-7a4b58473472
Eckert, Judith
729bfa49-7053-458d-8e84-3e70e4d98e57
Fleming, Thomas
2abf761a-e5a1-4fa7-a2c8-12e32d5d4c03

Khurana, Pooja, Smyth, Neil, Sheth, Bhavwanti, Velazquez, Miguel abraham A, Eckert, Judith and Fleming, Thomas (2021) Advanced maternal age perturbs mouse embryo development and alters the phenotype of derived embryonic stem cells. Journal of Developmental Origins of Health and Disease, 1-11. (doi:10.1017/S2040174421000325).

Record type: Article

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.

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Khurana et al accepted J DOHaD 2021 - Accepted Manuscript
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More information

Accepted/In Press date: 16 May 2021
e-pub ahead of print date: 1 July 2021
Keywords: Advanced maternal age, blastocyst, mouse embryonic stem cells

Identifiers

Local EPrints ID: 449355
URI: http://eprints.soton.ac.uk/id/eprint/449355
ISSN: 2040-1744
PURE UUID: cec2275d-9a3f-4021-b80f-dd8c52d86199

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Date deposited: 25 May 2021 16:59
Last modified: 21 Nov 2021 21:59

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Contributors

Author: Pooja Khurana
Author: Neil Smyth
Author: Bhavwanti Sheth
Author: Miguel abraham A Velazquez
Author: Judith Eckert
Author: Thomas Fleming

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