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Advanced maternal age causes adverse programming of mouse blastocysts leading to altered growth and impaired cardiometabolic health in post-natal life

Advanced maternal age causes adverse programming of mouse blastocysts leading to altered growth and impaired cardiometabolic health in post-natal life
Advanced maternal age causes adverse programming of mouse blastocysts leading to altered growth and impaired cardiometabolic health in post-natal life
Study question: does advanced maternal age (AMA) in mice affect cardiometabolic health during post-natal life in offspring derived from an assisted reproduction technology (ART) procedure?

Summary answer: offspring derived from blastocysts collected from aged female mice displayed impaired body weight gain, blood pressure, glucose metabolism and organ allometry during post-natal life compared with offspring derived from blastocysts from young females; since all blastocysts were transferred to normalized young mothers, this effect is independent of maternal pregnancy conditions.

What is known already: although studies in mice have shown that AMA can affect body weight and behaviour of offspring derived from natural reproduction, data on the effects of AMA on offspring cardiometabolic health during post-natal development are not available. Given the increasing use of ART to alleviate infertility in women of AMA, it is pivotal to develop ART–AMA models addressing the effects of maternal aging on offspring health.

Study design, size, duration: blastocysts from old (34–39 weeks) or young (8–9 weeks) C57BL/6 females mated with young CBA males (13–15 weeks) were either subjected to differential cell staining (inner cell mass and trophectoderm) or underwent embryo transfer (ET) into young MF1 surrogates (8–9 weeks) to produce young (Young-ET, 9 litters) and old (Old-ET, 10 litters) embryo-derived offspring. Offspring health monitoring was carried out for 30 weeks.

Participants/materials, setting, methods: all animals were fed with standard chow. Blood pressure was measured at post-natal Weeks 9, 15 and 21, and at post-natal Week 30 a glucose tolerance test (GTT) was performed. Two days after the GTT mice were killed for organ allometry. Blastocyst cell allocation variables were evaluated by T-test and developmental data were analysed with a multilevel random effects regression model.

Main results and the role of chance: the total number of cells in blastocysts from aged mice was decreased (P < 0.05) relative to young mice due to a lower number of cells in the trophectoderm (mean ± SEM: 34.5 ± 2.1 versus 29.6 ± 1.0). Weekly body weight did not differ in male offspring, but an increase in body weight from Week 13 onwards was observed in Old-ET females (final body weight at post-natal Week 30: 38.5 ± 0.8 versus 33.4 ± 0.8 g, P < 0.05). Blood pressure was increased in Old-ET offspring at Weeks 9–15 in males (Week 9: 108.5 ± 3.13 versus 100.8 ± 1.5 mmHg, Week 15: 112.9 ± 3.2 versus 103.4 ± 2.1 mmHg) and Week 15 in females (115.9 ± 3.7 versus 102.8 ± 0.7 mmHg; all P < 0.05 versus Young-ET). The GTT results and organ allometry were not affected in male offspring. In contrast, Old-ET females displayed a greater (P < 0.05) peak glucose concentration at 30 min during the GTT (21.1 ± 0.4 versus 17.8 ± 1.16 mmol/l) and their spleen weight (88.2 ± 2.6 ± 105.1 ± 4.6 mg) and several organ:body weight ratios (g/g × 103) were decreased (P < 0.05 versus Young-ET), including the heart (3.7 ± 0.06 versus 4.4 ± 0.08), lungs (4.4 ± 0.1 versus 5.0 ± 0.1), spleen (2.4 ± 0.06 versus 3.2 ± 0.1) and liver (36.4 ± 0.6 versus 39.1 ± 0.9).

Limitations, reasons for caution: results from experimental animal models cannot be extrapolated to humans. Nevertheless, they are valuable to develop conceptual models that can produce hypotheses for eventual testing in the target species (i.e. humans).

Wider implications of the findings: our data show that offspring from mouse embryos from aged mothers can develop altered phenotypes during post-natal development compared with embryos from young mothers. Because all embryos were transferred into young mothers for the duration of pregnancy to normalize the maternal in vivo environment, our findings indicate that adverse programming via AMA is already established at the blastocyst stage. Whilst human embryos display increased aneuploidy compared with mouse, we believe our data have implications for women of AMA undergoing assisted reproduction, including surrogacy programmes.

Study funding/competeing interest(s): this work was supported through the European Union FP7-CP-FP Epihealth programme (278418) to T.P.F. and the BBSRC (BB/F007450/1) to T.P.F. The authors have no conflicts of interest to declare
1970-80
Velazquez, M.A.
706e7de5-8cdb-4f2b-b47d-128166bdbea4
Smith, C.G.C.
858f52ff-fd35-4ffe-b7e8-346a69bd9995
Smyth, N.R.
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Osmond, C.
1c0618dd-a0ee-49fd-9306-050ec2982880
Fleming, Thomas
2abf761a-e5a1-4fa7-a2c8-12e32d5d4c03
Velazquez, M.A.
706e7de5-8cdb-4f2b-b47d-128166bdbea4
Smith, C.G.C.
858f52ff-fd35-4ffe-b7e8-346a69bd9995
Smyth, N.R.
e90b70d7-010a-427b-bb32-c78f9ab6d0b4
Osmond, C.
1c0618dd-a0ee-49fd-9306-050ec2982880
Fleming, Thomas
2abf761a-e5a1-4fa7-a2c8-12e32d5d4c03

Velazquez, M.A., Smith, C.G.C., Smyth, N.R., Osmond, C. and Fleming, Thomas (2016) Advanced maternal age causes adverse programming of mouse blastocysts leading to altered growth and impaired cardiometabolic health in post-natal life. Human Reproduction, 31 (9), 1970-80. (doi:10.1093/humrep/dew177). (PMID:27402911)

Record type: Article

Abstract

Study question: does advanced maternal age (AMA) in mice affect cardiometabolic health during post-natal life in offspring derived from an assisted reproduction technology (ART) procedure?

Summary answer: offspring derived from blastocysts collected from aged female mice displayed impaired body weight gain, blood pressure, glucose metabolism and organ allometry during post-natal life compared with offspring derived from blastocysts from young females; since all blastocysts were transferred to normalized young mothers, this effect is independent of maternal pregnancy conditions.

What is known already: although studies in mice have shown that AMA can affect body weight and behaviour of offspring derived from natural reproduction, data on the effects of AMA on offspring cardiometabolic health during post-natal development are not available. Given the increasing use of ART to alleviate infertility in women of AMA, it is pivotal to develop ART–AMA models addressing the effects of maternal aging on offspring health.

Study design, size, duration: blastocysts from old (34–39 weeks) or young (8–9 weeks) C57BL/6 females mated with young CBA males (13–15 weeks) were either subjected to differential cell staining (inner cell mass and trophectoderm) or underwent embryo transfer (ET) into young MF1 surrogates (8–9 weeks) to produce young (Young-ET, 9 litters) and old (Old-ET, 10 litters) embryo-derived offspring. Offspring health monitoring was carried out for 30 weeks.

Participants/materials, setting, methods: all animals were fed with standard chow. Blood pressure was measured at post-natal Weeks 9, 15 and 21, and at post-natal Week 30 a glucose tolerance test (GTT) was performed. Two days after the GTT mice were killed for organ allometry. Blastocyst cell allocation variables were evaluated by T-test and developmental data were analysed with a multilevel random effects regression model.

Main results and the role of chance: the total number of cells in blastocysts from aged mice was decreased (P < 0.05) relative to young mice due to a lower number of cells in the trophectoderm (mean ± SEM: 34.5 ± 2.1 versus 29.6 ± 1.0). Weekly body weight did not differ in male offspring, but an increase in body weight from Week 13 onwards was observed in Old-ET females (final body weight at post-natal Week 30: 38.5 ± 0.8 versus 33.4 ± 0.8 g, P < 0.05). Blood pressure was increased in Old-ET offspring at Weeks 9–15 in males (Week 9: 108.5 ± 3.13 versus 100.8 ± 1.5 mmHg, Week 15: 112.9 ± 3.2 versus 103.4 ± 2.1 mmHg) and Week 15 in females (115.9 ± 3.7 versus 102.8 ± 0.7 mmHg; all P < 0.05 versus Young-ET). The GTT results and organ allometry were not affected in male offspring. In contrast, Old-ET females displayed a greater (P < 0.05) peak glucose concentration at 30 min during the GTT (21.1 ± 0.4 versus 17.8 ± 1.16 mmol/l) and their spleen weight (88.2 ± 2.6 ± 105.1 ± 4.6 mg) and several organ:body weight ratios (g/g × 103) were decreased (P < 0.05 versus Young-ET), including the heart (3.7 ± 0.06 versus 4.4 ± 0.08), lungs (4.4 ± 0.1 versus 5.0 ± 0.1), spleen (2.4 ± 0.06 versus 3.2 ± 0.1) and liver (36.4 ± 0.6 versus 39.1 ± 0.9).

Limitations, reasons for caution: results from experimental animal models cannot be extrapolated to humans. Nevertheless, they are valuable to develop conceptual models that can produce hypotheses for eventual testing in the target species (i.e. humans).

Wider implications of the findings: our data show that offspring from mouse embryos from aged mothers can develop altered phenotypes during post-natal development compared with embryos from young mothers. Because all embryos were transferred into young mothers for the duration of pregnancy to normalize the maternal in vivo environment, our findings indicate that adverse programming via AMA is already established at the blastocyst stage. Whilst human embryos display increased aneuploidy compared with mouse, we believe our data have implications for women of AMA undergoing assisted reproduction, including surrogacy programmes.

Study funding/competeing interest(s): this work was supported through the European Union FP7-CP-FP Epihealth programme (278418) to T.P.F. and the BBSRC (BB/F007450/1) to T.P.F. The authors have no conflicts of interest to declare

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Accepted/In Press date: 17 June 2016
e-pub ahead of print date: 19 August 2016
Published date: September 2016
Organisations: Biomedicine

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Local EPrints ID: 402221
URI: http://eprints.soton.ac.uk/id/eprint/402221
PURE UUID: 9fe3ab80-4af8-4c1f-a517-9085757214dc

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Date deposited: 03 Nov 2016 10:07
Last modified: 15 Mar 2024 03:11

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Contributors

Author: M.A. Velazquez
Author: C.G.C. Smith
Author: N.R. Smyth
Author: C. Osmond
Author: Thomas Fleming

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