Maternal high-fat diet changes DNA methylation in the early embryo by disrupting the TCA cycle intermediary alpha ketoglutarate

in Reproduction
Authors:
Alexander Penn Robinson Research Institute, School of Biomedicine, Department of Reproduction and Development, University of Adelaide, Adelaide, South Australia, Australia

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https://orcid.org/0000-0002-3011-4397
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Nicole McPherson Robinson Research Institute, School of Biomedicine, Department of Reproduction and Development, University of Adelaide, Adelaide, South Australia, Australia
Repromed, Dulwich, South Australia, Australia
Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, South Australia, Australia

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https://orcid.org/0000-0002-3492-9403
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Tod Fullston Robinson Research Institute, School of Biomedicine, Department of Reproduction and Development, University of Adelaide, Adelaide, South Australia, Australia
Repromed, Dulwich, South Australia, Australia

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Bridget Arman Therapeutics Discovery and Vascular Function Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia

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Deirdre Zander-Fox Robinson Research Institute, School of Biomedicine, Department of Reproduction and Development, University of Adelaide, Adelaide, South Australia, Australia
Repromed, Dulwich, South Australia, Australia
Future Industries Institute, University of South Australia, Mawson Lakes, South Australia, Australia
Monash IVF Group, Melbourne, Victoria, Australia

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Correspondence should be addressed to A Penn; Email: alexander.penn@adelaide.edu.au
DOI:
https://doi.org/10.1530/REP-22-0302
Volume/Issue:
Volume 165: Issue 4
Page Range:
347–362
Article Type:
Research Article
Online Publication Date:
14 Feb 2023
Copyright:
© Society for Reproduction and Fertility 2023
Restricted access
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In brief

Maternal obesity can impair metabolism in the embryo and the resulting offspring. This study shows that metabolic disruptions through α-ketoglutarate may link altered metabolism with epigenetic changes in embryos.

Abstract

Maternal obesity can impair offspring metabolic health; however, the precise mechanism underpinning programming is unknown. Ten-Eleven translocase (TET) enzymes demethylate DNA using the TCA cycle intermediary α-ketoglutarate and may be involved in programming offspring health. Whether TETs are disrupted by maternal obesity is unknown. Five to six week-old C57Bl/6 female mice were fed a control diet (CD; 6% fat, n = 175) or a high-fat diet (HFD; 21% fat, n = 158) for 6 weeks. After superovulation, oocytes were collected for metabolic assessment, or females were mated and zygotes were cultured for embryo development, fetal growth, and assessment of global DNA methylation (5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxycytosine (5caC)) in the two-cell embryo. Zygotes collected from superovulated CBAF1 females were cultured in media containing α-ketoglutarate (0, 1.4, 3.5, or 14.0 mM) or with 2-hydroxyglutarate (2HG) (0 or 20 mM), a competitive inhibitor of α-ketoglutarate, with methylation and blastocyst differentiation assessed. After HFD, oocytes showed increased pyruvate oxidation and intracellular ROS, with no changes in Tet3 expression, while two-cell embryo global 5hmC DNA methylation was reduced and 5fC increased. Embryos cultured with 1.4 mM α-ketoglutarate had decreased two-cell 5mC, while 14.0 mM α-ketoglutarate increased the 5hmC:5mC ratio. In contrast, supplementation with 20 mM 2HG increased 5mC and decreased 5fC:5mC and 5caC:5mC ratios. α-ketoglutarate up to 3.5 mM did not alter embryo development, while culturing in 14.0 mM α-ketoglutarate blocked development at the two-cell. Culture with 2HG delayed embryo development past the four-cell and decreased blastocyst total cell number. In conclusion, disruptions in metabolic intermediates in the preimplantation embryo may provide a link between maternal obesity and programming offspring for ill health.

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Print ISSN:
1470-1626
Online ISSN:
1741-7899

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