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Acetoacetate and β-hydroxybutyrate reduce mouse embryo viability via differential metabolic and epigenetic mechanisms

Published:September 25, 2022DOI:https://doi.org/10.1016/j.rbmo.2022.09.018

      Abstract

      Research question

      Does the ketone acetoacetate (AcAc) alone, or combined with β-hydroxybutyrate (βOHB), impact mouse embryo development, metabolism, histone acetylation and viability?

      Design

      Pronucleate mouse oocytes were cultured in vitro in G1/G2 media supplemented with ketones (AcAc or AcAc + βOHB) at concentrations representing those in maternal serum during pregnancy (0.04 mmol/l AcAc, 0.1 mmol/l βOHB), standard diet consumption (0.1 mmol/l AcAc, 0.25 mmol/l βOHB), ketogenic diet consumption (0.8 mmol/l AcAc, 2 mmol/l βOHB) and diabetic ketoacidosis (2 mmol/l AcAc, 4 mmol/l βOHB). Day 5 blastocysts were assessed for cell allocation, glucose metabolism and histone acetylation. Day 4 blastocysts exposed to 0.8 mmol/l AcAc + 2 mmol/l βOHB were transferred to standard-fed recipient females, and E14.5 fetal and placental development assessed.

      Results

      Exposure to 2 mmol/l AcAc or 0.8 mmol/l AcAc + 2 mmol/l βOHB did not impair blastocyst development, but significantly increased glucose consumption (P = 0.001 each), lowered glycolytic flux (P = 0.01, P < 0.001) and elevated trophectoderm (TE) histone 3 lysine 27 acetylation (H3K27ac; P < 0.001 each) compared with unexposed controls. Preimplantation AcAc + βOHB exposure reduced post-implantation fetal development by 25% (P = 0.037), and delayed female-specific fetal limb development (P = 0.019) and estimated fetal age (P = 0.019) compared with controls.

      Conclusion

      Preimplantation exposure to ketones affects underlying metabolism and histone acetylation in blastocysts that are associated with persistent, female-specific perturbations in fetal development. A periconceptional diet that elevates ketone concentrations may impair human embryonic viability.

      Graphical abstract

      Keywords

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      Biography

      Emma Whatley is completing her PhD under the supervision of Professor David Gardner and Dr Alexandra Harvey at the University of Melbourne, Australia. Her interests are in understanding how nutrients in vivo and in vitro during preimplantation development programme offspring viability, development and long-term health.
      Key message
      A ketogenic diet elevates circulating concentrations of the ketones acetoacetate (AcAc) and β-hydroxybutyrate (βOHB). Exposure to AcAc + βOHB during preimplantation embryo development alters blastocyst metabolism and histone acetylation and is associated with persistent, female-specific perturbations in fetal development. A periconceptional ketogenic diet may compromise offspring development, viability and health.