When scientists consider metabolism and reproduction, their thoughts are drawn to energy balance and ATP synthesis. However, over the past decade our perception of the role of metabolites and co-factors as functional players in ATP formation and biosynthesis has shifted as they have been determined to be epigenetic regulators. This phenomenon, referred to as “Metaboloepigenetics”, is helping to elucidate how culture conditions and diet regulate preimplantation embryo development and viability.
Typically considered an end product of anaerobic glycolysis, lactic acid has been shown to have key roles in the initial phases of implantation, being involved in the breakdown of the endometrial extracellular matrix, the induction of angiogenesis, and modulation of local immune function through the formation of an “acid cloud” by the blastocyst, with both lactate and pH controlling events at peri-implantation. Lactic acid has also been shown to affect gene expression through a novel epigenetic modification of both histone and non-histone proteins, a process known as lactylation. NAD+, a key cofactor in the conversion of lactic acid to pyruvate, and whose cytosolic concentration is regulated by the ration of pyruvate:lactate in an embryo culture medium, also serves as a potent epigenetic regulator, being an activator of histone deacetylases (sirtuins).
Research on the impact of diet on gamete function and embryo development has focussed primarily on high fat/high sugar intake, but one of the fastest trending diets worldwide is the ketogenic diet (KD). Characterised by elevate levels of circulating ketone bodies (KBs; b hydroxybutyrate and acetoacetate), the KD has been shown to be effective in managing weight loss and even in the treatment of certain cancers. However, it transpires that KBs not only perturbs blastocyst metabolism, but also modifies histone acetylation leading to persistent female-specific alterations in fetal development. Other examples of metabolic regulation and their impact on embryo viability and the development of embryo culture systems will also be considered in the lecture.