Effect of lipotoxicity on mitochondrial function and epigenetic programming during bovine in vitro embryo production

Abstract

Maternal metabolic disorders may cause lipotoxic effects on the developing oocyte. Understanding the timing at which this might disrupt embryo epigenetic programming and how this is linked with mitochondrial dysfunction is crucial for improving assisted reproductive treatments, but has not been investigated before. Therefore, we used a bovine in vitro model to investigate if pathophysiological palmitic acid (PA) concentrations during in vitro oocyte maturation and in vitro embryo culture alter embryo epigenetic patterns (DNA methylation (5mC) and histone acetylation/methylation (H3K9ac/H3K9me2)) compared to control (CONT) and solvent control (SCONT), at the zygote and morula stage. Secondly, we investigated if these epigenetic alterations are associated with mitochondrial dysfunction and changes in ATP production rate, or altered expression of epigenetic regulatory genes. Compared to SCONT, H3K9ac and H3K9me2 levels were increased in PA-derived zygotes. Also, 5mC and H3K9me2 levels were increased in PA-exposed morulae compared to SCONT. This was associated with complete inhibition of glycolytic ATP production in oocytes, increased mitochondrial membrane potential and complete inhibition of glycolytic ATP production in 4-cell embryos and reduced SOD2 expression in PA-exposed zygotes and morulae. For the first time, epigenetic alterations in metabolically compromised zygotes and morulae have been observed in parallel with mitochondrial dysfunction in the same study.

Lipid Toxicity in the Cardiovascular-Kidney-Metabolic Syndrome (CKMS)

“…The ovary of an experimental animal exposed to C16 fatty acid (palmitic) demonstrates inhibition of oocyte maturation, a model of PCOS. The model also develops a disruption of ATP generation [70]. This disruption does not involve the tricarboxylic acid (Krebs) cycle or the electron transport system.…”

“…Two steps in the glycolytic cycle (Table 2) are the focal points of disruption of ATP production in this model of PCOS (females with type 2 diabetes have a higher incidence of cardiovascular morbidity / mortality if they also have insulin resistant polycystic ovary syndrome (PCOS)). The ovary of an experimental animal exposed to excess unsaturated palmitic acid (which may occur with PCOS) has been found to demonstrate inhibition of oocyte maturation, as well as disruption of generation of ATP [68][69][70].…”