Abstract
The rapid decline in fertility that has been occurring to high-producing dairy cows in the past 50 years seems to be associated with metabolic disturbances such as ketosis, supporting the need for research to improve our understanding of the relations among the diet, metabolism and embryonic development. Recently, the ketone body β-hydroxybutyrate (BOHB) was demonstrated to be a potent inhibitor of histone deacetylases (HDACs). Herein, we performed a series of experiments aiming to investigate the epigenetic effects of BOHB on histone acetylation in somatic cells, cumulus-oocyte complexes (COCs) and somatic cell nuclear transfer (SCNT) embryos. Treatment with BOHB does not increase histone acetylation in cells but stimulates genes associated with ketolysis and master regulators of metabolism. We further demonstrated that maturing COCs with high levels of BOHB does not affect their maturation rate or histone acetylation but increases the expression of PPARA in cumulus cells. Treatment of somatic cell nuclear transfer zygotes with BOHB causes hyperacetylation, which is maintained until the blastocyst stage, causing enhanced FOXO3A expression and blastocyst production. Our data shed light on the epigenetic mechanisms caused by BOHB in bovine cells and embryos and provide a better understanding of the connection between nutrition and reproduction.
Highlights
The rapid decline in fertility that has been occurring to high-producing dairy cows in the past 50 years seems to be associated with metabolic disturbances such as ketosis, supporting the need for research to improve our understanding of the relations among the diet, metabolism and embryonic development
The imbalance caused by the excessive expenditure of nutrients to produce high quantities of milk combined with reduced or insufficient food intake leads to a condition known as negative energy balance (NEB), which is characterized by elevated levels of nonesterified fatty acids (NEFAs) and ketone bodies in the blood serum[3]
We investigated whether body β-hydroxybutyrate (BOHB) treatment increases the abundance of forkhead box O3 (FOXO3A), superoxide dismutase 1 (SOD1) and 2 (SOD2), catalase (CAT) and glutathione peroxidase 1 (GPX1) transcripts
Summary
The rapid decline in fertility that has been occurring to high-producing dairy cows in the past 50 years seems to be associated with metabolic disturbances such as ketosis, supporting the need for research to improve our understanding of the relations among the diet, metabolism and embryonic development. The imbalance caused by the excessive expenditure of nutrients to produce high quantities of milk combined with reduced or insufficient food intake leads to a condition known as negative energy balance (NEB), which is characterized by elevated levels of nonesterified fatty acids (NEFAs) and ketone bodies (i.e., acetone, acetoacetate and β-hydroxybutyrate) in the blood serum[3] These molecules are known to affect the follicle and oviduct environment where the oocytes and early embryos develop, culminating in reduced fertility[4,5]. Several metabolites are altered by BOHB metabolism, such as acetyl-CoA, succinyl-CoA, and NAD+, which regulate cellular metabolism[11] An understanding of these critical and diverse signalling functions might give clues leading to better management of common disorders in dairy cows, such as ketosis and reproductive failure[12]. Since the oocytes/embryos are exposed to BOHB during their development, in vitro exposure may provide mechanistic insights about the aetiology of diminished fertility[2]
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