During IVF only around 30 percent of human embryos make it to the blastocyst stage, meaning only a fraction of the eggs collected become viable embryos that can be transferred to the uterus. Some other species, such as mice, have much higher success rates and so it hasn't been clear what makes human embryos different. Scientists have now shown that DNA changes affecting gene expression and metabolism underlie in vitro embryo arrest.
Dr Andrew Hutchins of Southern University of Science and Technology, Shenzhen, China and corresponding author of the study said: 'Human embryos are surprisingly difficult to grow in vitro, which is a major problem for the treatment of human fertility. Our study indicates that several biological processes are causing the arrest; including epigenetic and metabolic problems in the embryos.'
The team, publishing their work in PLOS Biology, categorised arrested embryos in to three groups depending on which stage they stopped developing at. Type one embryos were those which exhibited problems with the expression of genes around the two to four-cell stages, and types two and three were marked by dysregulation of genes usually expressed at the eight-cell stage and beyond.
Type one embryos were unable to switch on their own gene expression and convert from gene expression usually found in an egg cell to that found in a zygote. Levels of chromosomal aneuploidy were not significantly different between arrested and non-arrested embryos, so the authors looked for other changes which could be behind this.
The paper describes how the scientists analysed histone methylation, the addition of a small chemical group to the proteins which fold and regulate chromosomes, in the embryos. They looked at the mechanisms of methylation and found that the process was dysregulated in the arrested embryos, providing an explanation for their disrupted gene expression.
Type two and three embryos appeared to arrest mostly due to changes in metabolism, which is important considering that, after implantation and before they receive a blood supply, embryos start off in a low oxygen environment. To see if they could correct this, the team treated some of the embryos with drugs which affect cells' metabolic balance. This partially rescued some of the embryos but authors said this required further investigation.
Dr Hutchins remarked: 'Our results indicate that many IVF embryos enter a senescent-like state, in which changes in metabolism and gene expression prevent developmental progression. It appears to be possible to overcome this arrested state for some embryos, but much more work will be needed to determine the best strategy for doing so.'