Researchers in a 2022 study identified 3 types of arrested embryos with errors in embryonic genome activation or metabolism, some of which can be forced to resume development with resveratrol.
Embryo arrest occurs usually between day 3 and day 5, where a cleavage stage embryo fails to develop further. Embryo arrest is fairly common and can be due to a number of factors including aneuploidy, maternal age, mitochondrial dysfunction, lab conditions and other factors (reviewed in my post on embryo arrest, and for more background on embryo develop you can check out my complete guide to embryo grading and success rates).
In this study, the authors provide more information on what causes embryos to arrest, and identifies several distinct types of arrested embryos.
Note: this post may be confusing for people without a background in biology. I try to simplify as much as I can but it will help if you check my Biology 101 post to understand how DNA is transcribed to RNA (gene expression) and how RNA is translated to a protein. Accessing this post will not count toward the paywall’s monthly limit.
🔗 Original studies are referenced in this post or within the linked Remembryo posts.
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The three types of arrested embryos
First, the authors performed a gene expression analysis (RNA-seq) on 23 day 3 arrested embryos (they knew they were arrested because they didn’t divide further by day 4) and compared this to publicly available data from normal embryos.
From this the authors identified three types of arrested embryos: type 1-3.
They did this by comparing gene expression in arrested embryos and in normal embryos at different developmental stages.
The normal embryos had different gene expression signatures depending on their stage of development. So normal embryos at the zygote stage, or the 4 cell stage, or the morula stage, etc. all had their own unique signature. This is what we would expect, since a newly fertilized zygote is very different from the more advanced developmental stages of a morula or a blastocyst.
When they looked at the signatures of the arrested embryos, there were three different groups. Type 1 shared a signature with normal 2 cell and 4 cell embryos, type 2 shared a signature with normal 8 cell and early morulas, and type 3 shared a signature with normal late morulas and early blastocysts.
You can see this below where each point represents a different gene signature for normal embryos and arrested embryos (the arrested embryos are in pink):
What’s really interesting here is that all of these arrested embryos had 2-5 cells. So the type 2 and 3 arrested embryos had a more advanced gene expression signature (of an 8 cell or morula stage embryo) even though they only had a few cells!
Type 1 arrested embryos
Type 1 arrested embryos had a gene expression signature that was around the zygote to 4 cell stage in normal embryos. Around this time is when the embryo starts to activate the embryonic genome.
When the DNA of a sperm and egg come together to form the embryo’s DNA, this DNA is mostly unavailable for gene expression. The embryo’s DNA needs to be remodeled so it’s in a configuration that is appropriate to express the right genes for the embryo’s development. So while this remodeling is happening, the embryo primarily relies on stored maternal factors in the egg to get it through the first few days of division.
I have a bit more information on this in one of my older posts on embryo arrest.
There are a number of genes that are expressed that help promote the transition to the embryonic genome, as well as genes that help clear out maternal factors, and the expression of these genes is disrupted in type 1 arrested embryos.
The researchers went on to show that this disruption is due to faulty expression of key epigenetic genes that are needed to remodel the embryo’s DNA. Without expression of these genes, the embryo’s DNA can’t be remodeled appropriately and the embryo arrests.
In this study, 40% of arrested embryos were type 1.
Type 2 and 3 arrested embryos
Type 2 and 3 arrested embryos had a gene expression signature that was around the late morula and early blastocyst stages in normal embryos. At this point, these embryos have activated the embryonic genome.
These arrested embryos had low expression of genes involved in protein translation, ribosomes and cell cycle progression (involved in cell division), and high levels of activated p53, a protein that can force cells to enter senescence (a state where a cell is alive but no longer divides). Together this suggests that type 2 and 3 arrested embryos are in a senescent-like state.
They also found that a protein called SIRT was low in type 2 and 3 embryos. SIRT is involved in balancing different types of metabolism that are important in producing energy.
Cells can produce energy to perform their functions using a series of chemical reactions (metabolism). Two examples of this are glycolysis and oxidative phosphorylation. Type 2 arrested embryos had low levels of oxidative phosphorylation and type 3 had high levels. Both type 2 and 3 arrested embryos had low levels of glycolysis. Normally, the embryo switches to glycolysis as it prepares for implantation, so faulty SIRT levels may be affecting this transition.
Type 2 and 3 arrested embryos made up 60% of the arrested embryos they studied.
Correcting type 2 and 3 arrested embryos with resveratrol
Resveratrol is a small molecule that can activate the SIRT protein mentioned above.
When they treated type 2 and 3 arrested embryos with resveratrol, this activated SIRT and allowed the embryos to continue their development. You can see the resveratrol treated embryos grouping with the late morula/blastocyst development gene signatures below (circled red dots):
In this experiment, they had 42 arrested embryos that they treated with resveratrol, and after treatment 23/42 restarted development:
- 4 of those became highly fragmented
- 9 compacted and became morulas and then arrested
- 3 made it to the blastocyst stage
So in total, 3/42 = 7.1% of arrested embryos restarted development and became blasts. However, these treated embryos weren’t normal and they still had dysregulated levels of ribosomes and translation.
Conclusions
In this study, researchers discovered 3 types of arrested embryos: type 1-3. Type 1 arrested embryos had problems in converting from stored maternal egg factors to the embryo’s genome, while type 2 and 3 embryos showed a senescent-like state with metabolic issues. Resveratrol was able to rescue type 2 and 3 arrested embryos and restart their development. Approximately 7% of type 2 and 3 embryos were able to carry on to form blastocysts, however there were still molecular problems with these embryos.
The authors didn’t comment on whether or not these embryos would be useable but it’s unlikely due to these existing errors.
Resveratrol is a supplement that can be purchased, but it probably won’t help in preventing embryo arrest. The embryos in this experiment were treated directly with it inside the culture dish, so if anything this is something that would be done in the lab.
This is the first step in identifying these types of arrested embryos and more studies will need to be done before taking it into the clinic.
Reference
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About Embryoman
Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.
Related posts:
Embryo Arrest
Predicting how many day 3 embryos make it to blastocyst
Age-specific blastocyst conversion rates and other IVF outcomes in good prognosis women
Blastocyst and pregnancy rates of day 3 embryos based on cell number, fragmentation
Aneuploidy is a key factor in embryo arrest
Day 3 or Day 5 embryo transfer?
AI model predicts live births from blastocyst images with highest accuracy yet
Study examines association with embryo quality and male to female sex ratio