Study finds why many IVF embryos fail to develop

In humans, a fertilized egg is no guarantee of reproductive success. Most embryos stop developing and perish within days of fertilization, usually because they have an abnormal number of chromosomes. Now, researchers at Columbia University Vagelos College of Physicians and Surgeons have found that most of these mistakes are due to spontaneous errors in DNA replication in the earliest phase of cell division.

The findings provide new insights into the basic biology of human reproduction and in the long term could lead to improvements in the success rate of in vitro fertilization (IVF). The study was published online July 19 in the journal Cell.

Challenging task for early embryos

Approximately 24 hours after a human egg is fertilized, the process of cell division begins. During cell division, the entire genome -- 46 chromosomes containing more than 3 billion base pairs of DNA -- must be faithfully duplicated. The duplicate sets of chromosomes must then be separated so that each daughter cell receives a complete set.

In many human embryos created for IVF, something goes wrong and some cells within the embryo have too few or too many chromosomes.

"Duplicating the genome is a challenging task for the early embryo," says study leader Dieter Egli, PhD, the Maimonides Assistant Professor of Developmental Cell Biology (in pediatrics) at Columbia University Vagelos College of Physicians and Surgeons.

Researchers have long theorized that errors occur during the final phase of cell division, when the duplicate sets of chromosomes separate into two identical daughter cells. Most of these failures were attributed to issues with the microtubule spindle, the apparatus that pulls the two sets of chromosomes apart.

But Egli's studies found that chromosomal abnormalities stem from errors that occur much earlier in the process of cell division when the genome's DNA is duplicated. If the DNA is not copied precisely, his studies found, the spindle malfunctions and places the wrong number of chromosomes into each daughter cell. When DNA duplication is abnormal, the spindle does not function normally. "This has largely been overlooked in previous studies -- because why would the embryo allow the integrity of the genome to be compromised when this is such a critical requirement for normal development?" Egli says.

Though the studies were conducted with embryos created in a petri dish -- including from individuals undergoing IVF and egg donors who were not seeking fertility treatment -- the same problems may contribute to the failure of embryos created in natural human reproduction.

Clues to source of DNA errors

The source of DNA copying errors in embryos appears to spring from obstacles within the DNA's double helix. Though the precise reason for these obstacles is not yet known, they cause duplication of the DNA to pause, or even stop, which results in DNA breakage and an abnormal number of chromosomes.

Spontaneous DNA errors can occur as early as the first cycle of cell division in human embryos, the researchers found, as well as in subsequent cell divisions. If too many cells in the early embryo are affected by chromosomal abnormalities, the embryo cannot develop further.

IVF

Most human embryos created for IVF stop developing within days after fertilization. This inefficiency of human development is an obstacle to successful fertility treatments.

"Many women undergoing fertility treatment require multiple IVF cycles in order to get pregnant, and some never get pregnant at all. Not only is this enormously expensive, it's emotionally taxing," says Jenna Turocy, MD, a fertility specialist at Columbia University Fertility Center and a co-author of the study.

The researchers are planning additional studies looking at DNA damage during replication in the hope of understanding normal and disease-causing variations in the human germ line. In the long term, these studies may lead to methods to reduce the risk of genetic abnormalities and embryo attrition for patients undergoing IVF.

More information

The study is titled, "Replication stress impairs chromosome segregation and preimplantation development in human embryos."

The other contributors (all Columbia unless noted) are: Katherine L. PalmerolaSelma Amrane, Alejandro De Los Angeles, Shuangyi Xu, Ning Wang, Joao de Pinho, Michael V. Zuccaro, Angelo Taglialatela, Dashiell J. Massey (Columbia and Cornell University), Alex Robles, Anisa Subbiah, Bob Prosser, Rogerio Lobo, Alberto Ciccia, Amnon Koren (Cornell), and Timour Baslan (Memorial Sloan Kettering Cancer Center).

This research was supported by a NYSCF-Robertson Stem Cell Investigator award and grants from the United States-Israel Binational Science Foundation, Columbia Stem Cell Initiative, the American Society for Reproductive Medicine, the John M. Driscoll Jr. Children's Fund Scholarship, and by the Russell Berrie Foundation Program in Cellular Therapies.

Dieter Egli is a member of the Cell editorial board.

Journal Reference:

1. Katherine L. Palmerola, Selma Amrane, Alejandro De Los Angeles, Shuangyi Xu, Ning Wang, Joao de Pinho, Michael V. Zuccaro, Angelo Taglialatela, Dashiell J. Massey, Jenna Turocy, Alex Robles, Anisa Subbiah, Bob Prosser, Rogerio Lobo, Alberto Ciccia, Amnon Koren, Timour Baslan, Dieter Egli. Replication stress impairs chromosome segregation and preimplantation development in human embryos. Cell, 2022; DOI: 10.1016/j.cell.2022.06.028 

Courtesy:

Columbia University Irving Medical Center. "Study finds why many IVF embryos fail to develop." ScienceDaily. ScienceDaily, 19 July 2022. <www.sciencedaily.com/releases/2022/07/220719130213.htm>.

 

 

Vitamin B6 supplements could reduce anxiety and depression

Taking high-dose Vitamin B6 tablets has been shown to reduce feelings of anxiety and depression by new research.

Scientists at the University of Reading measured the impact of high doses of Vitamin B6 on young adults and found that they reported feeling less anxious and depressed after taking the supplements every day for a month.

The study, published in the journal Human Psychopharmacology: Clinical and Experimental, provides valuable evidence to support the use of supplements thought to modify levels of activity in the brain for preventing or treating mood disorders.

Dr David Field, lead author from the School of Psychology and Clinical Language Sciences at the University of Reading, said: "The functioning of the brain relies on a delicate balance between the excitatory neurons that carry information around and inhibitory ones, which prevent runaway activity.

"Recent theories have connected mood disorders and some other neuropsychiatric conditions with a disturbance of this balance, often in the direction of raised levels of brain activity.

"Vitamin B6 helps the body produce a specific chemical messenger that inhibits impulses in the brain, and our study links this calming effect with reduced anxiety among the participants."

While previous studies have produced evidence that multivitamins or marmite can reduce stress levels, few studies have been carried out into which particular vitamins contained within them drive this effect.

The new study focused on the potential role of Vitamins B6, which is known to increase the body's production of GABA (Gamma-Aminobutyric Acid), a chemical that blocks impulses between nerve cells in the brain.

In the current trial, more than 300 participants were randomly assigned either Vitamin B6 or B12 supplements far above the recommended daily intake (approximately 50 times the recommended daily allowance) or a placebo, and took one a day with food for a month.

The study showed that Vitamin B12 had little effect compared to placebo over the trial period, but Vitamin B6 made a statistically reliable difference.

Raised levels of GABA among participants who had taken Vitamin B6 supplements were confirmed by visual tests carried out at the end of the trial, supporting the hypothesis that B6 was responsible for the reduction in anxiety. Subtle but harmless changes in visual performance were detected, consistent with controlled levels of brain activity.

Dr Field said: "Many foods, including tuna, chickpeas and many fruits and vegetables, contain Vitamin B6. However, the high doses used in this trial suggest that supplements would be necessary to have a positive effect on mood.

"It is important to acknowledge that this research is at an early stage and the effect of Vitamin B6 on anxiety in our study was quite small compared to what you would expect from medication. However, nutrition-based interventions produce far fewer unpleasant side effects than drugs, and so in the future people might prefer them as an intervention.

"To make this a realistic choice, further research is needed to identify other nutrition-based interventions that benefit mental wellbeing, allowing different dietary interventions to be combined in future to provide greater results.

"One potential option would be to combine Vitamin B6 supplements with talking therapies such as Cognitive Behavioural Therapy to boost their effect."

 

Journal Reference:

1. David T. Field, Rebekah O. Cracknell, Jessica R. Eastwood, Peter Scarfe, Claire M. Williams, Ying Zheng, Teresa Tavassoli. High‐dose Vitamin B6 supplementation reduces anxiety and strengthens visual surround suppression. Human Psychopharmacology: Clinical and Experimental, 2022; DOI: 10.1002/hup.2852 

Courtesy:

University of Reading. "Vitamin B6 supplements could reduce anxiety and depression." ScienceDaily. ScienceDaily, 19 July 2022. <www.sciencedaily.com/releases/2022/07/220719091209.htm>.