The latest in fertility research using rodent models

Not only are rodents one the most diverse animal groups alive today, but they have huge value in medical research, continuously improving our lives.

“It’s very interesting that there seems to be in push in some countries to phase out animal experimentation. I don’t think it’s likely to happen and would be very bad if it did.” “So much of our fundamental understanding of biology comes from animal models, which we then apply to technologies in human reproductive medicine. All of the clinical tools we use now originated in animal models – IVF and embryo transfers – all happened first within other animals.” Says Dr Taylor Pini, reproductive veterinarian, from the University of Queensland.

This week we unpack some of the latest rodent-related research that focuses on improving fertility issues in humans.

Frozen testicular tissue still viable after two decades

While the survival rate for childhood cancers has increased in the past few decades, the impact of diminished fertility later in life is still a serious occurring side effect. A potential solution would be to harvest, freeze and reimplant testicular tissue, which contains stem cells, to potential restore fertility. Though we know how long freeze-dried mice sperm can survive in space, up until now, the long-term viability of cryogenically stored sperm has not been tested.

Recently, a new study from the University of Pennsylvania, published in PLoS Biology, has found that male testis tissue from rats cryopreserved for over 23 years contain viable spermatogenic stem cells (SSCs). These were implanted into the testes of mice, which produced all the cell types necessary for sperm production. However, the long-frozen SSCs had made fewer elongating spermatids, which go on to form swimming sperm, compared to SSCs frozen for a few months only. These findings show that viability is not lost during cryopreservation, but that fertility levels may be somewhat impacted from long-term storage, but provide a promising treatment options for young males with cancer who hope to have a family one day.

“Our study showed that rat spermatogonial stem cells can be successfully frozen for over 20 years, transplanted into an infertile recipient animal and regenerate the ability to produce sperm, albeit at a reduced rate.” Says lead author Eoin Whelan, from the School of Veterinary Medicine, University of Pennsylvania.

Dr Fleur Cattrall, a specialist in the field of Reproductive Endocrinology and Infertility, Melbourne IVF comments, “In human onco-fertility treatments, ovarian tissue grafting was once an experimental treatment, but the technique is now considered a standard treatment option. This research is promising and could help improve the reproductive options of boys who have overcome childhood cancers.”

Stress may be associated with fertility issues in women

Research conducted by a team at Tong University published in Endocrinology, have found that by stressing out female rats by exposing them to a recording of a scream for 3 weeks, significantly impacted their reproductive potential.

In general, woman are born with a finite number of eggs in their body, and their ovarian reserve is the reproductive potential left within the ovaries based on the number and quality of remaining eggs. Can stress have an impact on this?

“We examined the effect of stress on ovarian reserve using a scream sound model in rats,” said Wenyan Xi, lead author and PhD at Xi’an Jiao Tong University. “We found that female rats exposed to the scream sound had diminished ovarian reserve and decreased fertility.”

The female rats had a decreased level of rats’ estrogen and Anti-Mullerian hormone levels, that are important for reproductive development. The rats that were exposed to the screaming also had a lower number and quality of eggs and produced smaller litters.

“Based on these findings, we suggest stress may be associated with diminished ovarian reserve,” Xi said. “It is important to determine an association between chronic stress and ovarian reserve because doing so may expand our appreciation of the limitations of current clinical interventions and provide valuable insight into the cause of diminished ovarian reserve.”

“This is an exploding area of research.” says Pini. ”There are a lot of external factors that impact fertility including nutrition and lifestyle. The idea of stress being a significant factor in reproductive health has been around for a long time, but is something hard, if not impossible to test in humans. It’s much easier to test in other animal models.”

How sperm cells drive the evolution of the 3D genome

While we often think about DNA as a double stranded string of information, our two-metre long human genome is extensively folded into a condensed three-dimensional structure that fits into a micron-sized cell. This 3D organization is known as chromosomal folding, and the variation in the folds and loops impacts how genetic information is transcribed and how DNA is replicated.

A group of scientists at the Universitat Autònoma de Barcelona and University of Kent uncovered how the 3D genetic structure of male germ cells has driven evolution within rodents, and potentially other animals. This research, published in Nature Communications, compared the arrangement of genomes of 13 different rodent species, and identified regions that varied significantly, called evolutionary breakpoint regions (EBRs). They found that sperm production is the key behind how the genome regions are reorganised.

“We show that developing sperm cells retain a ‘memory’ of previous genome configurations. There are stretches of DNA that used to be part of a single chromosome in rodent common ancestor but are now located on different chromosomes in mouse – yet these still move close to each other and make physical contact specifically in developing sperm cells” says Dr Marta Farré, from the University of Kent, co-leader in the study.

These dispersed regions of genetic information act like magnets, and attract regions across different chromosomes to fold towards each other in order for the DNA to be transcribed, and sperm produced.

“Strikingly, EBRs were associated with regions that are active in later stages of spermatogenesis, when the developing male germ cells are called spermatids. Rearrangements occurring at EBRs were found to break and rejoin DNA stretches that are physically located close to each other in the spermatid nucleus”, says co-leader Dr Peter Ellis, also from the University of Kent.

In comparison, the DNA responsible for egg production is relatively conserved. This difference might have something to do with the further compaction of DNA to fit into the volume of individual sperm, that might cause fractures in DNA and produce this variation in genomic rearrangements. This shows that sperm development might be a critical factor for driving whole genome evolution.

“This is an interesting study evaluating the 3-D structure of the genome and how this influences chromosomal rearrangements. Given the highly conserved nature of spermatogenesis, the principles may also apply to humans. Not only does this help our understanding of how genomes evolve but also in our understanding of genetic disease.” Says Dr Fleur Cattrall from Melbourne IVF.