Prolific Research on Azoospermia

Published in August 2024, the article "A novel missense variant in PNLDC1 associated with nonobstructive azoospermia" discusses a new genetic mutation related to nonobstructive azoospermia, possibly causing faulty meiosis and spermatogenesis. The study was conducted by Mouness Rahimian, Masomeh Askari, and fellow genetics researchers.

The article states that approximately half of all infertility cases amongst couples are due to the male partner, the most common form being azoospermia. There are two types of azoospermia, obstructive (OA) and nonobstructive (NOA). This article focuses on nonobstructive, which has been associated with a number of genes. Through testing mice, the research team discovered that missing the PNLDC1 protein reduces testis size and causes infertility. In humans, the PNLDC1 gene is highly expressed in spermatocytes and having a mutated gene for the PNLDC1 protein results in NOA.

The bulk of the research involves clinical investigation of three men, all of whom were brothers, whose parents are first cousins. Blood samples were drawn, and then DNA isolation and sequencing was completed. A protein model for PNLDC1 was also created. The provided pedigree in the article shows that the infertile men received two copies of mutated recessive allele of the PNLDC1 gene. Siblings who were fertile had two wildtype alleles. A physical exam and karyotype analysis of the men showed normal results.

This was a recent publication that I personally found very interesting due to the clinical investigation subjects, who were all products of a consanguineous marriage. This resulted in three of the couple's children receiving mutated copies of a gene, which were seemingly recessive. This really goes to show that inbreeding depression is real, possible, and detectable even among a population as large and diverse as humans. 

Another great reminder from this article--mutated genes make mutated mRNA, makes mutated proteins, makes mutated phenotypes. One single mishap in the DNA can be fatal. In this case, one missense mutation in a single gene results in infertility or other spermatogenic failure disease. While not so sure if this single gene is the cause of NOA, there is strong reason to believe that the gene and NOA are related.

ARTICLES:

https://link.springer.com/article/10.1007/s12041-024-01478-6
https://www.hopkinsmedicine.org/health/conditions-and-diseases/azoospermia#:~:text=Azoospermia%20is%20the%20medical%20term,sperm%20production%20by%20the%20testis.
https://www.rcsb.org/

Sons or Daughters?

In an article posted by Science daily,  a scientist, Corry Gellatly, claims that a undisclosed gene carried by the male sperm is the reason why a couple produces a boy or girl baby. The idea behind the New Castle University scientist, is that the men inherit the tendency to have more sons or daughters from there parents. If the man has more brothers compared to sisters than it is likely that he will have more sons than daughters and vice versa. This idea was tested using 927 family trees and over 550,000 people. Scientifically, we know that men carry the X(male) and Y(female) chromosome while the female carries the X chromosome. If we end up with an XY then a male baby is produced and an XX produces a female. Gellatly's theory hypothesizes "that men carry two different types of alleles in which three combinations could possibly occur which control the ratio of the X and Y sperm".
They first combination is called "mm" and concludes that if there are more Y sperm than you end up with more male sons. The opposite is also true in which if we have more X sperm than we end up with more daughters. He calls this "ff". The last possibility is referred to as "mf" which produces equal amounts of sons or daughter because it has equal amounts of X and Y sperm. I find this article fairly interesting that we are coming very close to predicting whether someone will be having a baby boy or girl based upon family history.

The Genes You Inherit from Your Father Could Alter Your Metabolism

Recently there has been research done on mice that shows male mice carry RNA that can alter the metabolism of their offspring.  Usually DNA is the only sequence that can pass a trait from generation to generation. The research that has been done proved this wrong.  There are different factors in a male mouse that can affect the metabolism of its offspring including, diet and even stress levels. Researchers cannot figure out how the offspring can inherit the metabolic attributes of the father. They believe that it could be DNA that was chemically altered.

New research has brought tRNA into the picture.  In one study, a genomicist fed mice a low protein diet and the results showed that there was an increase of activity of the genes that are associated with cholesterol and lipid metabolism.  The researchers analyzed the sperm of the low protein diet mice and they discovered many different types of tRNA.  It was believed that the mice attained most of the tRNA when the sperm was passing through the epididymis.  Another study that was done compared the diet of male mice.  One group of male mice was fed a high-fat diet, while the other group of male mice was fed a low-fat diet.  They took sperm from both groups and injected it into an unfertilized egg.  The researchers then tracked the metabolic performance of each group’s offspring.  They made sure that the offspring were eating a normal diet, and ran tests on each.  The offspring of the high-fat fathers remained lean, but it was discovered that these mice had two abnormalities that are usually found in those that eat only a high-fat diet.  They found an abnormal absorption of glucose and insensitivity to insulin.  Both of these studies link the father's diet to its offspring.  The article finished by asking questions about more research.  Can they reverse these effects with diet? More research needs to be completed.

Here is another article about other research that has been done.

I was really shocked when I read this article.  This could be the link to why obesity occurs in humans. I believe that research needs to be done that does the same in humans. If they discover how to reverse this gene and reduce the abnormalities, then they could reduce the amount of people that become diabetic from inherited genes.

Fathers May Pass Down More Than Just Genes

In 2013, an obese man went to a hospital in Denmark to get his stomach stapled. It was a normal bariatric surgery, with one exception. The man donated a sperm sample a week before the procedure, then a week, after the procedure, then donated a third sample a year after the procedure. 

Scientists were determined to prove an interesting hypothesis: if a man's experiences can alter his sperm, and ultimately alter his offspring. This is a controversial idea, because the standard belief about heredity is that parents pass only genes down to their children. Genes that predispose children to factors like obesity, stress, or cancer, or they don't. Whether one's parents were actually obese or anxious does not rewrite the genes. 

But, in the past few years, a number of animal experiments have challenged this conventional understanding of heredity. For example, in 2010 Dr. Romaine Barres of the University of Copenhagen fed male rats a high-fat diet then mated them with females. Compared to male rats fed a regular diet, the high-fat rats fathered offspring who tended to gain more weight, develop more fat and have trouble regulating insulin levels.

Eating a high-fat diet was just one factor that could alter a father's offspring. High levels of stress have been thought to affect the offspring, too. Male rats exposed to stressful environments, such as smelling the odor of a fox, will father offspring with a dampened response to stress. 

Scientists have taken a close look at sperm to determine the link between a father's experiences and his offspring's biology. Genes are regulated by molecules called epigenetic factors. These molecules can respond to environmental influences and silence or activate certain genes as needed. Some studies have suggested that changes to epigenetic factors can be passed down to offspring. 

Dr. Tracy Bale, a neuroscientist at UPenn, examined the sperm of stressed rats and saw unusual levels of epigenetic molecules called microRNAs. Scientists have only started to investigate the epigenetics of fatherhood. The studies have been influential, but not clear-cut. 

Dr. Barres investigated the potential link between epigenetic differences of children with obese fathers vs. lean fathers. He collected sperm from ten obese Danish men and thirteen lean ones. They found numerous epigenetic differences, including the molecular caps that are placed on DNA in a process called methylation. He found more than 9,000 genes in which the methylation pattern differed between obese and lean men. 

After this finding, they recruited six obese men getting bariatric surgery to see if losing weight changes this pattern. Dr. Barres and his colleagues identified about 4,000 genes that were methylated differently a year after the surgery. These epigenetically altered genes are genes that control behavior such as appetite control. The new study does not prove that these changes have any affect on the father's children. Next, they will study the father's sperm and the pattern of the offspring's blood cells, to get a deeper understanding. To prove this finding, there must be more studies with many more people, such as hundreds, to prove this effect. 

I think this study is very interesting, it is something I never thought about before. I definitely have the standard belief about heredity, that genes are only passed on to offspring, not experiences. But after reading this article and thinking about the causes and effects, people always say that addiction "runs in the family." A person would not be addicted to something if they never tried alcohol, or a drug, so wouldn't we say that addiction is inherited by the parent's lifestyle? I don't have the best understanding of addiction or how it comes about, but if someone drinks on a daily basis and feels like they need alcohol, it is accepted by many people that the children can have an addictive personality too. So, why is it hard to believe that if a parent eats uncontrollably, and is ultimately addicted to food, will have the same effect on children just like alcoholism does? I agree that more studies need to be done to prove this, but I believe that a parent's (not just a father's) experiences and habits can be passed down to their offspring after reading this article.

A new study reveals that a man's sperm can "know" how lean or obese they are.  Their observations suggest that men can pass down information about the availability of food to their offspring which could increase the child's chance of being overweight.  For example, in a 1944 famine in the Netherlands, women who were pregnant had higher chances to give birth to a child who is prone to diabetes and obesity.  It is hard to say that the results they received are perfect due to the genetic differences of the patients in the study, but the results do coincide to a number of other studies.

Romain Barres, a genetic scientist from the University of Coppenhagen, and his colleagues conducted this study with 13 "lean" men with a median body mass index (BMI) of 23, and 10 "obese" men with a median BMI of 32.  To further explain BMI, a man who is 180 cm and 75 kg has a BMI of 23 and a man of the same height who has a BMI of 32 weighs 104 kg.  The scientists then obeserved different epigenetic markers of the patients sperm.  What they found were that the gene methylation patterns of the sperm differed between the two groups of men.  Gene methylation is a determining factor in whether or not a gene is turned on.  About 9000 genes were found to be methylated depending on the group, lean or obese, the patient was in.  Most of those genes were related to brain development, appetite control, and metabolism.

To further explain whether weight loss will or will not affect a persons epigenetic markers they ran an experiment with six men who are about to undergo gastric bypass surgery.  Prior to surgery the scientists collected sperm samples and then another sample a week later.  Their results show that epigenetic changes can happen very quickly because of the differences in methylation in 1509 genes.  A year later when their weight reached a stable level another sample was collected and they found 3910 gene changes. 

Egg Being Fertilized By More Than One Sperm In Birds?

Birds' eggs are fertilized by more than one sperm, a process called polyspermy.  Studies have shown that more sperm in an egg is correlated with more viable offspring.  In birds, when more sperm fertilize an egg, the developing chick will make it full term before hatching as opposed to eggs with less sperm that are more likely to die during development.  In humans, polyspermy is very uncommon but does occur on occasion.  Many times, in humans, polyspermy leads to the death of the developing baby due to complications during meiosis because of all the extra chromosomes that are made.  It is still unknown why birds have to have more than one sperm fertilize their eggs, but future studies may find a better understanding to explain this.  This is very interesting because of how polyspermy varies from species to species.  If humans were to survive after undergoing polyspermy in utero, how would they look, or function? 

To read the article publised by the New York Times on birds and polyspermy, click HERE

Fathers Sperm May Hold Clues to Autism Risk

          Autism is a disorder that causes social, communication, and behavioral challenges. According to a recent study, a fathers sperm may hold clues about whether or not his children could be at an increased risk for autism. Although many experts believe autism is inherited, there is no genetic test to assess the risk of autism.

          Scientists wanted to learn what happens before someone develops autism. To do this, researchers tested the sperm of 44 fathers of children with early signs of autism. As a result, they discovered 193 sites, many involved in brain development, where the presence or absence of an epigenetic tag was related to autism. They also found that 4 of the 10 sites that were closely related to autism were located closely to genes that were associated to prader-willi syndrome, a disorder that causes the same behavioral symptoms as autism. Researchers say that several of the altered epigenetic patterns were found in the brains of people with autism, supporting the theory that they might be related to autism.

          I find it interesting that a disorder such as autism is able to be diagnosed just by looking at the fathers sperm, especially since it is a disorder that doesn't really show up until early childhood. Hopefully, doctors and researchers will look more into this study and be able to find the exact cause of autism.


Original Article

Study turns skin tissue from infertile men into early-stage sperm cells

Scientists have currently turned skin tissue from infertile men into early-stage spermcells in a study that raises hopes for new therapies for the condition. It is said that about 1% of men cannot make any sperm, a condition known as azoospermia, while a fifth of men have low sperm counts

The success of this was actually unexpected and has surprised many scientists. Most scientists thought that it was impossible for infertile men to make any sperm, but this breakthrough has defied those odds. Most of the men that took part in the study had many genetic defects on their Y sex chromosome which meant that they could not produce healthy sperm. In this study researchers took skin cells from three infertile men and converted them into stem cells, which can actually grow into almost any tissue in the human body.

Cyril Ramathal of Stanford University said, "What we found was that cells from men who did not possess sperm at the time of clinical observation were able to produce the precursors for sperm.”

The study found that the skin cells from the infertile men grew into fewer early-stage sperm cells than cells taken from normally fertile men. Even though this research has just started scientist suspect that the converted skin cells might have grown into mature sperm cells if they had been transplanted into the infertile men's testes. If this suspicion is confirmed then it would be possible to restore male fertility by taking the skin cells of men and turning them into stem cells.

This is a great discovery and I think that the research for this should continue. Infertility in men seems to be growing and is a tragic thing. So, this study will definitely help those men that are completely infertile.

Protein Essential for Fertilization Discovered

Fertilization occurs when an egg and a sperm recognize each other and fuse together to form an embryo. In 2005, the Izumo protein, coded by the IZUMO-1 gene, was discover as the protein displayed on the sperm that recognizes the egg. But the protein on the egg that gets recognized was never known, until now. The  is Juno protein named after the Roman Goddess of fertility and marriage. Scientist found the Juno protein by making artificial Izumo proteins and using it to find where it binds best on the egg. Then the scientists from the Wellcome Trust Sanger Institute tested the affects of the absence of these proteins in mice and saw that it made them infertile. This interaction was so hard to find because it is a very weak interaction and also once fertilization occurs, the Juno protein becomes undetectable. This explains why once the egg is fertilized by one sperm cells, it shuts down its ability to recognize other sperm.
         This new information is extremely helpful. This can broaden the treatment of infertility in women. Doctors can finally examine the eggs of infertile women to determine if it is because of the lack of the Juno protein. Also this can create new forms of birth control which could maybe deactivate the Juno protein for a period of time.

Man Allegedly Fathered Over 600 Children

Talk about disrupting normal gene flow! A british man who owned a fertility clinic in Great Britain has allegedly fathered over 600 children by giving women who entered his clinic his own sperm. Bertold Weisner and his wife apparently owned a clinic during the 1940's and helped roughly 1,500 women conceive during that time. DNA tests were done to many individuals and the results indeed showed that all the men were conceived using Weisner's sperm. Two men, Barry Stevens and David Gollancz, both took part in the study and both were found to share very strong genetic similarities with Weisner, enough to prove that he was both of their fathers. Both men, whoa also aided in conducting the study took into account the number of chances there would be for twins, miscarriages, and found that Weisner most likely father between 300 and 600 children or births using his own sperm. 18 people who were conceived during the time of the clinic (1940s-1960s) were tested and it was found that about 2/3 (about 66%) of them were related to Weisner. The part of this story that makes it even more interesting is that his wife apparently destroyed all records from their clinic and Weisner, the man behind all the children, died almost 40 years ago. It is thought that since it was the time of Eugenics, this was socially accepted by many people.

At the time, it was thought to be a good idea that successful people (smart, fit, etc) should reproduce or be responsible for more children while those on the opposite side of the spectrum should be discouraged from doing so. UK law now bans anyone from donating more than 10 samples of sperm, and interestingly there are no similar or equivalent laws in the United States.

Tough Nut to Crack

Ever since we were taught the basics of family health, contraception was always stressed by our teachers. Now, recent studies find that it is not condoms that are keeping couples from procreating, it is men themselves. In this article, David Freedman explains about the ever so rapidly changing world has taken its toll on recent generations of sperm quality. The change in daily activities, dietary habits, drugs, and alcohol abuse has led to a worldwide decline in sperm efficiency. In vitro fertilization (IVF) has become more popular with couples worldwide, which is a hot button moral debate. What does this mean for the future? Men need to change their habits, or thi decline will continue.