A recent study reported that changes in microRNAs of spermatozoa of mice caused by aging can affect the growth and development of offspring. The discovery adds to the growing literature on the effects of paternal aging on offspring.
The results of the study were published in the journal Scientific Reports.
Aging of sperm: here's how it affects the development of offspring
Late-life marriage and pregnancy are increasingly becoming the norm. While the impacts of maternal age on offspring, such as a higher risk of miscarriage and Down syndrome, are widely understood, the impacts on the paternal side are less so.
Yet this is changing. Recent epidemiological studies have shown that sperm aging exerts a more substantial influence on increasing the risk of neurodevelopmental disorders such as autism spectrum disorder.
A research team led by Professor Noriko Osumi of the Department of Developmental Neuroscience at Tohoku University's Graduate School of Medicine previously revealed that epigenetic factors, including histone modifications in spermatogenesis and DNA methylation in mouse sperm , undergo changes with age. These alterations could lead to transgenerational effects.
However, the impact of sperm aging on microRNAs (miRNAs), small non-coding RNA molecules that play a crucial role in regulating gene expression, remains poorly explored.
To correct this problem, the same research team conducted a comprehensive analysis of age-related changes in microRNAs in mouse sperm. They compared microRNAs in the sperm of mice aged 3, 12 and 20 months and identified microRNAs that had changed in quantity.
The researchers discovered significant age-related differences in microRNAs. Some changes involved microRNAs responsible for regulating the nervous system and genes linked to autism spectrum disorder, and these altered microRNAs included those transferred into fertilized eggs.
“Our study reveals the potential association between the alteration of sperm microRNAs caused by sperm aging, underlining the importance of investigating the impact of sperm microRNAs on offspring, an aspect that has been relatively overlooked in previous research,” he says Osumi.
The anticipation is that further exploration of epigenetic factors, particularly microRNAs, will not only help unravel the pathogenic mechanisms underlying neurodevelopmental disorders, but will also offer insights into promoting the health and disease prevention of subsequent generations. .
Osumi points out that their study casts a wide net when it comes to exploring the link between paternal age and potential health complications in children. “While age-related changes in oocytes are well documented, attention has predominantly focused on sperm fertility. Recognizing the myriad of epigenetic transformations associated with sperm aging, as exemplified by the microRNAs examined in this study, becomes imperative.”
The findings also gain relevance in the context of Japan's rapidly declining birth rate, making it necessary to incorporate the perspective of sperm-related factors into the advancement of reproductive medicine.
Genetic factors play a role in determining whether children have neurodevelopmental disorders. Maternal exposure to drugs and viral or bacterial diseases can also be harmful.
An epidemiological survey of approximately 6 million people worldwide revealed that advanced paternal age and sperm aging is associated with the development of neurodevelopmental disorders. In other words, the older the parent, the greater the risk the child has of developing disorders such as autism, ADHD and other learning difficulties.
A research team from the Department of Developmental Neuroscience at Tohoku University Graduate School of Medicine has revealed further details about this phenomenon with their recent publication in PLOS ONE.
The research team, led by PhD student Misako Tatehana and Professor Noriko Osumi, performed immunohistochemical analysis of testes in three-month-old mice before performing the same analysis on mice aged 12 months and older.
Tatehana and his team analyzed histone proteins during the 12-step process of spermatogenesis. Histone proteins undergo chemical modifications during spermatogenesis, thus influencing gene expression. More specifically, the team looked at seven methylations and one acetylation.
They cataloged them as epigenetic markers, or changes that affect gene expression without changing the DNA base sequence of the genome itself.
Comparisons of markers between younger and older mice using imaging quantification techniques revealed that the latter had greater amounts of the modified histone protein, H3K79me3. A previous study by Professor Osumi found a correlation between the amount of H3K79me3 in sperm and paternal aging potentially affecting neurodevelopment in humans.
Further research on the topic hopes to develop more effective diagnostic methods for disorders resulting from the risk of advanced paternal age and sperm aging and abnormal vocal communication in puppies, making it a predictive indicator of neural developmental disorders.
The developmental origins of health and disease is a school of thought that focuses on how prenatal factors such as stress and diet affect the development of disease when children reach adulthood.
Experimental evidence indicates that environmental factors influencing parents play a role in reprogramming the health of their offspring throughout their lives. In particular, it is known that parents' low-protein diets are linked to metabolic disorders in their children, such as diabetes.
This phenomenon is believed to be regulated through epigenetics: hereditary changes in which genes are turned on and off without actually changing an individual's DNA. However, until now, the details of this process were unknown.
In their study published in Molecular Cell, a team led by Keisuke Yoshida and Shunsuke Ishii from RIKEN CPR addressed this question in a mouse model and found that a protein called ATF7 is essential for the intergenerational effect. ATF7 is a transcription factor, meaning it regulates the activation and deactivation of genes.
The researchers fed male and female mice normal diets or low-protein diets and then allowed them to mate. They compared gene expression – which genes were activated – in the adult offspring of male mice that ate the two different diets and found that expression differed for hundreds of genes in the liver, many of which are involved in cholesterol metabolism.
However, when they used genetically modified male mice lacking a copy of the ATF7 gene, the gene expression in the offspring did not differ from the expression in offspring whose parents ate a normal diet.
This finding means that a male mouse's diet can influence the health of future babies. Because male mice cannot affect the offspring of pregnant females, the researchers concluded that the most likely scenario was that epigenetic changes occurred in the male's sperm before conception and that ATF7 had a critical function in this process.
Based on this logic, the team searched for and found genes in sperm controlled by ATF7, including those for fat metabolism in the liver and cholesterol production. The experiments revealed that when expectant fathers ate low-protein diets, ATF7 was released and no longer bound to these genes.
This in turn reduced a particular modification to histone proteins, with the net effect that these sperm genes were activated, rather than the normal situation of being deactivated. “The most surprising and exciting finding was that the epigenetic change induced by the paternal low-protein diet is maintained in mature sperm during spermatogenesis and passed on to the next generation,” says Ishii.
Using a mouse model, this sperm study helps explain the molecular details underlying the developmental origins of the theory of health and disease, and the types of nutritional conditions that could lead to lifestyle diseases in children, such as diabetes .
Furthermore, it should now be possible to predict metabolic changes in the next generation by measuring epigenetic changes in identified paternal sperm genes.
“We hope that people, especially those who eat poor diets by choice, will pay more attention to their diets when planning for the next generation. Our findings indicate that diets with more protein and less fat are healthier not only for one's body, but also for sperm and the health of potential children.”
#Aging #sperm #increases #risk #neurological #disorders #offspring
