Male body weight linked to epigenetic effects in sperm

Differences between the epigenetic marks found in the sperm of lean and obese men have been observed in a small study. Epigenetic marks affect how genes function and can be passed on to children. The differences found by the researchers were in genes associated with appetite, leading them to suggest their findings provide a possible explanation for why obese fathers produce children who are predisposed to obesity. As well as looking at the sperm of 13 lean and 10 obese men, the researchers also looked at 6 men undergoing weight loss surgery, identifying epigenetic changes in their sperm before and after treatment.

 

Dr. John M. Denu, Director, Epigenetics Theme, Wisconsin Institute for Discovery, Professor, Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin (webpage):

Expertise: function of histone and chromatin modification, epigenetics and metabolism

“Donkin and colleagues provide evidence of epigenetic remnants in human sperm that differ between lean and obese individuals. These differences in epigenetic fingerprints are suggested to explain the possible pre-disposition of children of obese fathers to metabolic disorders. While these new data demonstrate there is indeed epigenetic information (small RNAs and DNA methylation) remaining in sperm and that differences among lean and obese individuals tend to track with genes of metabolism and the central nervous system, the study does not demonstrate causation and the sample size is quite small involving only 13 lean and 10 obese men. There are many lifestyle and environmental factors that could explain the differences. For example “obese men exercising more than twice/week were excluded.” So, exercise might explain the difference, as the lean men who exercise often were not excluded. Is this enough information to change the habits of obese, fertile men considering parenthood?

“At the molecular level, it remains to be determined what type of epigenetic information in sperm drives such difference in development or susceptibility to disease in the offspring. In this study, the authors point to DNA methylation and small RNAs, but the possible information contained within the protein modifications on the remaining nucleosomes was not evaluated, and could account for the altered epigenetic instructions.”

 

Dr. Peng Jin, Professor of Human Genetics, Emory University (webpage):

Expertise: functions and mechanisms of epigenetics and noncoding RNAs in neurodevelopment and neurodegenerative disorders.

“Overall this study has presented some interesting findings. By comparing obese to lean as well as pre vs. post-surgery, the data that they present on epigenetic changes are quite robust. The potential caveat could be that the number of samples that they have examined is small. Replication of their findings are certainly needed.

“The authors did observe the differences in DNA methylation marks at locations on the genome related to central nervous system development. Previous research has shown that gene expression and methylation between sperm and brain are generally correlated, so this finding is not a big surprise. However, whether they will alter eating behavior in subsequent generations certainly needs to be further investigated. It will be premature to claim that they could influence such complex behavior with small changes of methylation. They also need to take individual genetic variations into the consideration as well.

“The pre- and post-surgery comparison is particularly interesting, and will have direct implications on how the obesity could alter the epigenomic landscape in sperm. However, we have to be cautious not to over interpret these data. The authors only observe the difference, whether these differences could be translated into observable traits would need to be further examined.”

 

Dr. Christopher Gregg, Assistant Professor of Neurobiology & Anatomy and Human Genetics, University of Utah (webpage):

Expertise: genome analysis and epigenetics with applications to neuroscience and behavior

“The new study by Donkin and colleagues in Cell Metabolism is the first to test whether obesity in males changes epigenetic factors in human sperm. Studies have discovered that in addition to DNA, offspring inherit other material from their parents, some of which is stuck to DNA. We call this extra stuff “epigenetic”, which includes proteins called histones, as well as chemical modifications to DNA (called DNA methylation), and small RNA molecules.

“Overall, the study demonstrates that obesity has little impact on histone retention and small RNA expression in human sperm, but a more substantial influence on DNA methylation. The authors identified 9,081 genes that exhibit DNA methylation differences in the sperm of obese versus lean men. Many of these changes are associated with genes involved in brain development and function. Particularly striking, is the finding that gastric bypass surgery is associated with rapid changes to sperm DNA methylation in obese men. The study does not address whether sperm DNA methylation in lean men also changes over time or whether it is relatively stable, which is an important control that would help to interpret their findings.

“The number of participants in the study is small and the authors do not provide evidence that the observed changes can impact offspring. However, when taken in the context of other studies, the evidence that paternal diet/lifestyle can impact epigenetic factors in sperm is very compelling. The evidence that epigenetic changes in sperm can then impact offspring development is also compelling and has been reported by multiple groups. A recent study in mice that was published in the journal Science by Siklenka and colleagues from McGill University, demonstrated that epigenetic changes in a father’s sperm can impact offspring development for multiple generations.

“This study contributes to the growing and compelling body of evidence from multiple labs that paternal age, lifestyle and exposure to drugs/toxins can impact sperm and offspring. A healthy lifestyle is important for couples planning to have children.”

 

Dr. Sarah Kimmins, Associate Director, McGill Centre for the Study of Reproduction, Canada Research Chair Tier II, Epigenetics, Reproduction and Development, McGill University (webpage):

Expertise: how environmental changes affect the epigenome in development and disease, epigenetic effects of diet and toxins on sperm

“Donkin et al., show for the first time in men that body condition, specifically obesity can influence DNA methylation in sperm and to a lesser extent perhaps the sperm RNA content.

“A remarkable number of genes were identified as differentially methylated in sperm from lean versus obese men. What really stands out is that there were changes in methylation after just 1 week following the surgery. This is this first time that methylation effects have been shown to occur at a late stage in sperm development, emphasizing that they can respond rapidly to environmental changes. The implications for this in terms of having healthy babies are unknown, but it suggests that men need to consider what they put in their bodies and how they live their life as it may have an impact on sperm development and consequently offspring health.

“The impact of obesity on histone proteins, which are specifically retained in a highly predictable manner in sperm, was assessed at very general level. However not addressed in this study was whether specific histone modifications are altered by obesity and associated metabolic disturbances. There is a strong possibility this may indeed be the case based on our knowledge from previous research.

“The authors also speculate that changes in a specific small RNA molecules in sperm from obese men may influence the food intake behavior of offspring. However, whether it is possible for a sperm born small RNA to persist and affect development by altering gene expression in offspring is completely unknown. ”

 

Dr. Diana J. Laird, Associate Professor, Department of Obstetrics, Gynecology and Reproductive Science, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco (webpage):

Expertise: Reproductive system development, environmental exposures

“Although the importance of the womb for many aspects of development have been recognized, it has been assumed that the contribution of fathers is strictly genetic, at least until birth. That view is now changing.

“This study reveals changes in the epigenetic information carried by sperm that correlate with obesity. The researchers compared 13 lean and 10 obese young men, excluding anyone with sperm abnormalities or genetic mutations associated with obesity. They found differences between the two groups in gene regions involved in metabolism and neural development. The authors also examined small RNAs in sperm, finding obesity-associated changes in a particular class that is unique to sperm and eggs, known as piRNAs. Prior work has implicated piRNAs in the inheritance of epigenetic information in model organisms such as fruit flies, so the current finding raises the possibility of this mechanism in humans.

“What does the epigenetic state of sperm in fathers have to do with the prospects for obesity in the children? The speculation is that altered gene expression can “program” metabolism as well as appetite circuitry of the developing fetus, although much work remains to be done in fleshing out the details. A major question that emerges from this work is whether such epigenetic information could be passed to the grandchildren through the sperm. What are the cues, and would the misregulated piRNAs be sufficient to transmit obesity through sperm of mice?

“Although this may all seem depressing, the authors finish by giving us hope that our behavior can prevent obesity in our children. Examining the sperm of morbidly obese men before and after gastric bypass surgery, epigenetic changes were found, many of which matched those differences between the lean and obese cohorts. In all, this work was well executed and leads to some interesting possibilities for identifying markers of metabolic disease risk in sperm.”

 

Declared interests (see GENeS register of interests policy):

No interests declared

 

Reference

Obesity and Bariatric Surgery Drive Epigenetic Variation of Spermatozoa in Humans‘ by Donkin et al., published in Cell Metabolism on Thursday 3 December 2015.

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