December 3, 2015

expert reaction to study investigating epigenetic changes in the sperm of fat and lean men

The effect of a man’s weight on the markers which regulate activity of genes in their sperm is the subject of a paper published in the journal Cell Metabolism, with the authors reporting differences in the profile of such epigenetic markers between lean and obese men, and also following weight loss surgery.

Prof. Wolf Reik, Head of Epigenetics Programme, Babraham Institute, said:

“This is an interesting albeit preliminary study that identifies for the first time epigenetic changes (small RNAs, DNA methylation) in the sperm of obese men. The general interest here is to what extent acquired epigenetic marks (influenced by environment, nutrition etc) can be inherited across generations, influencing the health of our children and grandchildren. Indeed animal studies with altered nutrition (low protein, high fat) have shown that effects on altered metabolism can sometimes be transmitted through the male (as well as female) line to offspring, and DNA methylation and small RNA changes have been implicated in this transmission.

“In humans, it seems that children of obese men have increased risk of developing obesity themselves as well as of autism spectrum disorder. Hence the finding reported here of epigenetic alterations in sperm of obese men is clearly provocative.

“The study should be enlarged in the future as it is based on small numbers, needs validation of identified targets, and is as usual complicated by the fact that genetic factors will also differ between the subjects. Carefully controlled animal studies that probe more deeply into the molecular mechanisms will also be highly welcome and revealing.”

Prof. Vardhman Rakyan, Professor of Epigenetics, Barts and The London School of Medicine and Dentistry, Queen Mary University of London (QMUL), said:

“This is an interesting preliminary study and certainly the biggest so far that has integrated several potential molecular markers in human sperm. The main drawback is that there is no independent replication cohort so it is too early to draw any concrete conclusions. Robust replication seems to be an issue with published mouse studies as well for that matter. In the future, it will be very nice to find molecular perturbations that could link different models or dietary insults.”

Prof. Allan Pacey, Professor of Andrology, University of Sheffield, said:

“This is an interesting study which provides further evidence to support the theory that some characteristics can be passed by sperm from a father to his children, without altering the basic structure of the genetic code. Whilst the study examines a relative small number of individuals, the fact that such significant differences can be found in the epigenetic markers of lean and obese men is intriguing and in my opinion worthy of more detailed investigation. In addition, the fact that changes can be seen in men before and after significant weight loss also adds some validity to the findings.”

“In my opinion, it’s far too preliminary to conclude what these observations may mean for human health and reproduction. There is much work in this area that still needs to be done. But the authors observations are credible and I would encourage them and others to investigate this phenomenon further. Until we know more, would-be parents should just aim to be as healthy as possible at the time of conception and not be drawn to faddy diets or other activities in order to try and influence the health of their children in ways we don’t properly understand.”

Prof. Marcus Pembrey, Emeritus Professor of Paediatric Genetics, Institute of Child Health, UCL, and Visiting Professor, University of Bristol, said:

“The similar correlation between father’s and mother’s BMI and that of their offspring has been a puzzle, given that the mother nurtures the baby in the womb and into infancy. This Dorkin et al paper looks at just one piece of this puzzle. Do sperm carry regulatory molecules – beyond regular genes – that are associated with a man’s obesity per se? They compare sperm from lean and obese men. And, importantly, they also compare the sperm of morbidly obese men before and after they lost weight from stomach surgery.

“This is the first comprehensive epigenetic profiling of human sperm in relation to obesity. They looked for obesity associated changes in small non-coding RNAs and DNA methylation, and although the number of men studied is small, the results are important. The methylation differences between obese and lean men include seven genes already known to be associated with appetite control and obesity. Importantly four of these also show DNA methylation changes following weight loss surgery. This increases confidence in the findings and provides candidate genes for others to attempt replication of these results. Human studies are difficult to do, but this one starts the ball rolling in terms of obesity effects on sperm. The old idea that the sperm are protected from metabolic changes in the body has long been challenged by animal experiments. However, even when some of these results are replicated, showing obesity-related epigenetic changes in sperm is a long way from knowing if these sperm changes contribute to the paternal effect on offspring BMI. But that shouldn’t stop dads setting a good example to his children by keeping his weight in check.

“How robust are the conclusions that obesity per se influences DNA methylation at certain genes in sperm?  The small number of men means that a replicate study that compared lean with obese men is unlikely to get the same top hits in terms of specific genes with significant DNA methylation differences. However, the fact that some of the differential DNA methylation ‘hits’ also came up in the comparison of before and after weight loss surgery strengthens the conclusions with respect to these genes. Furthermore, these genes were already known – robustly – to be involved in appetite and variation in BMI. So there is some coherence with respect to the results. I would expect an independent replication of this study to confirm at least some of the DNA methylation changes at these ‘candidate’ genes in association with obesity.”

‘Obesity and bariatric surgery drive epigenetic variation of spermatozoa in humans’ by Donkin et al. published in Cell Metabolism on Thursday 3rd December. 

Declared interests

Prof. Wolf Reik: No conflicts of interest

Prof. Vardhman Rakyan: I have no conflict of interest other than I work on similar models.

Prof. Allan Pacey: Chairman of the advisory committee of the UK National External Quality Assurance Schemes in Andrology and Editor in Chief of Human Fertility (both unpaid). Also, recent work for the World Health Organisation, Merck Sharp and Dohme Ltd (Finland), Ferring Pharmaceuticals Ltd (paid consultancy with all monies going to University of Sheffield). Co-applicant on a research grant from the Medical Research Council (ref: MR/M010473/1).

Prof. Marcus Pembrey: I cannot think of any conflict of interest, financial or otherwise. I am preparing an MRC grant application at present, but it does not involve analysing sperm or investigating obesity. I do not know the authors.