May 15, 2016

expert reaction to review article on epigenetics, father’s lifestyle and offspring health

A group of scientists publishing in the American Journal of Stem Cells have looked at the evidence of the contribution of the father’s genes and their modification (epigenetics), environmental and lifestyle factors, and the effects on any offspring.

Dr Sarah Martins da Silva, Consultant Gynaecologist and Honorary Senior Lecturer, Ninewells Hospital and Medical School, Dundee, said:

“The paper is well written, and considers all relevant studies. The authors also acknowledge certain limitations, including potential differences between animal and human models, interpreting conclusions with caution where epigenetic influence is implicated rather than definitively demonstrated, and for the need for further studies.

“However, their review summarises some persuasive data, and highlights that we should be concerned about the impact of paternal age, smoking, drinking and diet on our offspring.

“Given that epigenetic inheritance is potentially amenable to lifestyle changes, this is a really important public health message for dads to-be.

On the other hand, unlike maternal age and BMI, paternal age and BMI are not currently considered criteria for eligibility for NHS-funded fertility treatment. Perhaps this should be re-visited? The concerns that this article raises are not insignificant, including recognition of the important contribution to a pregnancy, and subsequent health of the child, by both parents.”

Dr Helen O’Neill, Embryology, IVF and Reproductive Genetics Group, Institute for Women’s Health, UCL, said:

“While the molecular mechanisms for the causative relationships between exposures and sperm quality need to be further examined, this review highlights the much-needed emphasis for awareness on paternal preconception health.”

Dr Nadja Reissland, who works on maternal stress, depression and fetal development in relation to maternal stress, is Deputy Head of Faculty of Science and Senior Lecturer, Department of Psychology, University of Durham, said:

“This is a good and timely review highlighting the importance of the role of the father for healthy development of the unborn child. Although a number of studies in the review used animal models there are also data cited from human studies. Furthermore, the animal models used are generally well accepted in the experimental literature as being helpful representations of what may happen in humans.

“What are the real world implications of this review? Up till now if things go wrong during pregnancy we’ve mostly thought about the role of the mother – is she under stress, is she not eating well, is she smoking or drinking alcohol? This review shows that fathers also have an important role to play in the healthy development of their child. They also ought to be thinking about living healthily, not smoking, excessively drinking or taking drugs, all of which might have an effect on their genome via epigenetic changes.”

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

“We have known for a while that male age has a small but measurable impact on the health of any children born, which is why when we recruit sperm donors the professional guidance recommends that ideally they should be less than 40 years of age (see Association of Biomedical Andrologists, Association of Clinical Embryologists, British Andrology Society, British Fertility Society, Royal College of Obstetricians and Gynaecologists (2008) ‘UK Guidelines for the medical and laboratory screening of sperm, egg and embryo donors’ (2008). Human Fertility 11: 201-210).

“In addition, it has become clear in recent years that would-be fathers are not as immune from reproductive ageing as they might think, in spite of the occasional septuagenarian celebrity father being applauded in the media. So the best advice to men, in order to maximise their chances of fathering a healthy baby, is also to try and have a family before they are much older than 40. Above this age, we know that attempts at pregnancy are generally less successful (even with a younger partner), rates of miscarriage increase in frequency, and there are measurable increases in the incidence of some disorders (e.g. schizophrenia, autism, and birth defects) in their children.

“However, with regard to the impact of male lifestyle on male fertility and offspring health, the data is less clear in my view. We know from my own work on the CHAPS-UK study that there are relatively few lifestyle effects which have a direct effect on sperm quality and hence fertility. But our understanding of the genetic changes in the sperm of older men or men with different lifestyles (including epigenetic changes) is only really in its infancy and we have a lot more work to do in order to understand whether this is something worth worrying about.

“I think there is a real danger that men (and women) take on too much guilt and burden about their lifestyle when they are trying to start a family. This has the potential to cause significant stresses and strains within the relationship, which in itself is not healthy. I think the best advice to anyone is to try to start a family as early in their lives as possible (modern life permitting) and during the pre-conception period just try and be as healthy as possible. I don’t think men (or couples) should try and start faddy diets or do whacky lifestyle changes. It’s probably a good idea for smokers to try and give up as the chemicals in tobacco or cannabis smoke are quite harmful. But as for everything else, just be sensible and do it in moderation.”

Prof. Alastair Sutcliffe, Professor of Paediatrics, ICH, UCL said:

“This timely review of available evidence, albeit weak evidence, suggests perhaps unsurprisingly that particularly older fathers are at a slightly greater risk of progeny with increased risks of certain disorders such as autism. But nobody needs a license to reproduce and it may well be that the downsides of older fatherhood can be offset by the upsides such as being calmer and economically generally better off to provide for the child. This review does not offer any evidence about this.

“More controversially the review article raises the concern that excessive alcohol consumption in the father leads to a separate risk of so called fetal alcohol syndrome in that child. Here things are less proven and less plausible, and furthermore the article fails to acknowledge that the very phenotype of fetal alcohol syndrome has no agreed definition. Thus it is hard to talk about causation.

“Overall the piece is newsworthy in that it reviews available evidence and reiterates well know epigenetic mechanisms in humans, other mammals and insects, but of course there are many examples of animal studies which have not carried through to human studies as we are much more complicated creatures. But this review does focus on issues whereby paternity can influence the many factors previously largely attributed to maternity and maternal factors. Furthermore, if confirmed by substantial studies in this area both mechanistic and epidemiological, there is a possibility for lifestyle interventions pre-conceptional to reduce some of these putative ill effects in future fathers.”

Prof. Darren Griffin, Professor of Genetics and Director of the Centre for Interdisciplinary Studies of Reproduction (CISoR), University of Kent, said:

“This is largely a review of the literature, some recent, some older, that is nicely written and I’ll certainly recommend it to my students to read. As such however it does not, in itself, present any novel findings. The effects of age, alcohol consumption, diet and toxicants are all considered in the context of DNA methylation, histone modification and micro RNA expression. In truth, a lot of the underlying mechanisms are not known and many of the studies are simply associative.

“The sperm represents the end of a developmental pathway that is essentially a one way cul de sac.  As far as we know, once the sperm is formed there is no chance of alteration, unlike in our other cells, which can repair themselves. As with all things, the message of this paper is “everything in moderation”: don’t drink too much, don’t smoke and don’t expose yourself to too much irradiation. Ageing: well you’re stuck with that.”

Dr Channa Jayasena, Senior Clinical Lecturer in Reproductive Endocrinology, Imperial College London, said:

“We all know that men can father children later in life, but the quality of genetic information passed to their offspring is likely to deteriorate with advancing age. Such a concept is not new, and almost all children born to older dads are healthy. However, this review highlights our increasing awareness of how poorer sperm quality observed in older men may increase the risk of their offspring developing certain disorders.”

‘Influence of paternal preconception exposures on their offspring – through epigenetics to phenotype’ by Jonathan Day et al. published in the American Journal of Stem Cells on Sunday 15 May 2016. 

Declared interests

Dr Sarah Martins da Silva:

Paid employment : NHS Tayside and Allied Health Sciences Partnership (NHS research Scotland).

grant funding: TENOVUS Scotland, MRC.

Memberships: MRCOG, BFS, ESHRE, Scottish Fertility Group.

Decision-making positions: NHS Tayside infertility service lead, NHS consultant Ninewells Assisted Conception Unit.

Other financial interest: Ferring expert advisory board.

Dr Nadja Reissland: “I do not have any interests to declare.”

Prof. Allan Pacey: “Chairman of the advisory committee of the UK National External Quality Assurance Schemes in Andrology, Editor in Chief of Human Fertility and Trustee of the Progress Educational Trust (all unpaid). Also, recent work for the World Health Organisation, British Broadcasting Corporation, Purple Orchid Pharma (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. Darren Griffin: “No conflicts of interest.”

Dr Channa Jayasena: “No interests.”

No others received.