One of the great dogmas of twentieth-century biology was the strict equivalence between genotype and phenotype, i.e. between the inherited genetic heritage and the characteristics of the resulting organism. Since then, however, it has been shown that environmental factors exert control over gene expression. This is the field of epigenetics, a complex and rapidly expanding area of research in which many elements remain unknown [1]. Some of these modifications are long-lasting, and are passed on from generation to generation, without the basic DNA sequence being altered in any way - this is known as ‘epigenetic memory’. Without going into detail, several mechanisms are at work, one of the most common being methylation, the attachment of a methyl group (a small molecule made up of a carbon atom and 3 hydrogen atoms) to a gene, which will modulate its expression, via enzymes called DNMT (DNA methyl transferases).

It has been shown that external factors, whether social, nutritional or toxicological, influence methylation. While methylation acts as a normal developmental process, controlling cell specialisation from the fertilised egg onwards, it sometimes has pathogenic consequences, as in the inhibition of a tumour suppressor gene. It is at the embryonic stage that epigenetic reprogramming, which at least partially erases previous characteristics, is most active. Stress, smoking, a deficient or excessively fatty diet during pregnancy will, logically, lead to a developmental disorder in the embryo. The lessons learned from the famine in The Netherlands in 1944 following the flooding caused by the German army go much further. Firstly, when they became adults, the children who suffered from this deficiency at the early stage of embryogenesis developed metabolic diseases (diabetes, obesity, cardiovascular disease) that their brothers and sisters did not. Even more surprising, the daughters born to mothers who had suffered famine in turn gave birth to smaller babies, attesting to a transgenerational effect [2]. However, because of the lack of hindsight, we do not know how long this effect can last in the human species, but certain observations in animals point to very long-term consequences [3].

The fact remains that physical exercise, diet or, as we have shown in Cameroon [4], living in the city or in the forest, all have a reversible effect on the genome methylation. Hence, a woman who donates an egg does not give a ‘neutral’ cell untouched by any influence and limited to the genetic sequence that influences the child's somatic characteristics, such as eye or hair colour. Her egg cell, already carrying a parental imprint, will have undergone multiple methylations linked to its ‘exposome’, a concept introduced in 2005, which covers all the risk factors experienced during her life [5], and possibly those of her ancestors.

In IVF with egg donation (IVF-OD), there are no common traits between the gestating mother and the child (who carries the characteristics of its biological mother). However, the implantation of the fertilised egg in her uterus will in turn create a new physical and emotional environment, where other methylations could take place, which in turn would strengthen the neo-maternal bond and influence foetal development. As a result, some testimonies point to a resemblance between mothers and their children born from egg donation, despite their lack of genetic kinship. An anthropological study of intended parents [6] showed that they ‘cobble together’ their own interpretation of epigenetics to convince themselves of this link and ‘naturalise’ their social kinship.  To sum up their point of view, the biological mother, invisible in her anonymity, would ‘only’ pass on the genes, while the recipient would pass on ‘the blood’ and therefore life. Conversely, in the case of surrogacy, the biological parents' entire focus is centred on their own gametes, and the “surrogate” mother is reduced to the status of a carrier in their eyes.

Less is known about the epigenetic role of the paternal gamete, but there is evidence, for example, that methylated DNA in the sperm of obese men who have undergone bariatric surgery is remodelled after the operation [7]. Although certain effects are still highly controversial, such as the transmission of violent psychological traumas [8], such as those experienced by the victims of the Shoah or the Rwandan genocide. Epigenetics is involved in many phenomena, starting with the differences in medical trajectories between identical twins. In the words of P. Medawar, ‘genetics proposes, epigenetics defines’.

We know that pregnancies resulting from egg donation, especially multiple pregnancies, are more risky[9]; for example, the incidence of pre-eclampsia, a condition characterised by high blood pressure, is multiplied by four, rising from 2.8% to 11.2%. And there can be some unpleasant surprises over the course of the child's development. First of all, genetic and epigenetic traits inherited from the biological mother can be revealed at any time, even late in life. In addition, cryopreservation, hyper-ovulation, fertilisation methods or in vitro culture can affect the epigenetic reprogramming of the embryo [10]. Some observations relating to possible cellular stress, with a slight increase in congenital pathologies [11], point in this direction, whether for IVF or ICSI (intracytoplasmic sperm injection [12], to a certain ‘ethical discomfort’ [13]. However, in the current state of science, and notwithstanding the absence of prolonged hindsight, there is reason to assume that quality of lifestyle can repair any damage linked to family history or laboratory procedures.

In conclusion, egg donation and embryo transfer are new processes, created by technology, and therefore totally unprecedented in the evolution of our species, since they short-circuit cases of infertility that natural selection had established. These transplants work nonetheless, because they are in line with the laws of biology and provide a quasi-experimental framework for understanding the mechanisms of ontogenic development, the primary focus of epigenetics. More generally, DOHaD (Developmental Origins of Health and Disease) will be interested by the new configurations offered by third-party donor reproduction, particularly during the key period of 1,000 days from conception. A better understanding of embryonic genesis will follow, and new therapies, ‘epi-drugs’ acting on the epigenome, could result.

Alain Froment, médecin-anthropologue, IRD, Musée de l’Homme, Paris

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Notes

1 De Rosnay J. 2018.. La symphonie du vivant, Comment l'épigénétique va changer notre vie. Ed. Les Liens qui libèrent.

2 Lumey LH et al. 2007. Cohort profile: The dutch Hunger Winter Families Study. Int J Epidemiol. 36: 1196-1204.

3 Giacobino A. 2018. Peut-on se libérer de ses gènes ? L'épigénétique. Stock.

4 Fagny M. et al. 2015. The epigenomic landscape of African rainforest hunter-gatherers and farmers. Nature Communications 30: 10047.

5 Dagnino S. & Macherone A. 2018. Unraveling the Exposome, A Practical View. Springer.

6 Minders J. 2019. Bricolages « stratégiques » : l’épigénétique au secours des liens de parenté.  Anthropologie & Santé [en ligne], 18. URL : http://journals.openedition.org/anthropologiesante/4992.

7 Donkin I. et al. 2016. Obesity and Bariatric Surgery Drive Epigenetic Variation of Spermatozoa in Humans. Cell Metab .9: 369-378.

8 Lehrner A. & Yehuda R. 2018. Cultural trauma and epigenetic inheritance. Dev Psychopathol. 30: 1763-1777. Zammatteo N. 2014. L'impact des émotions sur l'ADN. Editions Quintessence. Perroud N. 2014. Maltraitance infantile et mécanismes épigénétiques. L’Information Psychiatrique 90: 733-739

9 Revue dans EPAIN L. & WILLI A. 2015. Rôle et implication de la PMA dans les phénomènes de programmation fœtale. A lire ici : http://dune.univ-angers.fr/fichiers/20090283/2015MFASMA3700/fichier/3700F.pdf

10 Maher E.R. et al. 2003. Epigenetic risks related to assisted reproductive technologies: epigenetics, imprinting, ART and icebergs? Human Reproduction 18: 2508-2511. Ventura-Juncá P. et al., 2015. In vitro fertilization (IVF) in mammals: epigenetic and developmental alterations. Scientific and bioethical implications for IVF in humans. Biological Research 48: 1-13. Vrooman L. A. & Bartolomei M. S. 2017. Can assisted reproductive technologies cause adult-onset disease? Evidence from human and mouse. Reproductive Toxicology 68: 72-84.

11 Rimm A. A. et al. 2004. A Meta-analysis of controlled studies comparing major malformation rates in IVF and ICSI infants with naturally conceived children. Journal of Assisted Reproduction and Genetics 21: 437-443. Simpson, J. L. 2014. Birth defects and assisted reproductive technologies. Seminars in Fetal and Neonatal Medicine 19: 177-182.

 12Catford S.R. et al. 2018. Long-term follow-up of ICSI-conceived offspring compared with spontaneously conceived offspring:a systematic review of healthoutcomes beyond the neonatalperiod. Andrology 6: 635-653. Hansen M. et al. Assisted reproductive technology and birth defects: a systematic review and meta-analysis. Hum. Reprod. Update 19: 330-353.

13 Roy M.-C. et al. 2017. The epigenetic effects of assisted reproductive technologies: ethical considerations. Journal of Developmental Origins of Health and Disease, 8: 436-442.