Epigenetics, pregnancy and the Holocaust: How trauma can shape future generations

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The Guardian has reported on an epigenetic study in an article titled “Study of Holocaust survivors finds trauma passed on to children’s genes“. It discusses a paper, “Holocaust exposure induced intergenerational effects on FKBP5 methylation“, in Biological Psychiatry. I get excited by teachable moments so I decided to take the opportunity to teach some more epigenetics (see my pages on Facebook or Google+ for my Intro to Epigenetics series).

Epigenetics literally means “over the genome”. It encompasses all meiotically and mitotically heritable changes in gene expression that are not coded in the DNA sequence itself. If we break that down, there are some key points to note:

  • “Not coded in the DNA”: There is no change in the DNA sequence. Thus, for these to be heritable, there must be mechanisms of inheritance besides DNA replication.
  • “Changes in gene expression”: The underlying assumption of all epigenetic studies should be that these changes alter gene expression (or change how inducible or repressible gene expression is, but that’s harder to measure).
  • “Meiotically and mitotically heritable”: This means heritable through cell division, but not necessarily heritable from parent to offspring.

Epigenetics generally refers to 4 mechanisms: DNA methylation (and other modifications to cytosine), histone modifications, non-coding RNAs, and long-range chromatin interactions (3D structure of chromosomes). In this paper, the authors focused on DNA methylation and identified changes in DNA methylation that occur in people who were in a Nazi concentration camp, witnessed or experienced torture, or hid from the Nazis during World War II. Similar changes were seen in their children. This transmission of a trait from parents to children is called intergenerational inheritance.

The effects of severe stress and other exposures has been shown to be inherited intergenerationally, multigenerationally (to grandchildren) and sometimes even transgenerationally (to great-grandchildren), both in animals and in people. The Dutch famine of 1944 and the polybrominated biphenyl exposure in Michigan in 1978 have provided evidence that exposures that occur prior to conception and in utero can have lasting effects on subsequent generations.

However, it is difficult to separate out the different mechanisms that contribute to the inheritance of traits to subsequent generations. Thus, it is an important research question to ask how the effects of trauma, stress and other exposures are passed from generation to generation. This is the question the scientists wanted to address in this paper: is there an epigenetic component to the intergenerational inheritance of the effects of trauma?

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This paper provides direct evidence in humans that the epigenetic effects of pre-conception stress can be seen in both parents and offspring. The authors looked at one specific gene only – FKBP5 – because it is known to be involved in the response to high glucocorticoid levels (a biological signal for stress) and is a possible novel target for antidepressant medication. They looked for changes in DNA methylation in glucocorticoid response elements within this gene. Response elements are sequences of DNA that bind to specific transcription factors and regulate transcription of genes. In this case, glucocorticoid response elements are bound by glucocorticoid hormones and their receptors to regulate expression of the gene containing the response element. They found changes in DNA methylation in these specific elements of the specific FKBP5 gene in Jewish Holocaust survivors and their children, but not in other Jewish people of similar age.

This observed change in DNA methylation of the FKBP5 gene was in the opposite direction in parents and offspring, yet we do not yet have an explanation as to why this change would be different in parents and offspring. Thus, it is actually impossible to say from the results of this paper if these epigenetic changes are due to direct effects of stress and high glucocorticoid levels (or other shared environmental factors) or to inheritance of epigenetic marks.

Let’s say a woman or girl lived through the Holocaust. She and her eggs were exposed to high glucocorticoid levels, and other effects, due to stress. If a woman was pregnant during this time, she, her eggs and her in utero daughters’ eggs were exposed. So that’s 2, and possibly, 3 generations directly exposed to the stress. Until you get to the 4th generation, there is still a possibility of direct exposure. It might be epigenetic, but it is also possible that it’s still a result of direct exposure. Changes must be observed in the generation the great-grandchildren to definitively say that they are epigenetically inherited and not a result of direct exposure. In general, the great-grandchildren are the first generation that was definitely not directly exposed to the stressor. However, in this case, they looked at preconception stress, so looking at the 3rd generation (grandchildren) would be sufficient to differentiate between epigenetic inheritance and direct exposure.

This paper only looks at parents and their children. So the eggs that produced ALL those children were directly exposed (since females are born with all their eggs) to the trauma. It’s possible that high glucocorticoid levels directly affect the methylation of FKBP5 in the eggs as well in cells of the parent. The discussion of the paper itself goes into this, but the article overlooked this point and it’s a really important point to understand if you are interested in epigenetic inheritance.

From the discussion section of the paper:

The main finding in this study is that Holocaust survivors and their offspring have methylation changes on the same site in a functional intronic region of the FKBP5 gene, a GR binding sequence in intron 7, but in the opposite direction. To our knowledge, these results provide the first demonstration of transmission of preconception stress effects resulting in epigenetic changes in both exposed parents and their offspring in adult humans. Bin 3/site 6 methylation was not associated with the FKBP5 risk-allele, and could not be attributed to the offspring’s own trauma exposure, their own psychopathology, or other examined characteristics that might independently affect methylation of this gene. Yet, it could be attributed to Holocaust exposure in the F0.

It is not possible to infer mechanisms of transmission from these data. It was not possible to disentangle the influence of parental gender, including in utero effects, since both Holocaust parents were survivors. Epigenetic effects in maternal or paternal gametes are a potential explanation for epigenetic effects in offspring, but blood samples will not permit ascertainment of gamete dependent transmission. What can be detected in blood samples is parental and offspring experience-dependent epigenetic modifications. Future prospective, longitudinal studies of high risk trauma survivors prior to conception, during pregnancy and postpartum may uncover sources of epigenetic influences.

The paper reports evidence that the epigenetic effects of stress and trauma can be seen in both parents and offspring. However, there are a lot of variables that may cause similar epigenetic changes in parents and offspring. Further studies are needed to really know what the mechanism of these shared epigenetic marks are, before we can confidently assert that the epigenetic changes observed in parents and offspring are due to epigenetic inheritance. As with all good science, this paper answers a question while, at the same time, raising additional questions for future research.

This article appeared in August 2015 in the now defunct Sound of Science blog as was recently reposed to MyScizzle.com, here.

Alison Bernstein a neuroscientist studying the role of epigenetics in neurodegenerative diseases and toxic exposures. She lives in Atlanta with her husband, 2 kids, and 2 cats. You can follow her on Facebook and G+, where she writes as “Mommy PhD”, and on Twitter @mommyphd2.

  • Daniel Goldstein

    We have a much deeper problem here. I agree with all of the comments made, and I am far from certain that the subtle changes observed have meaningful biological significance even if they in fact are not an artifact. The problem, however, applies much more deeply to the issue of epigenetics and environmental impacts, including the effects of so-called toxic stress.

    First- I have no idea what trauma or toxic stress are. I am not advocating that we ignore the adverse effects of stressors on adults or children- I am simply saying that we have no functional definition and no metric to attach to this mythical unicorn of a variable.

    Consequently, parents are left wondering what impact “toxic stress” in their own lives has had on their children, and those who have had stress and are considering pregnancy are wondering whether they should reproduce if one of the parents has been subject to “trauma” or “stress”. Should you have children if you lost a parent, had a severe accident, suffered a serious chronic illness in childhood, have a stressful job, or suffer from anxiety?

    In fact, unlike direct mutations, epigenetic regulation appears to be in part a way to respond trans-generationally to the external environment. If you grow up in a tropical climate you may well develop epigenetic changes which may in fact be function in the tropics- but may be far from ideal when you take a job in an antarctic research facility.

    In short- we seem to be treating epigenetics like we treat mutagenic chemicals- we seem to think we need to avoid anything that causes epigenetic change. In fact- not all change is bad, and WHATEVER environment you are in will seemingly leave an epigenetic signature.

    If various forms of stress do leave an epigenetic impact- is this good or bad? If we go out of our way to shelter our offspring from stressors, no matter how small, are we creating an adverse effect, or are we simply creating a generation far less able to cope with stress (definition issues aside)?

    In short- remember that just as there is no one optimal genome for all circumstances, there is clearly no universally optimal epigenetic signature. Eventually we will likely identify many epigenetic signatures related to disease risk. These may at some point be worth paying attention to from the preventive health standpoint but 1) be do not know what they are, 2) we may or may not know how to change them, 3) it is not likely we can change ONLY selected epigenetic markers when we know them and 4) markers will likely have different impacts on the risks of multiple diseases- and we are only just now beginning to pay serious attention to the problem of over-focusing on a single disease intervention.

    Again, given the nature of the underlying article, I want to emphasize that I am not “pro-trauma”- none of my own family is known to have survived the holocaust. I am not suggesting that we ignore child abuse, neglect, divorce, illness, war or other “trauma”- we already know they “are not good for children and other living things” even if the epigenetic implications are not entirely clear. The flip side- sheltering our children from dealing with any adversity at all, is neither broadly achievable nor likely to produce terribly functional adults in the real and sometimes ugly world we live in.

    What I am saying is that we have developed a new observational tool. Like the first telescope- we are suddenly realizing that there may be spots on the sun- and our initial reaction is “that’s bad!” when in fact it is the normal state of existence. We do not yet have even an approximate understanding of the broad impacts of epigenetic change related to “trauma”/”stress” and it is not appropriate to interpret all observable change as bad. This is, like the immune system, a biological system responsive to the environment- change may consequently be good, bad, or indifferent- and more critically, the net impact of changes may depend to a great extent on the precise environment in which our offspring must function and survive.

    • Vince

      Very good comments Daniel. Thanks for talking the time to write.

    • Eugene Lukjanenko

      my son was taken because i allegedly inherited Holocaust trauma from my dad who is 84. No medical history of me any diseases. Stop antisemites! Alleged Holocaust trauma did not prevent Israel to build one of the best armies in the world and become prosperious country1

      • Mathew

        You are an absolute nut case and you have only yourself to blame for what you have done to justin he hates you with a vengeance for ruining his life

  • David Ashton

    What stress situations other than those of Nazi concentration camps are comparable? Do I detect here yet another politically-driven focus on The Holocaust rather than on the biology of epigenetics?

    • Eric Bjerregaard

      Pol Pot in Cambodia, The long walk China, The Trail of Tears, Genocides in Armenia, Serbia etc, and the Burundi/Rwanda genocide for starters.. There are, unfortunately, plenty of examples.

      • David Ashton

        The Armenian genocide is too far in the past. But an investigation into the biological impacts of many recent examples would be welcome.

        Nathaniel Weyl argued that both the Soviet and Nazi democides were “aristocidal”.

        • nonosh

          My grandparents from both sides of my family were Armenian genocide survivors. I believe there could be room for epigenetic research among the survivors’ descendants.

          • David Ashton

            Good idea – but any takers? Possibly too small a sample and little monetary interest.

          • nonosh

            A volunteer-based group called Armenian DNA Project might be able to look into the subject.

            Info here:
            https://www.familytreedna.com/groups/armeniadnaproject/about

            I’ve submitted my sample to them to add to the pool.

        • Mark Raymond Derderian

          I think epigenetic changes can span many generations. My grandparents experienced the Armenian genocide and I am sure that has a direct psychological impact on me and most likely an epigenetic impact as well.