Genocide in the genome
Does the trauma experienced by a person affect his children and grandchildren
Daria Spasskaya, N+1
At the beginning of July, the results of a study by Czech neurophysiologists who studied how being in a Nazi concentration camp in childhood affected the brain structure of those who survived to our time were published. They were able to establish that the volume of gray matter in some parts of the brain of former prisoners is less than that of people from the control group. The authors of the study were also interested in what psychological impact the strongest stress suffered by a person in childhood could have on their own children and grandchildren. Meanwhile, a long stay on the verge of life and death affects not only neurophysiology and gives not only psychological consequences. Read more about this in our material.
Echo of the Hungry Winter
In September 1944, the Allies were preparing a military operation "Market Garden" to liberate the Netherlands from German occupation. On the eve of the Dutch operation, the vast majority of railway employees went on strike, which was supposed to disrupt the supply of ammunition for the German army.
However, the operation failed, and as punishment for the strike, the occupiers imposed a food embargo on the Netherlands, which led to mass starvation and the death of about 18 thousand people.
Immediately after the end of the war (in May 1945), normal food supplies were resumed. Children born during and for a short time after the "Dutch hungry winter" many years later became the object of close attention of scientists investigating the long-term effects of the stress experienced.
Dutch food stamps
A total of 2,414 men and women born between the end of 1943 and the beginning of 1947 were included in the cohort study. As the surveys showed decades later, the risk of cardiovascular diseases, type II diabetes, breast cancer, as well as schizophrenia was significantly increased in this group.
However, it is unlikely that anyone will be surprised by the fact that the stressful effect on a woman during pregnancy can affect the health of her unborn child - it is not for nothing that doctors recommend expectant mothers to give up alcohol and smoking and be less nervous.
It is more interesting that the children of the Dutch studied were also affected by the effects of the hungry winter. They had a higher body mass index compared to the control group (curiously, this effect only affected the children of male participants, but not women).
As a 2008 study showed, the Dutch from a cohort study 60 years after they experienced hunger while in the womb, the methylation level of the insulin-like growth factor IGF2 gene site was lowered.
In fact, this means that the stress experienced by parents caused changes in the DNA of their children at the level of epigenetic regulation. Perhaps it was by this mechanism that the echo of the hungry winter echoed in their grandchildren.
Epigenetics of trauma
Epigenetic regulation implies a change in gene expression by reversible chemical modification of nitrogenous bases in DNA or histone proteins associated with DNA. The main modification of DNA is the addition of a methyl residue -CH3 to cytosine, most often as part of special "islands" rich in cytosine-guanine pairs. Such islands are found in the regulatory regions of genes.
As a rule, an increase in the level of methylation leads to a decrease in gene expression, and vice versa. Epigenetic labels are reversible, but are often associated with a long-term change in gene expression, which occurs, for example, during embryonic development and malignant transformation of cells. Along with protein regulators, they determine which genes in a particular tissue should be "silent" and which ones should work.
The long-term consequences for the health of people born during the siege of Leningrad, which, unlike the relatively short-term famine in the Netherlands, lasted for 28 months and led to much larger human casualties, unfortunately, were not studied in such detail.
Nevertheless, a small study involving 169 people born directly during the blockade and 192 people born before it did not find among them an increased predisposition to cardiovascular diseases and diabetes compared to people of the same age from other regions.
In an attempt to explain why the famine among the Dutch led to more pronounced long-term consequences, the authors (from the scientific centers of Great Britain) propose, among other things, the following hypothesis. The "Dutch winter" became a relatively short stressful situation against the background of a prosperous existence, which was immediately followed by the restoration of a normal diet. The siege of Leningrad lasted so long that for children born during this period, an extremely low number of calories became a kind of norm. Moreover, according to the authors, Soviet women ate worse than Dutch women before the war.
Domestic genetic studies suggest the contribution of natural selection to this phenomenon: According to scientists from the St. Petersburg Ott Institute of Obstetrics and Gynecology, gene variants associated with more efficient metabolism in general predominate among the blockade survivors.
Rachel Yehuda from the Faculty of Psychiatry at Mount Sinai Medical School in New York has been studying the survivors of the Holocaust - the mass extermination of Jews by the Nazis in the occupied territories for many years. In addition, her research group is studying their children born after the events mentioned.
Many of these people who have been persecuted and tortured suffer from post-traumatic stress disorder (PTSD). According to American researchers, children of Holocaust victims also often have symptoms characteristic of PTSD and anxiety disorders.
Children of men who had been in Nazi concentration camps also had elevated levels of cortisol in their blood (compared with children of Jews not affected by the Holocaust) and decreased sensitivity to glucocorticoid hormones – a symptom observed, in particular, in major depressive disorder.
A diagram of regulatory regions of a gene with methyl tags (Wikimedia Commons).
Hypotheses explaining the transmission of physiological effects across generations include both the role of social learning and molecular mechanisms affecting gene expression.
Speaking of mental disorders, it is easiest to assume that people who have experienced a tragedy talk about it and broadcast the changed perception of the world to their children, which leads to mental disorders in the latter. In addition, people who are traumatized in this way can simply be bad parents and expose children to violence, both emotionally and physically.
Nevertheless, Euda's group conducted a small study that could clarify the molecular mechanisms of the observed neuroendocrine changes and provide an alternative explanation for the "hereditary transmission of trauma" involving epigenetics.
In a 2015 study, researchers from Mount Sinai showed on a small sample of participants by studying blood tests that both the victims of the Holocaust and their children had changed the methylation status of the site in the FKBP5 gene.
This gene encodes a protein that interacts with the glucocorticoid receptor, capable of changing the sensitivity of tissues to corticosteroid hormones (including cortisol, one of the main stress hormones), which help to adapt to stress and affect metabolism. It is known that different variants of this gene are associated with some mental disorders, including depression and PTSD.
At the same time, the changes in parents and children were multidirectional – in parents, the level of methylation of the site was increased, and in children it was lowered. At the same time, a low level of methylation correlated with a high level of cortisol in the blood.
Although this was not shown in the work, the authors suggested that hypermethylation of the FKBP5 site in the mother led to a chronic decrease in the level of corticosteroids in the blood, including during subsequent pregnancy, and this, in turn, led to a compensatory decrease in methylation and increased expression of FKBP5 in the fetus.
According to the results of the study, headlines like "You can inherit psychological trauma from your ancestors" appeared in the press. The high-profile conclusions, in turn, attracted the attention of critics who pointed out the small sample size (about 20 people in each group), the weakness of the established correlations and the limitations of experiments.
Dependence of cortisol concentration in saliva on the degree of methylation of a site in the FKBP5 gene in people whose parents survived the Holocaust (Rachel Yehuda et al / Biological Psychiatry 2015).
Despite the rather shaky connections traced between the experience of PTSD and epigenetics, the conclusions from both of these stories indicate that hunger, war and severe psychological trauma can change the work of your genes in such a way that these changes will affect your descendants (children, and probably grandchildren) years after the events that occurred.
Sperm and the "RNA code"
The influence of unfavorable environmental conditions on epigenetic labels that persist for several generations has been well studied for plants, nematodes and other model organisms. However, we are more interested in mammals, and here scientists have accumulated considerable experience during experiments on rodents.
In one of the studies, mice were separated from their mother at an early age, as a result of which they developed depressive behavior (such mice are less active and more often "fail" various behavioral tests, for example, the one where they are thrown into the water and forced to swim). Similar symptoms were observed in the sons of stressed males, and in their grandchildren.
As the authors of the work showed, depressive behavior was associated with a change in methylation for a number of genes both in the sperm of mice and in the brain tissues of their descendants. In the case of mice, it is implied that social learning contributes less to the mental health of offspring than in humans, although this factor cannot be excluded either.
However, an experiment in which mice were trained to be afraid of a certain smell made it possible to completely eliminate the factor of teaching children by parents. Brian Dias and Kerry Ressler from Emory University School of Medicine in Atlanta (USA) forced mice to associate the smell of a certain substance (acetophenone) with weak electric shocks, as a result of which the smell itself began to cause them a fear reaction. Moreover, the reaction to the smell persisted for another two generations of mice.
The authors of the work in Nature Neuroscience managed to clearly link this phenomenon with epigenetic inheritance. Acetophenone activates a known olfactory receptor that is encoded by the Olfr151 gene. In trained mice, the developed reflex eventually led to a decrease in the level of methylation in this gene, which was preserved in their offspring.
As Diaz and Ressler wrote in the abstract of their article, "inheritance of the traumatic experience of parents by offspring is a phenomenon that is often observed, but has no explanation." Indeed, the mechanisms of transmission of epigenetic labels are poorly understood, although in rodents, a change in methylation accompanied by inheritance of the trait was observed in the case of a variety of effects – hunger, a fatty diet, the effects of toxins, psychological stress.
In the case of inheritance of the trait by the first generation, the change in fetal physiology can be explained by the altered physiology of the mother, as the authors of the work on methylation in Holocaust victims tried to do. However, the transmission of the trait to the second generation (grandchildren) already requires the participation of germ cells.
The status of gene methylation in the egg and sperm cells can be changed, as well as in all other cells of the body. However, until now it was believed that after fertilization, the marks are mostly erased and re-hung as embryonic development progresses.
Diaz and Ressler were able to clearly demonstrate the role of spermatozoa in the process of epigenetic inheritance. They showed that artificial insemination with the sperm of a trained male of untrained females leads to the appearance of "trained" offspring. Thus, the inheritance of the trait occurred on the paternal side (we observed the same effect in the history of the descendants of the hungry Dutch).
In recent years, the role of a new player in the field of epigenetics has been actively discussed – small non-coding RNA molecules that can interact with both DNA and other RNAs and influence gene expression. These may be specific microRNAs or even "clippings" of large RNAs that have other functions (transport, for example).
Apparently, a large number of such molecules are transferred with sperm, which take part in epigenetic regulation. In one of the works, the injection of an RNA fraction from the sperm of mice with a certain coat color due to artificially introduced epigenetic modification into the already fertilized zygote of "wild" mice led to the development of an inherited colored phenotype in the latter.
Inherited phenotype in mice with epimutation in the Kit gene (Minoo Rassoulzadegan et al / Nature 2006).
Sperm contains so many different RNA molecules that some researchers introduce the concept of "RNA code", by changing which it will be possible to predict the epigenetic effect on offspring.
Sperm regions involved in the transfer of non-coding RNAs (Yunfang Zhang et al / Nature Reviews Endocrinology 2019).
A sufficiently large array of data obtained on animals suggests that epigenetic inheritance in humans most likely exists, but it will be very difficult to reliably distinguish its contribution from socio-cultural influence.
However, there are still enough military conflicts and catastrophes on the planet that supply material for research. For example, a new project by researchers from the University of Zurich focuses on Pakistani children who have lost their parents. Scientists collect blood and saliva samples for DNA analysis of children, and hope that many years later they will be able to do the same for their children.
If we recognize that the transferred trams may have long-term consequences affecting several generations, then the question arises as to whether it is possible to deal with them and how. As the participants of the discussion in the journal Neuropsychopharmacology note, today almost 500 thousand participants of military operations with signs of post-traumatic stress disorder live in the USA alone.
Thus, epigenetic inheritance potentially creates problems for public health and raises not only purely scientific, but also ethical issues.
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