Genocide in the Genome
In early July, Czech neurophysiologists published the results of a study examining how childhood experiences in Nazi concentration camps affected the brain structure of survivors who lived into the present day. They found that former prisoners had less gray matter in certain brain regions compared to a control group. The researchers also explored the psychological impact of severe childhood stress on the survivors’ children and grandchildren. However, prolonged exposure to life-threatening conditions affects not only neurophysiology and psychology, but can also leave deeper biological marks. Read on to learn more.
The Echo of the Dutch Hunger Winter
In September 1944, the Allies prepared Operation Market Garden to liberate the Netherlands from German occupation. Ahead of the operation, most railway workers went on strike to disrupt ammunition supplies to the German army. The operation failed, and in retaliation, the occupiers imposed a food embargo on the Netherlands, leading to mass starvation and the deaths of about 18,000 people.
After the war ended in May 1945, normal food supplies resumed. Children born during and shortly after the “Dutch Hunger Winter” became the focus of scientists studying the long-term effects of severe stress. A cohort study included 2,414 men and women born between late 1943 and early 1947. Decades later, this group showed a significantly higher risk of cardiovascular disease, type 2 diabetes, breast cancer, and schizophrenia.
It’s not surprising that stress during pregnancy can affect a child’s health—doctors routinely advise expectant mothers to avoid alcohol, smoking, and stress. What’s more interesting is that the children of those affected by the Dutch famine also showed consequences: they had a higher body mass index compared to a control group (notably, this effect was seen only in sons, not daughters).
A 2008 study found that, 60 years after experiencing famine in utero, Dutch cohort members had lower methylation levels in a region of the IGF2 gene (insulin-like growth factor 2). This means that parental stress caused changes in their children’s DNA at the level of epigenetic regulation. It’s possible that this mechanism also affected their grandchildren.
Epigenetics of Trauma
Epigenetic regulation involves changes in gene expression through reversible chemical modifications of DNA bases or histone proteins. The main DNA modification is the addition of a methyl group (-CH3) to cytosine, often in “islands” rich in cytosine-guanine pairs found in gene regulatory regions. Generally, increased methylation reduces gene expression, and vice versa. While epigenetic marks are reversible, they can lead to long-term changes in gene expression, such as during embryonic development or cancer. Alongside protein regulators, these marks determine which genes are active or silent in specific tissues.
The long-term health effects for people born during the Siege of Leningrad—which lasted 28 months and caused far more casualties than the Dutch famine—have not been studied as thoroughly. However, a small study of 169 people born during the siege and 192 born before it found no increased risk of cardiovascular disease or diabetes compared to people of the same age from other regions.
To explain why the Dutch famine had more pronounced long-term effects, British researchers proposed that the “Dutch Winter” was a short, acute stress followed by rapid recovery, while the Leningrad blockade lasted so long that extremely low calorie intake became the norm for children born during that time. Soviet women also had poorer nutrition even before the war. Russian genetic studies suggest natural selection may have played a role: survivors of the blockade tended to have gene variants associated with more efficient metabolism.
Rachel Yehuda, from the Department of Psychiatry at Mount Sinai School of Medicine in New York, has studied Holocaust survivors and their children for years. Many survivors suffer from post-traumatic stress disorder (PTSD), and their children often show symptoms of PTSD and anxiety disorders as well. Children of men who survived Nazi concentration camps had higher blood cortisol levels and reduced sensitivity to glucocorticoid hormones—symptoms also seen in major depressive disorder.
Hypotheses explaining the transmission of physiological effects across generations include both social learning and molecular mechanisms affecting gene expression. It’s easy to assume that traumatized parents pass on their altered worldview to their children, leading to psychological issues. Additionally, traumatized individuals may be less effective parents, exposing their children to emotional or physical abuse.
However, Yehuda’s group conducted a small study to clarify the molecular mechanisms behind observed neuroendocrine changes and to provide an alternative explanation for “inherited trauma” via epigenetics. In a 2015 study, Mount Sinai researchers found that both Holocaust survivors and their children had altered methylation in the FKBP5 gene, which interacts with the glucocorticoid receptor and affects tissue sensitivity to stress hormones like cortisol. Different variants of this gene are associated with psychiatric disorders, including depression and PTSD. Interestingly, parents and children showed opposite changes: parents had increased methylation, while children had decreased methylation, which correlated with higher cortisol levels.
Although the study did not prove causation, the authors suggested that increased methylation in mothers led to chronically low corticosteroid levels, including during pregnancy, which in turn caused compensatory changes in the fetus. Media headlines proclaimed, “You can inherit psychological trauma from your ancestors,” but critics pointed out the small sample size (about 20 per group) and weak correlations.
Despite these limitations, both stories suggest that famine, war, and severe psychological trauma can alter gene function in ways that affect descendants for generations.
Sperm and the “RNA Code”
The impact of adverse environmental conditions on epigenetic marks that persist for generations is well documented in plants, nematodes, and other model organisms. In mammals, much of the evidence comes from rodent studies. In one experiment, young mice separated from their mothers developed depressive behaviors, which were also seen in their sons and grandsons. This behavior was linked to changes in gene methylation in both sperm and brain tissue of the offspring. In mice, social learning likely plays a smaller role than in humans, but it cannot be ruled out entirely.
Another experiment eliminated the possibility of parental teaching: Brian Dias and Kerry Ressler at Emory University trained mice to fear a specific odor (acetophenone) by pairing it with mild electric shocks. The fear response to the odor persisted for two generations. The researchers linked this to epigenetic inheritance: acetophenone activates the Olfr151 gene, and trained mice showed reduced methylation in this gene, which was also seen in their offspring.
As Dias and Ressler wrote, “Inheritance of parental traumatic experience by offspring is a frequently observed but poorly understood phenomenon.” The mechanisms of epigenetic inheritance are not fully understood, but in rodents, changes in methylation and inherited traits have been observed after various exposures—famine, high-fat diets, toxins, and psychological stress.
For first-generation inheritance, changes in fetal physiology can be explained by changes in the mother. But for effects seen in grandchildren, germ cells must be involved. Methylation status in eggs and sperm can change, but it was long thought that these marks are mostly erased after fertilization. Dias and Ressler demonstrated the role of sperm in epigenetic inheritance: artificial insemination of untrained females with sperm from trained males produced “trained” offspring, showing paternal inheritance (similar to the Dutch famine study).
Recently, researchers have focused on small non-coding RNA molecules in sperm, which can interact with DNA and other RNAs to influence gene expression. These include specific microRNAs and fragments of larger RNAs. Injecting RNA from the sperm of mice with a certain coat color (due to an epigenetic modification) into fertilized eggs of wild-type mice produced offspring with the inherited coat color. The diversity of RNA molecules in sperm has led some scientists to propose an “RNA code” that could predict epigenetic effects on offspring.
Extensive animal data suggest that epigenetic inheritance likely exists in humans, but distinguishing it from sociocultural influences is challenging. Ongoing wars and disasters continue to provide material for research. For example, a new project at the University of Zurich is studying Pakistani children who lost their parents, collecting blood and saliva samples for DNA analysis, with hopes of following up with their children in the future.
If trauma can have long-term effects across generations, the question arises: can we fight these effects, and how? As noted in a Neuropsychopharmacology discussion, nearly 500,000 U.S. veterans currently live with PTSD. Thus, epigenetic inheritance poses potential public health challenges and raises not only scientific but also ethical questions.