Adverse experiences can change future generations through epigenetic pathways.
By Rachel Yehuda, July 1, 2022
After the twin towers of the World Trade Center collapsed on September 11, 2001, in a haze of horror and smoke, clinicians at the Icahn School of Medicine at Mount Sinai in Manhattan offered to check anyone who'd been in the area for exposure to toxins. Among those who came in for evaluation were 187 pregnant women. Many were in shock, and a colleague asked if I could help diagnose and monitor them. They were at risk of developing post-traumatic stress disorder, or PTSD—experiencing flashbacks, nightmares, emotional numbness or other psychiatric symptoms for years afterward. And were the fetuses at risk?
My trauma research team quickly trained health professionals to evaluate and, if needed, treat the women. We monitored them through their pregnancies and beyond. When the babies were born, they were smaller than usual—the first sign that the trauma of the World Trade Center attack had reached the womb. Nine months later we examined 38 women and their infants when they came in for a wellness visit. Psychological evaluations revealed that many of the mothers had developed PTSD. And those with PTSD had unusually low levels of the stress-related hormone cortisol, a feature that researchers were coming to associate with the disorder.
Surprisingly and disturbingly, the saliva of the nine-month-old babies of the women with PTSD also showed low cortisol. The effect was most prominent in babies whose mothers had been in their third trimester on that fateful day. Just a year earlier a team I led had reported low cortisol levels in adult children of Holocaust survivors, but we'd assumed that it had something to do with being raised by parents who were suffering from the long-term emotional consequences of severe trauma. Now it looked like trauma leaves a trace in offspring even before they are born.
In the decades since, research by my group and others has confirmed that adverse experiences may influence the next generation through multiple pathways. The most apparent route runs through parental behavior, but influences during gestation and even changes in eggs and sperm may also play a role. And all these channels seem to involve epigenetics: alterations in the way that genes function. Epigenetics potentially explains why effects of trauma may endure long after the immediate threat is gone, and it is also implicated in the diverse pathways by which trauma is transmitted to future generations.
The implications of these findings may seem dire, suggesting that parental trauma predisposes offspring to be vulnerable to mental health conditions. But there is some evidence that the epigenetic response may serve as an adaptation that might help the children of traumatized parents cope with similar adversities. Or could both possible outcomes be true?
IN THE AFTERMATH
My first encounter with intergenerational transmission of trauma was in the 1990s, soon after my team documented high rates of PTSD among Holocaust survivors in my childhood community in Cleveland. The first study of its kind, it garnered a lot of publicity; within weeks I found myself heading a newly created Holocaust research center at Mount Sinai staffed largely by professional volunteers. The phone was ringing off the hook. The callers weren't all Holocaust survivors, though; most were the adult children of Holocaust survivors. One particularly persistent caller—I'll call him Joseph—insisted that I study people like him. “I'm a casualty of the Holocaust,” he claimed.
When he came in for an interview, Joseph didn't look like a casualty of anything. A handsome and wealthy investment banker in an Armani suit, he could've stepped off the pages of a magazine. But Joseph lived each day with a vague sense that something terrible was going to happen and that he might need to flee or fight for his life. He'd been preparing for the worst since his early 20s, keeping cash and jewelry at hand and becoming proficient in boxing and martial arts. Lately he was tormented by panic attacks and nightmares of persecution, possibly triggered by reports of ethnic cleansing in Bosnia.
Joseph's parents had met in a displaced-persons camp after surviving several years at Auschwitz, then arrived penniless in the U.S. His father worked 14 hours a day and said very little, never mentioning the war. But almost every night he woke the family with shrieks of terror from his nightmares. His mother spoke endlessly about the war, telling vivid bedtime stories about how relatives had been murdered before her eyes. She was determined that her son succeed, and his decision to remain unattached and childless infuriated her. “I didn't survive Auschwitz so that my own child would end the family line,” she'd say. “You have an obligation to me and to history."
We ended up talking to many people like Joseph: adult children of Holocaust survivors who suffered from anxiety, grief, guilt, dysfunctional relationships and intrusions of Holocaust-related imagery. Joseph was right—I needed to study people like him. Because those who were calling us were (in research-speak) self-selecting, we decided to evaluate the offspring of the Holocaust survivors we had just studied in Cleveland. The results were clear. Survivors' adult children were more likely than others to have mood and anxiety disorders, as well as PTSD. Further, many Holocaust offspring also had low cortisol levels—something that we had observed in their parents with PTSD.
FIGHT, FLIGHT—OR FREEZE
What did it all mean? Unraveling the tangle of trauma, cortisol and PTSD has occupied me and many other researchers for the decades since. In the classic fight-or-flight response, identified in the 1920s, a threatening encounter triggers the release of stress hormones such as adrenaline and cortisol. The hormones prompt a cascade of changes, such as quickening the pulse and sharpening the senses to enable the threatened person or animal to focus on and react to the immediate danger. These acute effects were believed to dissipate once the danger receded.
In 1980, however, psychiatrists and other advocates for Vietnam War veterans won a prolonged struggle to get post-traumatic stress included in the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III). It was the first official recognition that trauma could have long-lasting effects. But the diagnosis was controversial. Many psychologists believed that its inclusion in the DSM-III had been politically, rather than scientifically, driven—in part because there were no scientific explanations for how a threat could continue to influence the body long after it was removed.
Complicating matters, studies of Vietnam veterans were generating perplexing results. In the mid-1980s neuroscientists John Mason, Earl Giller and Thomas Kosten of Yale University reported that veterans with PTSD had high levels of adrenaline but lower levels of cortisol than patients with other psychiatric diagnoses. Because stress usually causes stress hormones, including cortisol, to rise, many researchers, including myself, were skeptical of these observations. When I joined the Yale laboratory as a postdoctoral fellow a year later, I studied a different group of veterans using other methods for measuring cortisol. To my astonishment, I replicated the finding.
I still couldn't believe that the low cortisol levels had anything to do with trauma. Surely the Holocaust was as terrible as the Vietnam War, I reasoned—and growing up as a rabbi's daughter in a community full of Holocaust survivors, many of them my friends' parents, I'd noticed nothing out of the ordinary about them. I was sure that they didn't have either PTSD or low cortisol, I told my mentor, Giller. “That's a testable hypothesis,” he responded. “Why don't you study that, instead of conjecturing?"
So my team of five people landed in Cleveland, along with a centrifuge and other equipment. We stayed in my parents' home, walking door to door to interview people by day and returning to test blood and urine samples in the evening. When the results came in, they were clear: half the Holocaust survivors had PTSD, and those with PTSD had low cortisol. There was no question about it—even if the traumatic experience was long ago, PTSD went hand in hand with low cortisol.
But why? And which came first? An important clue came from a 1984 review by Allan Munck and other researchers at the Geisel School of Medicine at Dartmouth. They noted that among stress hormones, cortisol played a special, regulatory role. High levels of stress hormones, if sustained for a long time, harm the body in multiple ways—weakening the immune system and increasing susceptibility to problems such as hypertension. But in a context of acute trauma, cortisol may paradoxically also have a protective effect. It shuts down the release of stress hormones—including itself—reducing the potential damage to organs and the brain. Such a trauma-induced feedback loop could conceivably reset the cortisol “thermostat” to a lower level.
I picked up another piece of the puzzle and placed it. In the early 1990s we'd shown that Vietnam veterans were more likely to develop PTSD if they'd been abused as children. Slowly a shape was emerging that connected intense childhood adversity—a period of “freeze” because a child usually cannot fight or flee—with low cortisol and the possibility of future PTSD. We studied people who'd been raped or who'd been in auto accidents when they came into emergency rooms, finding that those with lower cortisol levels were more likely to develop PTSD after the attack or accident.
Could low cortisol levels have been present before the event that brought them into the emergency room? I wondered. If someone with low cortisol was subjected to a traumatic experience, we reasoned, the cortisol levels in their bodies might be too low to tamp down the stress reaction. Adrenaline levels might then shoot way up, searing the memory of the new trauma into the brain—from where it might later surface as flashbacks or nightmares. Perhaps low cortisol marked a vulnerability to developing PTSD.
The study of Holocaust offspring supported this conjecture. Children of Holocaust survivors with PTSD tended to have low cortisol even if they did not have their own PTSD. As we'd suspected, low cortisol seemed related to vulnerability to PTSD.
THE FEEDBACK LOOP
But what mechanism connected trauma exposure to low cortisol to future PTSD? We began a series of studies to answer this question. Significantly, we found that Vietnam veterans with PTSD had a greater number of glucocorticoid receptors. These are proteins to which cortisol binds to exert its diverse influences. That suggested a greater sensitivity to cortisol: a small increase in the hormone's concentration would precipitate a disproportionate physiological reaction. But it wasn't until we looked more closely at the molecular underpinnings of cortisol functioning—in part by examining epigenetics—that we understood how exposure to trauma might reset the cortisol feedback loop.
In the 1990s scientists were realizing that the output of our genes is sensitive to factors not written directly into our genetic code. Genes provide the templates for producing proteins. But much like cakes baked using the same ingredients may turn out differently depending on variations in the oven's temperature, how much of those proteins gets produced, or “expressed,” depends on the environment. The discovery gave rise to epigenetics, the study of what influences gene expression and how. It proved crucial to understanding both the neurobiology of PTSD and the intergenerational effects of trauma.
Epigeneticists explore the switches that turn gene expression on and off. One such mechanism, called methylation, involves a methyl group—a methane molecule that is missing one of its four hydrogen atoms, leaving a chemical bond free to attach to another atom or molecule. Methylation is a process by which, in the presence of specific enzymes, methyl groups attach to key sites on a strand of DNA or within the complex of DNA and proteins known as chromatin. By occupying these sites like roadblocks on a highway, methyl groups can alter transcription, a basic step in gene expression where a piece of RNA is made from a DNA template. Increased methylation generally impedes RNA transcription, whereas less methylation enhances transcription. These changes are enduring in that they survive normal cell division and require specific enzymes for their removal.
In 2015 our group became one of the first to pinpoint epigenetic changes on stress-related genes of veterans with PTSD. These alterations partially explained why trauma's effects were so persistent, lasting for decades. Specifically we observed reduced methylation in an important region of NR3C1, a gene that encodes the glucocorticoid receptor, likely increasing the sensitivity of these receptors.
This epigenetic modification suggests a potential explanation for how trauma might reset cortisol levels. The body regulates the stress response through a complicated feedback mechanism. A rise in cortisol levels will prompt the body to produce less of the hormone, which may drive up the numbers and responsiveness of glucocorticoid receptors. Given the epigenetic and other changes occurring with sustained responses to trauma, the feedback loop might become recalibrated. In people who have already endured trauma, their stress systems might be sensitized and their cortisol levels diminished—increasing their adrenaline response to further trauma and leading to PTSD.
EPIGENETIC INHERITANCE
Could some of these epigenetic changes in trauma survivors also be found in the children of trauma survivors? Finding low cortisol in the 9/11 babies back in 2002 had told us that we'd been thinking about some things all wrong. We'd assumed all along that trauma was behaviorally transmitted: Joseph's problems seemed to result from the stressful, bereaved atmosphere in his childhood home. But now it looked like the uterine environment also played a role. So did the sex of the traumatized parent.
In our early studies of Holocaust offspring, we had selected only those people with two parents who were Holocaust survivors. We redid the studies to figure out if the sex of the parent mattered—and it did. Those whose mother (or both parents) had PTSD tended to exhibit lower cortisol levels and showed evidence of more sensitive glucocorticoid receptors. In contrast, those whose fathers, but not mothers, had PTSD showed the opposite effect.
Taking a closer look, we again discovered lower methylation within the glucocorticoid receptor gene, NR3C1, in Holocaust offspring whose mothers, or both parents, had PTSD. These changes mirrored what we'd observed in the maternal survivors themselves. But in offspring with only paternal PTSD, we observed more methylation—the opposite effect. These findings raised the possibility that PTSD in mothers and fathers might lead to different epigenetic changes on the glucocorticoid receptor in children.
In a second series of studies beginning in 2016, we examined methylation within another gene, FKBP5, which encodes a protein involved in regulating the ability of the glucocorticoid receptor to bind cortisol. The findings showed related methylation patterns within the FKBP5 gene in both Holocaust parents and their children. But because of the small number of participants in that study—by this time it was difficult to find many living Holocaust survivors who could participate with their offspring—we couldn't examine how factors such as the parents' PTSD status might contribute to FKBP5 methylation.
We were able to replicate and extend this work in a substantially larger sample of just the Holocaust offspring, however. In 2020 we reported lower levels of FKBP5 methylation in the adult children whose mothers—and not fathers—were exposed to the Holocaust during childhood. This effect was independent of whether the mother had PTSD or not. It suggested that trauma might have affected the mothers' eggs decades before her children were conceived, while she was herself a child.
Given the obvious difficulties in studying generations of people, scientists often resort to animal studies to explore epigenetic transmission. In 2014 Brian Dias and Kerry Ressler, both at the Emory University School of Medicine, reported an intergenerational epigenetic pathway that ran through sperm. They gave a male mouse a mild electric shock as it smelled a cherry blossom scent, stimulating a fear response to the odor. The response was accompanied by epigenetic changes in its brain and sperm. Intriguingly, the male offspring of the shocked mice demonstrated a similar fear of cherry blossoms—as well as epigenetic changes in their brain and sperm—without being exposed to the shock. These effects were passed down for two generations. In other words, the lesson the grandfather mouse learned, that the cherry blossom scent means danger, was transmitted to its son and grandson.
In a recent study, my colleagues and I experimented with genome-wide gene expression, a tool that can identify links between protein expression and specific conditions across the entire human genome. With this approach, we again observed distinct patterns of gene expression linked with maternal and paternal trauma exposure and PTSD.
IN THE WOMB
Apart from altering the eggs and sperm that encapsulate our genetic inheritance, sometimes decades before conception, trauma also seems to influence the uterine environment. Meticulous studies of the offspring of women who were pregnant during the Dutch Famine—a six-month period during World War II when the Nazis blocked the food supply to the Netherlands, causing widespread starvation—provided an early indication of in utero effects. Researchers discovered that the combined effects of extreme stress and nutritional deprivation, such as deficits in metabolism and susceptibility to cardiovascular illness, depended on the trimester of exposure.
The 9/11 babies were also impacted in the womb, with those in the third trimester having significantly lower cortisol levels. What this condition meant for their future development I sadly never found out. At the wellness visit, mothers who had PTSD (and low cortisol) were more likely to report that their nine-month-olds were unusually anxious and afraid of strangers. But we didn't get the funding to follow the babies into adulthood.
How might the uterine environment leave a trauma trace in the offspring? Our work on Holocaust survivors and their adult children provided some clues. The story is again complicated, and it involves an enzyme known as 11-beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Holocaust survivors had lower levels of the enzyme than those who hadn't lived through the Holocaust—and such effects were particularly pronounced in those who were the youngest during World War II. The enzyme is normally concentrated in the liver, kidneys and brain. Under conditions of food deprivation, however, the body can lower levels of 11β-HSD2 to increase metabolic fuel in the interest of promoting survival. In adults, the enzyme level will return to what it was when there is no more starvation, but in children, the level may remain low. Our findings suggested that 11β-HSD2 levels might have been altered during childhood when Holocaust survivors were exposed to long periods of malnourishment; the change persisted well into old age.
In the children of women who were Holocaust survivors, however, we saw quite the opposite: 11β-HSD2 levels were higher than in Jewish control subjects. The result might seem contradictory, but there is a logic to it. During pregnancy, 11β-HSD2 also acts in the placenta, protecting the fetus from exposure to circulating maternal cortisol, which can be toxic to the developing brain. The enzyme, which is particularly active in the third trimester, converts maternal cortisol into an inactive form, creating a kind of chemical shield in the placenta that protects the fetus from the hormone's harmful effects. The high levels of this enzyme in the offspring of Holocaust survivors may thus reflect an adaptation, an effort to protect the fetus from the lowered 11β-HSD2 levels in their mothers.
All of this means that offspring are not always passive recipients of their parents' scars. Just as a parent was able to survive trauma by means of biological adaptations, offspring can sometimes adapt to the biological impact of their parents' trauma.
How traumatized parents interact with their children, of course, also influences their development. One of the most powerful nonfiction accounts of growing up with Holocaust survivor parents was Art Spiegelman's serialized graphic novel Maus; it broke through a cultural barrier, helping others to open up about their suffering. Many psychologists and neuroscientists have examined the traumatized family, finding ever more subtleties, and the story will continue to unfold for decades to come.
An important question is whether epigenetic alterations in stress-related genes, particularly those reflected in the offspring of traumatized parents, are necessarily markers of vulnerability or whether they may reflect a mechanism through which offspring become better equipped to cope with adversity. This is an area we're actively exploring.
It is tempting to interpret epigenetic inheritance as a story of how trauma results in permanent damage. Epigenetic influences might nonetheless represent the body's attempts to prepare offspring for challenges similar to those encountered by their parents. As circumstances change, however, the benefits conferred by such alterations may wane or even result in the emergence of novel vulnerabilities. Thus, the survival advantage of this form of intergenerational transmission depends in large part on the environment encountered by the offspring themselves.
Moreover, some of these stress-related and intergenerational changes may be reversible. Several years ago we discovered that combat veterans with PTSD who benefited from cognitive-behavioral psychotherapy showed treatment-induced changes in FKBP5 methylation. The finding confirmed that healing is also reflected in epigenetic change. And Dias and Ressler reconditioned their mice to lose their fear of cherry blossoms; the offspring conceived after this “treatment” did not have the cherry blossom epigenetic alteration, nor did they fear the scent. Preliminary as they are, such findings represent an important frontier in psychiatry and may suggest new avenues for treatment.
The hope is that as we learn more about the ways catastrophic experiences have shaped both those who lived through those horrors and their descendants, we will become better equipped to deal with dangers now and in the future, facing them with resolution and resilience.
AUTHOR
Rachel Yehuda is a professor of psychiatry and neuroscience and director of the Center for Psychedelic Psychotherapy and Trauma Research at the Icahn School of Medicine at Mount Sinai. She is also director of mental health at the James J. Peters Veterans Affairs Medical Center. Credit: Nick Higgins
(Sources: Scientific American)
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