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Epigenetic transgenerational transmission of Holocaust trauma: A Review



Abstract Transgenerational transmission of trauma (TTT) renders some children of survivors vulnerable to stress while others become more resilient. TTT was previously assumed to be caused primarily by environmental factors, such as the parents’ child-rearing behavior. Recent research findings, reviewed in this paper, suggest that it may also be inherited through epigenetic mechanisms. New data indicate that the glucocorticoid receptor gene may cause the stress hormones of the child to become allostatic rather than resilient. Six clinical case anecdotes on suicidality, depression and PTSD, as well as on certain olfactory, cardiac and pulmonary problems, are presented to illustrate such possible epigenetic transgenerational transmission of Holocaust trauma. Further studies may justify the introduction of a new diagnostic entity -- transgenerational stress disorder -- with immediate relevance for the assessment, prevention, and treatment of the offspring of many kinds of trauma survivors.
Epigenetic transgenerational transmission of Holocaust trauma:
A Review
Natan P.F. Kellermann
October 12, 2015
Transgenerational transmission of trauma (TTT) renders some children of survivors
vulnerable to stress while others become more resilient. TTT was previously assumed to be
caused primarily by environmental factors, such as the parents’ child-rearing behavior.
Recent research findings, reviewed in this paper, suggest that it may also be inherited
through epigenetic mechanisms. New data indicate that the glucocorticoid receptor gene
may cause the stress hormones of the child to become allostatic rather than resilient. Six
clinical case anecdotes on suicidality, depression and PTSD, as well as on certain olfactory,
cardiac and pulmonary problems, are presented to illustrate such possible epigenetic
transgenerational transmission of Holocaust trauma. Further studies may justify the
introduction of a new diagnostic entity -- transgenerational stress disorder -- with
immediate relevance for the assessment, prevention, and treatment of the offspring of
many kinds of trauma survivors.
Epigenetic transgenerational transmission of Holocaust trauma
Seventy years after the end of World War II, children of Holocaust survivors are now
middle-aged or older, becoming parents and grandparents themselves. While some were
able to transform the legacy of the Holocaust into post-traumatic growth, others are still
struggling with the effects of the war as if they were disposed to suffer the curse of
Holocaust trauma. These more vulnerable sons and daughters of survivors have Holocaust
associations throughout their lives. About a third of them suffer from manifest
psychopathology when a new trauma awakens the old one. During these periods, they have
nightmares and flashbacks of things they never experienced. Daily events remind them of
the horrors of the war and the agony their parents suffered. More than half a century after
World War 2, there is a prevailing sense of catastrophic expectancy. It has become an
automatic response among the Jews in Israel and elsewhere as shown in a recent study of
Israeli offspring who were more preoccupied with the Iranian nuclear threat than others
(Shrira, 2015).
Since even simple organisms learn fundamental survival skills and pass these on to their
offspring, it’s not surprising that life-changing experiences in humans, which result in
knowledge useful for survival, would be passed on to future generations. Children of
survivors are thus molded by the war experiences of their parents, especially since these
experiences were extremely negative, uncontrollable and sudden (Carlson & Dalenberg,
2000) and induced intense fear, helplessness, or horror. Essentially, Transgenerational
Transmission of Trauma (TTT) may be understood as a kind of vicarious encounter with
All famines, wars, persecutions and mass murder, which left a deep and enduring trace in
the body of the first generation, may be assumed to leave some kind of scar also upon
successive generations. Holocaust survivors narrowly escaped mortal threat and survived
against all odds. Many suffer from lifelong, sporadic and debilitating posttraumatic stress
disorder (PTSD) (Barak & Szor, 2000; Dasberg, 1987; Kellermann, 2009) which they
transmitted to their offspring. Indeed, there is a strong relationship between parental PTSD
and PTSD in offspring. Apparently, the more a person experienced traumatic events, the
more he or she suffered from PTSD (Hong & Efferth, 2015; Neuner et al., 2004; Schoedl et
al, 2014) and the more this disposition is passed on to the offspring. Research has shown
that parental Holocaust exposure is a strong predictor of lifetime emotional disorders in
offspring (Bowers & Yehuda, 2015; Lambert, Holzer & Hasbun, 2014; Yahyavi, Zarghami &
Marwah, 2013; Yehuda, Halligan & Bierer, 2001; Yehuda, Halligan & Bierer, 2002). A large
number of studies show how parental adaptive and pathological fear may be transmitted to
their offspring, such as in PTSD (Bosquet et al., 2011; Reul, 2014; Roth, 2014; True et al,,
1993; Yehuda et al., 2008).
Transgenerational Epigenetic Inheritance
Earlier explanations of such manifestations of TTT assumed that they were caused
primarily by environmental factors, such as the parents’ child-rearing behavior
(Kellermann, 2001). For many years, the prevalent notion was that children who had grown
up with traumatized parents had learned to become fearful as well. New research, however,
shows that transgenerational effects may be inherited also through epigenetic mechanisms
(Bohacek & Mansuy, 2013; Ennis, 2014; Harper, 2005; Kellermann, 2013; Thomson, 2015;
Yehuda & Bierer, 2009; Zannas, Petronis, 2010; Provençal, & Binder, 2014; Provençal &
Binder, 2015a). An increasing number of studies are trying to validate this claim and the
term transgenerational epigenetic inheritance - TEI has been coined to depict it (Choi &
Mango, 2014).
Within such a biological framework, the traumatic memories of the parents are transmitted
through epigenetic marks; the changes in gene functioning or to the DNA environment that
affects the way the DNA is read into RNA, and then how RNA is expressed into a protein.
This theory suggests that children of survivors are tainted with a chemical marking upon
their chromosomes similar to the numbers tattooed on their parents’ forearms.
Epigenetics integrates both hereditary and environmental factors, which adds a new and
more comprehensive psychobiological dimension to TTT. Not only can epigenetic measures
explain how an adverse social environment gets ‘under the skin’ of the survivors of trauma
(Toyokawa et al., 2012), but also why a latent predisposition sometimes becomes manifest
under stress in their children (Zovkic et al., 2013). After all, every person has a unique
variation of the human genome and there are often multiple factors that influence the
likelihood of developing PTSD.
This new epigenetic paradigm (Moore, 2015) assumes that biological and psychosocial
factors are in close interaction with one another (Crews et al., 2014; Hofer, 2014). Trying to
find the multiple hereditary and environmental causes of TTT, however, is a daunting task;
the assumed risk factors include not only epigenetic factors, but also personality traits and
social support, and traumatic experiences of the children themselves during their lives. It is
difficult to disentangle effects that reflect TEI from early rearing influences and subtle
attachment patterns experienced because of having trauma-exposed and/or symptomatic
parents. It is precisely because of this complexity that epigenetics makes so much sense as a
suitable explanation for TTT.
“Faulty” Programming
TEI can be metaphorically described in computer terminology. It is as if the child was born,
not only with the parents’ hardware (DNA), but also with traces of their old, and infected
“glucorticoid programming” software (Seckl & Meaney, 2006). Even though the computer
was reformatted (or reprogrammed) at conception, some traces of the old program
remains. At fertilization, the germ cells were supposed to have been wiped clean of any
chemical modifications to DNA. No memories were supposed to slip through the generation
barrier. Research from the last decade, however, has found evidence for what clinicians
have long observed, but were unable to verify. Some DNA methylation can escape the ‘reset’
mechanism or ‘reprogramming’ in human germ cells (Surani, 2001; Tang et al., 2015) and
this may explain why it’s possible that some memories can reappear in children of
Like a binary computer program that uses encoded switches with either 1 or 0, epigenetic
programming (or re-programming) may activate or suppress specific electrochemical
signals, or proteins, to either initiate or shut down the action potential of neurons. If these
mechanisms have been compromised in the parents and then inherited by the children,
there will be a kind of software bug in the nervous and endocrine systems and produces an
incorrect functioning of the ‘program’. When this happens, the body will function as if it
was infected by a computer virus that caused it to behave irrationally and send faulty
instructions to and from the brain. In other words, the epigenetic marks will change the
transcription potential of the genes and give them flawed instructions on certain cues. It
may appear as a subtle ‘somatic marker’ (Damasio, 1994) or a gut feeling, for example
instructing a child of Holocaust survivor not to leave food on the plate because ‘then and
there, they died from starvation’ (Bygren et al., 2014). This example highlights the
interconnectedness of body and mind and the two-way communication between the
gastrointestinal system and the brain, which are all signs of the malicious ‘Holocaust Virus’
in epigenetic TTT.
All such computer malware develop slowly over a long period and the overt signs may
emerge only after several years. It is observed repeatedly in the survivors themselves, in
their children and even in their grandchildren seventy years after the end of the war. When
it has taken root, it will linger and stay active for a lifetime, leading to pathological stress,
panic attacks and even to complex PTSD (Danielson, Hankin & Badanes, 2015). The
symptoms seem to be caused by long-term changes in the brain chemistry as confirmed in
many studies (Perry, 1999; Roberts et al., 2012; Thakur et al., 2015). If no help is received,
the ripple effects may produce chaos in the delicate inner hormonal balance of the entire
body and cause it to crash or freeze.
It may sound too simplistic to explain the often complex hereditary vulnerability to PTSD in
children of survivors as a software bug within a computer program. In reality, the biological
effects of parental trauma upon children are surely more complex. But epigenetics provides
a useful new psycho-biological paradigm for TTT. First and foremost, it has kicked off new
research as shown in the explosion of studies on epigenetics during the last decade
(Burggren & Crews, 2014; Lim & Brunet, 2013; Rodgers & Bale, 2015).
Research on Epigenetics
Within the past few years, several exhaustive reviews have been published with summaries
of the recent findings. Such reviews have been written, for example on fear memory and
biomarkers (Maddox, Schafe & Ressler, 2013), learned fear (Zovkic & Sweatt, 2013), neural
fear network and PTSD (Wilker & Kolassa, 2013), early life stress (Provençal & Binder,
2015b), epigenetic risk factors in PTSD and depression (Raabe & Spengler, 2013),
transgenerational epigenetics and psychiatric disorders (Franklin, 2014) and on the
inheritance of learned behaviors (Dias et al., 2015). These reviews have summarized
significant advances in cognitive neuroscience and they have begun to unravel the
biological mysteries and cellular basis of transmitted trauma. They suggest that there might
indeed be a biological basis for the long-term emotional effects of trauma, including its
transgenerational transmission on later generations.
The Cross-Disorder Group of the Psychiatric Genomics Consortium (2013) found that most
psychiatric disorders are moderately to highly heritable. Specifically, they concluded that
exposure to stress, particularly in early life, has both acute and lasting epigenetic effects. In
fact, such stress may even influence cognitive functions and behavior, as well as the risk for
suicide and psychiatric disorders across the lifespan and also unto future generations
(Griffiths & Hunter, 2014). It is now largely accepted that early-life stress produces changes
in the brain and periphery that can ultimately influence behavior through epigenetic
changes, such as DNA methylation, histone modification and microRNA processing (Bale,
2015; Blaze, Asok & Roth, 2015).
Studies on traumatized mice have demonstrated how unpredictable maternal separation
can induce depressive-like behaviors, not only in the first generation, but also in their
offspring (Debiec & Sullivan, 2014; Franklin et al., 2010). In addition, lab mice trained to
fear a particular smell transmitted this fear to their unborn sons and grandsons through a
mechanism in their sperm (Callaway, 2013; LeRoux, 2013). Many similar studies have
shown that animals can inherit a memory of their ancestors’ traumas, and respond as if
they had lived the events themselves (Dias & Ressler, 2014). Parental traumatic experience
may induce neuro-anatomical adaptations and related cue-specific behavioral
predispositions in offspring and thus, “the experiences of a parent, even before conceiving,
markedly influence both structure and function in the nervous system of subsequent
generations” (Gallagher, 2013).
Maternal Transmission
The embryo and the fetus during its various periods of development in the womb have been
of particular interest when trying to explain such transgenerational effects, A
comprehensive overview of such transgenerational epigenetic programming (Babenko,
Kovalchuk & Metz (2015) suggest that stress-induced epigenetic signatures are indeed
transmitted to the next generation. Based on existing evidence, prenatal stress, through
epigenetic alterations, becomes one of the most powerful influences on mental health in
later life.
What babies comprehend in utero will affect what they remember after they’re born and
that information will prepare them for the world outside the womb. Every meaningful
experiencewhether joyous or painfulis stored in memory and has a lasting impact on a
baby’s developing nervous system (Weaver et al., 2004). Studies on different populations
have confirmed these observations and validated them with data on how conditions in the
womb affect the health of a person not only as a fetus but well into adulthood (Li, Beard &
Jaenisch, 1993; Lillycrop et al., 2007). The epigenetic effects are profound since various
types of cells, including neural cells, differentiate during embryogenesis (Sakashita et al.,
2001; Takizawa et al., 2001). These effects are particularly visible during the last trimester
of pregnancy when babies begin to engage many of their senses and learn about the world
(Yehuda et al., 2005). When this period is influenced by severe stress in the mother, the
epigenetic changes produced by fetal programming may last throughout life and can be
passed on to future generations (Drake & Walker, 2004; Gluckman et al., 2007; Hazani &
Shasha, 2008; Onoye et al., 2013; St Clair et al., 2005).
TEI is more likely to occur during particular times in child development. The earliest stages
of life, beginning well before birth and immediately after are moments of maximal plasticity
(Burggren & Crews, 2014). When investigating the epigenetic effects on children of
Holocaust survivors, we therefore need to take the neurochemical responses to external
environmental exposures into account both during pregnancy and after birth. Such
investigations focus on the unfolding of the fetus and the maturation of the toddler and in
particular how pregnancy in times of hunger and stress may have affected the health of the
offspring (Heijmans et al., 2008). This effect was observed not only in the immediate
postnatal period but throughout their adult lives (Sperling, Kreil, & Biermann, 2012). For
example, childbearing women during the war in the ghettos and camps responded to the
emotional shock of persecution and the prolonged starvation with various hormonal
disturbances, such as the cessation of menstruation, hair loss, and irregularities in heart
function and the nervous system (Nachimovsky, 1948; Preiss, 2009). After the war,
mothers in DP-camps became pregnant while they were still recuperating from starvation,
typhus, TB or other illnesses. The long-term epigenetic effects of such exposure to early-life
stress on the offspring were profound (Provençal & Binder, 2015a; Yao et al., 2014). Such
harmful influence was observed already in 1948 by a gynecologist in Munich who found a
high percentage of congenital malformations in the newborn babies (Eitinger, 1993). It was
as if these mothers were symbolically feeding their babies with war-tainted milk, if they had
any milk at all.
Paternal Transmission of RNA
While maternal nutrition and metabolism are obvious determinants of the health of adult
offspring (Tollefsbol, 2014), recent reports also describe adverse effects on offspring
associated with the father’s diet, showing non-genetic inheritance of paternal experience.
These results were interpreted as “you are what your dad ate” (Ferguson-Smith & Patti,
Sperm may also contribute to TTT since it can carry RNA (Hosken & Hodgson, 2014).
Sharma (2014) suggested that extracellular mRNAs and proteins provide the much-needed
continuum inclusive of epigenetic inheritance. An imbalance in sperm microRNAs may also
be a key factor through which trauma can be passed on. Mansuy and her team (Gapp et al.,
2014) identified short RNA molecules as a key component of these processes. These RNAs
are synthesized from genetic information (DNA) by enzymes that read specific sections of
the DNA (genes) and use them as a template to produce corresponding RNAs (ETH Zurich,
Transmission of HPA Dysregulation
Considering that hormones (signaling molecules) regulate the proteins that control the
body’s stress-sensing system, they have been a major focus of research in transgenerational
PTSD. According to Jablonka & Raz (2009), “the involvement of hormones in the induction
of heritable epigenetic variations is no longer a mere speculation: several of the mammalian
examples suggest that changes in hormonal stimuli induce heritable epigenetic changes” (p.
159). During acute stress, the hypothalamic-pituitary-adrenal axis (HPA axis) is activated
(Hulme, 2011). Corticotropin-releasing hormone (CRH) is secreted from the hypothalamus
under the influence of serotonin from the Amygdala. CRH stimulates the pituitary gland to
release adrenocorticotropic hormone (ACTH), which then prompts the adrenal glands to
increase the production of glucocorticoids. This releases the stress hormone cortisol, which
stimulates noradrenaline to activate the fight-flight response. Cortisol serves to stop many
metabolic, neuronal defensive and immune reactions and energy can be mobilized to cope
with the stressor. Through these chemicals, the HPA-axis controls reactions to stressful
situations, triggering several physiological changes that prime the body for action
(Meewisse et al., 2007). The more stressed a person is, the more CRH is secreted, leading to
increased ACTH, and higher levels of cortisol. When cortisol activates the fight and flight
stress response, it also sends a signal back to the hypothalamus to inhibit CRH production
and the pituitary gland to inhibit ACTH. In this feedback loop, cortisol will reduce
norepinephrine activity, gradually calming the person down and creating a mutually
balanced system (Engelmann, Landgraf & Wotjak, 2004; Miller, Chen & Zhou, 2007). In
some people who have experienced trauma, however, this system doesn’t function as it
Rachel Yehuda and her team from the Traumatic Stress Studies Division at the Mount Sinai
School of Medicine have investigated such HPA-axis dysregulation in trauma survivors for
many years (Yehuda, 2005). People with PTSD seem to have higher corticotrophin-
releasing factor (CRF) levels, blunted adrenocorticotropic hormone response and low levels
of cortisol. Apparently, low cortisol levels have been found in saliva, urine, and blood in
many, but not all, populations with PTSD (de Kloet et al., 2006; Heim, Ehlert &
Helhammer, 2000; Meewisse et al., 2007). Children of Holocaust survivors with PTSD also
have significantly lower levels of cortisol, but better cortisol suppression in their blood than
offspring of survivors without PTSD (Yehuda et al., 2007; Yehuda, 2009). Such HPA axis
dysregulation leads to an inability to produce enough adrenal cortex hormones in response
to stress and is seen in populations who have struggled for generations to cope with trauma.
It gives rise to a kind of exhaustion, or ‘adrenal fatigue’, similar to secondary adrenal
insufficiency (Neary & Nieman, 2010). It’s as if these children continued the struggle for
survival of their parents, until their resources were depleted. They seem to have been
‘programmed’ by excessive glucocorticoids to be either predisposed or protected from PTSD
(Seckl & Meaney, 2006).
Transmission of Brain Functioning
The epigenetic machinery in the brain is both complex and intertwined and it’s difficult to
disentangle brain-region and cell-type specific epigenetic codes in a given environmental
condition (Graff, Kim, Dobbin, & Tsai, 2011). Nevertheless, neuroimaging studies have
shown that the amygdala, the hippocampus, and the prefrontal cortex all play a part in
stress and PTSD (McEwen, et al., 2015). For example, according to the ‘‘glucocorticoid
cascade hypothesis’’ (Sapolsky, Krey & McEwen, 1986), chronic stress may cause smaller
hippocampal and prefrontal cortex volume, deficits in declarative (conscious) memory and
some amnesia (Baker et al., 2005; Bremner et al., 1995; Samuelson, 2011). Stress hormones
triggered by way of the HPA-axis are encoded by the basolateral area of the amygdala
(BLA). This makes the person respond emotionally to anything that unconsciously is
associated with the event (Bokkon et al., 2014; LaBar & Cabeza, 2006; McGaugh, 2000).
Functioning independently of the hippocampus, the BLA thus conserved the emotional
trauma overload while repressing the cognitive recollections of the event, as also seen in
offspring of mothers who survived the Tutsi genocide in Rwanda (Perroud et al., 2014;
Roth, Neuner & Elbert, 2014).
Increased activity of the amygdala-HPA axis produced by experimental manipulation
represents several of the physiological signs of stress-related psychiatric disorders in
humans (Gillespie et al., 2009; Lee et al., 2013). The activation of both amygdala and
hippocampus and the interaction between them may be what gives emotionally based
memories their distinctiveness (Richter-Levin & Akirav, 2000). Infusion of glucocorticoids
in the hippocampus after fear conditioning induces PTSD-like memory impairments and an
altered pattern of neural activation in the hippocampal-amygdala circuit (Kaouane et al.,
2012). The hyperactive amygdala-mediated fear response to danger and the weakened
ability of the medial prefrontal cortex to regulate these responses are some of the common
responses to trauma (Yehuda & LeDoux, 2007).
Candidate Genes
Many years of research has shown that changes in gene expression happens when a
memory is formed and stored (Roth, 2014). Even though there are many difficulties in
identifying candidate genes implicated in psychiatric disease (Burmeister, McInnis, &
Zollner, 2008), there has been some progress in finding neurobiological alterations to
important components of the stress response system (Skelton et al., 2012). Specifically,
epigenetic changes have been found in different gene locations involved in the regulation of
the HPA axis (Voisey, Young, Lawford, & Morris, 2014). Wilker et al., (2014) concluded that
an epigenetic modification of the glucocorticoid receptor gene promoter is linked to inter-
individual and gender-specific differences in memory functions and PTSD risk. The
glucocorticoid receptor (GR) gene in the hippocampus was found to be critical for negative
feedback in the stress response (Champagne, 2013) and for increased corticotropin-
releasing hormone (CRH). Findings have indicated polymorphisms (phenotypical
aberrations) within two genes, FKBP5 and CRHR1 (Binder et al., 2008) that regulate HPA
axis function when the child is also exposed to child maltreatment (Klengel et al., 2013).
Significant associations were also found with a variable number tandem repeat (VNTR)
polymorphism (Segman & Shalev, 2003; Yehuda & LeDoux, 2007). Other genes, such as the
PRKCA were found to lead to improved memory, and therefore also to increased risk of
PTSD (de Quervain et al., 2012). In addition, increased DNA methylation at the NGFI-A
binding site of the NR3C1 promoter was associated with reduced PTSD risks in male
survivors of the Rwandan genocide (Vukojevic et al., 2014).
Recent Advances
There have been recent advances in this line of research. Daskalakis & Yehuda (2014)
looked at methylation of the exon 1F promoter of the glucocorticoid receptor (GR-1F) gene
(NR3C1), the most studied genomic region in human stress-related diseases. In order to
demonstrate alterations of GR-1F promoter methylation in relation to parental PTSD and
neuroendocrine outcomes, Yehuda et al., (2014a) sought to identify effects of parental
Holocaust exposure and PTSD on GR-1F promoter methylation to discovery epigenetic
marks connected to glucocorticoid dysregulation (Bader et al., 2014; Bierer et al., 2014;
Lehrner et al., 2014) in this population at risk for PTSD. They found that paternal PTSD,
only in the absence of maternal PTSD, was associated with higher levels of GR-1F promoter
methylation, while offspring with both maternal and paternal PTSD showed the least level
of methylation.
In August 2015, Yehuda and co-workers (Yehuda, et al., 2015) published the first findings of
epigenetic TTT in humans in both Holocaust survivor parents and their offspring.
Holocaust exposure had an effect on FKBP5 methylation both in parents and in their
offspring, a correlation not found in the control group and their children. Even if this study
had a small sample size and can be criticized for other methodological problems, it presents
a first glimpse of a possible epigenetic inheritance in this population. The findings, which
echo those of Klengel et al. (2013), suggest that methylation of the FKBP5 gene in the
parent may indeed be inherited. If this happens, the glucocorticoid receptor gene may be
silenced, making the stress hormone of the child allostatic rather than resilient (McEwen,
2000; Oken, Chamine & Wakeland, 2014). Thus, some vulnerable children of survivors may
become predisposed to stress while others will be more resilient.
Critique of Epigenetic TTT
Despite this large body of research, the jury is still out on whether transgenerational
epigenetic inheritance is possible in humans. It is still disputed in many quarters (Daxinger
& Whitelaw, 2010; Grossniklaus et al., 2013; Qiu, 2006) on the ground that it is guided
more by hype and hope (Albert, 2010) than on objective evidence. Available data is based
mostly on animal models, while neurobiological findings on humans are still insufficient
(Heard & Martienssen, 2014). A reason for this is that “controlled studies [on humans] are
neither feasible nor ethical and phenotypic as well as biological data across several
generations are lacking” (Dias et al., 2015, p. 105). But even if we had more such data, it
would be very difficult (if not impossible) to clearly separate the influence of biological
heredity from parental upbringing in humans.
Therapists have suspected for long that the risk for psychopathology in children of survivors
may be a multigenerational phenomenon (Klengel, Dias & Ressler, 2015). The severity and
persistence of mental problems in this population could not stem only from the
psychosocial environment (e.g. parents talked too much or too little about the war). There
had to be more to TTT and the possibility of parents actually being harmed by the war in a
neurobiological manner which their children might have inherited, was always at the back
of their minds. When the first studies on epigenetic transgenerational trauma were
published (Yehuda, Halligan, & Bierer, 2001), it therefore sounded very likely to therapists
working with these populations. It explained not only why some children became more
vulnerable while others remained resilient, but also why so many still suffer from the effects
of the war. The latest finding that there might be an epigenetic modification of the
glucocorticoid receptor gene in the traumatized parent which was then transmitted to the
child (Meaney & Szyf, 2005) resonate well with clinical experience. Learning that children
of trauma survivors may have had a ‘defective’ or methylated glucocorticoid receptor gene
ever since they were born also make sense to those children of survivors who have been
preoccupied by Holocaust associations for most of their lives. It may especially help those
previously bewildered by their lifelong difficulties in coping with stress to realize that there
is an actual hereditary disposition to their difficulties.
Case Anecdotes
To illustrate some of these difficulties and put them in a relevant parent-child context, I will
here present six case scenarios taken from clinical practice. These cases suggest that
suicidality, depression and PTSD, as well as certain psychosomatic olfactory, cardiac and
pulmonary manifestations, may have an epigenetic source based on specific parental
Holocaust trauma,
(1) Transmission of suicidality
Mrs. U from Poland was six years old during the war. She remembers being trapped in their
burning house, surrounded by Nazi soldiers who shot anyone who tried to get out. The
family members hid in the cellar, lying on the floor while hearing shots fired and barking
dogs. Mrs. U saw some of her family members being burned alive. Somehow she survived
and when it was all over, she could escape to the forest where she was hiding for three years
with the constant fear of being caught. After the war, she was sent to Israel with other
orphans. Because of her traumatic wartime experiences, the overwhelming fear,
powerlessness and loss of control had become a permanent learning experience she could
not overcome. Despite this, she married and gave birth to two girls, one of whom suffered
from depression in young adulthood and later committed suicide. Did the daughter inherit
hypermethylation of the ribosomal RNA gene promoter from her mother (McGowan et al.,
2008)? Specifically, was there an alteration in the CRHT1 gene: a marker found for suicidal
susceptibility (Wasserman et al., 2008; Niculescu et al., 2015)?
(2) Transmission of depression
Anna was only 12 years old during the mass killing of the Einsatzgruppen - the paramilitary
death squads of Nazi Germany. She watched her family being shot one after the other and
thrown into an open trench. Anna was holding her baby sister and trying to calm her as she
was waiting for her turn. The Nazi soldier, who tried to kill both of them with one bullet,
shot the baby in the head and pushed both in the trench full of bodies. Anna had not been
hit and crawled out from the open grave at night. A farmer found her, took care of her and
she survived the war. Many years later, Anna gave birth to a daughter and named her after
her baby sister. Anna was symbolically born from a grave and her daughter became a
‘memorial candle’ (Wardi, 1992), suffering from clinical depression for most of her life. Was
there an epigenetic transmission of depression (Sun, Kennedy & Nestler, 2013)?
Specifically, would there be similarities in diminished hippocampal activation on a
functional magnetic resonance imaging (fMRI) during a memory task (Milne, MacQueen &
Hall, 2012)?
(3) Olfactory transmission
A man forced to work in the crematoria in Auschwitz was exposed to the smell of burned
cadavers for almost a year. During this gruesome labor, he saw the corpse of his wife and
contemplated giving up. But with a lifelong sense of guilt, he decided to live and survived
the war. He preferred not talk to anyone about his experiences, shut down his emotional
life, remarried and gave birth to a child. When he was attending barbecue parties, however,
and smelled burned meat, he would get severe panic attacks. Many years later, this
symptom also appeared in his son. Might there have been a transgenerational epigenetic
transmission from father to son? Had exposure to stress during the war affected the miRNA
germ cells in the sperm of the father and were these passed on to his son via olfactory
neural pathways, as suggested in research on the neural basis for a strong “odor-emotional
memory” (Dias, & Ressler, 2014; Tong, Peace & Cleland, 2014).
(4) Cardiac disease transmission
A child of camp survivors shared that she could not tolerate cold weather and had to move
to a warmer place. She said that her heart goes into spasm when she got frozen; a medical
condition called ‘vasospastic cardiac disease’ which may be caused by epigenetic regulatory
mechanisms (Schleithoff et al., 2012). Was it possible that she had inherited this disease
from her parents who had endured the extreme cold weather in the camp and during the
Death March? Would a comparison of blood or saliva samples offer concrete, physical proof
of epigenetic transmission?
(5) Transmission of dyspnea and pulmonary hypertension
A Hungarian Jewish woman was sent to be exterminated in Auschwitz but was taken out of
the gas chamber because there was no more Zyklon B available. She somehow survived the
war and gave birth to a daughter called Michelle. Many years later Michelle was interviewed
and exclaimed: “When I go to work in the morning and see so many cars and exhaust
fumes, I tell myself, don’t breathe! I remember that this is how they would gas people . . .
and I think about the camps. There is not one day that I don’t think about those things.
They cross my mind twenty times a day, a hundred times a day!” (Gottschalk, 2003, p. 355).
Were her mother’s experiences passed down to her daughter through transgenerational
epigenetic transmission? Could the mother’s childhood trauma have affected selective
histone deacetylase inhibitors and targeted DNA methyltransferases and did they cause
pulmonary hypertension in the daughter (Saco et al., 2014)? Was mother’s anxiety so
intense at the time of near death that a torrent of hormones flowed into every cell of her
body, including her egg cells and hijacked her brain's epigenetic machinery? Did this cause
the Amygdala fear response threshold to violate its rules of evolutionary conservation by an
overload of adrenaline? Had the daughter inherited a specific epigenetic modification which
made her susceptible to anxiety throughout her life? If so, could this be the reason for her
thinking about the war all the time? Could it work like this for other children of Holocaust
(6) Transmission of susceptibility to PTSD in the military
The father was a well-functioning survivor of the Holocaust but had never talked about his
experiences. His eldest son suffered PTSD when fighting in one of the wars in Israel and
was dismissed from active duty. His condition became chronic, and he was unable to
function adequately for the rest of his life, receiving a disability pension from the
Department of Veterans Affairs. Was there a prior susceptibility to PTSD, which could be
traced back to his father’s war experiences? Could his predisposition be detected in a test of
the SNPs in a specific gene? Would it be visible on a brain scan, showing damage in the
hippocampus? Should all soldiers be tested for susceptibility to PTSD before being enlisted
(Boks et al, 2015; Dekel, Mandl & Solomon, 2013; Neylan, Schadt & Yehuda, 2014; Sipahi et
al., 2014; Yehuda et al., 2014b)?
These examples represent only a tiny part of all the possible epigenetic transmission
scenarios involved in TTT. They were chosen because of the extreme strain imposed on the
parents and their possible transgenerational epigenetic effects on the offspring (Rudan,
2010). Many more can be found in the clinical setting and they all pose urgent questions
about epigenetic transgenerational transmission with concrete testable hypotheses for
further investigation.
Clearly, many unanswered questions remain regarding the exact mechanisms of how
posttraumatic stress may be transmitted from generation to generation (Dias et al., 2015).
For example, how exactly did the Holocaust trauma enter into the mature sexual
reproductive cells of a traumatized parent? For how many generations do the biological
heredity and/or the psychosocial transmission continue? Do they become fixed or can they
be reversed? Most importantly; what causes some children to develop resilience while
others remain vulnerable to stress? With significant advances in neuroscience, cell biology
and molecular genetics, these questions are beginning to be answered.
Future studies on gene-environment interaction will surely provide additional
understanding of both the biomarkers and the psychosocial origins of PTSD and TTT. Since
TTT tends to highly volatile, future research should focus on the variability of the nervous
and endocrine systems in both parents and children, and also between children. Case-
dependent studies on actual parent-child combinations, rather than on the correlations of
both populations at large, may determine the risk factors in operation for certain
individuals with specific genetic vulnerability (Daskalakis et al, 2013).
The findings of such research may lead to the introduction of a new diagnostic entity --
transgenerational stress disorder -- as a separate subtype of PTSD, distinct from secondary
PTSD, with immediate relevance for the assessment, prevention, and treatment of children
of Holocaust survivors.
Albert, P. R. (2010). Epigenetics in mental illness: Hope or hype? Journal of Psychiatry &
Neuroscience: JPN, 35(6), 366368. doi:10.1503/jpn.100148
Babenko, O., Kovalchuk, I., & Metz, G. A. (2015). Stress-induced perinatal and transgenerational
epigenetic programming of brain development and mental health. Neurosci Biobehav Rev, 48,
70-91. doi: 10.1016/j.neubiorev.2014.11.013
Bader, H. N., Bierer, L. M., Lehrner, A., Makotkine, I., Daskalakis, N. P., & Yehuda, R. (2014).
Maternal Age at Holocaust Exposure and Maternal PTSD Independently Influence Urinary
Cortisol Levels in Adult Offspring. Front Endocrinol (Lausanne), 5, 103. doi:
Baker, D. G., Ekhator, N. N., Kasckow, J. W., Dashevsky, B., Horn, P. S., Bednarik, L., & Geracioti,
T. D., Jr. (2005). Higher levels of basal serial CSF cortisol in combat veterans with
posttraumatic stress disorder. Am J Psychiatry, 162(5), 992-994. doi:
Bale, T.L. (2015). Epigenetic and transgenerational reprogramming of brain development. Nat Rev
Neurosci, 16, 332344. doi:10.1038/nrn3818
Barak, Y., & Szor, H. (2000). Lifelong posttraumatic stress disorder: evidence from aging Holocaust
survivors. Dialogues Clin Neurosci, 2(1), 57-62.
Bierer, L. M., Bader, H. N., Daskalakis, N. P., Lehrner, A. L., Makotkine, I., Seckl, J. R., & Yehuda,
R. (2014). Elevation of 11beta-hydroxysteroid dehydrogenase type 2 activity in Holocaust
survivor offspring: evidence for an intergenerational effect of maternal trauma exposure.
Psychoneuroendocrinology, 48, 1-10. doi: 10.1016/j.psyneuen.2014.06.001
Binder, E. B., Bradley, R. G., Liu, W., Epstein, M. P., Deveau, T. C., Mercer, K. B., . . . Ressler, K. J.
(2008). Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic
stress disorder symptoms in adults. JAMA, 299(11), 1291-1305. doi: 10.1001/jama.299.11.1291
Blaze, J., Asok, A., & Roth, T. L. (2015). The long-term impact of adverse caregiving environments
on epigenetic modifications and telomeres. Front Behav Neurosci, 9, 79. doi:
Bohacek, J., & Mansuy, I. M. (2013). Epigenetic inheritance of disease and disease risk.
Neuropsychopharmacology, 38(1), 220-236. doi: 10.1038/npp.2012.110
Bokkon, I., Vas, J. P., Csaszar, N., & Lukacs, T. (2014). Challenges to free will: transgenerational
epigenetic information, unconscious processes, and vanishing twin syndrome. Rev Neurosci,
25(1), 163-175. doi: 10.1515/revneuro-2013-0036
Boks, M. P., van Mierlo, H. C., Rutten, B. P., Radstake, T. R., De Witte, L., Geuze, E., . . . Vermetten,
E. (2015). Longitudinal changes of telomere length and epigenetic age related to traumatic
stress and post-traumatic stress disorder. Psychoneuroendocrinology, 51, 506-512. doi:
Bosquet Enlow, M., Kitts, R. L., Blood, E., Bizarro, A., Hofmeister, M., & Wright, R. J. (2011).
Maternal posttraumatic stress symptoms and infant emotional reactivity and emotion
regulation. Infant Behav Dev, 34(4), 487-503. doi: 10.1016/j.infbeh.2011.07.007
Bowers, M. E., & Yehuda, R. (2015). Intergenerational Transmission of Stress in Humans.
Neuropsychopharmacology, Aug 17, 1-13. doi: 10.1038/npp.2015.247
Bremner, J. D., Randall, P., Scott, T. M., Bronen, R. A., Seibyl, J. P., Southwick, S. M., . . . Innis, R.
B. (1995). MRI-based measurement of hippocampal volume in patients with combat-related
posttraumatic stress disorder. Am J Psychiatry, 152(7), 973-981. doi: 10.1176/ajp.152.7.973
Burggren, W. W., & Crews, D. (2014). Epigenetics in comparative biology: why we should pay
attention. Integr Comp Biol, 54(1), 7-20. doi: 10.1093/icb/icu013
Burmeister, M., McInnis, M. G., & Zollner, S. (2008). Psychiatric genetics: progress amid
controversy. Nat Rev Genet, 9(7), 527-540. doi: 10.1038/nrg2381
Bygren, L. O., Tinghog, P., Carstensen, J., Edvinsson, S., Kaati, G., Pembrey, M. E., & Sjostrom, M.
(2014). Change in paternal grandmothers' early food supply influenced cardiovascular
mortality of the female grandchildren. BMC Genet, 15, 12. doi: 10.1186/1471-2156-15-12
Callaway, E. (2013). Fearful memories passed down to mouse descendants. Nature magazine,
December 1. Retrieved from
Carlson, E. B, & Dalenberg C, J, (2000), A eonceptual framework for the impact of traumatic
experiences. trauma, Violence, & Abuse, 1(1), 4-28. doi: 10.1177/1524838000001001002
Champagne, F. A. (2013). Early environments, glucocorticoid receptors, and behavioral epigenetics.
Behav Neurosci, 127(5), 628-636. doi: 10.1037/a0034186
Choi, Y., & Mango, S. E. (2014). Hunting for Darwin's gemmules and Lamarck's fluid:
transgenerational signaling and histone methylation. Biochim Biophys Acta, 1839(12), 1440-
1453. doi: 10.1016/j.bbagrm.2014.05.011
Crews, D., Gillette, R., Miller-Crews, I., Gore, A. C., & Skinner, M. K. (2014). Nature, nurture and
epigenetics. Mol Cell Endocrinol, 398(1-2), 42-52. doi: 10.1016/j.mce.2014.07.013
Cross-Disorder Group of the Psychiatric Genomics Consortium. (2013). Identification of risk loci
with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet,
381(9875), 13711379. doi:10.1016/S0140-6736(12)62129-1
Damasio, A. (1994). Descartes’ error. New York: Penguin.
Danielson, C. K., Hankin, B. L., & Badanes, L. S. (2015). Youth offspring of mothers with
posttraumatic stress disorder have altered stress reactivity in response to a laboratory stressor.
Psychoneuroendocrinology, 53, 170-178. doi: 10.1016/j.psyneuen.2015.01.001
Dasberg, H. (1987). Psychological distress of Holocaust survivors and offspring in Israel, forty years
later: a review. Isr J Psychiatry Relat Sci, 24(4), 243-256.
Daskalakis, N. P., Bagot, R. C., Parker, K. J., Vinkers, C. H., & de Kloet, E. R. (2013). The three-hit
concept of vulnerability and resilience: toward understanding adaptation to early-life adversity
outcome. Psychoneuroendocrinology, 38(9), 1858-1873. doi: 10.1016/j.psyneuen.2013.06.008
Daskalakis, N. P., & Yehuda, R. (2014). Site-specific methylation changes in the glucocorticoid
receptor exon 1F promoter in relation to life adversity: systematic review of contributing
factors. Front Neurosci, 8, 369. doi: 10.3389/fnins.2014.00369
Daxinger, L., & Whitelaw, E. (2010). Transgenerational epigenetic inheritance: more questions than
answers. Genome Res, 20(12), 1623-1628. doi: 10.1101/gr.106138.110
de Kloet, C. S., Vermetten, E., Geuze, E., Kavelaars, A., Heijnen, C. J., & Westenberg, H. G. (2006).
Assessment of HPA-axis function in posttraumatic stress disorder: pharmacological and non-
pharmacological challenge tests, a review. J Psychiatr Res, 40(6), 550-567. doi:
de Quervain, D. J., Kolassa, I. T., Ackermann, S., Aerni, A., Boesiger, P., Demougin, P., . . .
Papassotiropoulos, A. (2012). PKCalpha is genetically linked to memory capacity in healthy
subjects and to risk for posttraumatic stress disorder in genocide survivors. Proc Natl Acad Sci
U S A, 109(22), 8746-8751. doi: 10.1073/pnas.1200857109
Debiec, J., & Sullivan, R. M. (2014). Intergenerational transmission of emotional trauma through
amygdala-dependent mother-to-infant transfer of specific fear. Proc Natl Acad Sci U S A,
111(33), 12222-12227. doi: 10.1073/pnas.1316740111
Dekel, S., Mandl, C., & Solomon, Z. (2013). Is the Holocaust implicated in posttraumatic growth in
second-generation Holocaust survivors? A prospective study. J Trauma Stress, 26(4), 530-533.
doi: 10.1002/jts.21836
Dias, B. G., Maddox, S. A., Klengel, T., & Ressler, K. J. (2015). Epigenetic mechanisms underlying
learning and the inheritance of learned behaviors. Trends Neurosci, 38(2), 96-107. doi:
Dias, B. G., & Ressler, K. J. (2014). Parental olfactory experience influences behavior and neural
structure in subsequent generations. Nat Neurosci, 17(1), 89-96. doi: 10.1038/nn.3594
Drake, A. J., & Walker, B. R. (2004). The intergenerational effects of fetal programming: non-
genomic mechanisms for the inheritance of low birth weight and cardiovascular risk. J
Endocrinol, 180(1), 1-16. doi: 10.1677/joe.0.1800001
Eitinger, L. (1993). The aging Holocaust survivor. Echoes of the Holocaust, 2.
Engelmann, M., Landgraf, R., & Wotjak, C. T. (2004). The hypothalamic-neurohypophysial system
regulates the hypothalamic-pituitary-adrenal axis under stress: an old concept revisited. Front
Neuroendocrinol, 25(3-4), 132-149. doi: 10.1016/j.yfrne.2004.09.001
Ennis, C. (2014). Epigenetics 101: a beginner’s guide to explaining everything. The Guardian, 25
April. Retrieved from
ETH Zurich (2014). Hereditary trauma: Inheritance of traumas and how they may be mediated.
ScienceDaily. 13 April. Retrieved from
Ferguson-Smith, A. C., & Patti, M. E. (2011). You are what your dad ate. Cell Metab, 13(2), 115-117.
doi: 10.1016/j.cmet.2011.01.011
Franklin, T. B. (2014). Chapter 28 - Transgenerational (Heritable) Epigenetics and Psychiatric
Disorders. In J. Peedicayil, D. R. Grayson, & D. Avramopoulos (Eds.), Epigenetics in
Psychiatry, (pp. 577-591) Boston: Academic Press. doi: 10.1016/B978-0-12-417114-5.00028-0.
Franklin, T. B., Russig, H., Weiss, I. C., Graff, J., Linder, N., Michalon, A., . . . Mansuy, I. M. (2010).
Epigenetic transmission of the impact of early stress across generations. Biol Psychiatry, 68(5),
408-415. doi: 10.1016/j.biopsych.2010.05.036
Gallagher, J. (2013). Memories’ pass between generations. BBC. 1 December. Retrieved from
Gapp, K., Jawaid, A., Sarkies, P., Bohacek, J., Pelczar, P., Prados, J., . . . Mansuy, I. M. (2014).
Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in
mice. Nat Neurosci, 17(5), 667-669. doi: 10.1038/nn.3695
Gillespie, C. F., Phifer, J., Bradley, B., & Ressler, K. J. (2009). Risk and resilience: genetic and
environmental influences on development of the stress response. Depress Anxiety, 26(11), 984-
992. doi: 10.1002/da.20605
Gluckman, P. D., Seng, C. Y., Fukuoka, H., Beedle, A. S., & Hanson, M. A. (2007). Low birthweight
and subsequent obesity in Japan. Lancet, 369(9567), 1081-1082. doi: 10.1016/s0140-
Gottschalk, S. (2003). Reli(e)ving the past: Emotion work in the Holocaust’s second generation.
Symbolic Interaction, 26(3), 355-380. doi: 10.1525/si.2003.26.3.355
Graff, J., Kim, D., Dobbin, M. M., & Tsai, L. H. (2011). Epigenetic regulation of gene expression in
physiological and pathological brain processes. Physiol Rev, 91(2), 603-649. doi:
Griffiths, B. B., & Hunter, R. G. (2014). Neuroepigenetics of stress. Neuroscience, 275, 420-435. doi:
Grossniklaus, U., Kelly, W. G., Ferguson-Smith, A. C., Pembrey, M., & Lindquist, S. (2013).
Transgenerational epigenetic inheritance: how important is it? Nat Rev Genet, 14(3), 228-235.
doi: 10.1038/nrg3435
Harper, L. V. (2005). Epigenetic inheritance and the intergenerational transfer of experience.
Psychol Bull, 131(3), 340-360. doi: 10.1037/0033-2909.131.3.340
Hazani, E., & Shasha, S. M. (2008). Effects of the Holocaust on the physical health of the offspring
of survivors. Isr Med Assoc J, 10(4), 251-255.
Heard, E., & Martienssen, R. A. (2014). Transgenerational epigenetic inheritance: myths and
mechanisms. Cell, 157(1), 95-109. doi: 10.1016/j.cell.2014.02.045
Heijmans, B. T., Tobi, E. W., Stein, A. D., Putter, H., Blauw, G. J., Susser, E. S., . . . Lumey, L. H.
(2008). Persistent epigenetic differences associated with prenatal exposure to famine in
humans. Proc Natl Acad Sci U S A, 105(44), 17046-17049. doi: 10.1073/pnas.0806560105
Heim, C., Ehlert, U., & Helhammer, D. H. (2000). The potential role of hypocortisolism in the
pathophysiology of stress-related bodily disorders. Psychoneuroendocrinology, 25(1), 1-35.
doi: 10.1016/S0306-4530(99)00035-9
Hofer, M. A. (2014). The emerging synthesis of development and evolution: A new biology for
psychoanalysis. Neuropsychoanalysis, 16(1), 3-22. doi: 10.1080/15294145.2014.901022
Hong, C., & Efferth, T. (2015). Systematic Review on Post-Traumatic Stress Disorder Among
Survivors of the Wenchuan Earthquake. Trauma Violence Abuse. doi:
Hosken, D. J., & Hodgson, D. J. (2014). Why do sperm carry RNA? Relatedness, conflict, and
control. Trends in Ecology & Evolution, 29(8), 451-455.
Hulme, P. A. (2011). Childhood sexual abuse, HPA axis regulation, and mental health: an integrative
review. West J Nurs Res, 33(8), 1069-1097. doi: 10.1177/0193945910388949
Jablonka, E., & Raz, G. (2009). Transgenerational epigenetic inheritance: prevalence, mechanisms,
and implications for the study of heredity and evolution. Q Rev Biol, 84(2), 131-176. doi:
Kaouane, N., Porte, Y., Vallee, M., Brayda-Bruno, L., Mons, N., Calandreau, L., . . . Desmedt, A.
(2012). Glucocorticoids can induce PTSD-like memory impairments in mice. Science,
335(6075), 1510-1513. doi: 10.1126/science.1207615
Kellermann, N. P. (2001). Transmission of Holocaust trauma--an integrative view. Psychiatry,
64(3), 256-267. doi:10.1521/psyc.
Kellermann, N. P. (2009) Holocaust Trauma: psychological effects and treatment. Bloomington,
IN.: iUniverse.
Kellermann, N. P. (2013). Epigenetic transmission of holocaust trauma: can nightmares be
inherited? Isr J Psychiatry Relat Sci, 50(1), 33-39. Retrieved from
Klengel, T., Mehta, D., Anacker, C., Rex-Haffner, M., Pruessner, J. C., Pariante, C. M., . . . Binder, E.
B. (2013). Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma
interactions. Nat Neurosci, 16(1), 33-41. doi: 10.1038/nn.3275
Klengel, T., Dias, B. G., & Ressler, K. J. (2015). Models of intergenerational and transgenerational
transmission of risk for psychopathology in mice. Neuropsychopharmacology, Aug. 18.
LaBar, K. S., & Cabeza, R. (2006). Cognitive neuroscience of emotional memory. Nat Rev Neurosci,
7(1), 54-64. doi: 10.1038/nrn1825
Lambert, J. E., Holzer, J., & Hasbun, A. (2014). Association between parents' PTSD severity and
children's psychological distress: a meta-analysis. J Trauma Stress, 27(1), 9-17. doi:
Lee, S. H., Ripke, S., Neale, B. M., Faraone, S. V., Purcell, S. M., Perlis, R. H., . . . Wray, N. R. (2013).
Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.
Nat Genet, 45(9), 984-994. doi: 10.1038/ng.2711
Lehrner, A., Bierer, L. M., Passarelli, V., Pratchett, L. C., Flory, J. D., Bader, H. N., . . . Yehuda, R.
(2014). Maternal PTSD associates with greater glucocorticoid sensitivity in offspring of
Holocaust survivors. Psychoneuroendocrinology, 40, 213-220. doi:
LeRoux, M. (2013). Mice can ‘warn’ sons, grandsons of dangers via sperm. Medicalxpress.
December 1. Retrieved from
Li, E., Beard, C., & Jaenisch, R. (1993). Role for DNA methylation in genomic imprinting. Nature,
366(6453), 362-365. doi: 10.1038/366362a0
Lillycrop, K. A., Slater-Jefferies, J. L., Hanson, M. A., Godfrey, K. M., Jackson, A. A., & Burdge, G. C.
(2007). Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the
offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA
methyltransferase-1 expression is involved in impaired DNA methylation and changes in
histone modifications. Br J Nutr, 97(6), 1064-1073. doi: 10.1017/s000711450769196x
Lim, J. P., & Brunet, A. (2013). Bridging the transgenerational gap with epigenetic memory. Trends
Genet, 29(3), 176-186. doi: 10.1016/j.tig.2012.12.008
Maddox, S. A., Schafe, G. E., & Ressler, K. J. (2013). Exploring epigenetic regulation of fear memory
and biomarkers associated with post-traumatic stress disorder. Front Psychiatry, 4, 62. doi:
McEwen, B. (2000). Allostasis and Allostatic Load: Implications for Neuropsychopharmacology.
Neuropsychopharmacology, 22(2), 108-124. doi:10.1016/S0893-133X(99)00129-3
McEwen BS, Bowles NP, Gray JD, Hill MN, Hunter RG, Karatsoreos IN, Nasca C. (2015).
Mechanisms of stress in the brain. Nat Neurosci. 2015 Oct;18(10) 1353-1363.
doi:10.1038/nn.4086. PMID: 26404710.
McGaugh, J. L. (2000). Memory--a century of consolidation. Science, 287(5451), 248-251. doi:
McGowan, P. O., Sasaki, A., Huang, T. C., Unterberger, A., Suderman, M., Ernst, C., . . . Szyf, M.
(2008). Promoter-wide hypermethylation of the ribosomal RNA gene promoter in the suicide
brain. PLoS One, 3(5), e2085. doi: 10.1371/journal.pone.0002085
Meaney, M. J., & Szyf, M. (2005). Environmental programming of stress responses through DNA
methylation: life at the interface between a dynamic environment and a fixed genome.
Dialogues Clin Neurosci, 7(2), 103-123. PMC3181727
Meewisse, M. L., Reitsma, J. B., de Vries, G. J., Gersons, B. P., & Olff, M. (2007). Cortisol and post-
traumatic stress disorder in adults: systematic review and meta-analysis. Br J Psychiatry, 191,
387-392. doi: 10.1192/bjp.bp.106.024877
Miller, G. E., Chen, E., & Zhou, E. S. (2007). If it goes up, must it come down? Chronic stress and
the hypothalamic-pituitary-adrenocortical axis in humans. Psychol Bull, 133(1), 25-45. doi:
Milne, A. M., MacQueen, G. M., & Hall, G. B. (2012). Abnormal hippocampal activation in patients
with extensive history of major depression: an fMRI study. J Psychiatry Neurosci, 37(1), 28-36.
doi: 10.1503/jpn.110004
Moore, D. S, (2015). The developing genome: an introduction to behavioral epigenetics. New York:
Oxford University Press.
Nachimovsky, Y, (1948). Medical examinations at the employment office of the Kovno ghetto
(Yiddish). Fun Letzten Hurban (10), Munich: 2837.
Neary, N., & Nieman, L. (2010). Adrenal Insufficiency- etiology, diagnosis and treatment. Current
Opinion in Endocrinology, Diabetes, and Obesity, 17(3), 217223.
Neuner, F., Schauer, M., Karunakara, U., Klaschik, C., Robert, C., & Elbert, T. (2004). Psychological
trauma and evidence for enhanced vulnerability for posttraumatic stress disorder through
previous trauma among West Nile refugees. BMC Psychiatry, 4, 34. doi: 10.1186/1471-244x-4-
Neylan, T. C., Schadt, E. E. & Yehuda, R. (2014). Biomarkers for combat-related PTSD: focus on
molecular networks from high-dimensional data. Eur J Psychotraumatol. Published online
Aug 14. doi: 10.3402/ejpt.v5.23938
Niculescu, A. B., Levey, D. F. Phalen, P. L., Le-Niculescu, H., Dainton, H. D., Jain, N., . . . Salomon,
D. R. (2015). Understanding and predicting suicidality using a combined genomic and clinical
risk assessment approach. Molecular Psychiatry, Aug 18, doi: 10.1038/mp.2015.112
Oken, B. S., Chamine, I., & Wakeland, W. (2014). A systems approach to stress, stressors and
resilience in humans, Behavioural Brain Research, 282, 144-154.
Onoye, J. M., Shafer, L. A., Goebert, D. A., Morland, L. A., Matsu, C. R., & Hamagami, F. (2013).
Changes in PTSD Symptomatology and Mental Health During Pregnancy and Postpartum.
Archives of Women’s Mental Health, 16(6), 453463. doi:10.1007/s00737-013-0365-8
Perroud, N., Rutembesa, E., Paoloni-Giacobino, A., Mutabaruka, J., Mutesa, L., Stenz, L., . . .
Karege, F. (2014). The Tutsi genocide and transgenerational transmission of maternal stress:
epigenetics and biology of the HPA axis. World J Biol Psychiatry, 15(4), 334-345. doi:
Perry, B, D, (1999). Memories of fear: How the brain stores and retrieves physiological states,
feelings, behaviors, and thoughts from traumatic events. In J, Goodwin & R, Attias (Eds.),
Images of the body in trauma. New York: Basic Books, pp. 9-38.
Petronis, A. (2010). Epigenetics as a unifying principle in the aetiology of complex traits and
diseases. Nature, 465(7299), 721-727. doi: 10.1038/nature09230
Preiss, L (2009), Women’s health in the ghettos of eastern Europe. Jewish women: A
comprehensive historical encyclopedia. Jewish women’s archive. Retrieved from
Provençal, N., & Binder, E. B. (2015a). The effects of early life stress on the epigenome: From the
womb to adulthood and even before. Exp Neurol, 268, 10-20. doi:
Provençal, N., & Binder, E. B. (2015b). The neurobiological effects of stress as contributors to
psychiatric disorders: focus on epigenetics. Curr Opin Neurobiol, 30, 31-37. doi:
Qiu, J. (2006). Epigenetics: unfinished symphony. Nature, 441(7090), 143-145. doi:
Raabe, F. J., & Spengler, D. (2013). Epigenetic Risk Factors in PTSD and Depression. Front
Psychiatry, 4. doi: 10.3389/fpsyt.2013.00080
Reul, J. M. (2014). Making memories of stressful events: a journey along epigenetic, gene
transcription, and signaling pathways. Front Psychiatry, 5, 5. doi: 10.3389/fpsyt.2014.00005
Richter-Levin, G., & Akirav, I. (2000). Amygdala-hippocampus dynamic interaction in relation to
memory. Mol Neurobiol, 22(1-3), 11-20. doi: 10.1385/mn:22:1-3:011
Roberts, A. L., Galea, S., Austin, S. B., Cerda, M., Wright, R. J., Rich-Edwards, J. W., & Koenen, K.
C. (2012). Posttraumatic stress disorder across two generations: concordance and mechanisms
in a population-based sample. Biol Psychiatry, 72(6), 505-511. doi:
Rodgers, A. B., & Bale, T. L. (2015). Germ Cell Origins of Posttraumatic Stress Disorder Risk: The
Transgenerational Impact of Parental Stress Experience. Biol Psychiatry. doi:
Roth, M., Neuner, F., & Elbert, T. (2014). Transgenerational consequences of PTSD: risk factors for
the mental health of children whose mothers have been exposed to the Rwandan genocide. Int
J Ment Health Syst, 8(1), 12. doi: 10.1186/1752-4458-8-12
Roth, T. L. (2014). How Traumatic Experiences Leave Their Signature on the Genome: An Overview
of Epigenetic Pathways in PTSD. Front Psychiatry, 5, 93. doi: 10.3389/fpsyt.2014.00093
Rudan, I. (2010). New technologies provide insights into genetic basis of psychiatric disorders and
explain their co-morbidity. Psychiatr Danub, 22(2), 190-192. doi:
Saco, T. V., Parthasarathy, P. T., Cho, Y., Lockey, R. F., & Kolliputi, N. (2014). Role of epigenetics in
pulmonary hypertension. Am J Physiol Cell Physiol, 306(12), C1101-1105. doi:
Sakashita, K., Koike, K., Kinoshita, T., Shiohara, M., Kamijo, T., Taniguchi, S., & Kubota, T. (2001).
Dynamic DNA methylation change in the CpG island region of p15 during human myeloid
development. J Clin Invest, 108(8), 1195-1204. doi: 10.1172/jci13030
Samuelson, K. W. (2011). Post-traumatic stress disorder and declarative memory functioning: a
review. Dialogues Clin Neurosci, 13(3), 346-351.
Sapolsky, R., Krey, L., & McEwen, B. (1986). The neuroendocrinology of stress and aging: the
glucocorticoid cascade hypothesis. Endocr Rev, 7, 284306.;2002/38/cp21
Schleithoff, C., Voelter-Mahlknecht, S., Dahmke, I. N., & Mahlknecht, U. (2012). On the epigenetics
of vascular regulation and disease. Clin Epigenetics, 4(1), 7. doi: 10.1186/1868-7083-4-7
Schoedl, A. F., Costa, M. P., Fossaluza, V., Mari, J. J., & Mello, M. F. (2014). Specific traumatic
events during childhood as risk factors for posttraumatic stress disorder development in adults.
J Health Psychol, 19(7), 847-857. doi: 10.1177/1359105313481074
Seckl, J. R., & Meaney, M. J. (2006). Glucocorticoid "programming" and PTSD risk. Ann N Y Acad
Sci, 1071, 351-378. doi: 10.1196/annals.1364.027
Segman, R. H., & Shalev, A. Y. (2003). Genetics of posttraumatic stress disorder. CNS Spectr, 8(9),
Sharma, A. (2014). Bioinformatic analysis revealing association of exosomal mRNAs and proteins in
epigenetic inheritance. J Theor Biol, 357, 143-149. doi: 10.1016/j.jtbi.2014.05.019
Shrira, A. (2015). Transmitting the Sum of All Fears: Iranian Nuclear Threat Salience Among
Offspring of Holocaust Survivors. Psychol Trauma: Theory, Research, Practice, and Policy,
7(4). 364-371. doi: 10.1037/tra0000029
Sipahi, L., Wildman, D. E., Aiello, A. E., Koenen, K. C., Galea, S., Abbas, A., & Uddin, M. (2014).
Longitudinal epigenetic variation of DNA methyltransferase genes is associated with
vulnerability to post-traumatic stress disorder. Psychol Med, 44(15), 3165-3179. doi:
Skelton, K., Ressler, K. J., Norrholm, S. D., Jovanovic, T., & Bradley-Davino, B. (2012). PTSD and
gene variants: new pathways and new thinking. Neuropharmacology, 62(2), 628-637. doi:
Sperling, W., Kreil, S., & Biermann, T. (2012). Somatic diseases in child survivors of the Holocaust
with posttraumatic stress disorder: a comparative study. J Nerv Ment Dis, 200(5), 423-428.
doi: 10.1097/NMD.0b013e318253229e
St Clair, D., Xu, M., Wang, P., Yu, Y., Fang, Y., Zhang, F., . . . He, L. (2005). Rates of adult
schizophrenia following prenatal exposure to the Chinese famine of 1959-1961. JAMA, 294(5),
557-562. doi: 10.1001/jama.294.5.557
Sun, H., Kennedy, P. J., & Nestler, E. J. (2013). Epigenetics of the depressed brain: role of histone
acetylation and methylation. Neuropsychopharmacology, 38(1), 124-137. doi:
Surani, M. A. (2001). Reprogramming of genome function through epigenetic inheritance. Nature,
414(6859), 122-128. doi: 10.1038/35102186
Takizawa, T., Nakashima, K., Namihira, M., Ochiai, W., Uemura, A., Yanagisawa, M., . . . Taga, T.
(2001). DNA methylation is a critical cell-intrinsic determinant of astrocyte differentiation in
the fetal brain. Dev Cell, 1(6), 749-758.
Tang, W. W., Dietmann, S., Irie, N., Leitch, H. G., Floros, V. I., Bradshaw, C. R., . . . Surani, M. A.
(2015). A Unique Gene Regulatory Network Resets the Human Germline Epigenome for
Development. Cell, 161(6), 1453-1467. doi: 10.1016/j.cell.2015.04.053
Thakur, G. S., Daigle, B. J., Jr., Dean, K. R., Zhang, Y., Rodriguez-Fernandez, M., Hammamieh, R., .
. . Doyle, F. J., 3rd. (2015). Systems biology approach to understanding post-traumatic stress
disorder. Mol Biosyst, 11(4), 980-993. doi: 10.1039/c4mb00404c
Thomson, H. (2015). First evidence of how parents' lives could change children's DNA. New
Scientist. 4 June. doi: 10.1016/j.cell.2015.04.053
Tollefsbol, T. (Ed.) (2014). Transgenerational epigenetics. London: Academic Press.
Tong, M. T., Peace, S. T., & Cleland, T. A. (2014). Properties and mechanisms of olfactory learning
and memory. Front Behav Neurosci, 8, 238. doi: 10.3389/fnbeh.2014.00238
Toyokawa, S., Uddin, M., Koenen, K. C., & Galea, S. (2012). How does the social environment 'get
into the mind'? Epigenetics at the intersection of social and psychiatric epidemiology. Soc Sci
Med, 74(1), 67-74. doi: 10.1016/j.socscimed.2011.09.036
True, W. R., Rice, J., Eisen, S. A., Heath, A. C., Goldberg, J., Lyons, M. J., & Nowak, J. (1993). A
twin study of genetic and environmental contributions to liability for posttraumatic stress
symptoms. Arch Gen Psychiatry, 50(4), 257-264..doi:
Voisey, J., Young, R. M., Lawford, B. R., & Morris, C. P. (2014). Progress towards understanding the
genetics of posttraumatic stress disorder. J Anxiety Disord, 28(8), 873-883. doi:
Vukojevic, V., Kolassa, I. T., Fastenrath, M., Gschwind, L., Spalek, K., Milnik, A., . . . de Quervain, D.
J. (2014). Epigenetic modification of the glucocorticoid receptor gene is linked to traumatic
memory and post-traumatic stress disorder risk in genocide survivors. J Neurosci, 34(31),
10274-10284. doi: 10.1523/jneurosci.1526-14.2014
Wardi, D. (1992). Memorial Candles: Children of the Holocaust. London: Routledge.
Wasserman, D., Sokolowski, M., Rozanov, V., & Wasserman, J. (2008). The CRHR1 gene: a marker
for suicidality in depressed males exposed to low stress. Genes Brain Behav, 7(1), 14-19. doi:
Weaver, I. C., Cervoni, N., Champagne, F. A., D'Alessio, A. C., Sharma, S., Seckl, J. R., . . . Meaney,
M. J. (2004). Epigenetic programming by maternal behavior. Nat Neurosci, 7(8), 847-854. doi:
Wilker, S. & Kolassa, I-T. (2013). The formation of a neural fear network in posttraumatic stress
disorder: Insights from molecular genetics. Clinical Psychological Science, 1(4), 452469. doi:
Wilker, S., Pfeiffer, A., Kolassa, S., Elbert, T., Lingenfelder, B., Ovuga, E., . . . Kolassa, I. T. (2014).
The role of FKBP5 genotype in moderating long-term effectiveness of exposure-based
psychotherapy for posttraumatic stress disorder. Transl Psychiatry, 4, e403. doi:
Yahyavi, S. T., Zarghami, M., & Marwah, U. (2013). A review on the evidence of transgenerational
transmission of posttraumatic stress disorder vulnerability. Rev Bras Psiquiatr, 36(1), Dec 23.
doi: 10.1590/1516-4446-2012-0995
Yao, Y., Robinson, A. M., Zucchi, F. C., Robbins, J. C., Babenko, O., Kovalchuk, O., . . . Metz, G. A.
(2014). Ancestral exposure to stress epigenetically programs preterm birth risk and adverse
maternal and newborn outcomes. BMC Med, 12, 121. doi: 10.1186/s12916-014-0121-6
Yehuda, R. (2005). Neuroendocrine aspects of PTSD. Handb Exp Pharmacol, 169, 371-403.
Yehuda, R. (2009). Status of glucocorticoid alterations in post-traumatic stress disorder. Ann N Y
Acad Sci, 1179, 56-69. doi: 10.1111/j.1749-6632.2009.04979.x
Yehuda, R., Bell, A., Bierer, L. M., & Schmeidler, J. (2008). Maternal, not paternal PTSD, is related
to increased risk for PTSD in offspring of Holocaust survivors. J Psychiat Res, 42(13), 1104
1111. doi:10.1016/j.jpsychires.2008.01.002
Yehuda, R & Bierer, L. M. (2009). The relevance of epigenetics to PTSD: Implications for the DSM-
V. J Trauma Stress, 22, 427434. doi: 10.1002/jts.20448
Yehuda, R., Daskalakis, N.P., Bierer, L. M., Bader, H. N., Klengel, T., Holsboer, F. & Binder, E. B.
(2015). Holocaust Exposure Induced Intergenerational Effects onFKBP5 Methylation. Biol
Psychiat, Published Online Aug 12. doi:
Yehuda, R., Daskalakis, N. P., Lehrner, A., Desarnaud, F., Bader, H. N., Makotkine, I., . . . Meaney,
M. J. (2014a). Influences of maternal and paternal PTSD on epigenetic regulation of the
glucocorticoid receptor gene in Holocaust survivor offspring. Am J Psychiatry, 171(8), 872-
880. doi: 10.1176/appi.ajp.2014.13121571
Yehuda, R., Engel, S. M., Brand, S. R., Seckl, J., Marcus, S. M., & Berkowitz, G. S. (2005).
Transgenerational effects of posttraumatic stress disorder in babies of mothers exposed to the
World Trade Center attacks during pregnancy. J Clin Endocrinol Metab, 90(7), 4115-4118. doi:
Yehuda, R., Halligan, S. L., & Bierer, L. M. (2001). Relationship of parental trauma exposure and
PTSD to PTSD, depressive and anxiety disorders in offspring. J Psychiatr Res, 35(5), 261-270.
doi: 10.1016/S0022-3956(01)00032-2
Yehuda, R., Halligan, S. L., & Bierer, L. M. (2002). Cortisol levels in adult offspring of Holocaust
survivors: relation to PTSD symptom severity in the parent and child.
Psychoneuroendocrinology, 27(1-2), 171-180.
Yehuda, R., & LeDoux, J. (2007). Response variation following trauma: a translational neuroscience
approach to understanding PTSD. Neuron, 56(1), 19-32. doi: 10.1016/j.neuron.2007.09.006
Yehuda, R., Pratchett, L. C., Elmes, M. W., Lehrner, A., Daskalakis, N. P., Koch, E., . . . Bierer, L. M.
(2014b). Glucocorticoid-related predictors and correlates of post-traumatic stress disorder
treatment response in combat veterans. Interface Focus, 4(5), 20140048. doi:
Yehuda, R., Teicher, M. H., Seckl, J. R., Grossman, R. A., Morris, A., & Bierer, L. M. (2007).
Parental posttraumatic stress disorder as a vulnerability factor for low cortisol trait in offspring
of holocaust survivors. Arch Gen Psychiatry, 64(9), 1040-1048. doi:
Zannas, A. S., Provençal, N., & Binder, E. B. (2014). Epigenetics of posttraumatic stress disorder:
Current evidence, challenges, and future directions. Biological Psychiatry, 78(5), 327-335. doi:
Zovkic, I. B., Meadows, J. P., Kaas, G. A., & Sweatt, J. D. (2013). Interindividual variability in stress
susceptibility: A role for epigenetic mechanisms in PTSD. Front Psychiatry, 4, 60. doi:
Zovkic, I. B., & Sweatt, J. D. (2013). Epigenetic mechanisms in learned fear: implications for PTSD.
Neuropsychopharmacology, 38(1), 77-93. doi: 10.1038/npp.2012.79
... As a result, there is a lack of progress in new treatments that were assumed to come from this new knowledge (Fava, Guidi, Grandi, & Hasler, 2014;Krystal et al., 2017). Since no specific biomarker of HT has been clearly identified, the biological part of transgenerational transmission of trauma cannot be verified (Kellermann, 2015). ...
... Few societies in the world have experienced more traumatic loss than American Indians. New research also shows that trauma can be passed on from mother to child, though the implications of that for suicide are as yet unknown (Kellerman, 2015). ...
Full-text available
This chapter examines history and theories of suicide from the early modern period to the present. It examines changes in suicide practices, methods, and motivations. The suicides which occur in America today are consistent with those that occurred in the past. The historical focus will be on the peoples of North America who are of Native American, European, and African for the trends established there. Additionally, theories about who commits suicide and why are explained to establish the current state of the field of suicidology.
... Few societies in the world have experienced more traumatic loss than American Indians. New research also shows that trauma can be passed on from mother to child, though the implications of that for suicide are as yet unknown (Kellerman, 2015). ...
This chapter examines protective factors in greater depth. Books on suicide all examine motivations for suicide, but often do not examine the motivations for living. The mundane and ordinary aspects of life sustain people, and an approach to combatting suicide that recognizes those positive factors builds on what already exists. It is possible to construct communities that promote and foster social support systems, healthy lifestyles, and full use of people’s skills and gifts. This includes finding a reason to live, and that often comes from having responsibility—though not at such a level that it is overwhelming.
... Few societies in the world have experienced more traumatic loss than American Indians. New research also shows that trauma can be passed on from mother to child, though the implications of that for suicide are as yet unknown (Kellerman, 2015). ...
The 174 individuals who wrote notes actively sought to express their thoughts, desires, or emotions. They wanted to leave instructions, apologies, and explanations. Those direct communications helped inform us as to what motivated them to take their own lives. There are very different characteristics among and between groups of people who kill themselves. Prevention and intervention must be tailored to fit the groups. We summarize our findings as they represent multiple and complex motivations, and offer a simplified template for understanding motivations and risk factors.
... Few societies in the world have experienced more traumatic loss than American Indians. New research also shows that trauma can be passed on from mother to child, though the implications of that for suicide are as yet unknown (Kellerman, 2015). ...
In this chapter we discuss the desire to escape from pain, which represents the largest motivating factor in our sample. For some, that escape was from actual physical or psychological pain. For others, the escape was related to circumstances which they believed were too difficult to overcome. Of 936 people, 658 (70%) were escaping from pain. The source of the pain was psychological (32%), physical (18%), legal (8%), financial (3%), or a combination of many of these things (39%). When cases were sorted into these groups, clear patterns emerged. We discuss our findings related to these categories.
... Few societies in the world have experienced more traumatic loss than American Indians. New research also shows that trauma can be passed on from mother to child, though the implications of that for suicide are as yet unknown (Kellerman, 2015). ...
The motivations discussed in this chapter represent a very small proportion of individuals in our sample. One group (60 people) committed suicide because of grief issues (31 people), while others felt like a failure in life (22 people). We examined specific patterns that can be seen within both the bereavement and failure categories, which can provide information about risk and protective factors.
... Few societies in the world have experienced more traumatic loss than American Indians. New research also shows that trauma can be passed on from mother to child, though the implications of that for suicide are as yet unknown (Kellerman, 2015). ...
The rate of suicides across all age groups except the elderly is at its highest level in nearly 30 years. Suicide notes have long been thought to be valuable resources for understanding suicide motivation, but up to now the small sample sizes available have made an in-depth analysis difficult. Explaining Suicide: Patterns, Motivations, and What Notes Reveal represents the first large-scale analysis of suicide motivation across multiple ages in the same time period. This was made possible via a unique dataset of all suicide notes collected by the coroner’s office in southwestern Ohio 2000-2009. Based on an analysis of this dataset and those from other European and Oceanic studies, the book identifies top motivations for suicide, how these differ between note leavers and non-note leavers, and what this can tell us about better suicide prevention. The book reveals the extent to which suicide is motivated by interpersonal violence, substance abuse, physical pain, grief, feelings of failure, and mental illness. The book additionally discusses other risk factors, what differentiates suicide attempters from suicide completers, and lastly what might serve as protective factors toward resilience. I can't send you the full text, as this a book that just came out and our publisher wants us to sell copies. But there is a substantial portion of the book on google books.
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The debate of Chronic Disease is not a Evolvability Accident, hence parts of Evolvavility & Poliphenism itself. In the same way, genes is not the target of selection, but the long term units of evolutionary changes to serve adaptive requeriment, them the role of phenotype variation& behavioral plasticity and the role of epigenetic inheritance that regulate transcriptional activity are a dynamic adaptation in a highly dimensional adaptive way that includes chronic diseases in evolution.
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Posttraumatic stress disorder (PTSD) is a prevalent anxiety disorder marked by behavioral, physiologic, and hormonal alterations. PTSD is disabling and commonly follows a chronic course. The etiology of PTSD is unknown, although exposure to a traumatic event constitutes a necessary, but not sufficient, factor. A twin study of Vietnam veterans has shown significant genetic contribution to PTSD. The fact that PTSD's underlying genotypic vulnerability is only expressed following trauma exposure limits the usefulness of family-based linkage approaches. In contrast to the other major psychiatric disorders, large studies for the search of underlying genes have not been described in PTSD to date. Complementary approaches for locating involved genes include association-based studies employing case-control or parental genotypes for transmission dysequilibrium analysis and quantitative trait loci studies in animal models. Identification of susceptibility genes will increase our understanding of traumatic stress disorders and help to elucidate their molecular basis. The current review provides an up-to-date outline of progress in the field of PTSD.
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This book offers a comprehensive overview of the long-term psychological effects of Holocaust trauma. It covers not only the direct effects on the actual survivors and the transmission upon the offspring, but also the collective effects upon other affected populations, including the Israeli Jewish and the societies in Germany and Austria.
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The brain is the central organ involved in perceiving and adapting to social and physical stressors via multiple interacting mediators, from the cell surface to the cytoskeleton to epigenetic regulation and nongenomic mechanisms. A key result of stress is structural remodeling of neural architecture, which may be a sign of successful adaptation, whereas persistence of these changes when stress ends indicates failed resilience. Excitatory amino acids and glucocorticoids have key roles in these processes, along with a growing list of extra- and intracellular mediators that includes endocannabinoids and brain-derived neurotrophic factor (BDNF). The result is a continually changing pattern of gene expression mediated by epigenetic mechanisms involving histone modifications and CpG methylation and hydroxymethylation as well as by the activity of retrotransposons that may alter genomic stability. Elucidation of the underlying mechanisms of plasticity and vulnerability of the brain provides a basis for understanding the efficacy of interventions for anxiety and depressive disorders as well as age-related cognitive decline.
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The hypothesis that offspring are affected by parental trauma or stress exposure, first noted anecdotally, is now supported empirically, most famously by data from Holocaust survivor offspring cohorts. These findings have been extended to less extreme forms of stress, where differential physical, behavioral, and cognitive outcomes are observed in affected offspring. Parental stress-mediated effects in offspring could be explained by genetics or social learning theory. Alternatively, biological variations stemming from stress exposure in parents could more directly impact offspring, a concept we refer to here as "intergenerational transmission", via changes to gametes and the gestational uterine environment. We further extend this definition to include the transmission of stress to offspring via early postnatal care, as animal studies demonstrate the importance of early maternal care of pups in effecting offspring long-term behavioral changes. Here, we review clinical observations in offspring, noting that offspring of stress or trauma exposed parents may be at greater risk for physical, behavioral, and cognitive problems, as well as psychopathology. Furthermore, we review findings concerning offspring biological correlates of parental stress, in particular, offspring neuroendocrine, epigenetic, and neuroanatomical changes, in an attempt to determine when and how these parental stress effects were transmitted. Although understanding the etiology of effects in offspring is currently impeded by methodological constraints, among other limitations, we propose ways to overcome these issues, and conclude by presenting additional hypotheses that have been prompted by recent studies in the field.Neuropsychopharmacology accepted article preview online, 17 August 2015. doi:10.1038/npp.2015.247.
As the children of the Holocaust reach adulthood, they often need professional help in establishing a new identity and self-esteem. During their childhood their parents have unconsciously transmitted to them much of their own trauma, investing them with all their memories and hopes, so that they become 'memorial candles' to those who did not survive. The book combines verbatim transcriptions of dialogues in individual and group psychotherapy sessions with analyses of dreams, fantasies and childhood memories. Diana Wardi traces the emotional history of her patients, accompanying them on a painful and moving journey into their inner world. She describes the children's infancy in the guilt-laden atmosphere of survivor families, through to their difficult separation from their parents in maturity. she also traces in detail the therapeutic process which culminates in the patients' separation from the role of 'memorial candle'.
Epigenetic mechanisms allow for variations in the expression of genetic information that lead to phenotypic changes. During mitotic cell divisions the epigenetic states are inherited from one cell to another, but much of the epigenetic message of the genome is reset during reproduction of an organism. However, the epigenetic erasure process is not complete and meiotic epigenetic transfer of information may allow phenotypic traits to appear in subsequent generations, a process referred to as transgenerational epigenetics. The epigenetic information, often established by mechanisms such as DNA methylation, histone modifications, and non-coding RNA, may not only influence gene expression in the first generation of offspring, but may persist for multiple generations. Additionally, generational epigenetic transfer has been implicated in a number of medical disorders, such as metabolic diseases, mental disorders, and cardiovascular and reproductive diseases. Clinical intervention in disorders of generational epigenetic inheritance are rapidly developing and could provide significant advances in managing heritable disorders or diseases that have been relatively recalcitrant to more conventional approaches to therapy.
Although controversial, there is increasing evidence from a variety of disciplines suggesting that transgenerational epigenetic inheritance is a mechanism that can act as an environmentally driven rapid form of adaptation in mammals. It has been suggested that transgenerational epigenetic inheritance may play a role in psychiatric disorders because the risk of developing a psychiatric disorder is heightened by exposure to stressful events, and this increased risk appears to be passed on to the offspring of the individual, independent of parental factors. Here, I discuss studies across several disciplines that provide evidence for transgenerational epigenetic inheritance and the possible mechanisms involved, including DNA methylation, histone posttranslational modifications, and non-coding RNAs. Finally, recent findings demonstrating transgenerational epigenetic inheritance in animal models of stress-induced affective disorders and drug abuse are examined.
Over the past 5 yr, we have examined some of the sharpest edges of the pathology of aging. We have studied the capacity of aged organisms to respond appropriately to stress and the capacity of stress to cumulatively damage aging tissue. The idea of a relationship between stress and aging has permeated the gerontology literature in two forms. First, senescence has been thought of as a time of decreased adaptiveness to stress. This idea has been supported frequently, as many aged physiological systems function normally under basal conditions, yet do not adequately respond to a challenge. For example, aged and young humans have similar basal body temperatures, but the former are relatively impaired in thermoregulatory capacities when heat- or cold-challenged. A second theme in gerontology concerning stress is that chronic stress can accelerate the aging process. Selye and Tuchweber for example, postulated a finite "adaptational energy" in an organism, with prolonged stress prematurely depleting such reserves, thus accelerating the onset of senescence. This idea was derivative of earlier idea that the "rate of living" could be a pacemaker of aging. Experimentally, varied approaches have supported the notion that at least some biomarkers of age can be accelerated by stress. The above hypotheses led us to examine the adrenocortical axis, the endocrine axis which is among the most central to the stress response. Our findings support both of these concepts. We find that the aged male rat is impaired in terminating the secretion of adrenocortical stress hormones, glucocorticoids, at the end of stress. This hormonal excess may be due to degenerative changes in a region of the brain which normally inhibits glucocorticoid release; the degeneration, in turn, is caused by cumulative exposure to glucocorticoids. Together, these effects form a feed-forward cascade with potentially serious pathophysiological consequences in the aged subject. Reproduced by permission. Robert M. Sapolsky, Lewis C. Krey, Bruce S. McEwen, The Neuroendocrinology of Stress and Aging: The Glucocorticoid Cascade Hypothesis. Endocr. Rev. 7 , 284-301 (1986).
Background: The involvement of epigenetic mechanisms in intergenerational transmission of stress effects has been demonstrated in animals but not in humans. Methods: Cytosine methylation within the gene encoding for FK506 binding protein 5 (FKBP5) was measured in Holocaust survivors (n = 32), their adult offspring (n = 22), and demographically comparable parent (n = 8) and offspring (n = 9) control subjects, respectively. Cytosine-phosphate-guanine sites for analysis were chosen based on their spatial proximity to the intron 7 glucocorticoid response elements. Results: Holocaust exposure had an effect on FKBP5 methylation that was observed in exposed parents as well in their offspring. These effects were observed at bin 3/site 6. Interestingly, in Holocaust survivors, methylation at this site was higher in comparison with control subjects, whereas in Holocaust offspring, methylation was lower. Methylation levels for exposed parents and their offspring were significantly correlated. In contrast to the findings at bin 3/site 6, offspring methylation at bin 2/sites 3 to 5 was associated with childhood physical and sexual abuse in interaction with an FKBP5 risk allele previously associated with vulnerability to psychological consequences of childhood adversity. The findings suggest the possibility of site specificity to environmental influences, as sites in bins 3 and 2 were differentially associated with parental trauma and the offspring's own childhood trauma, respectively. FKBP5 methylation averaged across the three bins examined was associated with wake-up cortisol levels, indicating functional relevance of the methylation measures. Conclusions: This is the first demonstration of an association of pre-conception parental trauma with epigenetic alterations that is evident in both exposed parent and offspring, providing potential insight into how severe psychophysiological trauma can have intergenerational effects.