Epigenetics is the study of cellular variations that are caused by external, environmental causes that switch genes “on” or “off,” thus making changes in “phenotype” or genetic expression without concomitant changes in the DNA sequence. Epigenetic research attempts to describe dynamic alterations in the transcriptional potential of cells, alterations that may or may not be inherited (Tost, 2008). Epigenetics can be thought of as a very specific sort of memory. Most memories involve the brain storing experiences by altering the connections between brain cells. This ability, often referred to as “plasticity,” provides the basis for much alteration of behavior as well as for consciously recalled memories. In contrast, epigenetic changes are mediated by modifications of expression of specific genes and their protein production. These epigenetic changes in gene activity involve DNA and DNA-associated proteins but do not alter the DNA sequence itself. Gene expression can be turned “off” through the action of “repressor proteins” that attach themselves to the DNA, even though the DNA remains unchanged. Some epigenetic changes happen very rapidly as proteins change expression in a 24-hour cycle; however, the ones of interest to transmission of trauma involve much longer lasting alterations of gene expression.
Biologist C.H. Waddington introduced the word “epigenetic” in the 1940s to describe how growing cells acquire and maintain their identity through changing developmental stages. For example, the muscle cells, once differentiated, continue to divide into muscle cells, kidney cells into kidney cells, even though they all start from one universal cell and carry exactly the same DNA after they divide. Waddington (1952) speculated that there was an “epigenetic” effect because all cells continue to have the same chromosomes, the same set of genes, and the same DNA sequencing. “Epigenesis” means “extra growth” (from a Greek noun) and this term, dating back to the 17th century, was the basis for Waddington’s use of the adjective “epigenetic” because the observed effect is “extra,” something in addition to the basic genetic effect.
In the following decades, Waddington’s central questions were answered by scientists who found that the cells remember their states (e.g., muscle states, kidney states) through specific types of attachments to their DNA. Social insects, which often have an entire hive or anthill of genetic clones, differentiate into phenotypic queen vs. worker vs. drone bees or into forager vs. scout ants based on the same epigenetic programming mechanisms (Simola et al., 2016). There are several mechanisms through which epigenetics operate. Attachments may consist of DNA methylation (the replacement of hydrogen atoms with a methyl group) or through the modification of histones (the proteins that “package” DNA). A third process, involving “micro-DNA” by which small fragments of non-coding attach to the DNA of chromosomes also regulates gene expression and is usually included as a form of epigenetics. This research is important in understanding how life events can change an individual’s health and behavior. Epigenetic mechanisms have already been shown to explain the action of disease-causing mechanisms beyond those explainable by conventional genetics (Chen et al., 2016; Horowitz, 2015; Skinner, 2011; Skinner, Manikkam, & Guerrero-Bosagna, 2010). For example, rats on different diets show epigenetic effects, especially in regard to the repair of damaged DNA chains; the same might be true of humans (Fang et al., 2007). Epigenetic research has discovered instances in which cancer cells do not have the usual DNA mutations, but rather epigenetic changes have turned “off” or “on” genes that promote or block tumor formation (Struhl, 2014).
In an effort to unravel the epigenetic network underlying both short-term and long-term memory, Halder et al. (2015) examined changes in two regions of mice brains before and after contextual learning. They found that histone modifications changed during memory acquisition but showed little correspondence with gene expression. Although long-lasting changes were limited almost exclusively to neurons, learning-related histone modification and NDA methylation changes also occurred in non-neuronal cell types. This finding suggests a functional role for non-neuronal cells in epigenetic learning. These data also provide evidence for a molecular framework of memory acquisition and maintenance, wherein DNA methylation could alter the expression and splicing of genes involved in functional plasticity and wiring of the synapses, those parts of neurons that enable connections with other neurons (Farzadfard & Lu, 2014).
All of these phenomena of epigenetics discussed so far depend upon gene expression being altered in an initial generation. However, there is research on how these changes may sometimes be passed to future generations.
In Utero Epigenetic Reprogramming
The mildest, but best-established, form of cross-generational epigenetic change is that in which the second generation is conceived or gestated while the parent is being exposed to trauma. An early example of epigenetic impact was the study of maternal stress during the Dutch Famine of 1944-1945 at the end of World War II. Medical records reveal that female offspring exposed to a low-nutrient diet prenatally during the mother’s first trimester had a higher risk for both schizophrenia and breast cancer as adults. If the low-nutrient diet had occurred during the second trimester, the offspring had a high rate of lung and kidney problems. These epigenetic effects have been linked to the methylation patterns of a gene that coded for insulin-like growth factor 2 (IGF2); the 442 adults who lived through the famine showed the effect while a control group of 463 adults did not (Kennedy et al., 2014).
Several studies of the offspring of adults with histories of abuse as children, survival of war, and other forms of trauma leading to post-traumatic stress disorder (PTSD), reported a heritability effect. The offspring were more likely than others to develop PTSD through maternal epigenetic programming during pregnancy (Yahyavi, 2014). A study of 38 women who were pregnant when they witnessed the September 11, 2001 attacks on the World Trade Center in New York City demonstrated greater susceptibility to PTSD and lower levels of cortisol than members of a control group. Their offspring also had lower levels of cortisol, a hormone that assists recovery from trauma (Yehuda et al., 2005).
Indirect Transgenerational Epigenetic Inheritance
The studies above demonstrate that epigenetic effects can be observed in the offspring of parents who have survived stressful experiences such as the Holocaust, the September 11 attacks, famine, or other disasters. But can those effects be passed on to a third generation? For a direct biological effect, the affected DNA would have to be in the “germ” cell—the sperm or egg. Further it would also have to survive the “reset” at conception (Hackett et al., 2012). Ordinarily, there are two “cleansing and resetting” stages which remove all tags—one during the generation of the germ cell (egg and sperm) and one just after fertilization before implantation of the embryo. But some “tags” appear to slip through these “cleansing and resetting” stages (Tang, 2015). Before we explore this perhaps rare phenomenon, however, we will discuss the milder sense of multi-generational epigenetic effects: that methylation of DNA in a traumatized parent may result in behaviors around the offspring that cause similar methylation patterns anew in one or more generations.
Advocates of this explanation frequently point to studies of Holocaust survivors involving effects on their grandchildren. In one study, children and grandchildren of 32 men and women who survived the Holocaust were compared to descendants of Jewish parents who lived abroad during the Second World War. Members of the first group of parents had been tortured, imprisoned in concentration camps, or had remained hidden for several years. Members of the second parental group had undergone none of these traumatizing events. Both children and grandchildren of Holocaust survivors demonstrated symptoms of PTSD, more so if the mother had been the only survivor, but even if the father (and not the mother) had been oppressed by the Nazis (Yehuda, 2011). To explain the epigenetic effects on the grandchildren of Holocaust survivors, Yehuda (2011) noted that one region of a gene has been associated with the hormone cortisol, associated with the ability to recover from stress and trauma. Hypomethylation of this gene was found for both the children and grandchildren, but not for members of a control group. However, these children and grandchildren were being raised within their families, so the epigenetic markers may have been reinforced by behavioral interactions with the affected parents.
One rat study provides a model for how such effects might operate. Trauma to female rats affects how much contact they have with their pups, especially in terms of licking them. Researchers demonstrated that hormonal signals in the brain of rats were related to the amount of licking the rats received as pups (Skinner & Guerrero-Bosagna, 2009; Weaver et al., 2004). Rats that received less licking during infancy displayed markedly less gregarious and exploratory behavior and showed lower methylation on genes responsible for regulation of corticosteroids. There’s no demonstration that the methylation patterns were passed on by the germ cells in this case, but rather that traumatized maternal behavior instigates the methylation patterns anew. In further research by this group, they found that the effects of traumatizing mother rats decreased across each generation and disappeared entirely after five generations. They also observed that fostering the rat pups out to mothers who licked more completely prevented the effects on the offspring (Weaver, Meaney, & Szyf, 2006).
Most discussions of this study have referred to “inadequate maternal care” resulting in “impaired exploratory” behavior. However, from an evolutionary point of view, a mother rat who has lived her life in a relatively safe world grooming pups in a way that makes them explore and a mother who’s faced severe dangers and grooms hers in ways that produce cautious offspring both are equally adaptive and highlight the manner in which epigenetics can respond to environmental situations with adaptions in one generation vs. the centuries genes would take to alter (Barrett, 2007).
In a postmortem study on humans, the same research group found that this methylation pattern was seen to varying degrees in people who had either died of natural causes, died by suicide without a history of childhood abuse and those who died by suicide with a history of childhood abuse (McGowan et al., 2009). Normal individuals showed less methylation in key areas of the hippocampus than those who died by suicide and those who died by suicide with a history of childhood abuse showed the greatest degree of methylation. The genes affected in these areas are again responsible for glucocorticoid regulation. Interactive effects between parental genes and offspring phenotype have also been supported in more strictly evolutionary research as well (Wolf, 2000).
Direct Transgenerational Epigenetic Transmission of Trauma
Direct epigenetic transmission by germ cells across multiple generations has been demonstrated most frequently for toxic exposures. Men who begin smoking before puberty have a higher chance of fathering obese sons than those who start smoking after puberty—an effect that can not be accounted for by the smoke or nicotine exposure during sperm formation which would be equal for the two groups (Fang et al., 2007). Epigenetic effects have also been documented for environmental toxins such as vinclozolin (an endocrine disrupter); the DNA methylation pattern of the sperm for three generations after the initial exposure (F3 males) is altered at specific promoter regions (Guerrero-Bosagna et al., 2010). Third generation epigenetic alteration of sperm was also observed following exposure to pesticides, plastics, dioxin, and jet fuel (Manikkam et al., 2012; Manikkam et al., 2012a; Manikkam et al., 2012b; Manikkam et al., 2013).
Of more direct relevance to transgenerational effects of trauma, is a mouse experiment conducted by Dias and Ressler (2014) examining how the olfactory (smell) experience of male parent mice might influence their offspring. The parent mice were conditioned to manifest fear when they smelled cherry blossoms. This was accomplished by pairing the odor with a shock to the foot. This fear changed the organization of the animal’s nose, leading to more cells that were sensitive to that particular smell. This structural alteration was also found in future generations as was a fear-generated “startle” when the mice were exposed to the odor. The reaction to other odors was not affected. Their pups were found to be afraid of the odor and passed that fear down to their pups. The results suggest that the experiences of a parent, before conceiving offspring, markedly influence both structure and function in the nervous system of subsequent generations. The authors hypothesized that micro-RNA involved in gene expression enter the bloodstream and deliver odor information to sperm cells. From an evolutionary point of view, the offspring learned how to avoid a smell that had negative effects on their parents and grandparents. Dias and Kessler maintained that these behavioral and olfactory effects “were inherited and were not socially transmitted from generation to generation” (p. 89). They reached this conclusion after conducting in vitro fertilization so that there would be no contact between parent mice and their offspring. Micro-RNA maintains the activity of the gene and it is possible that these activities can be inherited, even when the original stimulus for their expression is no longer present (Mattick et al., 2009).
Another example highly analogous to human trauma involves a mouse model of early life stress by unpredictable maternal separation and maternal stress. This manipulation affects behavior severely across multiple generations (Franklin et al., 2010; Franklin et al., 2011; Weiss et al., 2011). The behavioral changes due to maternal separation and stress are accompanied by persistent molecular changes in the stress pathway as well as serotonergic signaling that are transmitted for three generations. The authors examined the sperm and found that DNA methylation was altered at gene promoters that correlated with changes observed in the brains of the stressed males from the subsequent generations (Franklin et al., 2010; Weiss et al., 2011). Another research group found that stress during the first week of gestation caused dysmasculanization in the male offspring that lasted multiple generations. (Morgan & Bale, 2011). An X-linked placental gene, O-linked-N-acetylglucosamine, which regulates proteins involved with chromatin remodeling, was decreased following prenatal stress (Howerton et al., 2013) and it is believed to play a role in the phenotype of masculinity. Another rodent model, using the chronic social defeat paradigm in adult male rats, also shows a stress-related phenotype being passed on to subsequent generations with both male and female offspring displayed increased anxiety and depressive-like behaviors (Dietz et al., 2011). However, it appears that at least some of these behavioral phenotypes are transmitted behaviorally, with only the forced swim test phenotype persisting following in vitro fertilization.
There has been some criticism of these studies. Ptashne (2013) noted that some transgenerational claims are based on experiments with a few dozen mice (e.g., Dias and Ressler’s experiment) or humans (e.g., Yehuda’s studies). Another critic (Callaway, 2013) singled out the Dias and Kessler experiment for special criticism alleging that some of the mice were not siblings, that the sample size was small, and that the statistical effect size was low.
Implications for Evolution
Advocates of “transgenerational epigenetic inheritance” argue that genes contained in DNA are the standard way that biological information is transmitted from one generation to succeeding generations but now point to the epigenetic ‘tags’ that attach themselves to the DNA, as a further mechanism for inheritance. It is generally agreed that some of these “tags” can be inherited by children, but the inheritance by grandchildren has only a few established examples in animals such as mice. In addition, there is agreement that “micro-RNA” can impact sperm cells and affect offspring. But to what extent may they affect future generations? And, will this demand changes in evolutionary theory?
Transgenerational transmission of epigenetic programming does not violate the major theses of biological evolution. Mechanisms such as DNA methylation and histone modification are still genetically inherited under the aegis of natural selection (Lynch, 2007). At the same time the rate of change due to epigenetics can be more rapid than rates due to adaptive mutations, especially for plants and insects (e.g., Rando & Verstrepen, 2007). A frequently cited example is how Mourning Cloak butterflies will change color through hormone changes in response to experimentally-induced changes of temperature (Davies, 2008). The two forms of heritable information, namely genetic and epigenetic, can be collectively denoted as dual inheritance. There is an overlap in molecular mechanisms, but – according to mainstream scientists — nothing that justifies premature application of the data to extensive transgenerational epigenetic effects (Rutherford, 2014).
There is a growing body of research for this possible “dual Inheritance” with humans and other animals seeming to inherit a predisposition for fear from their ancestors on a longer time scale presumably mediated by the DNA itself, and then a more specific fear conditioning through epigenetics. Primates’ brains are uniquely tuned to recognize spiders and snakes. Human infants are not afraid of snakes and spiders at birth but learn to fear them more quickly than they learn to fear other stimuli such as rabbits. Another study found that unborn crickets whose mothers were stalked by wolf spiders demonstrated a greater fear of those spiders after they were born than crickets protected from such exposure. Furthermore, the former offspring survived more often than the latter – crickets that had no fear of the lethal spiders (e.g., Barrett, 2010; Gruber, 1974). In his own age, Jean-Baptise Lamarck (1809) was reviled for his notion that acquired characteristics could be inherited. Today he is being hailed as ahead of his time.
Implications for Psychotherapy
Epigenetics in general, and especially its behavior effects, are fast-expanding research areas, so many implications will be emerging over the next decades. At present, the most important consequence for psychotherapists conceptualizing psychopathology is the knowledge that severe trauma may be passed along through direct germ line alterations rather than simply through parenting. Therapists working with children adopted out of war zones or dysfunctional families may want to consider that these patients may be reacting to traumas of their parents even if they have not been raised by them. While there are no human treatment implications at this time, these may be on the horizon. One study has already demonstrated that the maternal stress in mice affecting subsequent generations as described above can be erased by infusion of l-methionine, an amino acid widely available in oral form at health food stores. L-methionine eliminated both hypo-methylation patterns in DNA and the trauma-produced behaviors in offspring (Weaver et al., 2005). This has obvious implications for human dietary and pharmacological intervention pending further studies. In the future, it is also possible that methylation studies of cortisol-associated genes or micro-RNA attachment might become a means of assessing whether therapeutic interventions are working.
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The preparation of this article was supported by the Saybrook University Chair for the Study of Consciousness.