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Epigenetics- Implications for Mental Health

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Epigenetics is the field of study concerned with cellular variations triggered by external and environmental factors that toggle genes “on” and “off”. The changes occur in the phenotype of genetic expression without associated changes in the DNA sequence or genotype. The term “epigenetic” was coined by biologist C.H. Waddington in the 1940s in an effort to describe how “growing cells acquire and maintain their identity through changing developmental stages” [1]. Considered for a moment muscle cells, once differentiated, they continue to divide into muscle cells, kidney cells into kidney cells, despite having all started from one universal cell; in the end they carry the same DNA after cell division is completed [1] and because all cells continue to have the same chromosomes, the same set of genes, as well as the same DNA sequencing, Waddington speculated there existed an “epigenetic” effect [1].  The term “epigenesis” draws its roots from a Greek noun meaning “extra growth” and dates back to the seventeenth century. The concept of extra growth became the basis for Waddington’s use of the adjective “epigenetic” in relation to the additional observed effect beyond the basic genetic effect. [1].

In the decades that followed, scientists were able to answer Waddington’s central questions by discovering that cells remember their states (e.g., muscle states, kidney states) through specific types of attachment to their DNA. There exist several mechanisms through which epigenetics operate: DNA methylation, histone modifications and non-coding RNAs [2, 3].

DNA Methylation

DNA methylation was first recognized in the 1970s and is the most well-characterized epigenetic modification and the best-studied epigenetic modification in the context of altered environment [2, 3].  This modification common in mammalian genomes, Zheng and Xiao (2016) state that DNA methylation “constitutes a stable epigenetic symbol that can stable alter the expression of genes and transmit through DNA replication as cells divide and differentiate from embryonic stem cells into specific tissues and is essential for normal development [2]. It is also associated with a number of important processes, some of which include genomic imprinting, X-chromosome inactivation, the suppression of repetitive elements and carcinogenesis.

Histone Modification

Histone modification can influence gene expression by altering chromatin structure. Modifications are suggested to have an effect on chromosome structure as well as function, especially during the process of transcription and chromatin remodeling. Zheng and Xiao (2016) note that core modifications of histones may also act on DNA templated processes, such as replication and transcriptional processes and effect nucleosomal structure [2].

Non-Coding RNAs

MicroRNAs (miRNAs) and Non-coding RNAs are noted to be the most recently discovered and important epigenetic modification. The modulations of miRNAs can facilitate some key developmental processes such as cell proliferation, cell line differentiation and programmed cell apoptosis, cell cycle control, and cellular metabolism [2].

Numerous studies have investigated the relationship between miRNA and epigenetic regulations in diseases such as cancer, diabetes, diseases of neurologic and inflammatory etiologies as well as aging. Despite a lack of clear understanding in the underlying mechanism, miRNA dysregulation has been noted in all of the stated pathologies. The hypothesis is that miRNAs contribute to the formation of disease via epigenetic regulations, leading to miRNA modulation as a new therapeutic approach currently being extensively investigated in various disease processes [1, 2, 3].

Fetal Programming Hypothesis

The relationship between the quality of early life environment and future risk of disease in later life was first proposed by Forsdahl in 1977. Forsdahl discovered that the infant mortality rate positively correlated with an increased risk of cardiovascular diseases in middle age. However, it wasn’t until 1989 that Baker and his colleagues noted an inverses relationship between birth weight and increased cardiovascular mortality [2]. The most important studies to reveal the extent of epigenetic modification resulted from the infamous Dutch famine during the winter of 1944-1945 at the end of World War II. These studies examined the impact of maternal stress during this period, medical records revealed 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. However, if the low-nutrient diet occurred during the second trimester, the offspring had a higher rate of lung and kidney issues. Additionally, low-nutrient diet occurring in the late stage of gestation brought about lower birth weight as well as an increased risk of obesity, cardiovascular disease, insulin resistance and hypertension later in life compared with unexposed individuals (442 adults who, lived through the famine versus a control group of 463 adults) [1,2, 3, 4 – Kennedy et al., 2014).

The Mental Health Context

Epigenetics in the context of mental health is the basis for transgenerational trauma. There exist many studies that have examined the offspring of adults with histories childhood abuse, survival of war, and other forms of trauma leading to post-trauma stress revealing a heritability effect. For example, Yahyavi, Zarghami and Marwah (2014) reported in their work that, “the offspring were more likely than others to develop PTSD through adverse maternal epigenetic- related experiences during pregnancy” [5].  Yehuda et al. (2014) revealed in their study of 38 women who were pregnant at the time of the World Trade Centre attacks in New York City on September 11, 2001 and who witnessed the events, “demonstrated greater susceptibility to PTSD and lower levels of cortisol than members of a control group” [6]. It was also noted that their offspring were found to have had lower levels of cortisol, an important hormone that assists recovery from trauma [6].

Indirect Transgenerational Epigenetics Inheritance

The previously-noted studies demonstrate for us that epigenetic effects can be observed in the offspring of parents who have survived or witnessed stressful experiences, notably events such as the Holocaust, the Hungarian revolution of 1956, the September 11 attacks, famine and other disasters. However, is it possible for those effects to be passed on to a third or fourth generation? In short, the answer is yes. In order for direct biological effect to occur, the affected DNA would have to be located in the “germ” cell – either the sperm or the egg. Furthermore, according to Hackett et al. (2013), the DNA within the germ cell would also have to survive what is described a the “reset” at conception [7]. Tang et al. (2015) note that under usual circumstances there are two known “cleansing and resetting” stages which remove all tags. The first stage occurs during the generation of the germ cell, the second stage occurs just after fertilization, before the implantation of the embryo [8]. While the success of the “cleansing” and “resetting” stages are noted to be rare, the multi-generational epigenetic effect that is most important in the context of mental health is the concept, “that methylation of DNA in a traumatized parent may result in behaviours around the offspring that cause similar methylation patterns anew in one or more generations” [1].

The studies that best support this concept often examine Holocaust survivors involving effects on their grandchildren. For example, Yehuda (2011) demonstrated that the children and grandchildren of 32 men and women who had survived the Holocaust were compared to descendants of Jewish parents who lived abroad during the Second World War. The members of the first group of parents had been tortured, imprisoned in concentration camps, or had remained hidden for several years. The members of the second parental group however had not experienced any of these traumatizing events. The findings of the comparison revealed that the children and grandchildren of Holocaust survivors demonstrated symptoms of post-traumatic stress disorder; more so in the cases where the mother had been the only survivor, but even if the father (and not the mother) had been oppressed by the Nazis [9]. The explanation provided by Yehuda with respect to the epigenetic effects on the grandchildren of Holocaust survivors 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 members of a control group.” [9]. It was also noted however that these children and grandchildren were being raised within their respective families, therefore it is possible the epigenetic markers had been reinforced by behavioural interactions with the affected parents [9].

Direct Transgenerational Epigenetic Transmission of Trauma

The most frequent demonstration of direct epigenetic transmission by germ cells across multiple generations has been noted to occur through toxic exposures. For example, men who begin smoking before puberty are noted to have a higher chance of fathering obese sons versus men who started smoking after puberty [1]. Epigenetic effects have also been documented as a result of environmental toxins, for example vinclozolin – an endocrine disrupter; Krippner and Barrett (2016) noted a DNA methylation pattern of the sperm for three generations following the initial exposure. DNA had been altered at specific promoter regions. Furthermore, third generation epigenetic alteration of sperm was also observed following exposure to pesticides, plastics, dioxin, and jet fuel. Perhaps more relevant to the concept of transgenerational effects of trauma can be drawn from a mouse experiment conducted by Dias and Ressler (2014) and highlighted by Krippner and Barrett (2016).

Their goal was to examine how the olfactory experience of male parent mice may influence their offspring. The parent mice were noted to have been conditioned to manifest fear when they smelled cherry blossoms. The investigators accomplished this by pairing the odor with a shock to the foot, subsequently the fear changed the organization of the animal’s nose which led more cells becoming sensitive to that particular smell. The resulting structural changes was then noted in future generations as a “fear-generated “startle” when the mice were exposed to the odor” while their reaction to other odors was not affected [1]. Dias and Ressler (2014) noted that the pups of these parent mice were found to be afraid of the odor and passed that fear down to their pups, suggesting that, ‘the experiences of a parent, before conceiving offspring, markedly influence both structure and function in the nervous system of subsequent generations” [1].

Implications for Evolution and Mental Health Treatment

We understand that genes contained in DNA are the standard way that biological information is transmitted from one generation to the next. However, there is mounting evidence pointing epigenetic “tag” attachment to DNA deepening the mechanism for inheritance. Furthermore, transgenerational transmission of epigenetic programming is said to not violate the major theses of biological evolution. The mechanisms of DNA methylation and histone modification are noted to still be “inherited under the aegis of natural selection” while at the same time the rate of change due to epigenetics can potentially be more precipitous than rates due to adaptive mutation [1].

The behavioural effects of epigenetics are noted to be a rapidly growing area of research leading to the emergency of many implications over the next several decades. With respect to mental health treatment, the most important consequences currently pertain to psychotherapy in the conceptualization that psychopathology is, “the knowledge that severe trauma may be passed along through direct germ line alterations rather than simply through parenting”. This is an important concept to consider for anyone working with children adopted out of warzones or dysfunctional families because these patients may be reacting to the trauma experienced by their parents even if the children have not been raised by their parents [1, 9].

Currently, there are not human treatment implications However, there may be some on the horizon soon. One such study has already demonstrated that maternal stress in mice affecting subsequent generations can be “erased” through the infusion of l-methionine – a widely available amino acid in oral form found at health food stores. L-methionine was noted to eliminate both hypomethylation patterns in DNA and the trauma-produced behaviours in offspring mice. This finding has significant implications for human dietary and pharmacological intervention in the face of pending and future studies. Furthermore, methylation studies of cortisol-associated genes or micro-RNA attachment may in fact become a way of assessing whether therapeutic interventions are working [1]. In the meantime, we should focus our attention on understanding transgenerational trauma and lend more empathy towards the patients and clients (as well as ourselves) we encounter in our everyday practice.

“In the real world there is no nature vs. nurture argument, only an infinitely complex and moment-by-moment interaction between genetic and environmental effects” – Dr. Gábor Maté

Radio EMS

References

  1. Krippner S, Barrett D. Transgenerational Trauma: The Role of Epigenetics. Journal of Mind and Behavior [Internet]. 2019 Dec 1 [cited 2021 Dec 1];40(1):53–62. Available from: https://search-ebscohost-com.ezproxy.tru.ca/login.aspx?direct=true&db=phl&AN=PHL2387309&site=eds-live&scope=site
  2. Dincer Y, Zheng J, Xiao X. EPIGENETIC MODIFICATIONS AND DEVELOPMENTAL ORIGIN OF HEALTH AND DISEASES (DOHAD). In: Epigenetics: Mechanisms and clinical perspectives. New York, NY: Nova Biomedical; 2016. p. 1–14.
  3. Dincer Y, Baykara O. EFFECTS OF OXIDATIVE STRESS ON EPIGENETIC MECHANISMS. In: Epigenetics: Mechanisms and clinical perspectives. New York, NY: Nova Biomedical; 2016. p. 17–30.
  4. Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, Epel ES, et al. Geroscience: linking aging to chronic disease. Cell [Internet]. 2014 Nov 6 [cited 2021 Nov 30];159(4):709–13. Available from: https://search-ebscohost-com.ezproxy.tru.ca/login.aspx?direct=true&db=mnh&AN=25417146&site=eds-live&scope=site
  5. Yahyavi ST, Zarghami M, Marwah U. A review on the evidence of transgenerational transmission of posttraumatic stress disorder vulnerability. Revista Brasileira de Psiquiatria [Internet]. 2014 Jan [cited 2021 Nov 30];36(1):89–94. Available from: https://search-ebscohost-com.ezproxy.tru.ca/login.aspx?direct=true&db=a9h&AN=94937415&site=eds-live&scope=site
  6. Yehuda R, Daskalakis NP, Lehrner A, Desarnaud F, Bader HN, Makotkine I, et al. Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring. American Journal of Psychiatry. 2014;171(8):872–80.
  7. Hackett JA, Sengupta R, Zylicz JJ, Murakami K, Lee C, Down TA, et al. Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine. Science. 2013;339(6118):448–52.
  8. Tang WWC, Dietmann S, Irie N, Leitch HG, Floros VI, Bradshaw CR, et al. A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development. Cell [Internet]. 2015 Jun 4 [cited 2021 Dec 1];161(6):1453–67. Available from: https://search-ebscohost-com.ezproxy.tru.ca/login.aspx?direct=true&db=edselp&AN=S0092867415005644&site=eds-live&scope=site
  9. Yehuda R. Are different biological mechanisms involved in the transmission of maternal versus paternal stress-induced vulnerability to offspring? Biological Psychiatry. 2011;70(5):402–403.
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Chris Farnady

Chris Farnady

Chris is a graduate of Loyalist College’s Primary Care Paramedic program (Bancroft, ON), Durham College’s (Oshawa, ON) Advance Care Paramedic and currently pursuing his Bachelor of Health Science from Thompson Rivers University. Chris began his prehospital care career in 1997 working as an EMR in Alberta’s oil and gas industry and has enjoyed the privilege of working as a Primary Care and Advanced Care Paramedic in Ontario, Northern Manitoba and Alberta. In April 2018 Chris accepted a position with Advanced Paramedic Ltd. and returned to Northern Alberta as an Advanced Care Flight Paramedic for Alberta Health Services’ transport medicine program. In his time away from work, Chris enjoys being at home with his wife and two children. Chris can be reached for comment at chris.farnady@gmail.com.

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