Will traumas be passed on to the next generations?

will epigenetic effects be inherited?

The COVID-19 pandemic has not only imposed physical suffering on countless people around the world but also triggered a psychological “tsunami.” Sources of stress, such as the threats of the wide-spreading virus and unforeseen changes in work and life, have, to different degrees, constituted a type of trauma unique to our generation. Nonetheless, the impact of stress on every one of us is not confined to the present but can extend to the post-COVID period. The time may be ripe now for us to consider the question: will stress-caused traumas be passed on to the next generation, like hereditary diseases, and become part of their lives?

This is a tough question but part of the answer to it is possibly hidden in the great historical events that our ancestors underwent. Take the Dutch famine in 1944 for example, the Nazis plunged the Netherlands into the harsh test of the so-called “Hunger Winter” by blocking its food supplies. By May 1945, when the country was liberated, more than 20,000 people had died of starvation, and 4.5 million had suffered from severe malnutrition. However, the famine didn’t end with the WWII. Its influence seems to have lasted till this very day.

According to the research targeting this special period, the offspring of pregnant women affected by the famine experienced higher rates of such conditions as heart diseases, diabetes, schizophrenia, obesity, and shorter life spans when they became adults than their peers who were nutritionally adequate before labor. Likewise, research focusing on young pregnant women during the Great Leap Forward in China suggests that people influenced by famine at the fetal stage are more likely to develop high blood pressure and cognitive disorders in adulthood.

These astonishing consequences of famine are simply a tip of the iceberg of the so-called “intergenerational trauma”. There’s a vast amount of research into people who were once exposed to traumas, such as survivors of the Nazi holocausts, native Americans under the shadow of colonial invasions, witnesses to the 9/11 terrorist attacks, and even captives during the American Civil War. Findings from such research indicated that these people will not only suffer from multiple psychological and physical disorders, including post-traumatic stress disorder (PTSD) and immune system disorders themselves. Their offspring also tend to be troubled by health issues, including depression, anxiety, and diabetes, as well as shorter life spans than their peers.

Scientists have begun to speculate that there was an underlying cause to all these phenomena. From a biological perspective, trauma is not inherited via factors such as social status or family conditions but passed on to our offspring through a more profound and unique mechanism—epigenetics.

The physical imprint of environments

To understand epigenetics and its uniqueness, we must first bear in mind that the development course of life is not entirely determined by genes.

For instance, even though identical twins carry certain genes known to be associated with schizophrenia, they won’t necessarily develop the disease at the same time. Why are there potential discrepancies between them despite of identical DNAs? Does this mean that individual experiences will influence the respective fate of the twins to a large extent?

The answer lies in epigenetics, a genetic mechanism apart from genome. The epigenetic mechanism can control gene expressions without altering any DNA sequences. In other words, although the proteins or RNA sustaining our lives are transcribed from in vivo genes, they have deeper associations with external environments.

Researchers didn’t identify such associations until 1975, when scientists discovered a chemical modification mechanism of DNA, namely, “DNA methylation”. Other chemical modifiers, such as histone, were later discovered to “turn on” or “turn off” genes to control gene expressions, thus influencing intracellular activities.

That’s how trauma affects our body and brain, and it is highly possible throughout our lives. Take childhood trauma as an example, children who grew up under extreme stress such as parental divorce, abuse, and bully will face numerous health risks in adulthood, such as heart diseases, alcohol and drug abuse, depression, suicide, and even cancers, to name just a few. One possible reason is that their physical stress regulation mechanism has been undermined.

In the face of dangers, our body and brain will enter the “fight-or-flight” mode along with the immediate release of stress hormones–glucocorticoid. These hormones will bind with the specific receptors on nerve cells to help us cope with stress and overcome crises. However, for traumatized children who have experienced DNA methylation, the methyl groups have been added to the DNA molecule to repress gene transcription into receptor proteins. As a result, glucocorticoid receptors are reducing while glucocorticoid levels are on the rise. Thus, even if the stress has diminished, it’s difficult to terminate this chemical reaction, which will take a long-term toll on physical health. When we’re overwhelmed by stress, there are a lot more similar effects going on inside of us, such as the effect triggered by cortisol. By exerting epigenetic influence over the Hippocampus, the brain region responsible for memory, it will trigger emotional, metabolic and immune disorders.

These discoveries also gave rise to another intriguing question: will epigenetic effects, especially those caused by stress, be inherited by the next generation or even more generations to come?

With more research comes more controversies

Let’s cast our attention back on the Dutch famine. In the 1990s, L.H. Lumey, an epidemiologist at Columbia University, collected blood samples from thousands of Dutch subjects who had been in utero during the famine (known as the Dutch Hunger Winter cohort), and from their siblings, born before or after the famine.

Over a decade later, the researchers proposed that DNA analysis of these samples suggested correlations between certain DNA methylations and the health conditions of the Dutch Hunger Winter cohort. According to them, one methyl group might be able to silence a gene called PIM3, which led to a higher body mass caused by slower metabolism. In a paper published in the journal Science Advances, Lumey and the co-authors speculated that it was the famine that had added a methyl group to fetuses.

Methylation caused by extreme stress has also seemingly occurred to Holocaust survivors. An epigenetic study pointed out that Jews who were interned in a Nazi concentration camp, having witnessed or experienced torture, or having had to flee or hide to escape Nazi hunting, would show higher level of FKBP5 methylation which would be inherited by their offspring. Related to stress mechanism, the FKBP5 gene is believed by researchers to demonstrate intergenerational transmission of trauma if any.

Can these results prove that parental trauma can be transferred to their offspring? Many scientists remain skeptical because samples used in similar investigations are too small, or the paradigm is not rigorous enough (for example, different types of cells in the blood have not been separated), or social factors have not been excluded. Therefore, it’s not well-grounded to conclude that the transmission of trauma has an epigenetic basis. More importantly, it’s not an easy task to distinguish hereditary influence from epigenetic influence.

As geneticist Ewan Birney commented in an article published in The Guardian: “It’s also easy to oversimplify (epigenetics) and has been set up by some people as an inaccurate alternative to genetics.”

Paternal stress

In the biological circle, scientists have in fact found that the hereditary effects of epigenetics are quite common among plants but have barely scratched the surface of its impact on animals.

In a classic animal experiment, researchers discovered that male mice subject to a certain odor fear conditioning before conception will pass on the fear to the two subsequently conceived generations. If a male mouse was trained to associate the odor of cherry blossoms with mild foot shocks, then his offspring would keep the “memory” and display behaviors similar to anxiety when smelling the same odor. Other studies show that a high-fat diet, cocaine, chronic stress, etc., can also lead to intergenerational transmission.

In order to study the paternal modes of transmission, neurobiologist Tracy Bale led a series of experiments and announced her findings at the annual meeting of the Society for Neuroscience held in November 2018. Her research team had preliminarily observed that the paternal stress of male mice will weaken their offspring’s response to stress hormones. They had taken a further step to discover that extracellular vesicles can relay stress-related information to sperms by acting like cell-released “postal packages” carrying proteins, lipids, and nucleic acids. The extracellular vesicles used in the experiment were secreted by cells that interact with developing sperms.

Nevertheless, there’re other theories trying to explain why sperms carry epigenetic marks. A study on mice pointed out that non-coding RNAs in the epididymis may be added to the genes of sperms. Chris Morgan, a postdoc in Bale’s lab, performed a follow-up investigation on 20 young male subjects. Preliminary data suggested that several months after the subjects reported stress, their sperms showed changes in non-coding RNAs.

How can marks on sperms be passed on to the next generation? After all, in the process of sperm-egg fusion, the majority of the chemical marks carried by both sides will be “cleansed” and the subsequent development of zygote won’t contribute much to their “survival”. Studies believe that epigenetic modifications involving the non-coding RNAs of sperms may possess the signatures of the marked areas. If such epigenetic modifications are detached from the reprogramming events in pre-implantation embryos and the primordial germ cells of fetuses, they will be kept in the “memory” of gametes for transgenerational transmission.

We are still the masters of our own fate

More follow-up research seems to indicate that the intergenerational effects of epigenetics can be reversed.

In the follow-up cherry blossom experiments in mice, researchers tested what would happen to their offspring if male mice that feared the scent were later desensitized to the smell. The mice were repeatedly exposed to the scent without receiving a foot shock. Results showed that the mice formed a new association now this odor is no longer paired with the foot shock. The sperms of these male mice had also lost their characteristic “fearful” epigenetic signature after the desensitization process. The pups of these mice also no longer showed a heightened sensitivity to the scent.

Thus, if a mouse “unlearns” the association of an odor and traumatic experiences, then the next generation may escape the effects. It also suggests that if humans inherit stress and trauma in similar ways, the effect on our DNA could be undone using techniques such as cognitive behavioral therapy. Additionally, developing epigenetic medications for treating psychological disorders including depression and anxiety is now under the spotlight. As one of the cognitive behavioral treatments, exposure therapy exposes patients to the stimuli that can induce anxiety in a safely controlled environment. After a period of time, the patients will be “desensitized”, thus weakening associations between the stimuli and anxiety. Relevant findings have proved that brain-derived neurotrophic factor (BDNF) and N-methyl-D-aspartate (NMDA) receptors played a vital role in this process, and the enhanced acetylation of BDNF and NMDA could improve the therapeutic efficiency. Acetylation has activated the transcription of these genes, which further facilitated neuroplasticity. In conclusion, improving the acetylation of BDNF and NMDA are the current focus of research on developing epigenetic medicines for treating anxiety.

There are indeed obstacles on our way toward epigenetic medicine. For example, how can we ensure the specificity of the medicine to direct it at eliminating harmful genetic expressions without interfering with that of the normal genes? However, its potential as a breakthrough to psychological medications may still guide the development of medicine in the future that will “sweep away” stress-induced epigenetic modifications of chromatin and resume normal genetic expressions to break the cycles of intergenerational transmission of traumas.

The ebbs and flows of civilizations are records of unwavering explorations made by each generation. Trauma may be lurking around every corner of historical turns, but the mankind has never dwelled upon its vicissitudes attributable to the irreplaceable role of epigenetic plasticity. Against the backdrop of a pandemic, we should also be inspired to pay attention to populations with psychological or mental health problems. Let healing, rather than trauma, be passed on to the next generation.

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