We know from history that traumatic experiences in childhood can have long-lasting effects, impacting both the physical body and our mental health. Research has shown that these stressful experiences in life can also impact the offspring of individuals whom have endured trauma.This contradicts some of the basic underpinnings of genetic hereditary. How can experiences in life affect our gametes the sperm and egg cells which pass on hereditary information through DNA to our offspring? Scientists are focusing on the role that the epigenome plays here.

The epigenome, which regulates gene activity by mechanisms which, put simply, involve "switching on" and "switching off" of genes, can be influenced by biological molecules.

A new study led by Professor Isabelle Mansuy at the University of Zurich's Brain Research Institute explored how circulating factors in the blood communicate with the embryonic precursors of gametes (germ cells) in both animal models and human participants.1Mansuy and colleagues focused their efforts on studying the biological impact of trauma. They found that traumatic experiences in early life cause changes in the blood composition namely metabolites that are passed on to the next generation.

Technology Networks spoke with Mansuy to learn more about the field of epigenetic inheritance, the specifics of the study and the possible impact these data may have on matters of public health.

Molly Campbell (MC): Your new study contributes to a research field known as epigenetic inheritance. For our readers that may be unfamiliar, can you please tell us more about this field of research, and its applications?Isabelle Mansuy (IM): This field of research studies a form of heredity that has hardly been studied before and that involves epigenetic factors. Heredity is classically known as depending on genetics, and our genetic code (or genome), which is transferred from parent to offspring through gametes (reproductive cells: oocyte and sperm cell). This is innate heredity, which is the inheritance of natural or intrinsic traits. But there is also acquired heredity, which is the inheritance of traits acquired during life upon exposure to the environment and life experiences. This form of inheritance depends on the epigenome, which are factors around the DNA sequence that regulate its activity. The applications are broad, and include a better understanding of diseases linked to the environment/experiences such as psychiatric disorders, autoimmune diseases, cardiovascular diseases, cancer, etc whose causes and mechanisms remain poorly known and which have no treatment.

MC: Epigenetic inheritance is a field that has been deemed "controversial" in the past. In your opinion, are attitudes towards the research area changing? IM: Yes, because people realize how fundamental it is, and how it can answer questions that have remained unsolved for a long time, like the complex diseases, the transmission of the effects of life experiences (diet, stress or endocrine disruptors). Also, there is now a lot more evidence for its existence. Many studies and reports now document epigenetic inheritance in various species.

MC: Why did you decide to focus on the effects of trauma specifically in your study?IM: We are neurobiologists interested in brain functions and in the mechanisms of brain diseases, in particular psychiatric disorders. The possibility that adverse experiences in childhood can alter mental and physical health later in life and affect future generations is an extremely important public health issue. It needs to be understood mechanistically to help patients, doctors and the society.

MC: Why did you hypothesize that blood metabolites (an example of circulating factors) carry signals induced by exposure to germ cells? What previous research supported this hypothesis?IM: The hypothesis stems from our observation that many cells and tissues are affected by trauma exposure in early life and that some of the changes are comparable across tissues, suggesting that there is a common inducing factor. It was logical to think of blood since it provides nutrient to all tissues and cells across the body. The fact that blood factors can communicate with germ cells was not known before, it was even deemed impossible mid-19th century by August Weissmann, purely based on a theory he put forward that the soma cannot communicate with the germline (the Weismann barrier). It relied, for instance, on the observation that if you cut the tail of a mouse at each generation, the offspring will never be born with a cut tail. This theory was erroneous from the start but somewhat blocked proper thinking for a long time.

MC: In mice, you found that exposure to trauma upregulated certain metabolic pathways, and that this upregulation was also detected in the male progeny of these mice in adulthood. Can you expand on the metabolic pathways that you analyzed and why, and what the key results were?IM: Some metabolites are up-regulated but others are down-regulated. We analysed all metabolites by mass spectrometry (unbiased method) and observed that lipid metabolism is perturbed with polyinsaturated fatty acids metabolites being increased. We also saw that glucose and insulin are dysregulated.

MC: You also assessed the relevance of these findings in a cohort of children, specifically children from an SOS Children's Village in Lahore, Pakistan. Can you discuss the choice of human sample used in this study? Why is it representative? Are there any potential limitations?IM: The Pakistani cohort was selected to resemble as much as possible our mouse model. The children were separated from their mother after their lost their husband (father). Our mouse model uses unpredictable maternal separation combined with unpredictable maternal stress. It is representative of a severe family trauma. The limitations are that it is a small cohort (25 SOS and 14 controls) however we have now expanded this sample and that we have blood samples from only one time point. Ideally, we would like to follow the children across time. A positive point though is that we have a small group of adult men who were in the SOS village when younger and who do show changes in blood (this data is not published).

MC: How did the results of the human analyses compare to the results you obtained in mice?IM: There are lots of similarities in symptoms of trauma e.g. depression, and in physiological parameters e.g. altered glycemia, dyslipidemia, decreased HDL, etc

MC: What can the data tell us about how trauma is altering metabolic pathways, and why this might be passed on to the next generation?IM: We do not know exactly how trauma alters metabolic pathways, but it is likely by perturbing liver, pancreas, the endocrine system, etc. The effects are systemic, and every tissue is affected. The effects of trauma are passed to the next generation (demonstrated in mice) because germ cells (here sperm) carry molecular alterations e.g. altered RNA populations, that are passed to the embryo upon fertilization with the oocyte.

MC: What clinical applications might this research have?IM: Perhaps the identification of a signature of trauma in blood, saliva and/or sperm which could help diagnostics and treatment monitoring.

MC: Finally, what are your next steps in this research space?IM: Identify the mechanisms responsible for changes in germ cells (male and female) and how these changes are perpetuated/maintained in the offspring.

Professor Isabelle Mansuy was speaking to Molly Campbell, Science Writer for Technology Networks.

Reference:

1. van Steenwyk G, Gapp K, Jawaid A, et al. Involvement of circulating factors in the transmission of paternal experiences through the germline. EMBO J.. 2020;39(23):e104579. doi:10.15252/embj.2020104579.

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Exploring the Biological Inheritance of Childhood Trauma - Technology Networks

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