We know from history that traumatic childhood experiences can have lasting effects, affecting both the physical body and our mental health. Research has shown that these stressful life experiences can also impact the offspring of people who have experienced trauma.
This contradicts some of the basic foundations of genetic inheritance. How can life’s experiences affect our gametes – sperm and eggs – which pass hereditary information via DNA to our offspring? Scientists are focusing on the role the epigenome plays here.
The epigenome, which regulates gene activity by mechanisms that, in simple terms, involve the “switching on” and “switching off” of genes, can be influenced by biological molecules.
A new study led by Professor Isabelle Mansuy of the University of Zurich’s Institute for Brain Research has explored how factors circulating in the blood communicate with the embryonic precursors of gametes (germ cells) in animal models and human participants.1
Mansuy and his colleagues have focused their efforts on studying the biological impact of trauma. They found that traumatic experiences early in life cause changes in 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 this data may have on public health issues.
Molly Campbell (MC): Your New to study contributes to an area of research known as epigenetic inheritance. For our readers who may not be familiar, can you tell us more about this area of research and its applications?
Isabelle Mansuy (MI): This field of research studies a form of heredity little studied until now and which involves epigenetic factors. Heredity is classically known as dependent on genetics, and our genetic code (or genome), which is transmitted from parent to offspring through gametes (reproductive cells: oocyte and sperm). It 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 over the course of life through exposure to the environment and life experiences. This form of transmission depends on the epigenome, which are factors around the DNA sequence that regulate its activity. The applications are wide, and include a better understanding of environmental/experience-related diseases such as psychiatric disorders, autoimmune diseases, cardiovascular diseases, cancer, etc. whose causes and mechanisms remain poorly understood and which have no treatment.
MC: Epigenetic inheritance is an area that has been deemed “controversial” in the past. Do you think attitudes towards the field of research are changing?
I AM: Yes, because we realize how fundamental it is, and how it can answer questions that have remained unanswered for a long time, such as complex diseases, the transmission of the effects of life experiences (diet, stress or endocrine disruptors). Moreover, there is now much more evidence of its existence. Numerous studies and reports now document epigenetic inheritance in various species.
MC: Why did you decide to focus specifically on the effects of trauma in your study?
I AM: We are neurobiologists interested in brain functions and mechanisms of brain disease, especially psychiatric disorders. The possibility that negative experiences in childhood can impair mental and physical health later in life and affect future generations is an extremely important public health concern. It must be understood mechanistically to help patients, doctors and society.
MC: Why did you hypothesize that blood metabolites (an example of circulating factors) convey signals induced by exposure to germ cells? What previous research has supported this hypothesis?
I AM: The hypothesis stems from our observation that many cells and tissues are affected by exposure to trauma in early life and that some of the changes are comparable across tissues, suggesting that there there is a common inducing factor. It made sense to think of blood since it provides nutrients to all tissues and cells in the body. The fact that blood factors can communicate with germ cells was not known before, it was even deemed impossible in the middle of the 19and century by August Weissmann, purely based on a theory he put forward that the soma cannot communicate with the germ line (the Weismann barrier). He relied, for example, on the observation that if you cut off a mouse’s tail every generation, the offspring will never be born with a cut tail. This theory was wrong from the start but somewhat blocked correct 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 offspring of these mice as adults. Can you expand on the metabolic pathways you analyzed and why, and what were the key findings?
I AM: Some metabolites are upregulated but others are downregulated. We analyzed all metabolites by mass spectrometry (unbiased method) and observed that lipid metabolism is disturbed with an increase in metabolites of polyunsaturated fatty acids. We have also seen 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?
I AM: The Pakistani cohort was selected to resemble our mouse model as closely as possible. The children were separated from their mother after losing their husband (father). Our mouse model uses unpredictable maternal separation combined with unpredictable maternal stress. It is representative of severe family trauma. The limitations are that this is a small cohort (25 SOS and 14 controls) – but we have now expanded this sample – and we only have blood samples from one time point. Ideally, we would like to track children over time. One positive though is that we have a small group of adult men who were in the SOS Village when they were younger and are showing blood changes (this data is not published).
MC: How do the results of the human analyzes compare to the results you obtained in mice?
I AM: There are many similarities in trauma symptoms, eg depression, and in physiological parameters, eg altered blood sugar, dyslipidemia, decreased HDL, etc.
MC: What can the data tell us about How? ‘Or’ What trauma alters metabolic pathways, and why might this be passed on to the next generation?
I AM: We don’t know exactly how trauma alters metabolic pathways, but it’s likely to disrupt the liver, pancreas, endocrine system, and more. The effects are systemic and all tissues are affected. The effects of trauma are passed on to the next generation (demonstrated in mice) as germ cells (here sperm) carry molecular alterations, for example altered RNA populations, which are passed on to the embryo during fertilization with the oocyte.
MC: What clinical applications could this research have?
I AM: Perhaps the identification of a trauma signature in blood, saliva and/or semen that could aid in diagnosis and treatment monitoring.
MC: Finally, what are your next steps in this research space?
I AM: Identify the mechanisms responsible for changes in germ cells (male and female) and how these changes are perpetuated/maintained in offspring.
Professor Isabelle Mansuy was speaking to Molly Campbell, Science Writer for Technology Networks.
1. van Steenwyk G, Gapp K, Jawaid A, et al. Involvement of circulating factors in the transmission of paternal experiences through the germ line. EBO J.. 2020;39(23):e104579. do I:10.15252/embj.2020104579.