Identifying causative mechanisms linking early-life stress to psycho-cardio-metabolic multi-morbidity: The EarlyCause project
Nicole Mariani, Alessandra Borsini, Charlotte A. M. Cecil, Janine F. Felix, Sylvain Sebert, Annamaria Cattaneo, Esther Walton, Yuri Milaneschi, Guy Cochrane, Clara Amid, Jeena Rajan, Juliette Giacobbe, Yolanda Sanz, Ana Agustí, Tania Sorg, Yann Herault, Jouko Miettunen, Priyanka Parmar, Nadia Cattane, Vincent Jaddoe, Jyrki Lötjönen, Carme Buisan, Miguel A. González Ballester, Gemma Piella, Josep L. Gelpi, Femke Lamers, Brenda W. J. H. Penninx, Henning Tiemeier, Malte von Tottleben, Rainer Thiel, Katharina F. Heil, Marjo-Riitta Järvelin, Carmine Pariante, Isabelle M. Mansuy, Karim Lekadir
Depression, cardiovascular diseases and diabetes are among the major non-communicable diseases, leading to significant disability and mortality worldwide. These diseases may share environmental and genetic determinants associated with multimorbid patterns. Stressful early-life events are among the primary factors associated with the development of mental and physical diseases. However, possible causative mechanisms linking early life stress (ELS) with psycho-cardio-metabolic (PCM) multi-morbidity are not well understood. This prevents a full understanding of causal pathways towards the shared risk of these diseases and the development of coordinated preventive and therapeutic interventions.
Methods and analysis
This paper describes the study protocol for EarlyCause, a large-scale and inter-disciplinary research project funded by the European Union’s Horizon 2020 research and innovation programme. The project takes advantage of human longitudinal birth cohort data, animal studies and cellular models to test the hypothesis of shared mechanisms and molecular pathways by which ELS shapes an individual’s physical and mental health in adulthood. The study will research in detail how ELS converts into biological signals embedded simultaneously or sequentially in the brain, the cardiovascular and metabolic systems. The research will mainly focus on four biological processes including possible alterations of the epigenome, neuroendocrine system, inflammatome, and the gut microbiome. Life-course models will integrate the role of modifying factors as sex, socioeconomics, and lifestyle with the goal to better identify groups at risk as well as inform promising strategies to reverse the possible mechanisms and/or reduce the impact of ELS on multi-morbidity development in high-risk individuals. These strategies will help better manage the impact of multi-morbidity on human health and the associated risk.
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Epigenetics and the Impact of Early-Life Stress Across Generations (Chapter 28)
van Steenwyk, Gretchen, and Isabelle M. Mansuy. "Epigenetics and the Impact of Early-Life Stress Across Generations." Stress: Genetics, Epigenetics and Genomics. Academic Press, 2020. 297-307.
Exposure to stress during prenatal and postnatal life can have severe consequences on cognitive, behavioral, and physiological functions in adulthood. Experimental evidence in animals and humans suggests that the hypothalamic–pituitary–adrenal (HPA) axis is involved. At a molecular level, stress exposure can modify epigenetic processes and factors such as DNA methylation, histone posttranslational modifications, and noncoding RNA, which in turn underlie physical manifestations of the stress response. In severe cases, stress can increase the risk for mental and physical diseases. While such effects are well documented in exposed people, numerous studies have also reported similar increased risk in their children or grandchildren, suggesting that the effects of exposure can be inherited. This type of inheritance is thought to involve epigenetic factors embedded in the germline that are altered in response to exposure and transmitted to the progeny by fertilization. Developing germ cells are particularly vulnerable to gestational and prepubertal stress exposure, and several lines of evidence in human and animal studies show that early-life stress can modify epigenetic factors in germ cells and transmit phenotypes to the offspring.
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Impact of Parental Exposure on Offspring Health in Humans
Jawaid, Ali, Katherina-Lynn Jehle, and Isabelle M. Mansuy. "Impact of Parental Exposure on Offspring Health in Humans." Trends in Genetics (2020).
The possibility that parental life experiences and environmental exposures influence mental and physical health across generations is an important concept in biology and medicine. Evidence from animal models has established the existence of a non-genetic mode of inheritance. This form of heredity involves transmission of the effects of parental exposure to the offspring through epigenetic changes in the germline. Studying the mechanisms of epigenetic inheritance in humans is challenging because it is difficult to obtain multigeneration cohorts, to collect reproductive cells in exposed parents, and to exclude psychosocial and cultural confounders. Nonetheless, epidemiological studies in humans exposed to famine, stress/trauma, or toxicants have provided evidence that parental exposure can impact the health of descendants, in some cases, across several generations. A few studies have also started to reveal epigenetic changes in the periphery and sperm after certain exposures. This article reviews these studies and evaluates the current evidence for the potential contribution of epigenetic factors to heredity in humans. The challenges and limitations of this fundamental biological process, its implications, and its societal relevance are also discussed.
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Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma
Gapp, Katharina, et al. "Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma." Molecular psychiatry 25.9 (2020): 2162-2174
Psychiatric diseases have a strong heritable component known to not be restricted to DNA sequence-based genetic inheritance alone but to also involve epigenetic factors in germ cells. Initial evidence suggested that sperm RNA is causally linked to the transmission of symptoms induced by traumatic experiences. Here, we show that alterations in long RNA in sperm contribute to the inheritance of specific trauma symptoms. Injection of long RNA fraction from sperm of males exposed to postnatal trauma recapitulates the effects on food intake, glucose response to insulin and risk-taking in adulthood whereas the small RNA fraction alters body weight and behavioural despair. Alterations in long RNA are maintained after fertilization, suggesting a direct link between sperm and embryo RNA.
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Associations of hair cortisol concentrations with general and organ fat measures in childhood
Vehmeijer, Florianne OL, et al. "Associations of hair cortisol concentrations with general and organ fat measures in childhood." The Journal of Clinical Endocrinology & Metabolism (2020).
Stress may lead to an adverse body fat distribution from childhood onwards.
Objective: To examine the associations of hair cortisol concentrations (HCC) at 6 years with general and organ fat measures, risk of overweight and nonalcoholic fatty liver disease (NAFLD) at 10 years and to assess whether these were independent of adiposity measures at 6 years.
Conclusions: Higher HCC at 6 years were associated with higher BMI, FMI, liver fat fraction, and higher risks of overweight and NAFLD at 10 years. Only the associations for liver fat fraction and NAFLD were independent of FMI at 6 years.
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