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Epigenetic and Molecular Consequences of Early-Life Trauma

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (15 February 2021) | Viewed by 48266

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Dr. Jonathan Turner

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Guest Editor

Principal Investigator, Immune Endocrine and Epigenetics Research Group, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
Interests: behavioural epigenetics; molecular consequences of early life adversity; DNA methylation; HPA axis; glucocorticoid receptor; genetics and epigenetics of the stress response
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Dear Colleagues,

The environment in the early life period has a significant long-term impact on health and disease. This early-life exposome includes socioeconomic conditions, trauma exposure, parental separation, maltreatment, and many other factors. In many cases, suboptimal early-life conditions are a major contributor, not only to the lifelong disease burden but also to the cost of acute and chronic care. There is growing evidence that the early life social environment affects both the parents and the offspring. The direct action of the environment on the early-life epigenome as well as the inheritance of parental epigenetic marks is a rapidly expanding area of research. New and emerging research in the areas of epigenetics, biomedicine, and neuro-endocrinology hold great promise in relation to the development of our understanding of the complexity of the early life (social) environment and the multiplicity of factors that result in the long-term phenotype.

In this Special Issue of the International Journal of Molecular Sciences, the developmental origins of health and disease will be explored in the context of the early-life (social) environment. Potential topics include but are not limited to the early life (social) environment; methods of conceptualizing the early life environment, including SES, trauma, parental illness, or PTSD; long-term health consequences of the early life environment; long-term pathophysiological and phenotypic differences; biological markers of early-life exposure; and epigenetic or immunological mechanisms encoding exposure. Manuscripts exploring the relative strengths and weaknesses of competing hypotheses such as but limited to the hygiene hypothesis/microbiome establishment vs. EPIIC (Epigenetic Impact of Childbirth) that may explain long term differences in immune response are particularly welcome.

Although the impetus for this Special Issue comes from the COST Action CA18211 (Perinatal Mental Health and Birth-Related Trauma: Maximising Best Practice and Optimal Outcomes” (DEVoTION)), submissions are encouraged from the wider scientific community as well as action members.

Dr. Jonathan Turner
Guest Editor

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Keywords

Early-life exposome
Trauma
Epigenetic mechanisms
Behavioural epigenetics
Social epigenetics

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Published Papers (7 papers)

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17 pages, 4225 KiB

Open AccessArticle

Aberrations in FGFR1, FGFR2, and RIP5 Expression in Human Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)

by Nela Kelam, Anita Racetin, Mirjana Polović, Benjamin Benzon, Marin Ogorevc, Katarina Vukojević, Merica Glavina Durdov, Ana Dunatov Huljev, Ivana Kuzmić Prusac, Davor Čarić, Fila Raguž and Sandra Kostić

Int. J. Mol. Sci. 2022, 23(24), 15537; https://doi.org/10.3390/ijms232415537 - 8 Dec 2022

Cited by 6 | Viewed by 1973

Abstract

This study aimed to explore the spatio-temporal expression patterns of congenital anomalies of kidney and urinary tract (CAKUT) candidate genes, Fibroblast Growth Factor Receptor 1 (FGFR1), Fibroblast Growth Factor Receptor 2 (FGFR2) and Receptor-Interacting Protein Kinase 5 (RIP5), in human fetal kidney development (CTRL) and kidneys affected with CAKUT. Human fetal kidneys from the 22nd to 41st developmental week (duplex, hypoplastic, dysplastic, and controls) were stained with antibodies and analyzed by epifluorescence microscopy and RT−qPCR. The effect of CAKUT candidate genes on kidney nephrogenesis and function is confirmed by statistically significant variations in the spatio-temporal expression patterns of the investigated markers. The nuclear localization of FGFR1, elevated expression score of FGFR1 mRNA, the increased area percentage of FGFR1-positive cells in the kidney cortex, and the overall decrease in the expression after the peak at the 27th developmental week in dysplastic kidneys (DYS), suggest an altered expression pattern and protein function in response to CAKUT pathophysiology. The RT−qPCR analysis revealed a significantly higher FGFR2 mRNA expression score in the CAKUT kidneys compared to the CTRL. This increase could be due to the repair mechanism involving the downstream mediator, Extracellular Signal-Regulated Kinase 1/2 (ERK1/2). The expression of RIP5 during normal human kidney development was reduced temporarily, due to urine production and increased later since it undertakes additional functions in the maturation of the postnatal kidney and homeostasis, while the expression dynamics in CAKUT-affected kidneys exhibited a decrease in the percentage of RIP5-positive cells during the investigated developmental period. Our findings highlight the importance of FGFR1, FGFR2, and RIP5 as markers in normal and pathological kidney development. Full article

(This article belongs to the Special Issue Epigenetic and Molecular Consequences of Early-Life Trauma)

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13 pages, 2099 KiB

Open AccessArticle

Fetal Middle Cerebral Artery Pulsatility Index in No-Risk Pregnancies: Effects of Auditory Stimulation and Pregnancy Order

by Ljiljana Jeličić, Svetlana Janković, Mirjana Sovilj, Tatjana Adamović, Ivana Bogavac, Aleksandar Gavrilović and Miško Subotić

Int. J. Mol. Sci. 2020, 21(11), 3855; https://doi.org/10.3390/ijms21113855 - 29 May 2020

Cited by 1 | Viewed by 4782

Abstract

Pulsatility index (PI) values in a fetal middle cerebral artery (MCA) were compared in no-risk pregnancies to examine the differences related to auditory stimulation test and pregnancy order. The study included 196 women with no-risk pregnancies selected from the database of more than 1000 pregnant women divided into two groups. Group 1 consisted of 98 nulliparous women (C1 = 98) and Group 2 consisted of 98 parous women (C2 = 98). All pregnant women were of comparable age and fetal gestational age (GA) when MCA-PI values were recorded. Measurements of PI values in fetal MCA were obtained before and immediately after the application of fetal auditory stimulation test. The MCA-PI measuring was conducted in the period between the 36th and the 41st week of GA. The results showed that PI baseline values and PI values after defined auditory stimulation were significantly different when measured in nulliparous women compared to parous women (p = 0.001; p = 0.003, respectively), while no group differences were observed in relative PI value changes due to auditory stimulation. These findings suggest that hemodynamic changes in fetal MCA caused by defined auditory stimulation measured by PI value changes may be valuable in the assessment of fetal auditory perception functionality and its development. Full article

(This article belongs to the Special Issue Epigenetic and Molecular Consequences of Early-Life Trauma)

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17 pages, 1213 KiB

Open AccessReview

The ‘Jekyll and Hyde’ of Gluconeogenesis: Early Life Adversity, Later Life Stress, and Metabolic Disturbances

by Snehaa V. Seal and Jonathan D. Turner

Int. J. Mol. Sci. 2021, 22(7), 3344; https://doi.org/10.3390/ijms22073344 - 25 Mar 2021

Cited by 28 | Viewed by 10606

Abstract

The physiological response to a psychological stressor broadly impacts energy metabolism. Inversely, changes in energy availability affect the physiological response to the stressor in terms of hypothalamus, pituitary adrenal axis (HPA), and sympathetic nervous system activation. Glucocorticoids, the endpoint of the HPA axis, are critical checkpoints in endocrine control of energy homeostasis and have been linked to metabolic diseases including obesity, insulin resistance, and type 2 diabetes. Glucocorticoids, through the glucocorticoid receptor, activate transcription of genes associated with glucose and lipid regulatory pathways and thereby control both physiological and pathophysiological systemic energy homeostasis. Here, we summarize the current knowledge of glucocorticoid functions in energy metabolism and systemic metabolic dysfunction, particularly focusing on glucose and lipid metabolism. There are elements in the external environment that induce lifelong changes in the HPA axis stress response and glucocorticoid levels, and the most prominent are early life adversity, or exposure to traumatic stress. We hypothesise that when the HPA axis is so disturbed after early life adversity, it will fundamentally alter hepatic gluconeogenesis, inducing hyperglycaemia, and hence crystalise the significant lifelong risk of developing either the metabolic syndrome, or type 2 diabetes. This gives a “Jekyll and Hyde” role to gluconeogenesis, providing the necessary energy in situations of acute stress, but driving towards pathophysiological consequences when the HPA axis has been altered. Full article

(This article belongs to the Special Issue Epigenetic and Molecular Consequences of Early-Life Trauma)

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13 pages, 519 KiB

Open AccessReview

Are There Epigenetic Oxytocin-Mediated Effects on the Mother and Infant during Physiological Childbirth?

by Kerstin Uvnäs-Moberg, Mechthild M. Gross, Andee Agius, Soo Downe and Jean Calleja-Agius

Int. J. Mol. Sci. 2020, 21(24), 9503; https://doi.org/10.3390/ijms21249503 - 14 Dec 2020

Cited by 13 | Viewed by 9363

Abstract

Introduction: Studies have shown that long-term positive behavioural and physiological changes are induced in connection with vaginal, physiological birth, and skin-to-skin contact after birth in mothers and babies. Some of these effects are consistent with the effect profile of oxytocin. This scoping review explores whether epigenetic changes of the oxytocin gene and of the oxytocin receptor gene (OTR) are involved in these effects. Methods: We searched Pubmed, Medline, BioMed Central, Cochrane Library, OVID, and Web of Science for evidence of epigenetic changes in connection with childbirth in humans, with a particular focus on the oxytocin system. Results: There were no published studies identified that were related to epigenetic changes of oxytocin and its receptor in connection with labour, birth, and skin-to-skin contact after birth in mothers and babies. However, some studies were identified that showed polymorphisms of the oxytocin receptor influenced the progress of labour. We also identified studies in which the level of global methylation was measured in vaginal birth and caesarean section, with conflicting results. Some studies identified differences in the level of methylation of single genes linked to various effects, for example, immune response, metabolism, and inflammation. In some of these cases, the level of methylation was associated with the duration of labour or mode of birth. We also identified some studies that demonstrated long-term effects of mode of birth and of skin-to-skin contact linked to changes in oxytocin function. Conclusion: There were no studies identified that showed epigenetic changes of the oxytocin system in connection with physiological birth. The lack of evidence, so far, regarding epigenetic changes did not exclude future demonstrations of such effects, as there was a definite role of oxytocin in creating long-term effects during the perinatal period. Such studies may not have been performed. Alternatively, the oxytocin linked effects might be indirectly mediated via other receptors and signalling systems. We conclude that there is a significant lack of research examining long-term changes of oxytocin function and long-term oxytocin mediated adaptive effects induced during physiological birth and skin-to-skin contact after birth in mothers and their infants. Full article

(This article belongs to the Special Issue Epigenetic and Molecular Consequences of Early-Life Trauma)

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21 pages, 731 KiB

Open AccessReview

The COVID-19 Pandemic: Does Our Early Life Environment, Life Trajectory and Socioeconomic Status Determine Disease Susceptibility and Severity?

by Cyrielle Holuka, Myriam P. Merz, Sara B. Fernandes, Eleftheria G. Charalambous, Snehaa V. Seal, Nathalie Grova and Jonathan D. Turner

Int. J. Mol. Sci. 2020, 21(14), 5094; https://doi.org/10.3390/ijms21145094 - 19 Jul 2020

Cited by 38 | Viewed by 8513

Abstract

A poor socioeconomic environment and social adversity are fundamental determinants of human life span, well-being and health. Previous influenza pandemics showed that socioeconomic factors may determine both disease detection rates and overall outcomes, and preliminary data from the ongoing coronavirus disease (COVID-19) pandemic suggests that this is still true. Over the past years it has become clear that early-life adversity (ELA) plays a critical role biasing the immune system towards a pro-inflammatory and senescent phenotype many years later. Cytotoxic T-lymphocytes (CTL) appear to be particularly sensitive to the early life social environment. As we understand more about the immune response to SARS-CoV-2 it appears that a functional CTL (CD8+) response is required to clear the infection and COVID-19 severity is increased as the CD8+ response becomes somehow diminished or exhausted. This raises the hypothesis that the ELA-induced pro-inflammatory and senescent phenotype may play a role in determining the clinical course of COVID-19, and the convergence of ELA-induced senescence and COVID-19 induced exhaustion represents the worst-case scenario with the least effective T-cell response. If the correct data is collected, it may be possible to separate the early life elements that have made people particularly vulnerable to COVID-19 many years later. This will, naturally, then help us identify those that are most at risk from developing the severest forms of COVID-19. In order to do this, we need to recognize socioeconomic and early-life factors as genuine medically and clinically relevant data that urgently need to be collected. Finally, many biological samples have been collected in the ongoing studies. The mechanisms linking the early life environment with a defined later-life phenotype are starting to be elucidated, and perhaps hold the key to understanding inequalities and differences in the severity of COVID-19. Full article

(This article belongs to the Special Issue Epigenetic and Molecular Consequences of Early-Life Trauma)

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17 pages, 344 KiB

Open AccessReview

Nutri-Epigenetics and Gut Microbiota: How Birth Care, Bonding and Breastfeeding Can Influence and Be Influenced?

by Rosita Gabbianelli, Laura Bordoni, Sandra Morano, Jean Calleja-Agius and Joan G. Lalor

Int. J. Mol. Sci. 2020, 21(14), 5032; https://doi.org/10.3390/ijms21145032 - 16 Jul 2020

Cited by 23 | Viewed by 7594

Abstract

Maternal lifestyle is an important factor in the programming of an infant’s epigenome, in particular when considered alongside the mode of birth and choice of feeding method (i.e., breastfeeding or formula feeding). Beginning in utero, and during the first two years of an infant’s life, cells acquire an epigenetic memory of the neonatal exposome which can be influential across the entire lifespan. Parental lifestyle (e.g., malnutrition, alcohol intake, smoke, stress, exposure to xenobiotics and/or drugs) can modify both the maternal and paternal epigenome, leading to epigenetic inheritance in their offspring. This review aims to outline the origin of early life modulation of the epigenome, and to share this fundamental concept with all the health care professionals involved in the development and provision of care during childbirth in order to inform future parents and clinicians of the importance of the this process and the key role it plays in the programming of a child’s health. Full article

(This article belongs to the Special Issue Epigenetic and Molecular Consequences of Early-Life Trauma)

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18 pages, 311 KiB

Open AccessConcept Paper

Twin Research in the Post-Genomic Era: Dissecting the Pathophysiological Effects of Adversity and the Social Environment

by Jonathan D. Turner, Conchita D’Ambrosio, Claus Vögele and Martin Diewald

Int. J. Mol. Sci. 2020, 21(9), 3142; https://doi.org/10.3390/ijms21093142 - 29 Apr 2020

Cited by 12 | Viewed by 4529

Abstract

The role of twins in research is evolving as we move further into the post-genomic era. With the re-definition of what a gene is, it is becoming clear that biological family members who share a specific genetic variant may well not have a similar risk for future disease. This has somewhat invalidated the prior rationale for twin studies. Case co-twin study designs, however, are slowly emerging as the ideal tool to identify both environmentally induced epigenetic marks and epigenetic disease-associated processes. Here, we propose that twin lives are not as identical as commonly assumed and that the case co-twin study design can be used to investigate the effects of the adult social environment. We present the elements in the (social) environment that are likely to affect the epigenome and measures in which twins may diverge. Using data from the German TwinLife registry, we confirm divergence in both the events that occur and the salience for the individual start as early as age 11. Case co-twin studies allow for the exploitation of these divergences, permitting the investigation of the role of not only the adult social environment, but also the salience of an event or environment for the individual, in determining lifelong health trajectories. In cases like social adversity where it is clearly not possible to perform a randomised-controlled trial, we propose that the case co-twin study design is the most rigorous manner with which to investigate epigenetic mechanisms encoding environmental exposure. The role of the case co-twin design will continue to evolve, as we argue that it will permit causal inference from observational data. Full article

(This article belongs to the Special Issue Epigenetic and Molecular Consequences of Early-Life Trauma)

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