Mode of birth and DNA methylation at birth, in childhood, and in adolescence: Uncovering the relationship using ALSPAC data.

Mode of birth has been linked to offspring health. Changes in DNA methylation (DNAm) may represent a potential mechanism; however, findings are heterogeneous and limited to early infancy. This preregistered study examined whether mode of birth (vaginal birth compared with elective or emergency cesarean section) affects DNAm at birth, in childhood, and adolescence and whether these effects are modified by the postnatal care environment, specifically by breastfeeding and mother-infant bonding. Using data from 876 mother-infant dyads from the U.K. Avon Longitudinal Study of Parents and Children, we examined differentially methylated cytosine-phosphate-guanine dinucleotides and regions associated with mode of birth. DNAm was quantified using Illumina Infinium Human Methylation 450 K BeadChip in cord blood (at birth) and in peripheral blood (at 7 and 15-17 years). Analyses controlled for maternal age, education, smoking during pregnancy, child sex, gestational week at birth, and batch effects. We also examined interactions of mode of birth with breastfeeding practices and mother-infant bonding. In cord blood, two cytosine-phosphate-guanine dinucleotides (cg05230316; cg13230077) were linked to mode of birth (pFDR < .050). DNAm in childhood or adolescence was not statistically associated with mode of birth (pFDR > .050), and breastfeeding and mother-infant bonding were not moderators (p > .050). Overall, findings suggest mode of birth may have a small effect on cord blood DNAm, but these effects may not persist into later developmental stages. Other postnatal influences should be considered, and further investigation is needed to address study limitations. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

New approach methodologies to enhance human health risk assessment of immunotoxic properties of chemicals - a PARC (Partnership for the Assessment of Risk from Chemicals) project.

As a complex system governing and interconnecting numerous functions within the human body, the immune system is unsurprisingly susceptible to the impact of toxic chemicals. Toxicants can influence the immune system through a multitude of mechanisms, resulting in immunosuppression, hypersensitivity, increased risk of autoimmune diseases and cancer development. At present, the regulatory assessment of the immunotoxicity of chemicals relies heavily on rodent models and a limited number of Organisation for Economic Co-operation and Development (OECD) test guidelines, which only capture a fraction of potential toxic properties. Due to this limitation, various authorities, including the World Health Organization and the European Food Safety Authority have highlighted the need for the development of novel approaches without the use of animals for immunotoxicity testing of chemicals. In this paper, we present a concise overview of ongoing efforts dedicated to developing and standardizing methodologies for a comprehensive characterization of the immunotoxic effects of chemicals, which are performed under the EU-funded Partnership for the Assessment of Risk from Chemicals (PARC).

Developmental epigenomic effects of maternal financial problems.

Early-life adversity as neglect or low socioeconomic status is associated with negative physical/mental health outcomes and plays an important role in health trajectories through life. The early-life environment has been shown to be encoded as changes in epigenetic markers that are retained for many years.We investigated the effect of maternal major financial problems (MFP) and material deprivation (MD) on their children's epigenome in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Epigenetic aging, measured with epigenetic clocks, was weakly accelerated with increased MFP. In subsequent EWAS, MFP, and MD showed strong, independent programing effects on children's genomes. MFP in the period from birth to age seven was associated with genome-wide epigenetic modifications on children's genome visible at age 7 and partially remaining at age 15.These results support the hypothesis that physiological processes at least partially explain associations between early-life adversity and health problems later in life. Both maternal stressors (MFP/MD) had similar effects on biological pathways, providing preliminary evidence for the mechanisms underlying the effects of low socioeconomic status in early life and disease outcomes later in life. Understanding these associations is essential to explain disease susceptibility, overall life trajectories and the transition from health to disease.

Early-life influenza A (H1N1) infection independently programs brain connectivity, HPA AXIS and tissue-specific gene expression profiles.

Early-life adversity covers a range of physical, social and environmental stressors. Acute viral infections in early life are a major source of such adversity and have been associated with a broad spectrum of later-life effects outside the immune system or "off-target". These include an altered hypothalamus-pituitary-adrenal (HPA) axis and metabolic reactions. Here, we used a murine post-natal day 14 (PND 14) Influenza A (H1N1) infection model and applied a semi-holistic approach including phenotypic measurements, gene expression arrays and diffusion neuroimaging techniques to investigate HPA axis dysregulation, energy metabolism and brain connectivity. By PND 56 the H1N1 infection had been resolved, and there was no residual gene expression signature of immune cell infiltration into the liver, adrenal gland or brain tissues examined nor of immune-related signalling. A resolved early-life H1N1 infection had sex-specific effects. We observed retarded growth of males and altered pre-stress (baseline) blood glucose and corticosterone levels at PND42 after the infection was resolved. Cerebral MRI scans identified reduced connectivity in the cortex, midbrain and cerebellum that were accompanied by tissue-specific gene expression signatures. Gene set enrichment analysis confirmed that these were tissue-specific changes with few common pathways. Early-life infection independently affected each of the systems and this was independent of HPA axis or immune perturbations.

Multicomponent (bio)markers for obesity risk prediction: a scoping review protocol.

INTRODUCTION: Despite international efforts, the number of individuals struggling with obesity is still increasing. An important aspect of obesity prevention relates to identifying individuals at risk at early stage, allowing for timely risk stratification and initiation of countermeasures. However, obesity is complex and multifactorial by nature, and one isolated (bio)marker is unlikely to enable an optimal risk stratification and prognosis for the individual; rather, a combined set is required. Such a multicomponent interpretation would integrate biomarkers from various domains, such as classical markers (eg, anthropometrics, blood lipids), multiomics (eg, genetics, proteomics, metabolomics), lifestyle and behavioural attributes (eg, diet, physical activity, sleep patterns), psychological traits (mental health status such as depression) and additional host factors (eg, gut microbiota diversity), also by means of advanced interpretation tools such as machine learning. In this paper, we will present a protocol that will be employed for a scoping review that attempts to summarise and map the state-of-the-art in the area of multicomponent (bio)markers related to obesity, focusing on the usability and effectiveness of such biomarkers. METHODS AND ANALYSIS: PubMed, Scopus, CINAHL and Embase databases will be searched using predefined key terms to identify peer-reviewed articles published in English until January 2024. Once downloaded into EndNote for deduplication, CADIMA will be employed to review and select abstracts and full-text articles in a two-step procedure, by two independent reviewers. Data extraction will then be carried out by several independent reviewers. Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews and Peer Review of Electronic Search Strategies guidelines will be followed. Combinations employing at least two biomarkers from different domains will be mapped and discussed. ETHICS AND DISSEMINATION: Ethical approval is not required; data will rely on published articles. Findings will be published open access in an international peer-reviewed journal. This review will allow guiding future directions for research and public health strategies on obesity prevention, paving the way towards multicomponent interventions.

Methylation of serotonin regulating genes in cord blood cells: association with maternal metabolic parameters and correlation with methylation in peripheral blood cells during childhood and adolescence.

BACKGROUND: Serotonin (5-hydroxytryptamine, 5-HT) signaling is involved in neurodevelopment, mood regulation, energy metabolism, and other physiological processes. DNA methylation plays a significant role in modulating the expression of genes responsible for maintaining 5-HT balance, such as 5-HT transporter (SLC6A4), monoamine oxidase A (MAOA), and 5-HT receptor type 2A (HTR2A). Maternal metabolic health can influence long-term outcomes in offspring, with DNA methylation mediating these effects. We investigated associations between maternal metabolic parameters-pre-pregnancy body mass index (pBMI), gestational weight gain (GWG), and glucose tolerance status (GTS), i.e., gestational diabetes mellitus (GDM) versus normal glucose tolerance (NGT)-and cord blood methylation of SLC6A4, MAOA, and HTR2A in participants from our PlaNS birth cohort. CpG sites (15, 9, and 2 in each gene, respectively) were selected based on literature and in silico data. Methylation levels were quantified by bisulfite pyrosequencing. We also examined the stability of methylation patterns in these genes in circulating blood cells from birth to adolescence using longitudinal DNA methylation data from the ARIES database. RESULTS: None of the 203 PlaNS mothers included in this study had preexisting diabetes, 99 were diagnosed with GDM, and 104 had NGT; all neonates were born at full term by planned Cesarean section. Methylation at most CpG sites differed between male and female newborns. SLC6A4 methylation correlated inversely with maternal pBMI and GWG, while methylation at HTR2A site -1665 correlated positively with GWG. None of the maternal metabolic parameters statistically associated with MAOA methylation. DNA methylation data in cord blood and peripheral blood at ages 7 and 15 years were available for 808 participants from the ARIES database; 4 CpG sites (2 in SLC6A4 and 2 in HTR2A) overlapped between the PlaNS and ARIES cohorts. A positive correlation between methylation levels in cord blood and peripheral blood at 7 and 15 years of age was observed for both SLC6A4 and HTR2A CpG sites. CONCLUSIONS: Methylation of 5-HT regulating genes in cord blood cells is influenced by neonatal sex, with maternal metabolism playing an additional role. Inter-individual variations present in circulating blood cells at birth are still pronounced in childhood and adolescence.

Traumatic birth and childbirth-related post-traumatic stress disorder: International expert consensus recommendations for practice, policy, and research.

BACKGROUND: Research suggests 1 in 3 births are experienced as psychologically traumatic and about 4% of women and 1% of their partners develop post-traumatic stress disorder (PTSD) as a result. AIM: To provide expert consensus recommendations for practice, policy, and research and theory. METHOD: Two consultations (n = 65 and n = 43) with an international group of expert researchers and clinicians from 33 countries involved in COST Action CA18211; three meetings with CA18211 group leaders and stakeholders; followed by review and feedback from people with lived experience and CA18211 members (n = 238). FINDINGS: Recommendations for practice include that care for women and birth partners must be given in ways that minimise negative birth experiences. This includes respecting women's rights before, during, and after childbirth; and preventing maltreatment and obstetric violence. Principles of trauma-informed care need to be integrated across maternity settings. Recommendations for policy include that national and international guidelines are needed to increase awareness of perinatal mental health problems, including traumatic birth and childbirth-related PTSD, and outline evidence-based, practical strategies for detection, prevention, and treatment. Recommendations for research and theory include that birth needs to be understood through a neuro-biopsychosocial framework. Longitudinal studies with representative and global samples are warranted; and research on prevention, intervention and cost to society is essential. CONCLUSION: Implementation of these recommendations could potentially reduce traumatic births and childbirth-related PTSD worldwide and improve outcomes for women and families. Recommendations should ideally be incorporated into a comprehensive, holistic approach to mental health support for all involved in the childbirth process.

How can early life adversity still exert an effect decades later? A question of timing, tissues and mechanisms.

Exposure to any number of stressors during the first 1000 days from conception to age 2 years is important in shaping an individual's life trajectory of health and disease. Despite the expanding range of stressors as well as later-life phenotypes and outcomes, the underlying molecular mechanisms remain unclear. Our previous data strongly suggests that early-life exposure to a stressor reduces the capacity of the immune system to generate subsequent generations of naïve cells, while others have shown that, early life stress impairs the capacity of neuronal stem cells to proliferate as they age. This leads us to the "stem cell hypothesis" whereby exposure to adversity during a sensitive period acts through a common mechanism in all the cell types by programming the tissue resident progenitor cells. Furthermore, we review the mechanistic differences observed in fully differentiated cells and suggest that early life adversity (ELA) may alter mitochondria in stem cells. This may consequently alter the destiny of these cells, producing the lifelong "supply" of functionally altered fully differentiated cells.

The epigenetic hallmark of early-life α-hexabromocyclododecane exposure: From cerebellar 6-mA levels to locomotor performance in adulthood.

There is a growing evidence that methylation at the N6 position of adenine (6-mA), whose modulation occurs primarily during development, would be a reliable epigenetic marker in eukaryotic organisms. The present study raises the question as to whether early-life exposure to α-hexabromocyclododecane (α-HBCDD), a brominated flame retardant, may trigger modifications in 6-mA epigenetic hallmarks in the brain during the development which, in turn could affect the offspring behaviour in adulthood. Pregnant Wistar rats were split into two groups: control and α-HBCDD (66 ng/kg/per os, G0-PND14). At PND1, α-HBCDD levels were assessed in brain and liver by LC-MS/MS. At PND14, DNA was isolated from the offspring's cerebellum. DNA methylation was measured by 6-mA-specific immunoprecipitation and Illumina® sequencing (MEDIP-Seq). Locomotor activity was finally evaluated at PND120. In our early-life exposure model, we confirmed that α-HBCDD can cross the placental barrier and be detected in pups at birth. An obvious post-exposure phenotype with locomotor deficits was observed when the rats reached adulthood. This was accompanied by sex-specific over-methylation of genes involved in the insulin signaling pathway, MAPK signaling pathway as well as serotonergic and GABAergic synapses, potentially altering the normal process of neurodevelopment with consequent motor impairments crystalized at adulthood.

Children's internalizing behavior development is heterogeneously associated with the pace of epigenetic aging.

BACKGROUND: Internalizing behaviors are an indicator of children's psychological and emotional development, predicting future mental disorders. Recent studies have identified associations between DNA methylation (DNAm) and internalizing behaviors. This prospective study aimed at exploring the associations between pace of biological aging and the developmental trajectories of internalizing behaviors. METHODS: Participants were children from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (N = 974). Measures of DNA methylation were collected at birth, age 7 and ages 15-17. The pace of aging was estimated using the DunedinPoAm algorithm (PoAm). Internalizing behaviors reported by caregivers between ages 4 and 16 using the Strengths and Difficulties Questionnaire. To explore heterogeneity in the association between PoAm and internalizing behaviors we use Poisson quantile regression in cross-section heterogeneity and longitudinal latent class analysis over the childhood and adolescence. RESULTS: Internalizing behavior trajectories were identified: low-risk, childhood limited, late onset and early onset (persistent). Accelerated aging at birth was negatively associated with internalizing behaviors in early childhood but positively correlated during adolescence. Higher PoAm at birth increased chance of low-risk profile, while decreasing likelihood of childhood limited trajectory. PoAm at age 15 was negatively associated with childhood limited profile and positively linked to late onset trajectories. Associations were larger at higher values of internalizing symptoms. CONCLUSIONS: The heterogeneity in the association between biological age acceleration and internalizing behaviors suggests a complex dynamic relationship, particularly in children with high or increased risk of adverse mental health outcomes.

A Holistic View of the Goto-Kakizaki Rat Immune System: Decreased Circulating Immune Markers in Non- Obese Type 2 Diabetes.

Type-2 diabetes is a complex disorder that is now considered to have an immune component, with functional impairments in many immune cell types. Type-2 diabetes is often accompanied by comorbid obesity, which is associated with low grade inflammation. However,the immune status in Type-2 diabetes independent of obesity remains unclear. Goto-Kakizaki rats are a non-obese Type-2 diabetes model. The limited evidence available suggests that Goto-Kakizaki rats have a pro-inflammatory immune profile in pancreatic islets. Here we present a detailed overview of the adult Goto-Kakizaki rat immune system. Three converging lines of evidence: fewer pro-inflammatory cells, lower levels of circulating pro-inflammatory cytokines, and a clear downregulation of pro-inflammatory signalling in liver, muscle and adipose tissues indicate a limited pro-inflammatory baseline immune profile outside the pancreas. As Type-2 diabetes is frequently associated with obesity and adipocyte-released inflammatory mediators, the pro-inflammatory milieu seems not due to Type-2 diabetes per se; although this overall reduction of immune markers suggests marked immune dysfunction in Goto-Kakizaki rats.

PARK7/DJ-1 promotes pyruvate dehydrogenase activity and maintains Treg homeostasis during ageing.

Pyruvate dehydrogenase (PDH) is the gatekeeper enzyme of the tricarboxylic acid (TCA) cycle. Here we show that the deglycase DJ-1 (encoded by PARK7, a key familial Parkinson's disease gene) is a pacemaker regulating PDH activity in CD4+ regulatory T cells (Treg cells). DJ-1 binds to PDHE1-ß (PDHB), inhibiting phosphorylation of PDHE1-α (PDHA), thus promoting PDH activity and oxidative phosphorylation (OXPHOS). Park7 (Dj-1) deletion impairs Treg survival starting in young mice and reduces Treg homeostatic proliferation and cellularity only in aged mice. This leads to increased severity in aged mice during the remission of experimental autoimmune encephalomyelitis (EAE). Dj-1 deletion also compromises differentiation of inducible Treg cells especially in aged mice, and the impairment occurs via regulation of PDHB. These findings provide unforeseen insight into the complicated regulatory machinery of the PDH complex. As Treg homeostasis is dysregulated in many complex diseases, the DJ-1-PDHB axis represents a potential target to maintain or re-establish Treg homeostasis.

Early-Life Adversity Leaves Its Imprint on the Oral Microbiome for More Than 20 Years and Is Associated with Long-Term Immune Changes.

The early-life microbiome (ELM) interacts with the psychosocial environment, in particular during early-life adversity (ELA), defining life-long health trajectories. The ELM also plays a significant role in the maturation of the immune system. We hypothesised that, in this context, the resilience of the oral microbiomes, despite being composed of diverse and distinct communities, allows them to retain an imprint of the early environment. Using 16S amplicon sequencing on the EpiPath cohort, we demonstrate that ELA leaves an imprint on both the salivary and buccal oral microbiome 24 years after exposure to adversity. Furthermore, the changes in both communities were associated with increased activation, maturation, and senescence of both innate and adaptive immune cells, although the interaction was partly dependent on prior herpesviridae exposure and current smoking. Our data suggest the presence of multiple links between ELA, Immunosenescence, and cytotoxicity that occur through long-term changes in the microbiome.

TERT Promoter Mutations Increase Sense and Antisense Transcription from the TERT Promoter.

Background: Chief among mechanisms of telomerase reverse transcriptase (TERT) reactivation is the appearance of mutations in the TERT promoter. The two main TERT promoter mutations are C>T transitions located -146C>T and -124C>T upstream from the translational start site. They generate a novel Ets/TCF binding site. Both mutations are mutually exclusive and -124C>T is strikingly overrepresented in most cancers. We investigated whether this mutational bias and mutual exclusion could be due to transcriptional constraints. Methods: We compared sense and antisense transcription of a panel of TERT promoter-luciferase vectors harboring the -124C>T and -146C>T mutations alone or together. lncRNA TAPAS levels were measured by RT-PCR. Results: Both mutations generally increased TERT transcription by 2-4-fold regardless of upstream and downstream regulatory elements. The double mutant increased transcription in an additive fashion, arguing against a direct transcriptional constraint. The -146C>T mutation, alone or in combination with -124C>T, also unleashed antisense transcription. In line with this finding, lncRNA TAPAS was higher in cells with mutated TERT promoter (T98G and U87) than in cells with wild-type promoter, suggesting that lncRNA TAPAS may balance the effect of TERT promoter mutations. Conclusions: -146C>T and -124C>T TERT promoter mutations increase TERT sense and antisense transcription, and the double mutant features higher transcription levels. Increased antisense transcription may contain TERT expression within sustainable levels.

Unbiased Screening Identifies Functional Differences in NK Cells After Early Life Psychosocial Stress.

Early Life Adversity (ELA) is closely associated with the risk for developing diseases later in life, such as autoimmune diseases, type-2 diabetes and cardiovascular diseases. In humans, early parental separation, physical and sexual abuse or low social-economic status during childhood are known to have great impact on brain development, in the hormonal system and immune responses. Maternal deprivation (MD) is the closest animal model available to the human situation. This paradigm induces long lasting behavioral effects, causes changes in the HPA axis and affects the immune system. However, the mechanisms underlying changes in the immune response after ELA are still not fully understood. In this study we investigated how ELA changes the immune system, through an unbiased analysis, viSNE, and addressed specially the NK immune cell population and its functionality. We have demonstrated that maternal separation, in both humans and rats, significantly affects the sensitivity of the immune system in adulthood. Particularly, NK cells' profile and response to target cell lines are significantly changed after ELA. These immune cells in rats are not only less cytotoxic towards YAC-1 cells, but also show a clear increase in the expression of maturation markers after 3h of maternal separation. Similarly, individuals who suffered from ELA display significant changes in the cytotoxic profile of NK cells together with decreased degranulation capacity. These results suggest that one of the key mechanisms by which the immune system becomes impaired after ELA might be due to a shift on the senescent state of the cells, specifically NK cells. Elucidation of such a mechanism highlights the importance of ELA prevention and how NK targeted immunotherapy might help attenuating ELA consequences.

Concentrated Raw Fibers Enhance the Fiber-Degrading Capacity of a Synthetic Human Gut Microbiome.

The consumption of prebiotic fibers to modulate the human gut microbiome is a promising strategy to positively impact health. Nevertheless, given the compositional complexity of the microbiome and its inter-individual variances, generalized recommendations on the source or amount of fiber supplements remain vague. This problem is further compounded by availability of tractable in vitro and in vivo models to validate certain fibers. We employed a gnotobiotic mouse model containing a 14-member synthetic human gut microbiome (SM) in vivo, characterized a priori for their ability to metabolize a collection of fibers in vitro. This SM contains 14 different strains belonging to five distinct phyla. Since soluble purified fibers have been a common subject of studies, we specifically investigated the effects of dietary concentrated raw fibers (CRFs)-containing fibers from pea, oat, psyllium, wheat and apple-on the compositional and functional alterations in the SM. We demonstrate that, compared to a fiber-free diet, CRF supplementation increased the abundance of fiber-degraders, namely Eubacterium rectale, Roseburia intestinalis and Bacteroides ovatus and decreased the abundance of the mucin-degrader Akkermansia muciniphila. These results were corroborated by a general increase of bacterial fiber-degrading α-glucosidase enzyme activity. Overall, our results highlight the ability of CRFs to enhance the microbial fiber-degrading capacity.

Adverse Life Trajectories Are a Risk Factor for SARS-CoV-2 IgA Seropositivity.

Asymptomatic individuals, called "silent spreaders" spread SARS-CoV-2 efficiently and have complicated control of the ongoing COVID-19 pandemic. As seen in previous influenza pandemics, socioeconomic and life-trajectory factors are important in disease progression and outcome. The demographics of the asymptomatic SARS-CoV-2 carriers are unknown. We used the CON-VINCE cohort of healthy, asymptomatic, and oligosymptomatic individuals that is statistically representative of the overall population of Luxembourg for age, gender, and residency to characterise this population. Gender (male), not smoking, and exposure to early-life or adult traumatic experiences increased the risk of IgA seropositivity, and the risk associated with early-life exposure was a dose-dependent metric, while some other known comorbidities of active COVID-19 do not impact it. As prior exposure to adversity is associated with negative psychobiological reactions to external stressors, we recorded psychological wellbeing during the study period. Exposure to traumatic events or concurrent autoimmune or rheumatic disease were associated with a worse evolution of anxiety and depressive symptoms throughout the lockdown period. The unique demographic profile of the "silent spreaders" highlights the role that the early-life period plays in determining our lifelong health trajectory and provides evidence that the developmental origins of health and disease is applicable to infectious diseases.

N6-Methyladenine in Eukaryotic DNA: Tissue Distribution, Early Embryo Development, and Neuronal Toxicity.

DNA methylation is one of the most important epigenetic modifications and is closely related with several biological processes such as regulation of gene transcription and the development of non-malignant diseases. The prevailing dogma states that DNA methylation in eukaryotes occurs essentially through 5-methylcytosine (5mC) but recently adenine methylation was also found to be present in eukaryotes. In mouse embryonic stem cells, 6-methyladenine (6mA) was associated with the repression and silencing of genes, particularly in the X-chromosome, known to play an important role in cell fate determination. Here, we have demonstrated that 6mA is a ubiquitous eukaryotic epigenetic modification that is put in place during epigenetically sensitive periods such as embryogenesis and fetal development. In somatic cells there are clear tissue specificity in 6mA levels, with the highest 6mA levels being observed in the brain. In zebrafish, during the first 120 h of embryo development, from a single pluripotent cell to an almost fully formed individual, 6mA levels steadily increase. An identical pattern was observed over embryonic days 7-21 in the mouse. Furthermore, exposure to a neurotoxic environmental pollutant during the same early life period may led to a decrease in the levels of this modification in female rats. The identification of the periods during which 6mA epigenetic marks are put in place increases our understanding of this mammalian epigenetic modification, and raises the possibility that it may be associated with developmental processes.