A Brief Historic Review of Research on Early Life Stress and Inflammation across the Lifespan Open Access

The negative effects of stress experience on health and disease risk are well established. In line with the developmental programming or developmental origins of health and disease risk concept, the magnitude and duration of such effects are particularly potent when stress exposures occur during critical developmental periods [1]. While stress is a common aspect of modern life, certain stressors are particularly severe in terms of their impact. Traumatic experiences during childhood, or exposure to early life stress (ELS), including abuse, neglect, maltreatment, or loss of a parent, likely represent the most pernicious stressors in society in terms of their widespread prevalence and devastating short- and long-term consequences. Large population-based surveys suggest many children are exposed to traumatic experiences [2] and that more than 20% of adults have experienced at least one type of abuse or neglect in their childhood [3]. When other forms of ELS or adverse childhood experiences (ACEs) are considered, this number rises to nearly 60% [4]. Furthermore, a growing number of children worldwide are exposed to traumatic experiences related to armed conflict, war, and forced migration, adding to the burden of ELS [5]. A wealth of evidence indicates that exposure to ELS significantly and consistently raises the risk for various major psychiatric disorders, such as depression, anxiety, and substance abuse. It also contributes to a lifelong risk of chronic physical conditions, including cardiovascular disease, obesity, diabetes, certain cancers, chronic pain, and immune-related illnesses, ultimately leading to reduced life expectancy [6]. The relationship between different types of stressful experiences in early life and disease outcomes seems to be nonspecific, implying that ELS creates a fundamental dysfunction within stress-regulatory systems, which contribute to the development of a range of disorders [6]. Based on the considerations that in the majority of the diseases that are associated with ELS inflammatory processes play a dominant pathological role, chronic immune activation (defined as persistent low-grade inflammation in the absence of acute infection) has been suggested as one biological pathway through which these experiences may become “biologically embedded” [7‒9].

During the past decades, evidence from preclinical, clinical, and epidemiological studies has accumulated suggesting consequences of ELS exposure for immune function, particularly increased chronic inflammation or inflammatory responses. The scientific approaches to study the effects of ELS on the immune system have changed since the first studies on this topic were published. This paper does not purport to comprehensively discuss all the available findings on ELS/childhood trauma and inflammation; several reviews and perspectives on this topic have been published and are available elsewhere (e.g., [10‒13]). Instead, we focus here on select key findings and questions that first emerged in the literature and started the field and then examine how research methods have evolved over time and which aspects we submit warrant further consideration and discussion.

As described in Danese and Lewis [12], the first evidence that experiences during early life have effects on immune function comes from experimental studies in animal models. More than 70 years ago, Seymour Levine, intrigued by Freud’s theory that early trauma has long-lasting effects on behavior and risk for psychopathology, initiated experimental work in animals to elucidate the underlying mechanisms of this phenomenon that so far was only supported by clinical reports [14]. He published a series of studies on the effects of traumatic experience during the early life period on behavior and physiology during subsequent exposure to stressors. To his surprise, animals that were removed from their cages and “handled” for about 15 min daily during the preweaning period showed adaptive behavioral and physiological responses to stress exposure, e.g., moderate corticosterone increases to mild stressors and greater increases to more severe stressors, as well as faster recovery to basal hormone levels following termination of stress compared to a group of animals that was exposed to electrical food shocks or that was left undisturbed [15, 16]. Thus, in these experiments, contrary to the expected effects, “early handling” that involved short-term separation of the pups from the mothers was associated with beneficial effects on resistance to stress and attenuated or better modulated hypothalamic-pituitary-adrenal (HPA) axis response to stressors. Later studies observed that the mother-pup interaction was enhanced after handling by provoking bursts of maternal sensory stimulation of the pups immediately after their return to the home cage, thereby potentially modulating the development of the stress response system in an adaptive way [17]. Expanding these findings to effects on the immune system, Ader and Friedman [18] reported beneficial effects of handling during the preweaning period on the immune system by showing that early handling was associated with slower growth of a transplanted tumor in later life, and a further study reported effects of handling during early development on increased antibody titer response to an immune challenge (exposure to flagellin, a bacterial protein) [19]. These findings built the foundation for the field of “developmental psychoneuroimmunology” [9, 20] that studies the interactions between psychological processes, neurological development, and the immune system across the lifespan, with a particular focus on early developmental stages such as infancy and childhood.

While studies on early handling in rodents suggest potential beneficial effects on stress regulation and immune function, seminal studies conducted by Coe and Scheffler [21] in nonhuman primates that manipulate the bonding process between mother and infant by separating them over prolonged periods of time showed that this has consequences on several aspects of the offspring’s immune system, including lymphocyte redistribution and increased macrophage activity [22] within 24 h after separation from the mother, and reduction of the number of lymphocytes after 7 days of separation [23]. In the following years, a large number of studies were published, from several independent research groups, suggesting that across different stress paradigms, species, and ages, a pattern emerged suggesting that early life adversity leads to increased pro-inflammatory responsivity in early adolescence or later life (summarized, e.g., in [24]).

The next set of animal studies in the field of developmental psychoneuroimmunology was driven by the growing appreciation for immunological contribution to mental illness [24]. Pro-inflammatory immune activation has been linked to psychiatric disorders such as depression [25]. It was hypothesized that early immune programming through ELS may sensitize later pro-inflammatory processes, thereby leading to greater vulnerability to depression and anxiety in adulthood [26]. Several rodent studies addressed the role of neuroinflammation in this context, with a focus on microglia, which are important for the adaptive immune response in the brain. Animals exposed to repeated maternal separation exhibit greater microglial activation and elevated pro-inflammatory cytokine signaling in key brain regions implicated in human psychiatric disorders (summarized in [27]). A recent systematic review and multilevel meta-analysis of rodent studies shows that ELS is associated with increased microglia density, increased microglia soma size, and decreased oligodendrocytes, suggesting that alterations in glial cells could play a role in ELS-induced dysfunctions and risk for psychopathology throughout development [28]. Furthermore, early-life immune activation can bias microglia response to subsequent inflammatory stimuli [29‒31], thereby influencing later-life immune and behavioral responses to physical and psychological stressors [32].

In 1998, Felitti et al. [33] published results of the Adverse Childhood Experiences (ACE) Study. In this seminal study, they administered a questionnaire to almost 10,000 adults in a primary care setting that retrospectively assessed seven categories of ACEs including physical, psychological, and sexual abuse, household dysfunction like exposure to parental substance abuse, mental illness, or domestic violence before the age of 18 years. They then linked those exposures to health risk behaviors and diseases. The authors reported a graded relationship between the number of categories of childhood exposure and each of the adult health risk behaviors and diseases that were studied, including markedly increased risks for alcoholism, drug abuse, depression, suicide attempt, and severe obesity [33]. This study has sparked scientific interest in the link between early traumatic experiences and disease risk in later life. In the following years, many human studies confirming these associations between ACEs and risk for somatic and psychiatric diseases across different populations were published. A study by Taylor et al. [34] then reported for the first time that low childhood socioeconomic status and a harsh early family environment while growing up are related to higher concentrations of a systemic marker of inflammation, C-reactive protein (CRP), assessed in blood samples during adulthood. This relationship between early adversity and adult inflammation has been replicated many times since then and extended to other inflammatory markers assessed in peripheral blood samples, including interleukin (IL)-6, tumor necrosis factor-α, and IL-1β, as summarized in several meta-analyses and reviews [10‒13].

Among the main functions of glucocorticoids (cortisol in humans) are their anti-inflammatory and immunosuppressive actions. The “glucocorticoid resistance” hypothesis [35] suggests that the glucocorticoid receptor (GR) – which physiologically mediates the negative feedback effects of cortisol on the HPA axis and downregulates the production of pro-inflammatory cytokines by immune cells – is less sensitive for the effects of cortisol, resulting in HPA axis hyperactivity and higher levels of pro-inflammatory cytokines, especially after acute stress exposure [36]. The observation that hyperactivity of the HPA axis – resulting in high levels of cortisol – and increased inflammation often co-occur in major depression seemed counterintuitive at first [25] but can be explained with this model.

To investigate the mediating role of the immune response in linking ELS and major depression, Pace et al. [35] studied IL-6 and DNA binding of nuclear factor (NF)-κB, a transcription factor of the inflammatory signaling cascade, in peripheral immune cells in patients with major depression before and after exposure to an acute psychosocial stress paradigm in the laboratory. They observed a higher increase in IL-6 and NF-κB DNA binding to acute stress in major depression patients as a function of the degree of exposure to ELS, thereby providing the first evidence for an enhanced inflammatory responsiveness to psychosocial stress in ELS-exposed individuals in humans. In line with the GR resistance hypothesis, Heim et al. [37] observed relative GR resistance as identified with the dexamethasone/corticotropin-releasing hormone challenge test in patients with a history of childhood abuse and major depression. Furthermore, they reported enhanced inflammatory system activity (i.e., increased NF-κB pathway activity) in combination with a decreased immune cell glucocorticoid sensitivity in patients with childhood abuse-related post-traumatic stress disorder compared to healthy controls [38]. A research group led by Elisabeth Binder studied the protein FKBP5 in this context that has been implicated in the regulation of GR sensitivity and HPA axis feedback [39]. They demonstrated that aging, childhood trauma, and depression were associated with epigenetically upregulated FKBP5 expression, which, in turn, in cellular models promoted a pro-inflammatory gene expression profile driven by alterations in NF-κB-related gene networks [40].

Most of these earlier studies on childhood trauma exposure and inflammatory biomarkers assessed in later life relied on retrospective reports of childhood events by study members once they were adults, and there is an ongoing debate in the literature whether or not this is a limitation of the research field [41]. It is therefore reassuring regarding the validity of these findings that the association between childhood trauma and plasma inflammatory biomarkers was confirmed in prospective longitudinal studies. For example, in the Dunedin Multidisciplinary Health and Development Study that followed up individuals from birth to adulthood, childhood maltreatment was associated with higher concentrations of CRP and other blood-based markers of inflammation at the age of 32 years [42].

How soon after exposure to severe stress or maltreatment in early life do these alterations in the immune system emerge? To date, only a limited number of studies have tested the link between childhood adversity and inflammatory markers in childhood. In the E-Risk study, a longitudinal study with several waves of assessments from birth to adolescence, concentrations of CRP were already elevated by age 12 in maltreated children who developed depression compared to a control group [43]. Additionally, elevated CRP levels were observed in 10-year-old children who had recently experienced maltreatment and carried a genotype linked to higher CRP levels [44]. Another prospective longitudinal study found that exposure to traumatic experiences before the age of 8 is associated with increased CRP concentrations at the ages of 10 and 15 years [45]. In preschool-aged children, a pro-inflammatory cytokine (IL-1β) assessed in saliva samples was linked to the degree of exposure to childhood adversity [46]. And in one of our own studies for which we recruited children shortly after maltreatment exposure and followed them up twice a year over a period of 2 years, we found that salivary CRP levels were higher in maltreated children compared to nonexposed children at study entry and over the entire study period, and this effect was specific to girls [47]. Taken together, these results indicate that the impact of maltreatment on inflammation may begin to manifest shortly after early exposure and persist until adulthood.

Studies dating back to the 1970s provided the first evidence that exposure to adversity is linked to a higher risk for autoimmune diseases (summarized in [48]), suggesting a transition from an increased inflammatory state to a chronic inflammatory disease state that manifests as a chronic autoimmune disease [48]. Henoch et al. [49] reported that among children with arthritis, the number of children whose parents were unmarried as a result of divorce, separation, or death was much higher than in a healthy comparison group (CG), and this link between stressful circumstances and arthritis during childhood was confirmed in an independent study [50]. In adults, ACEs were associated with a higher likelihood of hospitalization with a diagnosed autoimmune disease [51, 52], and in various other studies with rheumatoid arthritis [52], systemic lupus erythematosus [53], multiple sclerosis [54, 55], psoriasis [56], and type-1 diabetes [57].

Accumulating evidence suggests that not only stress and adversity during childhood but also during the prenatal period in the form of maternal stress and emotions during pregnancy may shape development and later life disease risk [58, 59]. Coe and Lubach [60] conducted a series of studies in primates to assess whether maternal stress during gestation and exposure of the fetus to the synthetic glucocorticoid dexamethasone could exert effects on the development of immune function in the offspring (summarized in [60]). They report effects on functional immune responses, such as the ability of natural killer cells to lyse virally transformed or cancerous cells, that were impaired in prenatally exposed monkeys compared to controls. Furthermore, leukocytes of these animals showed an impaired capacity to produce pro-inflammatory cytokines following exposure to a bacterial protein (LPS), which can be an indicator of a compromised immune competence to fight off a bacterial infection. A study in mice shows that offspring of prenatally stressed dams have an increased vulnerability toward airway hyperresponsiveness and inflammation, accompanied by a Th2-biased immune response after viral antigen challenge [61]. Furthermore, Vanbesien-Mailliot et al. [62] described a pro-inflammatory immunologic state in prenatally stressed adult rats. In a human study, we report findings that are in line with these observations from animal models. We carried out a study in young adults. The prenatal stress group was born to mothers who retrospectively reported that they had experienced a severely stressful life event during pregnancy, whereas CG reported no maternal exposure to stress during pregnancy. Individuals in the prenatal stress group exhibited a more pro-inflammatory cytokine response to phytohemagglutinin (PHA) that was in line with a TH2 shift in the TH1/TH2 balance (suggesting an increased risk of asthma and autoimmune disorders [63]). A comprehensive review paper summarizing animal work and human studies on this topic concludes that the effects of maternal stress during pregnancy on offspring immune outcomes depend on timing, type, and duration of the prenatal stressor and the age, sex, and species of the offspring [64].

Growing evidence suggests that the consequences of exposure to childhood trauma and adversity are not restricted to the exposed individual but also may get transmitted to the next generation, thus significantly extending the long-term impact of ELS exposure [65]. Unfavorable circumstances experienced during infancy and childhood by the offspring of mothers or fathers who were exposed to traumatic experiences during their own childhood, such as exposure to maternal depression or suboptimal parenting, have been postulated as the primary pathways of intergenerational transmission. We proposed that the intergenerational transmission of childhood adverse experience may start even earlier during the highly sensitive period of gestation and embryonic and fetal development [65] and that the application of the fetal programming paradigm (i.e., the processes by which the in utero environment shapes the long-term regulation of tissue physiology and homeostasis) may shed new light on this potential intrauterine pathway.

As reviewed above, an underlying factor in the long-term effects of childhood trauma exposure on disease risk is the dysregulation of the inflammatory system, including elevated concentrations of pro-inflammatory cytokines. Because elevated inflammation during pregnancy is associated with a variety of detrimental pregnancy, birth, and offspring health outcomes, it is also likely to be a key pathway in the context of the intergenerational transmission of childhood trauma. Furthermore, childhood trauma exposure can produce persistent epigenetic alterations in certain tissues, and through epigenetic inheritance (i.e., transmission of epigenetic marks that ELS exposure may have produced in the paternal or maternal germ line), these can be passed on to the offspring at conception. In addition, prenatal de novo methylation or demethylation in genetically susceptible offspring exposed to maternal systemic inflammation during pregnancy may constitute a potential mechanism by which the effects of maternal childhood maltreatment exposure may be propagated in the subsequent generation, as discussed in Buss et al. [65].

Indeed, associations between childhood trauma and elevated inflammation have been described during pregnancy, with studies reporting associations between early life adversity and increased inflammation during pregnancy [66‒73]. Results of other studies, including our own, suggest that the association between ELS and peripheral levels of CRP and pro-inflammatory cytokines during pregnancy was moderated by additional risk factors present during pregnancy like poor nutrition and depression [74, 75]. Taken together, these studies support the notion that a pro-inflammatory phenotype during pregnancy may serve as a mechanistic pathway for intergenerational transmission of the effects of ELS on mental and physical health.

So far, only very few human studies have considered sex as moderator of the effects of ELS on the immune system. In our own study, salivary CRP concentrations in ELS-exposed children were higher compared to the control group in girls but not in boys [47], while Engel et al. [76] reported that circulating levels of IL-6 and tumor necrosis factor-α were higher in adopted male but not female adolescents institutionalized as infants compared to a nonadopted CG. In older children, sex hormones may partly explain these sex-specific effects because testosterone levels in male adolescents are associated with CRP [77]. Stress-related immune activation is also moderated by sex [78, 79], and inflammation-related genes are differentially expressed in men versus women due to interactions between estrogen and GRs [80].

Brenhouse [81] recently reviewed the available animal studies on sex differences in ELS effects on the immune system and concluded that while sex differences have not been studied much in this context, immediate inflammatory effects are present in both sexes, while programming of a long-term pro-inflammatory phenotype by ELS exposure is more often reported in males compared to female animals.

Several potential biological and behavioral pathways and mechanisms that are interconnected and operate synergistically to promote chronic immune activation in individuals exposed to ELS have been discussed [12, 47] (shown in Fig. 1). The brain, through its intricate network of neural and hormonal pathways, continuously communicates with the immune system, influencing its activity and vice versa. One key pathway is through the vagus nerve, which acts as a bidirectional conduit between the brain and peripheral organs. The vagus nerve can modulate immune responses by detecting inflammatory signals and conveying this information to the brain, which in turn can activate anti-inflammatory pathways to regulate immune function. This bidirectional communication is essential for orchestrating appropriate immune responses to pathogens, maintaining immune tolerance and regulating inflammatory processes. ELS has been shown to program an imbalance of the autonomic nervous system with downregulation of vagus nerve and cholinergic anti-inflammatory pathway resulting in pro-inflammatory conditions [82]. The blood-brain barrier (BBB), a neurovascular unit, is a selectively permeable barrier that protects the brain from peripheral immune cells and cytokines. A growing number of studies suggest that stress exposure, including during early life, can lead to leakage or hyperpermeability of the BBB, thereby promoting cerebral neuroinflammation [83].

Almost all immune cells have receptors for one or more hormones that are associated with the HPA axis and the sympathetic-adrenal-medullary axis [84]. Acute stress exposure, by activating the sympathetic nervous system, can trigger an immediate inflammatory response and increase the expression of transcription factor NF-κB, a central mediator of innate and adaptive immune functions, in immune cells [85‒87]. As previously noted, ELS may contribute to inflammation through alterations in HPA axis regulation. ELS is linked to increased activity of the HPA axis, likely due to impaired sensitivity or increased resistance of the GR, which regulates negative feedback of the HPA axis [88]. Since GR resistance extends to immune cells, cortisol’s anti-inflammatory effects are diminished, leading to elevated inflammation levels, especially following acute stress exposure [35]. Epigenetic alterations that have been reported after ELS may further contribute to dysregulation of HPA axis feedback regulation and increased inflammation (see [89] for a recent overview on immune and epigenetic pathways linking childhood adversity and health across the lifespan). One such epigenetic mechanism is DNA methylation or the addition of a methyl group to DNA that can impact the expression of a gene. Zannas et al. [40] reported that in a human study, childhood trauma exposure was associated with lower methylation of age-related CpGs in the FKBP5 gene in whole blood cells, and this lower methylation, in turn, was associated with an upregulation of FKBP5 expression. In unbiased genome-wide analyses in human blood, higher FKBP5 mRNA was linked with a pro-inflammatory profile and altered NF-κB–related gene networks [40]. Most studies in this context focus on DNA methylation. Epigenetic mechanisms other than DNA methylation (e.g., histone modifications and noncoding RNAs) may also contribute to early life programming of stress- and immune-related pathways [90].

As discussed by Danese and Lewis [12], psychological trauma may coincide with physical injuries, thereby potentially facilitating pathogen infection that can also trigger inflammation. Additionally, ELS has been associated with poor sleep quality and health-compromising behaviors like smoking, poor diet, and sedentary lifestyle, all of which can intensify a pro-inflammatory state [12]. ELS could also impact the composition of the gut microbiome, and in turn, gut dysbiosis could influence child immune function, brain development, and behavior [91].

A growing body of research suggests that ELS is one factor that may accelerate immunological aging – age-associated declines in immune function (immunosenescence) and increases in inflammation (inflammaging) [92]. For example, a study by Renna et al. [93] assessed pro-inflammatory cytokines at three time points during adulthood over a 3-year period. Individuals exposed to childhood abuse showed a steeper increase in inflammation compared to nonexposed individuals over this period. Results of this study confirm the persistence of the effect of childhood adversity on inflammation in adulthood, and they show that the effect seems to increase over time with age, potentially leading up to an “inflammaging” phenotype. The observed low-grade inflammation that increases with age potentially results in responses that lead to tissue degeneration, thereby constituting a highly significant risk factor for both morbidity and mortality in elderly people [94]. These findings converge with results of many studies reporting a link between childhood adversity and telomere length (TL) of immune cells. Telomeres are protective structures at the end of chromosomes that shorten with each cell replication and are therefore considered as biomarker of cellular aging and senescence. Shortened telomeres of immune cells have been linked to several age-related risk factors, diseases, and longevity [95]. There have been three meta-analyses that all show a significant relationship between early life adversity and TL, suggesting dose-response effects – greater severity or more types of traumatic exposures are associated with shorter TL [96‒99]. There also appears to be an effect of prenatal stress exposure on offspring TL. In the first study testing this idea, using maternal reports of serious life events during pregnancy, we found that greater maternal exposure to stress predicted shorter TL of immune cells in young healthy adult offspring who were free of psychiatric conditions [100]. Next, we examined a sample of pregnant women in whom we prospectively measured pregnancy-related anxiety and cord blood TL at birth and confirmed the expected relationship [101]. This finding has now been replicated several times in independent cohorts across various prenatal stressor types (e.g., [98, 102‒105]). In addition to TL, DNA methylation-based age predictors (“epigenetic clocks”) have been developed that are measured in a range of tissues, including immune cells, and can predict life- and health span. An increasing body of literature has linked ELS with accelerated epigenetic aging (e.g., [106‒110]). To summarize, it appears that ELS may affect fundamental processes underlying immune cell genomic integrity and senescence, which, in turn, may have major implications for health and disease susceptibility for aging-related disorders.

As noted above, the majority of findings on the immunological correlates of prenatal and childhood stress exposure are based on cross-sectional, adult retrospective study designs. Also, studies to date have not investigated how ELS converts into biological signals embedded simultaneously or sequentially across different systems, e.g., the brain, immune, and metabolic systems. Future studies should address this by taking advantage of recent methodological developments, thereby integrating biological processes across various domains like the genome, epigenome, transcriptome, metabolome, inflammatome, and the gut microbiome. Life-course models, ranging from preconceptual to pubertal experiences, studying outcomes from pregnancy to advanced age, should integrate the role of modifying factors like sex and social determinants of health. Measures of immune function that are often restricted to peripheral concentrations of cytokines in human studies should be complemented by functional immune measures assessed in specific immune cell populations. Given the large body of evidence from animal models linking ELS with neuroinflammation, studies assessing this link in humans with proxy measures of inflammation that can now be obtained with multimodal brain imaging (magnetic resonance imaging, MR spectroscopy, multiparameter mapping) are needed.

So far, the effects of ELS on immune function have been described primarily at the level of differentiated immune cells. However, if ELS, including prenatal stress exposure, has lifelong effects on immune function, biological embedding of the effects of chronic stress may extend all the way down to the level of stem cells, and specifically to the effects of prenatal and postnatal ELS on hematopoietic stem cell (HSC) biology. This is supported by a murine model by Kamimae-Lanning et al. [111] who reported that fetal HSCs of dams exposed to metabolic stress exhibited a range of deficits, including restricted expansion of the fetal HSC pool (reduced self-renewal), compromised repopulation (impaired cell migration), and altered differentiation. Notably, the impact on the immune system of such developmental exposures to HSCs seems to persist over the entire lifespan (well after the cessation of the stress exposure) [112]. Our current ongoing studies incorporate ELS-related biological embedding processes at the level of stem cells.

These studies will provide a foundation for the development of interventions that will target immune-related mechanisms early on to reverse or prevent these processes before disease manifestation. Interventions that impact the immune system have already been described. For example, in a mouse model, environmental enrichment had beneficial effects on immune function [113]. Dietary supplementation with polyunsaturated fatty acids has been explored in its ability to modulate immune system processes via reduction of microglial activation and pro-inflammatory cytokine release which also led to a decrease in anxiety- and depression-like behaviors in rats [114, 115]. Regular, sustained physical activity, including endurance and resistance-type exercise, may provide a protective impact on chronic low-grade inflammatory conditions [116]. A meta-analysis of 56 randomized clinical trials in which participants received psychotherapeutic interventions and were also assessed immunologically concludes that psychosocial interventions were associated with positive changes in immunity over time [117]. The suppression of cytokines and their signaling pathways represents another therapeutic option, and findings show that blocking peripheral cytokines is sufficient to tighten the BBB, thereby exhibiting antidepressant actions [118]. These kinds of interventions should be developed further and applied in the context of ELS exposure in humans, ideally during sensitive periods of development across the lifespan to make use of the developmental plasticity of physiological systems that not only gives rise to the adverse outcomes of ELS but that could potentially be used to prevent or reverse biological embedding of ELS and resulting disease manifestation [6]. This will promote optimal development, health, and longevity in all children, with significant impact on the public health system and society [6].

The authors have no conflicts of interest to declare.

This study was funded by Federal Ministry of Education and Research grant BMBF 01GL1743A and B to C.H. and by NIH/National Institute for Child Health and Development (NICHD) research grant R01 HD107176 to S.E.

S.E.: preparation of first draft. C.H.: critical review for important intellectual content. S.E. and C.H.: conception of the paper and final approval of the version to be published.