Programming effects of stress on respiratory outcomes may operate at a more fundamental molecular level, i.e., through epigenetic programming. Epigenetics may be at the roots of developmental plasticity imprinting environmental experiences on the fixed genome (148
) albeit data are scare for respiratory health and allergic disorders (149
). Determining the range of environmental exposures that impact the epigenome during development was a research priority identified at the recent NHLBI Pediatric Pulmonary Disease Strategic Planning Workshop
). DNA methylation is an adaptable epigenetic mechanism that modifies genome function through the addition of methyl groups to cytosine to form 5-methyl-cytosine (5mC). DNA methylation marks are largely established early in life (16
) and may ensure stable regulation that mediates persistent changes in biological and behavioral phenotypes over the lifespan. DNA methylation of many genes changes with disease status and in response to environmental signals including chemical exposures such as diet, drugs and toxins. Recent findings also implicate psychological stress given behavioral studies demonstrating epigenetic changes during fear conditioning (152
) and evidence for epigenetic programming related to maternal care (154
The epigenome may be particularly sensitive to dysregulation in early development when DNA synthesis rates are highest. Genes involved in hypothalamic-pituitary-adrenal (HPA) axis functioning seem particularly susceptible to stress-related programming (73
). These include glucocorticoid receptor expression, the activation of which alters HPA activity through negative feedback inhibition. The human glucocorticoid receptor (GR) promoter region is extensively methylated with diverse methylation profiles demonstrated in normal donors (156
). The intracellular access of glucocorticoids to their receptors is also modulated by the 11 beta-hydroxysteroid dehydrogenase (11βHSD) enzymes, which interconvert biologically active 11 β-hydroxyglucocorticoids and inactive 11-ketosteroids (157
). While compromised 11βHSD2 activity can be caused by loss of function mutations of the gene encoding 11βHSD2, the frequency of such mutations is extremely low. Thus, other mechanisms accounting for the inter-individual variability in 11βHSD2 enzyme activity should be considered. The 11βHSD2 promoter comprises a highly G + C-rich (or GC-rich) core, contains more than 80% GC, lacks a TATA-like element, and has two typical CpG islands raising the possibility that methylation may play a role in the epigenetically determined inter-individual variable expression of 11βHSD2. Another candidate pathway implicated in both airway inflammation (158
) and autonomic response (159
) is the nitric oxide (NO) signaling pathways. Alterations of NO expression occur in the context of psychological stress and stress-related behaviors (160
). The inducible nitric oxide synthase (NOS) genes are also susceptible to epigenetic programming (161
The notion that variability in methylation between subjects may reflect an important epigenetic mechanism is suggested by recent studies in both animals and humans. Epigenetic modulation of the 11βHSD2 gene has been recently demonstrated in a rodent model and cultured cell lines (162
), albeit epigenetic regulation of this gene is not well characterized in humans. Weaver and colleagues have demonstrated differential methylation patterns of the Ngfi-A-binding site in GR promoter 17
in the rat brain in offspring that had received poor maternal care versus those that had received better maternal care (163
). When pups were cross-fostered between dams providing good or poor post-natal care, the pups developed the epigenome of the foster mother. This same group reported increased methylation in a neuron-specific GC receptor (NR3C1) promoter as well as decreased levels of GC receptor mRNA from hippocampus tissue obtained from suicide victims with a history of childhood abuse (164
). Recent human data demonstrates that methylation of exon 1F in fetal cord blood was sensitive to maternal mood in the perinatal period and the infants HPA stress reactivity (165
In summary, genetic and epigenetic studies tell us that exposure to altered glucocorticoid receptor response through early development, even beginning in utero, programs major changes in the endogenous neuroendocrine and immune mechanisms that may, in turn, lead to increased vulnerability to asthma. Whether alterations in DNA methylation underlie stress-induced phenotypic plasticity related to lung structure and function or asthma risk remains largely unexplored. It will be important to begin to understand factors related to developmental programming of glucocorticoid sensitivity during critical periods of development which may play a role in disease etiology as well as subsequent morbidity.
Characterizing stress in epidemiologic studies
The etiology of health problems is increasingly recognized as a result of the complex interplay of influences operating at several levels, including the individual, the family, and the community (). Ecological views on health recognize that individual-level health risks and behaviors have multi-level determinants, in part influenced by the social context within which subjects live.(166
) That is, chronic stress experiences are significantly influenced by the characteristics of the families, homes, and communities in which we live (167
). Both physical and social factors can be a source of environmental demands that contribute to stress experienced by populations living in a particular area (169
Characterizing stress across the life course: an ecological approach
Taking a multi-level approach to examining stress effects on asthma expression may be particularly relevant to the understanding of disparities based on race/ethnicity and socioeconomic status (168
). This includes an environmental justice perspective underscoring the role of structural and macrosocial forces that shape exposure and vulnerability to diseases may better inform the complex social patterning of asthma (168
). According to this framework, asthma rates are higher and the associated morbidity is greater among the poor because they bear a disproportionate burden of exposure to suboptimal, unhealthy environmental conditions. Upstream social and economic factors determine differential exposures to relevant asthma pathogens and toxicants (170
). Also, understanding the upstream factors (e.g., social and economic policies) that contribute to the varying social conditions for populations and individuals being studied will better inform needed interventions.
Thus, a challenge in any epidemiologic study linking stress to health is how to measure and characterize the stressor(s). An important consideration is the prevalence of the stressor(s) of interest in a particular population. The decision can also be theoretically guided by our empirical understanding of how certain stressor characteristics influence behavioral and physiological correlates that may have a particular pathogenic effect. The latter may vary based on the condition being considered and our understanding of the natural history of the disorder being considered. While it can be acknowledged that there are inconsistencies in the literature with regard to the physiological changes (e.g., hormonal disruption) that are associated with various disease outcomes, a blunted HPA axis (more typically characterized by lower morning cortisol; flattening of the diurnal slope) has been specifically associated with increased susceptibility to autoimmune/inflammatory diseases (77
). This is also a pattern frequently described in the setting of extreme chronic stress which includes traumatic stressors (even occurring remote to the timing of study) and cumulative stressors that are chronic or co-occur. Stress exposure can be conceptualized as extreme if the individual experiences (a) multiple stressors over the same period or (b) chronic stressors over repeated developmental periods; or (c) the nature of the stress is extreme (e.g., trauma).
Given the discussion above on perinatal programming, experiences of women of child bearing age is particularly relevant. Low-income women, especially ethnic minorities, report greater and more frequent exposure to chronic extreme stress and greater psychological distress as a result. For example, in a study examining stressors immediately before or during pregnancy among a sample of 143,452 women (171
), stress exposure increased as income decreased, with 57% of low-income women experiencing at least one chronic stressor [e.g., economic hardship (37%), job loss (19%), separation or divorce (15%), incarceration of partner (8%), and domestic violence (5%)]; 29% experienced multiple stressors concurrently. Effects of these stress exposures may be compounded among minorities by racism-related stressors.
Traumatic stressors may warrant particular consideration for many reasons (73
). Trauma, like other stress, occurs at increased rates among low-income, minority populations (172
). Holman and colleagues (173
) examined the rates of trauma in an ethnically diverse, community-based sample (N=1456). Nearly 10% experienced a trauma in the past year; 57% reported at least one lifetime event including interpersonal violence occurring outside the family (21%), acute losses or accidents (17%), witnessing death or violence (13%), and domestic violence (12%). Hien and Bukszpan (174
) examined lifetime interpersonal violence among a “control” group of urban, low-income women, predominantly Latina or blacks, who had been screened for the absence of psychopathology. Almost 28% of these urban women reported a history of childhood abuse, compared to general population estimates of 10%. Urban minority women also experience heightened levels of community violence (175
). Other studies have documented increased rates of PTSD and depression in urban samples (73
). The perinatal period is a vulnerable time to experience more intense psychological symptoms, particularly for low-income women. Compared to other forms of stress, trauma is more likely to result in psychological morbidity [e.g., posttraumatic stress disorder (PTSD), depression] and persistent psychophysiological changes (HPA axis, sympathetic-adrenal-medullary [SAM] system). These effects often persist years after the exposure, particularly when the exposure occurs during a critical developmental window (e.g. when stress regulatory systems are becoming consolidated in the mother).
Life course perspective and intergenerational effects
Other studies provide evidence supporting the intergenerational transmission of psychophysiological vulnerability in traumatized populations. While studies of maternal stress and infant outcomes typically examine events occurring during pregnancy, we recently considered stress (interpersonal trauma, IPT) across the mother’s life course in relation to early immune markers in their children (177
). The life course perspective posits that some stressors may influence health through two mechanisms, early programming and cumulative pathways, in addition to more immediate effects. Early programming may occur if exposures during sensitive developmental periods in the mother have lasting psychobiologic sequelae. Exposure to IPT in earlier life can generate disrupted physiological stress responses even several years following the trauma. Thus, maternal interpersonal trauma may be linked to infant health through more latent effects (i.e., lasting effects from abuse in childhood/adolescence), proximate effects (i.e., trauma experienced in or around the pregnancy) and cumulative life course effects (i.e., allostatic load of accumulated traumas over the mother’s life). We investigated the relationship between maternal IPT experienced over her life course and cord blood total IgE, a biomarker of atopic risk at birth, in an urban population-based study. We demonstrated that infants born to mothers with chronic trauma exposure—that is, both early in life and more proximate to the pregnancy—would be at greatest risk of expressing elevated IgE.
Indicators of neighborhood disadvantage, characterized by the presence of a number of area-level stressors including poverty, unemployment/underemployment, percentage of unskilled laborers, limited social capital or social cohesion, substandard housing, and high crime/violence exposure rates, have been investigated in relation to urban children’s development (168
). Such stress is chronic and can affect all subjects in a given environment regardless of their individual-level risks.
For example, accumulating evidence suggests that community violence may contribute to the burden of asthma in urban populations.(5
) Increased exposure is associated with more symptom days,(10
) higher hospitalization rates,(11
) increased asthma prevalence among children in communities with both elevated crime/violence and other environmental hazards (i.e., ambient air pollutants),(12
) and increased risk of wheezing at ages 2–3.(13
) In a longitudinal, multilevel study including 2071 children aged 0–9 at enrollment from the Project on Human Development in Chicago Neighborhoods (PHDCN), we demonstrated a significant association between community violence exposure and increased risk for asthma development in urban children (178
). This association was robust to controlling for important individual-level factors (race/ethnicity, SES, maternal health behaviors, family violence), and neighborhood-level confounders (concentrated disadvantage, social disorder and collective efficacy).
Recent reviews highlight a number of subjective housing characteristics that have been linked to adverse psychological outcomes. This subjective emotional dimension of housing may influence asthma outcomes (179
) although this is only starting to be empirically explored (180
There have been a number of examples from the asthma epidemiology literature showing associations between early caregiver stress and the development of asthmatic phenotypes in early childhood (181
). We recently demonstrated that maternal ability to maintain positive caregiving processes in the context of even more extreme stress may buffer the effects on child asthma risk. We examined the prospective relationship between maternal intimate partner violence (IPV) and asthma onset in children in the Fragile Families and Child Wellbeing Study (N=3117), a birth-cohort. Maternal-report of IPV was assessed after the child’s birth and at 12 and 36 months. Mothers also indicated how many days a week they participated in activities with the child and the amount and type of educational/recreational toys available for the child. Maternal-report of physician-diagnosed asthma by age 36 months was the outcome. In adjusted analysis, children of mothers experiencing IPV chronically (at all time periods), compared to those not exposed, had a 2-fold increased risk of developing asthma. In stratified analysis, children of mothers experiencing IPV and low levels of mother-child activities (RR 2.7, 95% CI 1.6, 4.7) had a significant increased risk for asthma. Those exposed to IPV and high levels of mother-child activities had a lower risk for asthma (RR 1.6, 95% CI 0.9, 3.2). Earlier the relationship between parental support and glucocorticoid resistance in adolescent asthmatics was discussed (86
Although beyond the scope of the current discussion given space limitations, one also must consider the developmental timing of exposures over the lifecourse relative to specific asthma outcomes whether individual or contextual factors are being considered. Factors leading to the onset, remission, or persistence of asthma across the lifecourse may be influenced by social experiences and physical exposures beginning in utero, a series of social and biologic experiences initiated by early childhood exposure or cumulative exposure to toxic biologic or social factors over critical periods of development (). It is important to consider stress at these multiple levels given that they are interrelated throughout the lifecourse. If we can understand at what level stress is occurring and perhaps has the greatest impact on asthma expression, this may inform the most effective interventions.
Stress-enhancing effects on physical environmental exposures
Because of the covariance across exposures and evidence that social stress and other environmental toxins (e.g., pollutants, tobacco smoke) may influence common physiological pathways (e.g., oxidative stress, pro-inflammatory immune pathways, autonomic disruption), understanding the potential synergistic effects promises to more completely inform children’s asthma risk (4
). Epidemiological studies have demonstrated synergistic effects of stress and air pollution on asthma expression among children and adolescents (183
). We need to better understand how the physical and psychological demands of living in a relatively deprived environment may potentiate an individual’s susceptibility to cumulative exposures across these domains.
Taken together, these lines of evidence point toward the need to consider social environmental factors (i.e., stress) as mainstream in asthma epidemiologic research. The likelihood of multiple mechanistic pathways with complex interdependencies must be considered when examining the integrative influence of stress independently as well as the interaction of social and physical environmental toxins on asthma and atopy. Because these factors tend to cluster in the most socially disadvantaged, this line of research may better inform the etiology of growing health disparities. Design of future epidemiologic studies and effective intervention programs will need to address social stress and physical environmental toxins jointly to impact outcomes on a public health scale more effectively.