Epidemiology of stress and asthma: From constricting communities and fragile families to epigenetics

doi:10.1016/j.iac.2010.09.011

Immunol Allergy Clin North Am. Author manuscript; available in PMC 2012 February 1.

Published in final edited form as:

Immunol Allergy Clin North Am. 2011 February; 31(1): 19–39.

doi: 10.1016/j.iac.2010.09.011

PMCID: PMC3052958

NIHMSID: NIHMS237923

Epidemiology of stress and asthma: From constricting communities and fragile families to epigenetics

Rosalind J. Wright, MD MPH¹

¹ Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston MA

² Department of Environmental Health, Harvard School of Public Health, Boston, MA

The publisher's final edited version of this article is available at Immunol Allergy Clin North Am

See other articles in PMC that cite the published article.

Publisher's Disclaimer

Abstract

A number of epidemiologic frameworks, exemplified through extant research examples, provide insight into the role of stress in the expression of asthma and other allergic disorders. Biological, psychological, and social processes interact throughout the life course to influence disease expression. Studies exploiting a child development framework focus on critical periods of exposure, including the in utero environment, to examine the influence of stress on disease onset. Early stress effects that alter the normal course of morphogenesis and maturation that affect both structure and function of key organ systems (e.g., immune, respiratory) may persist into adult life underscoring the importance of a life course perspective. Other evidence suggests that maternal stress influences programming of integrated physiological systems in their offspring (e.g., neuroendocrine, autonomic, immune function) starting in pregnancy, consequently stress effects may be transgenerational. A multi-level approach which includes an ecological perspective may help to explain heterogeneities in asthma expression across socioeconomic and geographic boundaries that to date remain largely unexplained. Evolving studies incorporating psychological, behavioral, and physiological correlates of stress more specifically inform underlying mechanisms operating in these critical periods of development. The role of genetics, gene by environment interactions, and epigenetic mechanisms of gene expression have been sparsely examined in epidemiologic studies on stress and asthma although overlapping evidence provides proof of concept for such studies in the future.

Evidence increasingly links psychosocial stress, including early life stress-related programming of key response systems, to asthma, atopic disorders more broadly, and lung function (1, 2). In order to more fully understand the potential role of psychological stress in the etiology of asthma and other allergic or inflammatory disorders, it is necessary to consider a number of key theoretical and methodological frameworks from social sciences, psychology, immunology, and child development and extend these to epidemiological research. Application of recent advances in developmental biology, neurogenomics and genomic plasticity, may inform underlying mechanisms at the most fundamental level. An area of particular interest in childhood asthma research is the search for mechanisms responsible for health disparities across economic and racial/ethnic groups. The psychosocial stress model has been increasingly adopted in this regard (3) given the increasing recognition that children are being raised in social contexts that may be as detrimental to their development as established physical environmental factors associated with disease risk (4). This review highlights the growing number of epidemiologic studies exploiting these transdisciplinary concepts to uniquely inform our understanding of the role of stress and the expression of asthma and allergy over the life course.

Need for a Prospective Developmental Framework

This overview considers the developmental origins of both asthma risk (1) and lung structure and function (2) given that both involve coordinated maturation of interrelated systems - immune, neural, and endocrine. Moreover, while the origins of chronic lung diseases are multi-factorial, the underlying mechanisms leading to reduced lung function and exaggerated airway responsiveness involve chronic airway inflammation associated with a cycle of injury, repair and remodeling (5, 6). Notably, airway inflammation and remodeling begin and progress even in the presymptomatic state in early childhood (7–10). Moreover, the fundamental cause of the airway inflammation is aberrant and/or excessive immune responses to various environmental factors (5) and the most common cause of chronic airway inflammation in early childhood is arguably asthma (11).

An important step toward identifying children at risk for costly respiratory (i.e., asthma, reduced lung function) and other allergic disorders is characterizing mechanisms that lead to and maintain early predisposition. Immune and lung development occur largely in utero and during early childhood. Research continues to delineate early immunophenotypes and early airway response outcomes among children predisposed to asthma (atopic and nonatopic) and other chronic atopic disorders (12–15). Regulatory pathways that involve the collaboration of innate and adaptive immune responses are involved. Influences of factors outside the immune system, i.e., neurohormonal and autonomic nervous system functioning, may also be involved.

Critical Periods of Development & Perinatal Programming

Plasticity is a consequence of environmental exposures in critical periods affecting key physiological systems involved in developmental processes (16). Although both asthma and lung function are polygenic traits (17, 18), maternal factors in particular contributes to the intergenerational correlation (17, 19, 20). The risk of developing atopic disorders is particularly increased if a positive parental history of atopy is present with effects being strongest for maternal history (19, 20). Studies have also shown a greater correlation in forced expiratory volume in 1 second (FEV1) and other lung function parameters between mothers (compared with fathers) and offspring (17). In addition to heritable traits, this may be due to perinatal programming - the influence of nongenetic or environmental factors in the perinatal period that organize or imprint physiological systems (1) (Figure 1).

Figure 1

Conceptual model for stress-induced perinatal programming of asthma, atopy, and lung function

Stress as a Programming Agent

The list of potential programming agents includes psychological stress. In general, stress may result in biobehavioral states [e.g., posttraumatic stress disorder (PTSD), anxiety, depression] which lasting physiological affects that influence disease risk (21–23). Under stress, physiological systems may operate at higher or lower levels than in normal homeostasis (24). Disturbed regulation of maternal stress systems [e.g., HPA axis, autonomic nervous system (ANS)] in pregnancy may modulate offspring immune function starting in utero (25, 26). Likewise, non-optimal early childhood caregiving experiences may impact these processes in children (e.g., maternal psychopathology or insensitivity) (27–29).

Immune programming

Mechanisms of inflammation central to the pathophysiology of asthma phenotypes overlap and may include immune-mediated inflammation associated with a Th2-biased response (30–32) and a tendency to produce immunoglobulin E (IgE) in response to environmental stimuli (e.g., allergens). The Th1 - Th2 paradigm involves a complex interaction of T and B lymphocytes, resulting in the production of higher levels of particular cytokines, such as interleukin-4 (IL-4) or IL-13 and the more recently described IL-9, IL-25, and IL-31 as well as lower levels of interferon-γ (IFN-γ)](33). Evidence suggests that those with early (i.e., starting in the first 2 to 3 years) sensitization to allergens are at greatest risk of developing chronic atopic disorders, airway inflammation and obstruction [as reviewed in (2)].

However, not all asthma cases are associated with allergy and/or eosinophilic airway inflammation; neutrophilic inflammation may account for a substantial subgroup (34, 35). Thus, while this paradigm has been useful in understanding the large fraction of subjects with allergic asthma and airway inflammation, it is now accepted that the Th2 biased polarization of adaptive immunity may be only one of several axes that result in enhanced susceptibility to airway inflammation and altered reactivity (36). Antigen-independent responses including innate immune cells (e.g., bronchial epithelial cells, alveolar macrophages, and dendritic cells) may also be important (37, 38) and involve novel cytokines (e.g., IL-17)(39). Factors, including stress (1, 38), that disrupt maturation of local immune networks (e.g., dendritic cells [DCs], epithelial cells [ECs], regulatory T cells) may predispose to ongoing eosinophilic and neutrophilic inflammation. This may be manifested through the increased expression of both atopic and nonatopic persistent wheeze phenotypes in early childhood albeit prospective data in humans is sparse.

Immune mechanisms have their roots in utero with an immunological bias towards a Th2 phenotype (40–46). Immune programming can also be influenced by early postnatal environmental influences (47, 48). Consequently, researchers have begun to examine in vitro responses of peripheral blood mononuclear cells (pBMCs) to allergens or mitogens to gain a better understanding of the immunodeviations that facilitate the manifestation of asthma and atopy in response to environmental factors (12) including stress (49, 50). Epidemiological studies also incorporate other markers of the developing immune response (e.g., IgE). Elevated cord blood total IgE, for example, has been associated with aeroallergen sensitization and the development of allergic diseases in children, particularly in those with a maternal history of atopy (51–53). Levels of allergen-specific IgE begin to rise at age 18 to 24 months (54). Reactivity to two or more allergens is detected in infants as early as 3 months with polysensitization documented after 18 to 24 months (55) and may develop even in subjects labeled ‘nonatopic’ based on skin prick test (SPT) negativity (56). The influence of stress on the timing and trajectory of these immunophenotypes and their relationship to the later development of clinical disorders has only begun to be studied.

In primates, prenatal stress impacts the newborn’s antigen response (57). Evidence in prenatally stressed adult mice shows dysregulated cellular and humoral immune response upon antigen challenge reflected by a Th2 adaptive response and increased IgE (58). My group was first to prospectively link early life caregiver stress to dysregulation of immune function in a birth cohort predisposed to allergy, i.e., greater antigen-specific TNF-alpha production (49). Stress has also been associated with increased NK and NKT cells as well as altering their functional mechanisms (59, 60), effects correlated with changes in cortisol and ANS input (61). Our group has also demonstrated an association between increased prenatal maternal stress and increased IL-8 and TNF-α production following microbial stimulation suggesting that stress may operate through Toll-like receptor dependent pathways (62).

As detailed in earlier reviews, both glucocorticoid (GC) action and sympathovagal balance play a role in immunomodulation as well as fetal and postnatal lung development (1, 2, 63). While research has advanced around the assessment of immune function in the field of stress and asthma (33, 49, 50, 64), studies assessing the hypothalamic-pituitary-adrenal (HPA) axis (65) are scarce and none consider the autonomic response in early development (i.e., pregnancy, early childhood). Notably, the HPA axis and ANS seem particularly susceptible to stress-induced programming as summarized below.

HPA Axis

Maternal-fetal stress stimulates placental corticotrophin-releasing hormone (CRH), which in turn is elevated in the neonatal circulation (1, 66–69). This may stimulate the fetal HPA axis, amplify GC excess and activate additional elements of the fetal stress response (i.e., catecholamines) influencing developing immune function and the ANS (26). Alterations in stress-induced maternal cortisol may influence fetal immune system development and Th2 cell predominance, perhaps through direct influence of stress hormones on cytokine production (70, 71). This may induce selective suppression of the Th1-mediated cellular immunity and trigger a shift towards Th2-mediated humoral immunity (72). The HPA system is also influenced postnatally through child-caregiver transactions (73). Caregiving during early development predicts the emergence of self-regulation abilities, with sensitive caregiving associated with optimal stress regulation and functioning of the child’s HPA system (1).

Studies assessing cortisol and HPA axis responses in early childhood as related to allergy and asthma risk remain sparse and none to date examine the relationship between maternal prenatal cortisol HPA axis responses (hypo- vs. hyperreactivity) and childhood risk for asthma and/or allergy (65). Bruske-Kirschbaum and colleagues (74) found an enhanced cortisol responses to stress in infants at high risk for atopic disorders based on parental history and elevated cord blood IgE. Ball et al., (75) also reported a hyperreactive HPA axis in response to stress among 6-month-old infants with an allergic mother. This is in contrast to other data showing a hyporesponsive HPA axis in children who already have allergic disease (65, 76). As proposed by Bruske-Kirschbaum and others (65), it may be that the natural history in children predisposed to developing allergy and/or asthma in relation to perinatal stress have a hyperresponsive HPA axis that evolves to become hyporesponsive as time goes on and a specific disorder is expressed and becomes more chronic. While 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 in overlapping research (77, 78). How disruption of the maternal prenatal HPA axis is related to childhood asthma and allergy risk and whether children of mothers with a blunted prenatal cortisol response are more likely to develop these disorders is not known. This will only be worked out through prospective epidemiologic studies incorporating biomarkers of the HPA response during these critical perinatal periods of development (for both mothers and children) and their relationship to evolving immunophenotypes and the later development of asthma and atopy.

An alternative hypothesis linking stress, neuroendocrine disruption (i.e., HPA axis) and immune function considers a glucocorticoid resistance model (79, 80). Insight into the cellular and molecular mechanisms underlying stress-induced steroid resistance is provided in a number of recent studies. Oxidative stress pathways have been implicated in the link between psychosocial stress and asthma (71) as well as steroid resistant asthma (81, 82). This may particularly be relevant in airway inflammation where neutrophilc rather than eosinophilic inflammation predominates (83, 84). Indeed, it was recently shown that oxidative stress contributes to steroid resistance in the context of neutrophilic inflammation in a mouse model of acute asthma exacerbations (85). Notably, psychological stress is also an oxidant and may thus operate through these same pathways (71). While human data in the context of lung disease are sparse in this regard, one recent cross-sectional analysis in adolescents demonstrated that peripheral blood mononuclear cells harvested from asthmatics who perceived low parental support (i.e., greater stress) were more resistant to hydrocortisone’s effects on cytokine expression (IL-5, IFN-γ) and activation of eosinophils relative to asthmatics reporting higher parental support (86). Examination of mechanisms contributing to steroid resistance in relation to perinatal stress may provide insight into the link between stress, asthma and airway hyperresponsiveness over subsequent development.

Going forward, studies designed to examine mechanisms underlying stress-induced programming of asthma and allergy should consider the theoretical and methodological challenges to the study of the HPA axis in early development highlighted in prior reviews (87–91). Given the need for repeated sampling, saliva is often the preferred method given it is non-invasive and salivary cortisol follows a time course nearly identical to plasma cortisol (92). In pregnant women, hair sampling has been proposed as a way of providing a retrospective calendar of cortisol production over the course of pregnancy (93, 94). The HPA system remains highly reactive and labile in early infancy and starts to become organized between 2 and 6 months of age through transactions between the child and caregiver (95, 96). Studies of children in naturalistic environments suggest interesting individual differences exist (96–99). By a few months after birth, cortisol production follows a circadian rhythm and is entrained to the sleep-wake cycle (100). However, individuals may vary in the age at which they acquire particular components of this variation [e.g., diurnal rhythm, coritsol awakening response (CAR)] (95, 101). It has been proposed that the age of appearance (i.e., early vs. late), stability, and curve profile may be characteristic of developmentally distinct groups of infants and may have differential influence on subsequent health (95, 102). Children’s sleep-wake cycle varies greatly over the day in early development and, as in older samples, analyses must consider time from awakening but also napping characteristics (e.g., time of napping, total number and duration of naps)(103). There are also gender effects (104). Moreover, different methods of analysis may contribute to different conclusions related to profiles across the day and age of appearance of the circadian rhythm (95, 105). Understanding this complexity and accounting for these factors in research examining alterations in adaptations of HPA axis activity in relation to perinatal stress and subsequent disease risk (e.g., asthma) is important – not doing so may obscure true patterns and associations.

When incorporating salivary collection protocols into larger epidemiological studies (90, 91) one needs to consider the burden on participants and staff in light of other activities and balancing the number of samples needed to accurately assess the HPA response versus the likelihood that the most interesting participants (e.g., those most stressed, mothers/children with psychopathology) may be overwhelmed. How samples are collected may need to vary by the age and developmental stage of the participant (e.g., absorbent cotton rolls, passive drool, etc), each with their own tradeoffs. One also needs to address possible confounders, mediators and moderators of stress effects relevant to the life stage being examined. For example, dysregulation of the HPA axis in pregnant women (and older children) may differ based on current psychological functioning (depression, PTSD) as different biological profiles may be associated with specific psychopathology (106, 107). Also in pregnant women, stage of gestation (weeks pregnant at time of cortisol sampling) and other prenatal factors [e.g., prenatal alcohol and tobacco use, maternal body mass index (BMI)] may be important [for reviews see (108, 109)]. Child temperament (110), an individual characteristic that dictates the tendency to express particular emotions with a certain intensity, is an important factor to consider in early child development.

Autonomic Reactivity

Animal and human studies support the connection between an adverse intrauterine environment as well as experiences in early postnatal life and alterations of ANS functioning (e.g., sympathovagal balance) (111–114). The ANS, in turn, plays an important role in immunoregulation (115–117). Animal research suggests that neural control of airway smooth muscle and irritant receptor systems are sensitive to environmental programming (111). Respiratory and vagal systems undergo postnatal maturation to establish an integration of respiratory and cardiovascular function (118, 119). Much remains to be learned about the vulnerability of these systems to perinatal environmental influences and early programming (120). In humans, autonomic responses show developmental changes with relative stability between 6 to 12 months of age (121). It seems plausible that disruption of neuroendocrine and vagal anti-inflammatory pathways may predispose some individuals to immunodeviations and consequent excessive inflammatory responses that may result in altered respiratory responses in early life. The balance between functional parasympathetic and sympathetic activity in relation to emotional stimuli and immune function may be important for airway inflammation and enhanced airway reactivity to a psychological stressor, albeit this has not been examined in human research. My group has demonstrated differential stress reactivity as indexed by prenatal HPA axis disruption (122) and cardiorespiratory parameters in infancy (123) in an urban pregnancy cohort designed to study the effects of prenatal maternal and early-life stress on urban childhood asthma risk. Future analyses will examine links between stress-elicited changes in these systems and asthma risk and lung function as these children get older.

Prenatal stress increases allergen-induced airway inflammation in mice offspring (124, 125). Similarly, allergen aerosol challenge is associated with increased airway hyperresponsiveness (AHR) in prenatally stressed mice (58). Others show exacerbations in airway inflammation in OVA-sensitized rats following repeated psychosocial challenge (126–130). In humans, reversible airway obstruction has been demonstrated during psychological challenge; cholinergic blockade supports a vagal origin (131, 132). Negative affect in particular increase airway resistance (133). Vagal excitation to the airways is the supported mechanism (134). Airway responses to induction of depressed mood is correlated with increased respiratory sinus arrhythmia (RSA) in asthmatics (135, 136). Individuals with a tendency toward greater vagal system responding to distress may be prone to exaggerated airway narrowing in such situations albeit this has not been studied in young children.

Need for the integration of stress systems in research

Taken together these data suggest that stress elicited disruption of interrelated systems - autonomic, neuroendocrine, and immune systems - may lead to increased vulnerability to early allergic sensitization which predisposes to persistent atopic disorders. To date, the majority of studies examining links between stress-elicited disruption of physiological systems and various health outcomes have examined one system in isolation from the others. However, recent findings specifically related to HPA and ANS functioning highlight the need to consider these systems simultaneously due to interactive influences (137–139). Studies that do not assess the interactions among these systems may obscure stress-related influences on asthma and allergy expression.

Genetics

Most advances in our knowledge of the genetic and molecular events underlying the neurobiology of the stress response have occurred in animal models (140) and psychiatric outcomes in humans (141). These animal data suggest that studies to determine the role of genetics in modifying the risk of the social/physical environment experienced through psychological stress may further inform pathways through which stress may impact asthma expression. Genetic factors of potential import include those that influence immune development and airway inflammation in early life, corticosteroid regulatory genes, adrenergic system regulatory genes, biotransformation genes, and cytokine pathway genes.

Genes expressed in the lung involved in determining the effects of oxidative stress, specifically the glutathione S tranferases, have been found to be functionally and clinically significant in recent studies related to atopic risk. Guilliland and colleagues found that specific GSTP1 variants are associated with increased histamine and IgE responses to air pollution oxidants and allergen in vivo (142). Maternal genetics related to oxidative stress genes may influence the child’s atopic risk beginning in utero (143). Variants of the glucocorticoid receptor gene may contribute to interindividual variability in HPA axis activity and glucocorticoid sensitivity in response to stress (144, 145). Studies related to factors regulating the feedback mechanisms involved in the glucocorticoid response to stress are also of interest (146). A recent study examined polymorphisms of the TNF-alpha promoter region (TNF-308G/A) and linked specific variants to increased C-reactive protein (CRP), a proinflammatory marker (147). These are potentially interesting candidate genes to include in future studies of risk for atopic disease. Such studies that consider gene x environment interactions (i.e., stress by pathway genes) may inform specific mechanisms related to stress and atopy.

Epigenetics – A Fundamental Programming Mechanism

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, 150). 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 (151). 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, 153) and evidence for epigenetic programming related to maternal care (154, 155).

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 (Figure 2). 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, 168). 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).

Figure 2

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, 78). 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, 173). 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, 176). 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.

Constricting Communities

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).

Housing stressors

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).

Family Factors

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, 182). 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 (Figure 2). 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 (183–185). 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.

Summary

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.

Acknowledgments

During preparation of this manuscript Dr. Wright was supported by R01HL080674 and R01HL095606.

Footnotes

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

1. Wright RJ. Prenatal maternal stress and early caregiving experiences: Implications for childhood asthma risk. Pediatric and Perinatal Epidemiology. 2007;21:8–14. [PubMed]

2. Wright RJ. Perinatal stress and early life programming of lung structure and function. Biological Psychology. 2010;84:46–56. [PMC free article] [PubMed]

3. Gee GC, Payne-Sturges DC. Environmental health disparities: A framework integrating psychosocial and environmental concepts. Environmental Health Perspectives. 2004;112:1645–1653. [PMC free article] [PubMed]

4. Wright RJ. Moving towards making social toxins mainstream in children’s environmental health. Current Opinion in Pediatrics. 2009;21:222–229. [PMC free article] [PubMed]

5. Holt PG, Upham JW, Sly PD. Contemporaneous maturation of immunologic and respiratory functions during early childhood: Implications for development of asthma prevention strategies. Journal Allergy and Clinical Immunology. 2005;116:16–24. quiz 25. [PubMed]

6. Holgate ST. Asthma: A dynamic disease of inflammation and repair. In: Chadwick DJ, Cardew G, editors. The rising trends in asthma. West Sussex, England: John Wiley & Sons; 1997. pp. 5–34.

7. Pohunek P, Warner JO, Turzikova J, Kudrmann J, Roche WR. Markers of eosinophilic inflammation and tissue re-modelling in children before clinically diagnosed bronchial asthma. Pediatr Allergy Immunol. 2005;16:43–51. [PubMed]

8. van den Toorn LM, Overbeek SE, de Jongste JC, Leman K, Hoogsteden HC, Prins JB. Airway inflammation is present during clinical remission of atopic asthma. American Journal of Respiratory and Critical Care Medicine. 2001;164:2107–2113. [PubMed]

9. Morgan WJ, Stern DA, Sherrill DL, Guerra S, Holberg CJ, Guilbert TW, Taussig LM, Wright AL, Martinez FD. Outcome of asthma and wheezing in the first 6 years of life: Follow-up through adolescence. American Journal of Respiratory and Critical Care Medicine. 2005;172:1253–1258. [PMC free article] [PubMed]

10. Rasmussen F, Taylor DR, Flannery EM, Cowan JO, Greene JM, Herbison GP, Sears MR. Risk factors for airway remodeling in asthma manifested by a low postbronchodilator fev1/vital capacity ratio: A longitudinal population study from childhood to adulthood. American Journal of Respiratory and Critical Care Medicine. 2002;165:1480–1488. [PubMed]

11. Prescott SL. The development of respiratory inflammation in children. Paediatr Respir Rev. 2006;7:89–96. [PubMed]

12. Heaton T, Rowe J, Turner S, Salberse RC, de Klerk N, Suriyaarahchi D, Seralha M, Holt GJ, Holloms E, Yerkovich S, et al. An immunoepidemiological approach to asthma: Identification of in-vitro T-cell response patterns associated with different wheezing phenotypes in children. Lancet. 2005;365:142–149. [PubMed]

13. Saglani S, Bush A. The early-life origins of asthma. Current Opinions in Allergy and Clinical Immunology. 2007;7:83–90. [PubMed]

14. Williams HE, Flohr C. How epidemiology has challenged 3 prevailing concepts about atopic dermatitis. Journal of Allergy and Clinical Immunology. 2006;118:209–213. [PubMed]

15. Hahn EL, Bacharier LB. The atopic march: The pattern of allergic disease development in childhood. Immunology & Allergy Clinics of North America. 2005;25:231–246. [PubMed]

16. Feinberg AP. Phenotypic plasticity and the epigenetics of human disease. Nature. 2007;447:433–440. [PubMed]

17. Holberg CJ, Morgan WJ, Wright AL, Martinez FD. Differences in familial segregation of FEV1 between asthmatic and nonasthmatic families: Role of maternal component. American Journal of Respiratory and Critical Care Medicine. 1998;158:162–169. [PubMed]

18. Kumar A, Ghosh B. Genetics of asthma: A molecular biologist perspective. Clinical and Molecular Allergy. 2009;7:7. [PMC free article] [PubMed]

19. Litonjua AA, Carey VJ, Burge HA, Weiss ST, Gold DR. Parental history and the risk for childhood asthma. Does mother confer more risk than father? American Journal of Respiratory and Critical Care Medicine. 1998;158:176–181. [PubMed]

20. Bjerg A, Hedman L, Perzanowski MS, Platts-Mills T, Lundback B, Ronmark E. Family history of asthma and atopy: In-depth analyses of the impact on asthma and wheeze in 7- to 8-year-old children. Pediatrics. 2007;120:741–748. [PubMed]

21. Cohen S, Herbert T. Health psychology: Psychological factors and physical disease from the perspective of human psychoneuroimmunology. Annual Review of Psychology. 1996;47:113–142. [PubMed]

22. Cohen S, Janicki-Deverts D, Miller GE. Psychological stress and disease. Journal of the American Medical Association. 2007;298:1685–1687. [PubMed]

23. Cacioppo JT, Berntson CG, Malarkey WB, Kiecolt-Glaser JK, Sheridan JF, Poehlmann KM, Burleson MH, Ernst JM, Hawkley LC, Glaser R. Autonomic, neuroendocrine, and immune responses to psychological stress: The reactivity hypothesis. Annals of the New York Academy of Sciences. 1998;840:664–673. [PubMed]

24. McEwen BS. Protective and damaging effects of stress mediators: The good and bad sides of the response to stress. Metabolism: Clinical & Experimental. 2002;51:2–4. [PubMed]

25. de Weerth C, Buitelaar JK. Physiological stress reactivity in human pregnancy – a review. Neuroscience & Biobehavioral Reviews. 2005;29:295–312. [PubMed]

26. Arck PC, Knackstedt MK, Blois SM. Current insights and future perspecitves on neuro-endocrine-immune circuitry challenging pregnancy maintenance and fetal health. Journal Reproduktionsmed Endokrinol. 2006;3:98–102.

27. Vallee M, Mayo W, Dellu F, Le Moal M, Simon H, Maccari S. Prenatal stress induces high anxiety and postnatal handling induces low anxiety in adult offspring: Correlation with stress-induced corticosterone secretion. Journal of Neuroscience. 1997;17:2626–2636. [PubMed]

28. Liu D, Diorio J, Tannenbaum B, Caldji C, Francis DJ, Freedman A, Sharma S, Pearson D, Plotsky PM, Meaney MJ. Maternal care, hippocampal gluccocorticoid receptors, and hypothalamic-pituitary-adrenal response to stress. Science. 1997;277:1659–1662. [PubMed]

29. Anisman H, Zaharia MD, Meaney MJ, Merali Z. Do early-life events permanently alter behavioral and hormonal responses to stressors? International Journal of Developmental Neuroscience. 1998;16:149–164. [PubMed]

30. Mossman TR, Coffman RL. Th1 and th2 cells: Different patterns of lymphokine secretion lead to different functional properties. Annual Review Immunology. 1989;7:145–173. [PubMed]

31. Mossman TR, Sad S. The expanding universe of t-cell subsets: Th1, th2 and more. Immunology Today. 1996;17:138–146. [PubMed]

32. Robinson DS, Hamid Q, Ying S, Tsicopoulos A, Barkans J, Bentley AM, Corrigan C, Durham SR, Kay AB. Predominant Th2 like bronchoalveolar T-lymphocyte population in atopic asthma. New England Journal of Medicine. 1992;326:298–304. [PubMed]

33. Commins SP, Borish L, Steinke JW. Immunologic messenger molecules: Cytokines, interferons, and chemokines. Journal of Allergy and Clinical Immunology. 2010;125:S53–72. [PubMed]

34. Fahy JV. Eosinophilic and neutrophilic inflammation in asthma: Insights from clinicial studies. Proceedings of the American Thoracic Society. 2009;6:256–259. [PubMed]

35. Haldar P, Pavord ID. Noneosinophilic asthma: A distinct clinical and pathologic phenotype. Journal Allergy and Clinical Immunology. 2007;119:1043–1052. [PubMed]

36. Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, Koth LL, Arron JR, Fahy JV. Th2-driven inflammation defines major sub-phenotypes of asthma. American Journal of Respiratory and Critical Care Medicine. 2009 [Epub ahead of print]

37. Suarez CJ, Parker NJ, Finn PW. Innate immune mechanism in allergic asthma. Current Allergy & Asthma Reports. 2008;8:451–459. [PubMed]

38. Joachim RA, Handjiski B, Blois SM, Hagen E, Paus R, Arck PC. Stress-induced neurogenic inflammation in murine skin skews dendritic cells towards maturation and migration. Key role of intercellular adhesion molecule-1/leukocyte function-associated antigen interactions. American Journal Pathology. 2008;173:1379–1388. [PubMed]

39. Cua DJ, Tato CM. Innate IL-17-producing cells: The sentinels of the immune system. Nature Reviews Immunology. 2010 [Epub ahead of print] [PubMed]

40. Peden DB. Development of atopy and asthma: Candidate environmental influences and important periods of exposure. Environ Health Perspect. 2000;108:475–482. [PMC free article] [PubMed]

41. Devereux G, Barker RN, Seaton A. Antenatal determinants of neonatal immune responses to allergens. Clinical and Experimental Allergy. 2002;32:43–50. [PubMed]

42. Devereux G, Seaton A, Barker RN. In utero priming of allergen-specific helper T cells. Clinical and Experimental Allergy. 2001:1686–1695. [PubMed]

43. Prescott SL, Macaubas C, Holt BJ, Smallacombe TB, Loh R, Sly PD, Holt PG. Transplacental priming of the human immune system to environmental allergens: Universal skewing of initial T cell responses toward the th2 cytokine profile. Journal Immunology. 1998;160:4730–4737. [PubMed]

44. Miles EA, Warner JA, Jones AC, Colwell BM, Bryant TN, Warner JO. Peripheral blood mononuclear cell proliferative responses in the first year of life in babies born to allergic parents. Clinical and Experimental Allergy. 1996:26. [PubMed]

45. Liao SY, Liao TN, Chiang BL, Huang MS, Chen CC, Chou CC, Hsieh KH. Decreased production of ifn gamma and increased production of il-6 by cord blood mononuclear cells of newborns with a high risk of allergy. Clinical and Experimental Allergy. 1996;26:397–405. [PubMed]

46. Tang MLK, Kemp AS, Thorburn J, Hill DJ. Reduced interferon-gamma secretion in neonates and subsequent atopy. Lancet. 1994;344:983–985. [PubMed]

47. Taussig LM, Wright AL, Holberg CJ, Halonen M, Morgan WJ, Martinez FD. Tucson children’s respiratory study: 1980 to present. Journal of Allergy and Clinical Immunology. 2003;111:661–675. [PubMed]

48. Willwerth BM, Schaub B, Tantisira KG, Gold DR, Palmer LJ, Litonjua AA, Perkins DL, Schroeter C, Gibbons FK, Gillman MW, et al. Prenatal, perinatal, and heritable influences on cord blood immune responses. Annals of Allergy Asthma Immunology. 2006;96:445–453. [PMC free article] [PubMed]

49. Wright RJ, Finn PW, Contreras JP, Cohen S, Wright RO, Staudenmayer J, Wand M, Perkins DL, Weiss ST, Gold DR. Chronic caregiver stress and IgE expression, allergen-induced proliferation and cytokine profiles in a birth cohort predisposed to atopy. Journal of Allergy and Clinical Immunology. 2004;113:1051–1057. [PubMed]

50. Chen E, Fisher EB, Bacharier LB, Strunk RC. Socioeconomic status, stress, and immune markers in adolescents with asthma. Psychosomatic Medicine. 2003;65:984–992. [PubMed]

51. Tariq SM, Arshad SH, Matthews SM, Hakim EA. Elevated cord serum IgE increases the risk of aeroallergen sinsitization without increasing respiratory allergic symptoms in early childhood. Clin Exp Allergy. 1999;29:1042–1048. [PubMed]

52. Odelram H, Bjorksten B, Leander E, Kjellman NI. Predictors of atopy in newborn babies. Allergy. 1995;50:585–592. [PubMed]

53. Halken S. Early sensitization and development of allergic airway disease - risk factors and predictors. Paediatric Respiratory Review. 2003;4:128–134. [PubMed]

54. Rowntree S, Cogswell JJ, Platts-Mills TAE, Mitchell EB. Development of IgE and igg antibodies to food and inhalant allergens in children at risk of allergic disease. Archives Diseases of Child. 1985;60:727–735. [PMC free article] [PubMed]

55. Johnke H, Norberg LA, Vach W, Host A, Andersen KE. Patterns of sensitization in infants and its relation to atopic dermatitis. Pediatric Allergy & Immunology. 2006;17:591–600. [PubMed]

56. Burney PGJ, Newson RB, Burrows MS, Wheeler DM. The effects of allergens in outdoor air on both atopic and nonatopic subjects with airway disease. Allergy. 2008;63:542–546. [PubMed]

57. Coe CL, Lubach GR, Karaszewski JW. Prenatal stress and immune recognition of self and nonself in the primate neonate. Biology of the Neonate. 1999;76:301–310. [PubMed]

58. Pincus-Knackstedt MK, Joachim RA, Blois SM, Douglas AJ, Orsal AS, Klapp BF, Wahn U, Hamelmann E, Arck PC. Prenatal stress enhances susceptibility of murine adult offspring toward airway inflammation. Journal of Immunology. 2006;177:8484–8492. [PubMed]

59. Lutgendorf SK, Moore MB, Bradley S, Shelton BJ, Lutz CT. Distress and expression of natural killer receptors on lymphocytes. Brain Behav Immun. 2005;19:185–194. [PubMed]

60. Oya H, Kawamura T, Shimizu T, Bannai M, Kawamura H, Minagawa M, Watanabe H, Hatakeyama K, Abo T. The differential effect of stress on natural killer t (nkt) and nk cell function. Clinical and Experimental Immunology. 2000;121:384–390. [PubMed]

61. Sagiyama K, Tsuchida M, Kawamura H, Wang S, Li C, Bai X, Nagura T, Nozoe S, Abo T. Age-related bias in function of natural killer T cells and granulocytes after stress: Reciprocal association of steroid hormones and sympathetic nerves. Clinical and Experimental Immunology. 2004;135:56–63. [PubMed]

62. Wright RJ, Visness CM, Calatroni A, Grayson MH, Gold DR, Sandel MT, Lee-Paritz A, Wood RA, Kattan M, Bloomberg GR, et al. Prenatal maternal stress and cord blood innate and adaptive cytokine responses in an inner-city population. American Journal of Respiratory and Critical Care Medicine. in press. [PMC free article] [PubMed]

63. Bolt RJ, van Weissenbruch MM, Lafever HN, Delemarre-van de Waal HA. Glucocorticoids and lung development in the fetus and preterm infant. Pediatric Pulmonology. 2001;32:76–91. [PubMed]

64. Wright RJ, Visness CM, Calatroni A, Grayson MH, Gold DR, Sandel MT, Lee-Paritz A, Wood RA, Kattan M, Bloomberg GR, et al. Prenatal maternal stress and cord blood innate and adaptive cytokine responses in an inner-city population. American Journal of Respiratory and Critical Care Medicine. 2010 Epub ahead of print. [PMC free article] [PubMed]

65. Buske-Kirschbaum A. Cortisol responses to stress in allergic children: Interaction with the immune response. Neuroimmunomodulation. 2009;16:325–332. [PubMed]

66. Seckl J. Glucocorticoids, feto-plaental 11-beta-hydroxysteroid dehydrgenase type 2, and the early life origins of adult disease. Steroids. 1997;62:89–94. [PubMed]

67. Seckl JR. Glucocorticoid programming of the fetus: Adult phenotypes and molecular mechanisms. Molecular and Cellular Endocrinology. 2001;185:61–71. [PubMed]

68. Reinisch JM, Simon NG, Karwo WG, Gandelman R. Prenatal exposure to prednisone in humans and animals retards intra-uterine growth. Science. 1978:202. [PubMed]

69. Goland RS, Jozak S, Warren WB, Conwell IM, Stark RI, Tropper PJ. Elevated levels of umbilical cord plasma corticotropin-releasing hormone in growth-related fetuses. Journal of Clinical Endocrinology and Metabolism. 1993:77. [PubMed]

70. von Hertzen LC. Maternal stress and t-cell differentiation of the developing immune system: Possible implications for the development of asthma and atopy. Journal of Allergy and Clinical Immunology. 2002;109:923–928. [PubMed]

71. Wright RJ. Stress and atopic disorders. Journal of Allergy & Clinical Immunology. 2005;116:1301–1306. [PubMed]

72. Elenkov IJ, Iezzoni DG, Daly A, Harris AG, Chrousos GP. Cytokine dysregulation, inflammation and well-being. Neuroimmunomodulation. 2005;12:255–269. [PubMed]

73. Wright R, Bosquet EM. Maternal stress and perinatal programming in the expression of atopy. Expert Reviews in Clinical Immunology. 2008;4:535–538. [PMC free article] [PubMed]

74. Buske-Kirschbaum A, Fischbach S, Rauh W, Hanker J, Hellhammer D. Increased responsiveness of the hypothalamus-pituitary-adrenal (hpa) axis to stress in newborns with atopic disposition. Psychoneuroendocrinology. 2004;29:705–711. [PubMed]

75. Ball TM. Cortisol circadian rhythms and stress responses in infants at risk of allergic disease. Neuroimmunomodulation. 2006;13:294–300. [PubMed]

76. Landstra AM, Postma DS, Boezen M, van Aalderen MC. Role of serum cortisol levels in children with asthma. American Journal of Respiratory and Critical Care Medicine. 2002;165:708–712. [PubMed]

77. Eskandari F, Webster JI, Sternberg EM. Neural immune pathways and their connection to inflammatory diseases. Arthritis Research & Therapy. 2003;5:251–265. [PMC free article] [PubMed]

78. Raison CL, Miller AH. When not enough is too much: The role of insufficient gluccocorticoid signaling in the pathophysiology of stress-related disorders. American Journal Psychiatry. 2003;260:1554–1565. [PubMed]

79. Miller GE, Cohen S, Ritchey AK. Chronic psychological stress and the regulation of pro-inflammatory cytokines: A glucocorticoid-resistance model. Health Psychology. 2002;21:531–541. [PubMed]

80. Haczku A, Panettieri RA. Social stress and asthma: The role of corticosteroid insensitivity. Journal Allergy and Clinical Immunology. 2010;125:550–558. [PMC free article] [PubMed]

81. Marwick JA, Wallis G, Meja K, Kuster B, Bouwmeester T, Chakravarty P, Fletcher D, Whittaker PA, Barnes PJ, Ito K, et al. Oxidative stress modulates theophylline effects on steroid responsiveness. Biochemistry Biophysics Research Communications. 2008;377:797–802. [PubMed]

82. Adcock IM, Barnes PJ. Molecular mechanisms of corticosteroid resistance. Chest. 2008;134:394–401. [PubMed]

83. Wenzel SE, Schwartz LB, Langmack EL, Haliday JL, Trudeau JB, Gibbs RL, Chu HW. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. American Journal of Respiratory & Critical Care Medicine. 1999;160:1001–1008. [PubMed]

84. Bush A. How early do airway inflammation and remodeling occur? Allerology International. 2008;57:11–19. [PubMed]

85. Ito K, Herbert C, Diegle JS, Vuppusetty C, Hansbro N, Thomas PS, Foster PS, Barnes PJ, Kumar RK. Steroid-resistant neutrophilic inflammation in a mouse model of an acute exacerbation of asthma. American Journal of Respiratory Cellular and Molecular Biology. 2008;39:543–550. [PMC free article] [PubMed]

86. Miller GE, Gaudin A, Zysk E, Chen E. Parental support and cytokine activity in childhood asthma: The role of glucocorticoid sensitivity. Journal of Allergy and Clinical Immunology. 2009;123:824–830. [PubMed]

87. Field T, Diego M. Cortisol: The culprit prenatal stress variable. International Journal of Neuroscience. 2008;118:1181–1205. [PubMed]

88. Levine A, Zagoory-Sharon O, Feldman R, Lewis JG, Weller A. Measuring cortisol in human psychobiological studies. Physiolgy and Behavior. 2007;90:43–53. [PubMed]

89. Egliston K-A, McMahan C, Austin M-P. Stress in pregnancy and infant hpa axis function: Conceptual and methodological issues relating to the use of salivary cortisol as an outcome measure. Psychoneuroendocrinology. 2007;32:1–13. [PubMed]

90. Adam EK, Kumari M. Assessing salivary cortisol in large-scale, epidemiological research. Psychoneuroendocrinology. 2009;34:1423–1436. [PubMed]

91. Adam EK, Doane LD, Mendelsohn K. Spit, sweat, and tears: Measuring biological data in naturalistic settings. In: Hargittai E, editor. Research confidential: Solutions to problems most social scientists pretend they never have. Ann Arbor, MI: University of Michigan Press; in press.

92. Dom LD, Lucke JF, Loucks TL, Berga SL. Salivary cortisol reflects serum cortisol: Analysis of circadian profiles. Annals of Clinical Biochemistry. 2007;44:281–284. [PubMed]

93. Kirschbaum C, Tietze A, Skoluda N, Dettenborn L. Hair as a retrospective calendar of cortisol production - increased cortisol incorporation into hair in the third trimester of pregnancy. Psychoneuroendocrinology 2009 [PubMed]

94. Kalra S, Einarson A, Karaskov T, Van Uum S, Koren G. The relationship between stress and hair cortisol in healthy pregnant women. Clinical and Investigative Medicine. 2007;30:E103–107. [PubMed]

95. de Weerth C, Zijl RH, Buitelaar JK. Development of cortisol circadian rhythm in infancy. Early Hum Dev. 2003;73:39–52. [PubMed]

96. Gunnar MR, Quevedo K. The neurobiology of stress and development. Annual Reviews in Psychology. 2007;58:145–173. [PubMed]

97. Flinn MV. Evolution an ontogeny of stress response to social challenge in teh human child. Developmental Reviews. 2006;26:138–174.

98. Lupien SJ, King S, Meaney MJ, McEwen BS. Child’s stress hormone levels correlate with mother’s socioeconomic status and depressive state. Biological Psychiatry. 2000;48:976–980. [PubMed]

99. Franco Suglia S, Staudenmayer J, Cohen S, Wright RJ. Posttraumatic stress symptoms related to community violence and children’s diurnal cortisol response in an urban community-dwelling sample. International Journal of Behavioral Medicine. 2009 [Epub ahead of print] [PMC free article] [PubMed]

100. Spangler G. The emergence of adrenocortical circadian function in newborns and infants and its relationship to sleep, feeding, and maternal adrenocortical activity. Early Human Development. 1991;25:197–208. [PubMed]

101. Saridjan NS, Huizink AC, Koetsier JA, Jaddoe VW, Mackenbach JP, Hofman A, Kirschbaum C, Verhulst FC, Tiemeier H. Do social disadvantage and early family adveristy affect teh diurnal cortisol rhythm in infants? The generation r study. Hormones and Behavior. 2010 doi: 10.1016/j.yhbeh.2009.12.001. [PubMed] [Cross Ref]

102. de Weerth C, van Geert P. A longitudinal study of basal cortisol in infants: Intra-individual variability, circadian rhythm and developmental trends. Infant Behavior and Development. 2002;25:375–398.

103. Watamura SE, Donzella B, Kertes DA, Gunnar MR. Developmental changes in baseline cortisol activity in early childhood: Relations with napping and effortful control. Developmental Psychobiology. 2004;45:125–133. [PubMed]

104. van Cauter E, Leproult R, Kupfer DJ. Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. Journal fo Clinical Endocrinology and Metabolism. 1996;81:2468–2473. [PubMed]

105. Van Ryzin MJ, Chatham M, Kryzer E, Kertes DA, Gunnar MR. Identifying atypical cortisol patterns in young children: The benefits of group-based trajectory modeling. Psychoneuroendocrinology. 2009;34:50–61. [PMC free article] [PubMed]

106. Yehuda R. Biology of posttraumatic stress disorder. Journal of Clinical Psychiatry. 2001;62:41–46. [PubMed]

107. Pluess M, Bolten M, Pirke KM, Helhammer D. Maternal trait anxiety, emotional distress, and salivary cortisol in pregnancy. Biological Psychology. 2009 [Epub ahead of print] [PubMed]

108. Harville EW, Savitz DA, Dole N, Herring AH, Thorp JM, Light KC. Patterns of salivary cortisol secretion in pregnancy and implications for assessment protocols. Biol Psychiatry. 2007;74:85–91. [PubMed]

109. Jones NM, Holzman CB, Zanella AJ, Leece CM, Rahbar MH. Assesing mid-trimester salivary cortisol levels across three consecutive days in pregnant women using an at-home collection protocol. Paediatric and Perinatal Epidemiology. 2006;20:425–437. [PubMed]

110. Fox NA. Temperament and regulation of emotion in the first years of life. Pediatrics. 1998;102:1230–1235. [PubMed]

111. Card JP, Levitt P, Gluhovsky M, Rinaman L. Early experience modifies the postnatal assembly of autonomic emotional motor circuits in rats. Journal of Neuroscience. 2005;25:9102–9111. [PubMed]

112. Jansson T, Lambert GW. Effect of intrauterine growth restriction on blood pressure, glucose tolerance and sympathetic nervous system activity in the rat at 3–4 months of age. Journal of Hypertension. 1999;17:1239–1248. [PubMed]

113. Pryce CR, Ruedi-Bettschen D, Dettling AC, Feldon J. Early life stress: Long-term physiological impact in rodents and primates. News Physiologocial Science. 2002;17:150–155. [PubMed]

114. Herlenius E, Lagercrantz H. Development of neurotransmitter systems during critical periods. Experimental Neurology. 2004;190:S8–21. [PubMed]

115. Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. Journal Clinical Investigation. 2007;117:289–296. [PMC free article] [PubMed]

116. Sternberg EM. Neuroendocrine regulation of autoimmune/inflammatory disease. Journal of Endocrinology. 2001;169:429–435. [PubMed]

117. Sternberg EM. Neural regulation of innate immunity: A coordinated nonspecific host response to pathogens. Nat Rev Immunol. 2006;6:318–328. [PMC free article] [PubMed]

118. Carroll JL. Developmental plasticity in respiratory control. Journal Applied Physiology. 2003;94:375–389. [PubMed]

119. Eckberg DL. The human respiratory gate. Journal Physiology. 2003;548:339–352. [PubMed]

120. Bavis RW, Mitchell GS. Long-term effects of the perinatal environment on respiratory control. Journal of Applied Physiology. 2008;104:1220–1229. [PubMed]

121. Alkon A, Lippert S, Vujan N, Rodriguez ME, Boyce WT, Eskenazi B. The ontogeny of autonomic measures in 6- and 12-month-old infants. Developmental Psychobiology. 2006;48:197–208. [PubMed]

122. Suglia SF, Staudenmayer J, Cohen S, Bosquet Enlow M, Rich-Edwards JW, Wright RJ. Cumulative stress and cortisol disruption among black and hispanic pregnant women in an urban cohort. Psychological Trauma. in press. [PMC free article] [PubMed]

123. Bosquet-Enlow M, Kullowatz A, Staudenmayer J, Spasojevic J, Ritz T, Wright RJ. Associations of maternal lifetime trauma and perinatal traumatic stress symptoms with infant cardiorespiratory reactivity to psychological challenge. Psychosomatic Medicine. 2009;71:607–614. [PMC free article] [PubMed]

124. Nogueira PJ, Ferreira HHA, Antunes E, Teixeira NA. Chronic mild prenatal stress exacerbates the allergen-induced airway inflammation in rats. Mediators of Inflammation. 1999;8:119–122. [PMC free article] [PubMed]

125. Quarcoo D, Pavlovic S, Joachim RA. Stress and airway reactivity in a murine model of allergic airway inflammation. Neuroimmunomodulation. 2009;16:318–324. [PubMed]

126. Datti F, Datti M, Antunes E, Teixeira NA. Influence of chronic unpredictable stress on the allergic responses in rats. Physiology & Behavior. 2002;77:79–83. [PubMed]

127. Forsythe P, Ebeling C, Gordon JR, Befus AD, Vliagoftis H. Opposing effects of short- and long-term stress on airway inflammation. Am J Respir Crit Care Med. 2004;169:220–226. [PubMed]

128. Joachim RA, Quarcoo D, Arck PC, Herz U, Renz H, Klapp BF. Stress enhances airway reactivity and airway inflammation in an animal model of allergic bronchial asthma. Psychosom Med. 2003;65:811–815. [PubMed]

129. Joachim RA, Sagach V, Quarcoo D, Dinh QT, Arck PC, Klapp BF. Neurokinin-1 receptor mediates stress-exacerbated allergic airway inflammation and airway hyperresponsiveness in mice. Psychosom Med. 2004;66:564–571. [PubMed]

130. Okuyama K, Ohwada K, Sakurada S, Sato N, Sora I, Tamura G, Takayanagi M, Ohno I. The distinctive effects of acute and chronic psychological stress on airway inflammation in a murine model of allergic asthma. Allergol Int. 2007;56:29–35. [PubMed]

131. McFadden ERJ, Luparello T, Lyons HA, Bleecker ER. The mechanism of action of suggestion in the induction of acute asthma attacks. Psychosomatic Medicine. 1969;31:134–143. [PubMed]

132. Neild JE, Cameron IR. Bronchoconstriction in response to suggestion: Its prevention by an inhaled anticholinergic agent. British Medical Journal. 1985;290:674. [PMC free article] [PubMed]

133. Ritz T, Kullowatz A. Effects of stress and emotion on lung function in health and asthma. Current Respiratory Medicine Review. 2005;1:208–219.

134. Kullowatz A, Smith H-J, Weber S, Kannie F, Mangnussen H, Dahme B, Ritz T. The role of the cholinergic pathway in airway response to emotional stimuli. Psychophysiology. 2007;44:S71.

135. Ritz T, Thoens M, Dahme B. Modulation of respiratory sinus arrhythmia by respiration rate and volume: Stability across postures and volume variations. Psychophysiology. 2001;38:858–862. [PubMed]

136. Ritz T, Thoens M, Fahrenkrug S, Dahme B. The airways, respiration, and respiratory sinus arrhythmia during picture viewing. Psychophysiology. 2005;42:568–578. [PubMed]

137. Bauer AM, Quas JA, Boyce WT. Associations between physiological reactivity and children’s behavior: Advantages of a multisystem approach. Journal of Developmental and Behavioral Pediatrics. 2002;23:102–113. [PubMed]

138. El-Sheikh M, Erath SA, Buckhalt JA, Granger DA, Mize J. Cortisol and children’s adjustment: The moderating role of sympathetic nervous system activity. Journal of Abnormal Child Psychology. 2008;36:601–611. [PubMed]

139. Smeets T. Autonomic and hypothalamic-pituitary-adrenal stress resilience: Impact of cardiac vagal tone. Biological Psychology. 2010;84:290–295. [PubMed]

140. Steckler T. The molecular neurobiology of stress - evidence from genetic and epigenetic models. Behaviorural Pharmacology. 2001;12:381–427. [PubMed]

141. Mann JJ, Currier DM. Stress, genetics and epigenetic effects on the neurobiology of suicidal behavior and depression. European Psychiatry. 2010;25:268–271. [PMC free article] [PubMed]

142. Gilliland FD, Li YF, Saxon A, Diaz-Sanchez D. Effect of glutathione-s-transferase m1 and p1 geotypes on xenobiotic enhancement of allergic responses: Randomised, placebo-controlled crossover study. Lancet. 2004 Jan 10;363:119–125. [PubMed]

143. Child F, Lenney W, Clayton S, Davies S, Jones PW, Alldersea JE, Strange RC, Fryer AA. The association of maternal but not paternal genetic variation in gstp1 with asthma phenotypes in children. Respir Med. 2003 Dec;97:1247–1256. [PubMed]

144. Wust S, Van Rossum EF, Federenko IS, Koper JW, Kumsta R, Hellhammer DH. Common polymorphisms in the glucocorticoid receptor gene are associated with adrenocortical responses to psychosocial stress. J Clin Endocrinol Metab. 2004;89:565–573. [PubMed]

145. Yamada Y, Nakamura H, Adachi T, Sannohe S, Oyamada H, Kayaba H, Yodoi J, Chihara J. Elevated serum levels of thioredoxin in patients with acute exacerbation of asthma. Immunology Letters. 2003;86:199–205. [PubMed]

146. Uhart M, McCaul ME, Oswald LM, Choi L, Wand GS. Gabra6 gene polymorphism and an attenuated stress response. Mol Psychiatry. 2004 [PubMed]

147. Jeanmonod P, von Kanel R, Maly FE, Fischer JE. Elevated plasma c-reactive protein in chronically distressed subjects who carry the a allele of the tnf-alpha -308 g/a polymorphism. Psychosom Med. 2004;66:501–506. [PubMed]

148. Jaenisch R, Bird A. Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals. Nature Genetics. 2003;35:245–254. [PubMed]

149. Miller RL, Ho SM. Environmental epigenetics and asthma: Current concepts and call for studies. Am J Respir Crit Care Med. 2008;177:567–573. [PMC free article] [PubMed]

150. Prescott SL, Clifton V. Asthma and pregnancy: Emerging evidence of epigenetic interactions in utero. Current Opinion in Allergy and Clinical Immunology. 2009;9:417–426. [PubMed]

151. Castro M, Ramirez MI, Gern JE, Cutting G, Redding G, Hagood JS, Whitsett J, Abman S, Raj JU, Barst R, et al. Strategic plan for pediatric respiratory diseases research: An nhlbi working group report. Proceedings of the American Thoracic Society. 2009;15:1–10. [PubMed]

152. Levenson JM, Sweatt JD. Epigenetic mechanisms: A common theme in vertebrate and invertebrate memory formation. Cell Mol Life Sci. 2006;63:1009–1016. [PubMed]

153. Miller GE, Chen E, Zhou ES. If it goes up, must it come down? Chronic stress and the hypothalamic-pituitary-adrenal axis in humans. Psychological Bulletin. 2007;133:25–45. [PubMed]

154. Meaney MJ, Szyf M. Maternal care as a model for experience-dependent chromatin plasticity? Trends in Neuroscience. 2005;28:456–463. [PubMed]

155. Szyf M, McGowan P, Meaney MJ. The social environment and the epigenome. Environmental and Molecular Mutagenesis. 2008;49:46–60. [PubMed]

156. Turner JD, Pelascini LP, Macedo JA, Muller CP. Highly individual methylation patterns of alternative glucocorticoid receptor promoters suggest individualized epigenetic regulatory mechanisms. Nucleic Acids Research. 2008;36:7207–7218. [PMC free article] [PubMed]

157. Krozowski ZS, Provencher PH, Smith RE, Obeyesekere VR, Mercer WR, Albiston AL. Isozymes of 11 beta-hydroxysteroid dehydrogenase: Which enzyme endows mineralocorticoid specificity? Steroids. 1994;59:116–120. [PubMed]

158. Esposito E, Cuzzocrea S. The role of nitric oxide synthases in lung inflammtion. Current Opinion in Investigative Drugs. 2007;8:899–909. [PubMed]

159. Danson EJ, Li D, Wang I, Dawson TA, Paterson DJ. Targeting cardiac sympatho-vagal imbalance using gene transfer of nitric oxide synthase. Journal of Molecular and Cellular Cardiology. 2009;46:482–489. [PubMed]

160. McLeod TM, Lopez-Figueroa AL, Lopez-Figueroa MO. Nitric oxide, stress, and depression. Psychopharmacology Bulletin. 2001;35:24–41. [PubMed]

161. Tarantini L, Bonzini M, Apostoli P, Pegoraro V, Bollati V, Marinelli B, Cantone L, Rizzo G, Hou L, Schwartz J, et al. Effects of particulate matter on genomic DNA methylation content and inos promoter methylation. Environ Health Perspect. 2009;117:217–222. [PMC free article] [PubMed]

162. Alikhani-Koopaei R, Fouladkou F, Frey FJ, Frey BM. Epigenetic regulation of 11 beta-hydroxysteroid dehydrogenase type 2 expression. Journal of Clinical Investigation. 2004;114:1146–1157. [PMC free article] [PubMed]

163. Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ. Epigenetic programming by maternal behavior. Nature Neuroscience. 2004;7:847–854. [PubMed]

164. McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labonte B, Szyf M, Turecki G, Meaney MJ. Epigenetic regulation of the glucocorticoid receptor in human brain associated with childhood abuse. Nature Neuroscience. 2009;12:342–348. [PMC free article] [PubMed]

165. Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM. Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (nr3c1) and infant cortisol stress responses. Epigenetics. 2008;3:97–106. [PubMed]

166. Stokols D. Establishing and maintaining healthy environments: Toward a social ecology of health promotion. American Psychology. 1992;47:6–22. [PubMed]

167. Francis DD. Conceptualizing child health disparities: A role for developmental neurogenomics. Pediatrics. 2009;124:S196–S202. [PMC free article] [PubMed]

168. Wright RJ, Subramanian SV. Advancing a multilevel framework for epidemiological research on asthma disparities. Chest. 2007;132:757S–769S. [PubMed]

169. Evans G. Environmental stress and health. In: Baum A, Revenson T, Singer J, editors. Handbook of health psychology. Mahwah, NJ: Lawrence Erlbaum Associates, Inc; 2001. pp. 365–385.

170. Williams DR, Sternthal M, Wright RJ. Social determinants: Taking the social context of asthma seriously. Pediatrics. 2009;3:S174–184. [PMC free article] [PubMed]

171. Braveman P, Marchi K, Egerter S, Kim S, Metzler M, Stancil T, Libet M. Poverty, near-poverty, and hardship around the time of pregnancy. Maternal Child Health Journal. 2008 [Epub ahead of print] [PubMed]

172. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CR. Posttraumatic stress disorder in the national comorbidity survey. Archives of General Psychiatry. 1995;52:1048–1060. [PubMed]

173. Holman EA, Silver RC, Waitzkin H. Traumatic life events in primary care patients: A sutdy in an ethnically diverse sample. Archive of Family Medicine. 2000;9:802–810. [PubMed]

174. Hien D, Bukszpan C. Interpersonal violence in a “Normal” Low-income control group. Women Health. 1999;29:1–16. [PubMed]

175. Clark C, Ryan L, Kawachi I, Jacobson Canner M, Berkman LF, Wright RJ. Witnessing community violence in residential neighborhoods: A mental health hazard for urban women. Journal of Urban Health. 2007;85:22–38. [PMC free article] [PubMed]

176. Brown JR, Hill HM, Lambert SF. Traumatic stress symptoms in women exposed to community and partner violence. Journal of Interpersonal Violence. 2005;20:1478–1494. [PubMed]

177. Sternthal MJ, Bosquet Enlow M, Cohen S, Jacobson Canner M, Staudenmayer J, Tsang K, Wright RJ. Maternal interpersonal trauma and cord blood IgE levels in an inner-city cohort: A life-course perspective. Journal Allergy and Clinical Immunology. 2009;124:954–960. [PubMed]

178. Sternthal MJ, Hun HJ, Earls F, Wright RJ. Community violence and urban childhood asthma: A multilevel analysis. European Respiratory Journal. 2010 [Epub ahead of print] [PubMed]

179. Sandel M, Wright RJ. Expanding dimensions of housing that influence asthma morbidity: When home is where the stress is. Archives Diseases of Childhood. 2006;91:942–948. [PMC free article] [PubMed]

180. Quinn K, Kaufman JS, Siddiqi A, Yeatts KB. Stress and the city: Housing stressors are associated with respiratory health among low socioeconomic status chicago children. Journal Urban Health. 2010 [Epub ahead of print] [PMC free article] [PubMed]

181. Mrazek DA, Klinnert M, Mrazek PJ, Brower A, McCormick D, Rubin B, Ikle D, Kastner W, Larsen G, Harbeck R, et al. Prediction of early-onset asthma in genetically at-risk children. Pediatric Pulmonology. 1999;27:85–94. [PubMed]

182. Wright RJ, Cohen S, Carey V, Weiss ST, Gold DR. Parental stress as a predictor of wheezing in infancy: A prospective birth-cohort study. American Journal of Respiratory & Critical Care Medicine. 2002;165:358–365. [PubMed]

183. Clougherty J, Levy JI, Kubzansky LD, Ryan B, Franco Suglia S, Jacobson Canner M, Wright RJ. The effects of traffic-related air pollution and exposure to violence on urban asthma etiology. Environ Health Perspect. 2007;115:1140–1146. [PMC free article] [PubMed]

184. Chen E, Schreier HM, Strunk RC, Brauer M. Chronic traffic-related air pollution and stress interact to predict biologic and clinical outcomes in asthma. Environmental Health Perspectives. 2008;116:970–975. [PMC free article] [PubMed]

185. Shankardass K, McConnell R, Jerrett M, Milam J, Richardson J, Berhane K. Parental stress increases the effect of traffic-related air pollution on childhood asthma incidence. Porceedings of the National Academy of Sciences. 2009;106:12406–12411. [PubMed]